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Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder

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Abstract

Background

Many studies have recently been conducted to assess the antidepressant efficacy of glutamate modification in mood disorders. This is an update of a review first published in 2015 focusing on the use of glutamate receptor modulators in unipolar depression.

Objectives

To assess the effects ‐ and review the acceptability and tolerability ‐ of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with unipolar major depressive disorder.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020.  We did not apply any restrictions to date, language or publication status.

Selection criteria

Double‐ or single‐blinded randomised controlled trials (RCTs) comparing ketamine, memantine, esketamine or other glutamate receptor modulators with placebo (pill or saline infusion), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression.

Data collection and analysis

Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes were response rate (50% reduction on a standardised rating scale) and adverse events. We decided a priori to measure the efficacy outcomes at different time points and run sensitivity/subgroup analyses. Risk of bias was assessed using the Cochrane tool, and certainty of the evidence was assessed using GRADE.

Main results

Thirty‐one new studies were identified for inclusion in this updated review. Overall, we included 64 studies (5299 participants) on ketamine (31 trials), esketamine (9), memantine (5), lanicemine (4), D‐cycloserine (2), Org26576 (2), riluzole (2), atomoxetine (1), basimglurant (1), citicoline (1), CP‐101,606 (1), decoglurant (1), MK‐0657 (1), N‐acetylcysteine (1), rapastinel (1), and sarcosine (1).

Forty‐eight studies were placebo‐controlled, and 48 were two‐arm studies. The majority of trials defined an inclusion criterion for the severity of depressive symptoms at baseline: 29 at least moderate depression; 17 severe depression; and five mild‐to‐moderate depression. Nineteen studies recruited only patients with treatment‐resistant depression, defined as inadequate response to at least two antidepressants.

The majority of studies investigating ketamine administered as a single dose, whilst all of the included esketamine studies used a multiple dose regimen (most frequently twice a week for four weeks). Most studies looking at ketamine used intravenous administration, whilst the majority of esketamine trials used intranasal routes.

The evidence suggests that ketamine may result in an increase in response and remission compared with placebo at 24 hours odds ratio (OR) 3.94, 95% confidence interval (CI) 1.54 to 10.10; n = 185, studies = 7, very low‐certainty evidence). Ketamine may reduce depression rating scale scores over placebo at 24 hours, but the evidence is very uncertain (standardised mean difference (SMD) ‐0.87, 95% CI ‐1.26 to ‐0.48; n = 231, studies = 8, very low‐certainty evidence). There was no difference in the number of participants assigned to ketamine or placebo who dropped out for any reason (OR 1.25, 95% CI 0.19 to 8.28; n = 201, studies = 6, very low‐certainty evidence).

When compared with midazolam, the evidence showed that ketamine increases remission rates at 24 hours (OR 2.21, 95% CI 0.67 to 7.32; n = 122,studies = 2, low‐certainty evidence). The evidence is very uncertain about the response efficacy of ketamine at 24 hours in comparison with midazolam, and its ability to reduce depression rating scale scores at the same time point (OR 2.48, 95% CI 1.00 to 6.18; n = 296, studies = 4,very low‐certainty evidence). There was no difference in the number of participants who dropped out of studies for any reason between ketamine and midazolam (OR 0.33, 95% CI 0.05 to 2.09; n = 72, studies = 1, low‐certainty evidence).

Esketamine treatment likely results in a large increase in participants achieving remission at 24 hours compared with placebo (OR 2.74, 95% CI 1.71 to 4.40; n = 894, studies = 5, moderate‐certainty evidence). Esketamine probably results in decreases in depression rating scale scores at 24 hours compared with placebo (SMD ‐0.31, 95% CI ‐0.45 to ‐0.17; n = 824, studies = 4, moderate‐certainty evidence). Our findings show that esketamine increased response rates, although this evidence is uncertain (OR 2.11, 95% CI 1.20 to 3.68; n = 1071, studies = 5, low‐certainty evidence). There was no evidence that participants assigned to esketamine treatment dropped out of trials more frequently than those assigned to placebo for any reason (OR 1.58, 95% CI 0.92 to 2.73; n = 773, studies = 4,moderate‐certainty evidence).

We found very little evidence for the remaining glutamate receptor modulators.

We rated the risk of bias as low or unclear for most domains, though lack of detail regarding masking of treatment in the studies reduced our certainty in the effect for all outcomes.

Authors' conclusions

Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear. The evidence for use of the remaining glutamate receptor modulators is limited as very few trials were included in the meta‐analyses for each comparison and the majority of comparisons included only one study.

Long term non‐inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real‐world monitoring are needed to establish comprehensive data on safety and efficacy.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Ketamine and other glutamate receptor modulators for depression in adults

Why is this review important?

Depression is one of the most common mental disorders, estimated to affect 350 million people worldwide. Antidepressant medication tends to be given as a first treatment for people with major depression. These drugs are however only effective in about one in four people at one year. Effective alternative medications to treat depression are needed, especially for rapid treatment. A new group of medications is called ‘glutamate receptor modulators’, which act on the glutamergic system. This group includes the medicine ketamine. In this review we examined the evidence for glutamate receptor modulators, including ketamine, as a treatment for depression.

Who will be interested in this review?

‐ People with depression, their friends and families.

‐ General practitioners, psychiatrists, psychologists and pharmacists.

‐ Professionals working in adult mental health services.

What questions does this review aim to answer?

1. Is treatment with ketamine and other glutamate receptor modulators more effective than treatment with placebo (dummy pill) or other drugs?

2. Is treatment with ketamine and other glutamate receptor modulators more acceptable than placebo or other drugs?

Which studies were included in the review?

We searched medical databases to find all relevant studies (specifically randomised controlled trials) completed up to 30 July 2020. To be included in the review, studies had to compare ketamine or other glutamate receptor modulators with placebo, other medicines or electroconvulsive therapy (ECT) for depression in adults (aged 18 and over). The studies also had to be single‐blind (the participant does not know which treatment they are receiving) or double‐blind (neither the participant or researcher know which treatment the participant is receiving), to attempt to reduce bias. We included 64 studies in the review, involving a total of 5299 people. The studies investigated16 different glutamate receptor modulator medications. The majority of participants had treatment‐resistant depression (depression which had not responded to two or more medications) at the start of the studies. Most studies were two‐armed, where the glutamate receptor modulator was compared with one other intervention.

What does the evidence from the review tell us?

Among the 16 drugs included in this review, only ketamine and esketamine were more effective than placebo at reducing symptoms of depression. The effects of ketamine lasted no more than one week after treatment and clearly disappeared after two weeks. Ketamine did, however, cause more side effects than placebo. The effects of esketamine were seen at 24 hours and could last up to four weeks with repeated doses. Esketamine caused a lot more side effects than placebo. The certainty of evidence varied considerably.

There was no evidence of a difference between the other glutamate receptor modulators included in this review and placebo or other medications.

What should happen next?

Ketamine and esketamine appear to reduce the symptoms of depression. However, the trials were all short term so we do not know about the long‐term effects. It is important to note that in some trials attempts to prevent participants and investigators from knowing what medicine was being given were not successful and this may have inflated the positive effects of the active drugs.

Future studies should examine what happens when people are repeatedly given the drug, with the aim to mimic the real‐world practice and assess longer‐term effects. More non‐inferiority trials should be conducted, where glutamate receptor modulators are compared with other active medications rather than placebo to find out whether they are better than alternative treatments.

In most of the ketamine trials in this review, participants were given the drug by injection into a vein. This restricts the wide‐scale application of ketamine in clinical settings, so trials of ketamine by other routes are needed. Esketamine trials usually used nasal sprays, which are easier to use and could potentially be taken at home if further monitoring and trials found that it was safe to do so. Further studies assessing administration are needed in order to draw more reliable and firm conclusions.

Authors' conclusions

Implications for practice

The present review has provided evidence for a short‐term antidepressant effect of ketamine compared with placebo and midazolam, and esketamine compared with placebo in adults with unipolar depression. Our confidence in the findings of the review is limited by the risk of performance bias and low number of trials contributing data to the meta‐analysis for each comparison (Cipriani 2019). The majority of comparisons contain only one study, with the largest body of evidence included in a single analysis being only from eight studies. There was no robust evidence for the use of other glutamate receptor modulators in depression.

This review continues to support the rapid antidepressant effect of ketamine, and also found a rapid antidepressant effect of esketamine, an important finding given the typical delayed onset of action of traditional antidepressants, especially since many of these studies recruited patients with severe or treatment‐resistant depression. There was no evidence for a longer‐term effect of acute ketamine administration after one week, and whilst continued esketamine was effective over placebo at four weeks there was no effectiveness at 72 hours or one week. More studies with longer‐term outcomes are needed to confirm these results.

The majority of studies included in this review which compared ketamine with placebo, administered the ketamine intravenously, with only one trial administering the drug orally. The difficulties of administering via intravenous infusion in a clinical setting (i.e. equipment, time, staff requirements), create limitations to the accessibility of this treatment. Most esketamine trials studied intranasal administration, which may be a promising alternative in improving applications to clinical practice.

The present review provides additional information about the side‐effect profile of ketamine and esketamine, with additional data on a multitude of adverse events associated with this drug. Given these identified side effects, and the adverse effects that have been linked to ketamine abuse, such as cognitive impairments and bladder dysfunction, it is important that both the short and long‐term side effects are carefully considered for clinical application.

Whilst this updated review has demonstrated some promising evidence for the use of ketamine as an antidepressant, it is clear that there are still challenges for clinical application that require careful consideration and further research.

Implications for research

Thecertainty of the evidence in the present review was assessed as very low to high quality according to GRADE (Atkins 2004). There were very few trials included in each comparison, and furthermore, the numbers of participants included in each trial were small (Jones 2019). It is therefore apparent that in order to draw robust conclusions about ketamine's antidepressant effects, there is a need for studies to be conducted that are of high methodological standard and that assess important outcomes such as cognition and adverse events, as well as efficacy.

Most trials included in the present meta‐analysis examining the efficacy of ketamine used intravenous administration, for which there are practical limitations as outlined above. Additional routes of administration should be explored in further randomised controlled trials (RCTS) to understand whether different modes of administration can be effective in order to improve accessibility.

There were limited data regarding long‐term effects of ketamine and esketamine, but the available evidence suggested that neither drug has sustained anti‐depressant effects after the end of treatment or prevents relapse at three months. Therefore further research could examine the use and efficacy of the delivery of psychotherapy (such as cognitive behavioral therapy (CBT)) or other medications following administration of glutamate receptor modulators (Zhou 2020).

Only six RCTs were identified that compared a psychoactive drug to ketamine, five in which midazolam efficacy was compared with ketamine, and one comparing ketamine and esketamine. This highlights the need for future research to focus on conducting RCTs which compare antidepressants with other psychoactive drugs (Cipriani 2010; Koesters 2013; Watanabe 2008). Furthermore, given the inadequate blinding methods that could potentially occur when comparing ketamine versus placebo (given its side‐effect profile), conducting more head‐to‐head comparisons that use an active control drug with similar effects to ketamine are needed.

In the present review the majority of studies provided patients with concomitant medication alongside the trial, demonstrating heterogeneity in the methodology (Efthimiou 2019). The role that concomitant medication may play in ketamine's antidepressant effect is currently unclear, and thus future research should explore and clarify this.

Summary of findings

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Summary of findings 1. Ketamine compared to placebo for adults with unipolar major depressive disorder

Ketamine compared to Placebo for adults with unipolar major depressive disorder

Patient or population: adults (aged 18 years+) with unipolar major depressive disorder 
Setting: any setting (outpatient, inpatient, or both) 
Intervention: ketamine 
Comparison: placebo

Outcomes

Relative effect
(95% CI)

Anticipated absolute effects* (95% CI)

Certainty of the evidence
(GRADE)

What happens

Without ketamine

With ketamine

Difference

Efficacy: number of participants who respond to treatment ‐ at 24 hours (Response)
assessed with: HDRS, HDRS‐17, MADRS
№ of participants: 185
(7 RCTs)

OR 3.94
(1.54 to 10.10)

Study population

⊕⊝⊝⊝
VERY LOW 1 2

 

8.8%

27.4%
(12.9 to 49.2)

18.7% more
(4.1 more to 40.4 more)

Efficacy: number of participants who achieve remission ‐ at 24 hours (Remission)
assessed with: MADRS, HDRS
№ of participants: 75
(3 RCTs)

OR 5.60
(1.07 to 29.46)

Study population

⊕⊝⊝⊝
VERY LOW 3 4

 

2.4%

12.0%
(2.5 to 41.8)

9.6% more
(0.2 more to 39.4 more)

Depression rating scale score ‐ at 24 hours
assessed with: HDRS, HDRS‐17, MADRS
№ of participants: 231
(8 RCTs)

SMD 0.87 lower
(1.26 lower to 0.48 lower)

⊕⊝⊝⊝
VERY LOW 1 2 5

 

Acceptability: total dropouts
№ of participants: 201
(6 RCTs)

OR 1.25
(0.19 to 8.28)

Study population

⊕⊝⊝⊝
VERY LOW 1 2 6

 

34.0%

39.1%
(8.9 to 81)

5.2% more
(25.1 fewer to 47 more)

Acceptability: dropouts due to adverse effects ‐ not reported

 

 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 

CI: Confidence interval; HDRS: Hamilton Depression Rating Scale; MADRS: Montgomery‐Asberg Depression Rating Scale; OR: Odds ratio;RCT: randomised controlled trial;SMD: standardised mean difference.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1 Downgraded by one point due to the low number of participants available for this outcome and the associated width of the confidence intervals.

2 Downgraded by two points due to the majority of trials being unclear or high risk regarding the blinding of outcome assessments.

3 Downgraded by two points due to the very low number of participants available for this outcome and the associated width of the confidence intervals.

4 Downgraded by one point due to the majority of trials being unclear regarding blinding of outcome assessments.

5 Downgraded by one point due to moderately large heterogeneity (I2 value = 30% to 60%).

6 Downgraded by two points due to substantially large heterogeneity (I2 value = 50% to 90%).

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Summary of findings 2. Ketamine compared to midazolam for adults with unipolar major depressive disorder

Ketamine compared to Midazolam for adults with unipolar major depressive disorder

Patient or population: adults (aged 18 years+) with unipolar major depressive disorder 
Setting: any setting (outpatient, inpatient, or both) 
Intervention: ketamine 
Comparison: midazolam

Outcomes

Relative effect
(95% CI)

Anticipated absolute effects* (95% CI)

Certainty of the evidence
(GRADE)

What happens

Without ketamine

With ketamine

Difference

Efficacy: number of participants who respond to treatment ‐ at 24 hours
assessed with: HAM‐D‐6, HAM‐D‐17, MADRS
№ of participants: 296
(4 RCTs)

OR 2.48
(1.00 to 6.18)

Study population

⊕⊝⊝⊝
VERY LOW 1 2 3

 

25.9%

46.5%
(25.9 to 68.4)

20.5% more
(0 fewer to 42.5 more)

Efficacy: number of participants who achieve remission ‐ at 24 hours
assessed with: MADRS
№ of participants: 122
(2 RCTs)

OR 2.21
(0.67 to 7.32)

Study population

⊕⊕⊝⊝
LOW 2 3

 

18.0%

32.7%
(12.8 to 61.6)

14.7% more
(5.2 fewer to 43.6 more)

Depression rating scale score ‐ at 24 hours
assessed with: MADRS
№ of participants: 297
(4 RCTs)

SMD 0.49 lower
(0.87 lower to 0.1 lower)

⊕⊝⊝⊝
VERY LOW 1 2 3

 

Acceptability: total dropouts
№ of participants: 72
(1 RCT)

OR 0.33
(0.05 to 2.09)

Study population

⊕⊕⊝⊝
LOW 4

 

12.0%

4.3%
(0.7 to 22.2)

7.7% fewer
(11.3 fewer to 10.2 more)

Acceptability: dropouts due to adverse effects ‐ not reported

 

 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 

CI: Confidence interval;HAM‐D: Hamilton Depression Rating Scale; MADRS: Montgomery‐Asberg Depression Rating Scale;OR: Odds ratio; RCT: randomised controlled trial; SMD: standardised mean difference.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1 Downgraded by two points due to the majority of trials being unclear or high risk regarding the blinding of outcome assessments.

2 Downgraded by one point due to moderately large heterogeneity (I2 value = 30% to 60%).

3 Downgraded by one point due to the low number of participants available for this outcome and the associated width of the confidence intervals.

4 Downgraded by two points due to the very low number of participants available for this outcome and the associated width of the confidence intervals.

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Summary of findings 3. Esketamine compared to placebo for adults with unipolar major depressive disorder

Esketamine compared to Placebo for adults with unipolar major depressive disorder

Patient or population: adults (aged 18 years+) with unipolar major depressive disorder 
Setting: any setting (outpatient, inpatient, or both) 
Intervention: esketamine 
Comparison: placebo

Outcomes

Relative effect
(95% CI)

Anticipated absolute effects* (95% CI)

Certainty of the evidence
(GRADE)

What happens

Without esketamine

With esketamine

Difference

Efficacy: number of participants who respond to treatment ‐ at 24 hours (Response)
assessed with: MADRS
№ of participants: 1071
(5 RCTs)

OR 2.11
(1.20 to 3.68)

Study population

⊕⊕⊝⊝
LOW 1 2

 

15.0%

27.1%
(17.5 to 39.4)

12.1% more
(2.5 more to 24.4 more)

Efficacy: number of participants who achieve remission ‐ at 24 hours (Remission)
assessed with: MADRS
№ of participants: 894
(5 RCTs)

OR 2.74
(1.71 to 4.40)

Study population

⊕⊕⊕⊝
MODERATE 1

 

7.2%

17.5%
(11.7 to 25.4)

10.3% more
(4.5 more to 18.2 more)

Depression rating scale score ‐ at 24 hours
assessed with: MADRS
№ of participants: 824
(4 RCTs)

SMD 0.31 lower
(0.45 lower to 0.17 lower)

⊕⊕⊕⊝
MODERATE 1

 

Acceptability: total dropouts
№ of participants: 773
(5 RCTs)

OR 1.58
(0.92 to 2.73)

Study population

⊕⊕⊕⊝
MODERATE 1

 

8.5%

12.9%
(7.9 to 20.3)

4.3% more
(0.6 fewer to 11.8 more)

Acceptability: dropouts due to adverse effects ‐ not reported

 

 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 

CI: Confidence interval; MADRS: Montgomery‐Asberg Depression Rating Scale; OR: Odds ratio; RCT: randomised controlled trial; SMD: standardised mean difference.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1 Downgraded by one point due to the majority of trials being unclear regarding blinding of outcome assessments.

2 Downgraded by one point due to moderately large heterogeneity (I2 value = 30% to 60%).

Background

Description of the condition

Major depressive disorder is among the most commonly encountered psychiatric disorder, with reported lifetime and one‐year prevalence rates of 10.8% and 7.2%, respectively (Lim 2018) . Although an episode of depression may happen only once over a person's span, more commonly it is a recurrent condition. During an episode, symptoms are present most of the day, nearly every day, and may include feelings of sadness, emptiness, or unhappiness; loss of interest and pleasure in normal activities; sleep disturbances; tiredness and lack of energy; changes in appetite; frequent thoughts of death; suicidal thoughts; cognitive impairment; and unexplained physical problems. Major depressive disorder is diagnosed clinically by the presence of one or more major depressive episodes, in the absence of manic or hypomanic symptoms, and is also referred to as ’unipolar depression’ (APA 2013WHO 2008a). Currently estimated to affect 350 million people worldwide, the disorder has been increasingly recognised as a major global health concern (De Leo 2014WHO 2012), leading to substantial disability (WHO 2008b), impaired quality of life (Rapaport 2005), and considerable economic burden (Donohue 2007). Moreover, depressive illness is associated with an increased risk of suicide (Hawton 2009). Despite the clinical importance of depression, its underlying pathophysiology is still incompletely understood, with various factors suggested to be involved, as well as to serve as potential targets for treatment (Hasler 2010a). One of the most well‐researched theories of previous decades has been the monoamine hypothesis of depression, implying a dysregulation of the 5‐hydroxytryptamine (5‐HT, serotonin), noradrenaline, and dopamine systems (Coppen 1967Hirschfeld 2000). However, even though robust evidence supports the idea that monoamine neurotransmitters, and serotonin in particular, have a role in the pathophysiology of depression, it appears that simple monoamine depletion is insufficient to account for the development of the disorder (Ruhe 2007).

Description of the intervention

The mainstay of the pharmacological treatment of depression for the last 40 or more years has been monoamine potentiating antidepressants. Tricyclic antidepressants (TCAs) were introduced in the 1950s, the first being imipramine (NICE 2009). The mode of action thought to be responsible for the mood‐elevating properties of this class of drugs is their ability to block the synaptic reuptake of noradrenaline and 5‐HT, exerting re‐uptake of these neurotransmitters at different levels. Although the introduction of the TCAs was welcome, their ability to blockade cholinergic, histaminergic, and other receptor systems resulted in side effects that reduced the acceptability of the drugs. Most TCAs were also potentially lethal in overdose. In response to this, new classes of antidepressants have been developed, including the selective serotonin reuptake inhibitors and related drugs; and also a range of other pharmacologically unrelated antidepressants, like mirtazapine or trazodone. The side effect profile of these agents varies considerably, although their mood‐elevating effects are again thought to be mediated through increasing intrasynaptic levels of monoamines, some primarily affecting noradrenaline, some 5‐HT, and others affecting both noradrenaline and 5‐HT to varying degrees and in different ways (NICE 2009). Generally, they have an improved safety profile relative to TCAs.

In addition to monoamines, various other neurotransmitters have been implicated in the pathogenesis of depression, including the amino acid neurotransmitters, ƴ‐aminobutyric acid (GABA) and glutamate. While decreased plasma levels of GABA have been demonstrated in depressed patients (Petty 1984), results from studies using magnetic resonance spectroscopy (MRS) to measure GABA levels in the brain have been less consistent. Overall, however, it seems likely that brain GABA levels in depression measured by MRS are decreased in depressed patients (Godfrey 2018). Generally, drugs that increase GABA activity, for example, benzodiazepines (Birkenhager 1995) are not thought to be effective antidepressants. Nevertheless, there is recent interest in the rapid antidepressant effect of a GABA‐modulating neurosteroid, brexanolone, which has been licensed for the treatment of post‐partum depression (Zheng 2019).

The discovery of the rapid antidepressant effects of the N‐methyl‐D‐aspartate (NMDA) receptor antagonist, ketamine, has been a great stimulus for investigations into the role of glutamatergic mechanisms in the pathophysiology of depression and its treatment. Magnetic resonance spectroscopy studies of glutamate again are somewhat inconsistent. Overall there may be a decrease in glutamate levels in frontal brain regions in depressed patients (Moriguchi 2019). However, some patient groups appear to have elevated glutamate metabolism in subcortical regions (Godlewska 2018). Post‐mortem findings of glutamate levels in people dying with depression are also inconsistent (Moriguchi 2019). Post‐mortem and in vivo positron emission tomography (PET) imaging evidence more reliably indicate a reduction in cortical and subcortical binding of the mGluR5 receptor, a metabotropic glutamate receptor (Moriguchi 2019). In addition, post‐mortem studies also reveal loss of glial cells in the medial frontal cortex of patients with depression. Glial cells play a key role in the metabolism and synthesis of neuronal glutamate and their loss would have a significant impact on glutamate cycling (Cotter 2001).

The first randomised cross‐over trial demonstrating antidepressant efficacy of a sub‐anaesthetic dose of ketamine (0.5mg/kg) took place in seven depressed patients with evidence of a fast (onset within 24 hours) antidepressant effect (Berman 2000). Since then, researchers have attempted to supplement these findings, mainly by increasing the size of the study population, as well as studying longer‐term effects like durability of benefit following repeated infusions (Diamond 2014; Murrough 2013; Valentine 2011; Zarate 2006a). Esketamine, the s‐enantiomer of ketamine, has recently been licensed for the treatment of resistant depression, following the completion of both acute and maintenance treatment trials. In these studies, nasal esketamine was usually administered once or twice weekly. Similar to intravenous ketamine, nasal esketamine requires administration in a supervised clinical setting.

How the intervention might work

The main pharmacological mechanism of action of ketamine is non‐competitive blockade of the ion channel associated with NMDA receptor complex. However, other drugs with an apparently similar pharmacological profile, for example, memantine, are not apparently effective antidepressants (Zarate 2006b). Therefore, other factors must be involved in ketamine’s antidepressant effect. The currently favoured hypothesis is that blockade of NMDA receptors on inhibitory GABA neurones leads to a glutamate ‘surge’ which then activates 2‐amino‐3‐ (5‐methyl‐3‐oxo‐1,2‐oxazol‐4‐yl)propanoic acid (AMPA) receptors. Simulation of AMPA receptors leads to increased neuroplasticity, with elevated levels of brain‐derived neurotrophic factor (BDNF) and phosphorylation of tropomyosin receptor kinase B (TrkB) (Wilkinson 2019).

Another suggested downstream effector of ketamine is the mammalian target of rapamycin (mTOR) pathway (Li 2010). Activation of the mTOR pathway by ketamine in a rat model has resulted in both an antidepressant effect and formation of spine synapses in the prefrontal cortex, whereas blockade of this pathway abolished this response (Li 2010). An unexplained, contradictory finding which has not yet been replicated is that in depressed patients, blockade of mTOR with rapamycin actually enhanced the antidepressant response to ketamine (Abdallah 2018). Ketamine also has some effects on opiate receptors and one study has shown that pre‐treatment with the opiate receptor blocker, naltrexone, prevented the antidepressant effect of ketamine, suggesting a possible role for opiate mechanisms in its antidepressant action (Williams 2018), although contradictory evidence has also been found in a pilot study (Yoon 2019). Thus, the precise way in which ketamine relieves depressive symptoms is not clear. Ketamine also has several disadvantages in its clinical use as an antidepressant, such as the risk of transient dissociative states following acute administration. There are also concerns about potential adverse effects during longer‐term maintenance treatment; for example, tolerance, dependence, adverse cognitive effects and bladder toxicity.

The surprising antidepressant efficacy of ketamine together with its disadvantages had led to the search for other glutamate modifying drugs as antidepressants. This includes well‐known compounds such as riluzole and d‐cycloserine, as well as agents newly discovered by Industry such as rapastinel and lanicemine. In this respect it is worth noting that the NMDA receptor has several binding sites that can be targeted pharmacologically. In addition, drugs working at the AMPA receptor or metabotropic glutamate autoreceptors may have clinical utility in depression (Wilkinson 2019).

Why it is important to do this review

This review is an update of the previous Cochrane Review (Caddy 2015) and is one of a pair; the other Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults is currently being updated (Dean 2021; McCloud 2015). Reliable information about ketamine and other glutamate receptor modulators in unipolar depression (including modes of administration, comparative efficacy, duration of effect, and safety) is not only clinically useful but also urgently needed because such evidence can improve patients’ outcomes in the treatment of depression and provide a basis for future clinical research and treatment guidelines.

Objectives

  1. To assess the effects of ketamine and other glutamate receptor modulators in comparison to placebo (pill or saline infusion), other pharmacologically active agents, or electroconvulsive therapy (ECT) in alleviating the acute symptoms of depression in people with unipolar major depressive disorder.

  2. To review the acceptability of ketamine and other glutamate receptor modulators in comparison to placebo (pill or saline infusion), other pharmacologically active agents, or ECT in people with unipolar major depressive disorder.

Methods

Criteria for considering studies for this review

Types of studies

We included only double‐blind or single‐blind randomised controlled trials (RCTs) (both published and unpublished) comparing ketamine, memantine, or other glutamate receptor modulators with other active psychotropic drugs or placebo (pill or saline infusion) in people with unipolar major depression.

For trials with a cross‐over design, we considered only results from the first period prior to cross‐over (see Unit of analysis issues for further details).

We planned to include cluster randomised trials (CRTs) where the effect of clustering was or could be accounted for in the statistical analysis (see Unit of analysis issues). However, no CRTs were identified.

We excluded quasi‐randomised trials, such as those allocating by using alternate days of the week, as well as trials that did not explicitly describe the method of allocation as randomised.

Types of participants

Participant characteristics and diagnosis

We considered for inclusion people of both sexes aged 18 years or older with a primary diagnosis of unipolar major depressive disorder according to any of the following standard operational criteria: Feighner criteria (Feighner 1972), Research Diagnostic Criteria (Spitzer 1978), DSM‐III (APA 1980), DSM‐III‐R (APA 1987), DSM‐IV (APA 1994), DSM‐IV‐TR (APA 2000), DSM‐5 (APA 2013), or ICD‐10 (WHO 1992). We included studies using operational diagnostic criteria essentially similar to the above.

We excluded studies using ICD‐9 ((International Classification of Diseases, 9th erevision), as it has only disease names and no diagnostic criteria. We also excluded studies that define depression as scoring above a certain cut‐off on a screening questionnaire.

We included studies recruiting participants with treatment‐resistant depression, and examined this in a sensitivity analysis.

Comorbidities

We included studies in which less than 20% of participants were diagnosed with bipolar depression, and thus at least 80% of participants had unipolar depression, and examined the validity of this decision in a sensitivity analysis. We did not consider concurrent secondary diagnosis of another psychiatric disorder an exclusion criterion. However, we excluded studies in which all participants had concurrent primary diagnosis of another Axis I or II disorder. We also excluded participants with a serious concomitant medical illness or with postpartum depression.

Setting

We applied no restriction on setting.

Subset data

We also included in the analysis studies with a subset of participants that met the review inclusion criteria, provided that we could extract data for this subset from the study report.

Types of interventions

Experimental interventions

  1. Ketamine: any dose and pattern of administration

  2. Riluzole: any dose and pattern of administration

  3. Amantadine: any dose and pattern of administration

  4. Dextromethorphan (alone or in combination with quinidine)

  5. Quinolinic acid: any dose and pattern of administration

  6. Memantine: any dose and pattern of administration

  7. Atomoxetine: any dose and pattern of administration

  8. Tramadol: any dose and pattern of administration

  9. Lanicemine: any dose and pattern of administration

  10. MK‐0657: any dose and pattern of administration

  11. Any other glutamate receptor modulators (for example, D‐cycloserine, GLYX‐13)

Comparator interventions

  1. Placebo (pill or saline infusion)

  2. Any pharmacologically active agent (either conventional, like midazolam, or non‐conventional, like scopolamine or Hypericum) or agent included to mimic the psychotropic side effects of the glutamate agent

  3. Electroconvulsive therapy (ECT)

All interventions could be either as monotherapy or combined with other treatments. We applied no restrictions on dose, frequency, intensity, route, and duration. We included trials that allowed rescue medications (as required, short‐term, infrequent use of medications aimed at emergent symptom relief only, for example short‐term use of hypnotics) as long as these medications were equally distributed among the randomised arms.

We did not include lamotrigine among the list of comparisons because the randomised evidence about this drug has been synthesised elsewhere (Goh 2019; Solmi 2016).

Types of outcome measures

We included studies that met the above inclusion criteria regardless of whether they reported on the following outcomes.

Primary outcomes

  1. Efficacy outcome (dichotomous): number of participants who respond to treatment, where treatment response is defined as (1) a reduction of at least 50% compared to baseline on the Hamilton Rating Scale for Depression (HRSD) (Hamilton 1960), Montgomery‐Åsberg Depression Rating Scale (MADRS) (Montgomery 1979), or any other depression scale, depending on the study authors' definition, or (2) 'much or very much improved' (score 1 or 2) on the Clinical Global Impression‐Improvement scale (CGI‐S) (Guy 1976). Where both scales were provided we preferred the former criteria for judging response. We used the response rate instead of a continuous symptom score for the primary efficacy analysis in order to make the interpretation of results easier for clinicians (Guyatt 1998). To avoid possible outcome reporting bias, we did not use the original authors' definitions of response or remission, if different from above (Furukawa 2007a).

  2. Adverse events outcome (dichotomous): We evaluated adverse events using the following outcome measures.

    1. Total number of participants experiencing at least one side effect.

    2. Total number of participants experiencing the following specific side effects:

      1. agitation/anxiety;

      2. constipation;

      3. delusions;

      4. diarrhoea;

      5. dissociative symptoms;

      6. dizziness;

      7. dry mouth;

      8. hallucinations;

      9. headache;

      10. hypo/hypertension;

      11. insomnia;

      12. mania/hypomania;

      13. nausea;

      14. seizure;

      15. sleepiness/drowsiness;

      16. urination problems;

      17. vomiting;

      18. tremor.

In order to avoid missing any relatively rare or unexpected, yet important side effects (for instance, sexual side effects), in the data extraction phase we collected information on all side effects data reported in the studies and discussed ways to summarise them post hoc. We extracted descriptive data regarding adverse‐effect profiles from all available studies. Due to a lack of consistent reporting of adverse effects (which came primarily from the study authors' descriptions), we combined terms describing similar side effects. For example, we combined 'dry mouth', 'reduced salivation', and 'thirst' into 'dry mouth'. We then grouped all adverse effect categories by organ system, such as neuropsychiatric, gastrointestinal, respiratory, sensory, genitourinary, dermatological, and cardiovascular.

Secondary outcomes

  1. Efficacy outcome (dichotomous): number of participants who achieve remission. Remission is defined as (1) a score of less than 7 on the HRSD‐17 (Furukawa 2007b), or less than 8 for all the other longer versions of the HRSD, or less than 11 on the MADRS (Bandelow 2006), or less than 6 on the Quick Inventory of Depressive Symptomatology (16‐Item) (Self Report) (http://www.ids-qids.org/); or (2) participants who were 'not ill or borderline mentally ill' (score 1 or 2) on the Clinical Global Impression‐Severity scale out of the total number of randomised participants. Where both are provided, we used the former criterion for judging remission.

  2. Efficacy outcome (continuous): mean endpoint scores or mean change scores in depression severity from baseline to the time point in question. We allowed a looser form of intention‐to‐treat (ITT) analysis, whereby all the participants with at least one post‐baseline measurement were represented by their last observations carried forward (LOCF), but in any pooled analysis we planned to examine the impact of the LOCF in a sensitivity analysis).

  3. Suicidality, including suicidal ideation, suicide attempts (nonfatal self‐harm), and deaths by suicide. We examined suicidality and suicide ideation according to the outcome measures reported in the original studies (either as spontaneously reported or as a score on a standardised rating scale).

  4. Cognition. We examined this according to the outcome measures reported in the original studies.

  5. Loss of hope and other health‐related quality of life measures. We included data on any validated quality of life instruments.

  6. Costs to healthcare services. We collected data according to what was reported in the original studies.

  7. Acceptability (dichotomous), evaluated using the following outcome measures:

    1. overall number of participants who dropped out during the trial as a proportion of the total number of randomised participants;

    2. number of participants who dropped out due to lack of efficacy during the trial as a proportion of the total number of randomised participants

    3. number of participants who dropped out due to side effects during the trial as a proportion of the total number of randomised participants.

Timing of outcome assessment

As study authors report response rates at various time points of trials, we decided a priori to subdivide the treatment indices as follows.

  1. Ultra‐rapid response: at 24 hours, ranging between 12 and 36 hours (primary efficacy outcome).

  2. Rapid response: at 72 hours, ranging between 37 and less than 96 hours.

  3. Early response: at one week, ranging between four and 10 days.

  4. Acute response: at two weeks, ranging between 11 days and less than three weeks.

  5. Medium response: at four weeks, ranging between three and six weeks.

  6. Long‐term response: at three months, ranging between seven weeks and six months.

Hierarchy of outcome measures

When several possible outcome measures are reported for the same outcome, we used the primary outcome according to the original study.

Search methods for identification of studies

Electronic searches

1. Bibliographic databases

For the second version of this review (first published in September 2015 (Caddy 2015)), the Information Specialist with the Cochrane Common Mental Disorders Group (CCMD) conducted update searches (30 July 2020) directly on the core bibliographic databases, from 2015 onwards (Appendix 1):

  • Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7) in the Cochrane Library (searched 30 July 2020);

  • MEDLINE Ovid (2015 to July 28 2020);

  • Embase Ovid (2015 to 2020 Week 30);

  • PsycINFO Ovid (2015 to July Week 3).

Earlier searches of these databases was conducted via the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all years to 9 January 2015) (Appendix 2).

2. International trial registries

International trial registries were searched via CENTRAL on the Cochrane Library and directly via the World Health Organization's trials portal (ICTRP) and ClinicalTrials.gov to identify unpublished or ongoing studies (30 July 2020).

3. Adverse events search

The information Specialist with CCMD also conducted a companion search for adverse events data (30 July 2020) on Ovid MEDLINE, Embase and PsycINFO (Appendix 3), although we have not incorporated these data into this version of the review.

We applied no restrictions on language or publication status to the searches.

Searching other resources

Grey literature

We conducted complementary searches on the websites of the following drug regulatory authorities for additional unpublished data: the US Food and Drug Administration (FDA), the Medicines and Healthcare products Regulatory Agency in the UK, the European Medicines Agency in the EU, the Pharmaceuticals and Medical Devices Agency in Japan, and the Therapeutic Goods Administration in Australia.

Reference lists

We checked the reference lists of all included studies and relevant systematic reviews and major textbooks of affective disorder written in English to identify additional studies missed from the original electronic searches (for example, unpublished or in‐press citations).

Correspondence

We contacted trialists and subject experts for information on unpublished or ongoing studies, or to request additional trial data.

Data collection and analysis

Selection of studies

Two review authors (RD, SH, SS, RS, AB) independently screened titles and abstracts for inclusion of all the potential studies we identified as a result of the search and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We retrieved the full‐text study reports/publication, and two review authors (RD, SH, SS, RS, AB) independently screened the full text and identified studies for inclusion, and identified and recorded reasons for exclusion of the ineligible studies. Any disagreements were resolved through discussion or, if required, by consulting a third person (CH, AC). We identified and removed duplicate records and collated multiple reports that related to the same study so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA (Moher 2009) flow diagram (Figure 1) and Characteristics of excluded studies tables.


Study flow diagram.

Study flow diagram.

Data extraction and management

We used a data collection form to extract study characteristics and outcome data that had been piloted on at least one study in the review. Two review authors (RD, SH, SS, RS, AB) extracted study characteristics and outcome data from included studies. We extracted the following study characteristics.

  1. Participant characteristics (age, sex, depression diagnosis, comorbidity, depression severity, antidepressant treatment history for the index episode, study setting).

  2. Intervention details (intended dosage range, mean daily dosage actually prescribed, cointervention if any, ketamine as investigational drug or as comparator drug, sponsorship).

  3. Outcome measures of interest from the included studies.

Depression severity was defined using the same criteria set out by Cipriani 2012, with severe depression defined by a baseline score of 25 or more on the HRSD and 31 or more on the MADRS (Dozois 2004; Muller 2003).

We noted in the Characteristics of included studies tables if outcome data were not reported in a usable way. We resolved disagreements by consensus or by involving a third person (AC, CH). Two review authors (RD, SH, SS, RS, AB) transferred data into the Review Manager 5 (Revman 2020) file. We double‐checked that data were entered correctly by comparing the data presented in the systematic review with the study reports. A third review author (RD) checked study characteristics for accuracy against the trial report. The comparisons were done by individual drug (see Types of interventions).

Main comparisons

  1. Ketamine versus placebo

  2. Ketamine versus other glutamate receptor modulators

  3. Ketamine versus other pharmacologically active agents (either conventional, like midazolam, or nonconventional, like scopolamine or Hypericum)

  4. Other glutamate receptor modulators versus placebo

  5. Other glutamate receptor modulators versus other pharmacologically active agents (either conventional, like midazolam, or nonconventional, like scopolamine or Hypericum)

  6. Ketamine versus ECT

  7. Other glutamate receptor modulators versus ECT

Other glutamate receptor modulators will be considered individually as separate comparisons. All interventions could be either as monotherapy or combined with other treatments. We applied no restrictions on dose, frequency, intensity, route, and duration.

Assessment of risk of bias in included studies

Five review authors (RD, SH, SS, RS, AB) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020). Any disagreements were resolved by discussion or by involving another review author (AC, CH). We assessed the risk of bias according to the following domains.

  1. Random sequence generation

  2. Allocation concealment

  3. Blinding of participants and personnel

  4. Blinding of outcome assessment

  5. Incomplete outcome data

  6. Selective outcome reporting

  7. Other bias

We judged each potential source of bias as high, low, or unclear and provide a supporting quotation from the study report together with a justification for our judgement in the risk of bias tables. We summarised the risk of bias judgements across different studies for each of the domains listed. We considered blinding separately for different key outcomes where necessary (for example, for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a participant‐reported mood scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we noted this in the risk of bias table.

When considering treatment effects, we took into account the risk of bias for the studies that contribute to that outcome.

Measures of treatment effect

Dichotomous data

We calculated the odds ratio (OR) with corresponding 95% confidence interval (95% CI) for dichotomous or event‐like outcomes. We calculated response rates out of the total number of randomised participants. We applied ITT analysis whereby all dropouts not included in the analysis were considered as nonresponders. For statistically significant results, we calculated the number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH).

Continuous data

We calculated the mean difference (MD) or standardised mean difference (SMD) along with corresponding 95% CI for continuous outcomes. We used the MD where the same scale was used to measure an outcome. We employed the SMD where different scales were used to measure the same underlying construct.

For both continuous and dichotomous data, we undertook meta‐analyses only where this was meaningful, that is if the treatments, participants, and the underlying clinical question were similar enough for pooling to make sense. We described narratively skewed data reported as medians and interquartile ranges.

Where multiple trial arms were reported in a single trial, we included only the relevant arms.

Unit of analysis issues

Cluster‐randomised trials

No cluster‐randomised trials were found in the search, however we would have included cluster‐randomised trials if either of the two methods below were possible.

  1. \if the cluster‐randomised trial was correctly analysed in the original report, we would have entered the effect estimate and standard error using the generic inverse variance method in RevMan 5 (Revman 2020).

  2. If the original report failed to adjust for cluster effects, we planned to include such a trial in the meta‐analysis if we were able to extract the following information:

    1. number of clusters randomised to each intervention or the average size of each cluster;

    2. outcome data ignoring the cluster design for the total number of participants;

    3. estimate of the intracluster correlation coefficient (ICC).

The ICC could be borrowed from similarly‐designed studies when such were available. We then conducted the approximately correct analysis following the procedures described in section 16.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020).

Cross‐over trials

A major concern of cross‐over trials is the potential of carry‐over effects, which occur when an effect (for example, pharmacological, physiological, or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase, the participants can differ systematically from their initial state, despite a washout phase. For the same reason, cross‐over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in major depression, we only used data from the first phase of cross‐over studies. However, we are aware that cross‐over trials for which only first period data are available should be considered to be at risk of bias (Higgins 2020).

Studies with multiple treatment groups

Where a study involved more than two treatment arms, we included all relevant treatment arms in comparisons. If data were binary, we simply added and combined them into one group or divided the comparison arm into two (or more) as appropriate. If data were continuous, we combined data following the formula in section 6.5.2.10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020).

Dealing with missing data

Dichotomous data

We calculated treatment responders and treatment remitters on a strict ITT basis; we included dropouts in the analysis. Where participants were excluded from the trial before the endpoint, we assumed that they experienced a negative outcome (for example, failure to respond to treatment). We examined the validity of this decision in sensitivity analyses by applying worst‐ and best‐case scenarios (that is we assumed missing data to be responders or nonresponders in the corresponding sensitivity analyses). When dichotomous outcomes were not reported but baseline mean, endpoint mean, and corresponding standard deviations (SDs) of the HRSD (or other depression scale) were reported, we converted continuous outcome data expressed as mean and SD into the number of responding and remitted participants, based on a validated imputation method (Furukawa 2005). If a more sophisticated and arguably more valid imputation method was reported in the original study (for example mixed‐effects model), we used these numbers to impute the number of responders. We examined the validity of this imputation in sensitivity analyses.

Continuous data

When there were missing continuous data and the method of LOCF was used to perform an ITT analysis, we used the LOCF data.

Missing data

We contacted the original study authors for missing data.

Missing statistics

When only the standard error or t‐test or P values were reported, we calculated SDs as suggested by Altman 1996. Where SDs were not reported, we contacted trial authors and asked them to supply the data. In the absence of a response from the trial authors, we borrowed SDs from other studies in the review, if possible, or calculated the SDs according to a validated imputation method (Furukawa 2006). We examined the validity of this imputation in sensitivity analyses.

Assessment of heterogeneity

We first investigated heterogeneity between studies by visual inspection of the forest plots. If the 95% confidence intervals (CIs) of the ORs for each study in the pooled analysis did not include means of other studies, we investigated potential sources of heterogeneity. We also calculated the I2 statistic (Higgins 2020). We used the Cochrane Handbook for Systematic Reviews of Interventions' rough guide to its interpretation as follows: 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; and 75% to 100%, considerable heterogeneity. We also kept in mind that the importance of the observed value of I2 depends on (i) the magnitude and direction of effects and (ii) the strength of evidence for heterogeneity (for example P value from the Chi2 test, or a CI for I2). If the I2 value was below 50%, but the direction and magnitude of treatment effects were suggestive of important heterogeneity, we investigated the potential sources of heterogeneity. Finally, we planned to perform subgroup analyses to investigate heterogeneity. We reported I2 values in all analyses including two or more studies.

Assessment of reporting biases

We planned to enter data from included studies into a funnel plot (trial effect against trial variance) to investigate small‐study effects (Sterne 2000), but none of our analyses contained sufficient studies to allow this. In future updates of this review, we plan to use the test for funnel plot asymmetry only when at least 10 studies are included in the meta‐analysis, as per protocol. In the event of using a funnel plot, we will interpret results cautiously, with visual inspection of the funnel plots (Higgins 2011a). If we identify evidence of small‐study effects, we will investigate possible reasons for funnel plot asymmetry, including publication bias (Egger 1997).

Data synthesis

For the primary analysis, we calculated the pooled OR with corresponding 95% CI for dichotomous outcomes. We calculated the pooled MD or SMD as appropriate with corresponding 95% CIs for continuous outcomes. We presented any skewed data and non quantitative data descriptively. An outcome that has a minimum score of zero could be considered skewed when the mean is smaller than twice the SD. However, the skewness of change scores is difficult to depict as the possibility of negative values exists. We therefore used change scores for meta‐analysis of mean difference MDs. We considered a P value of less than 0.05 and a 95% CI that does not cross the line of no effect statistically significant. In forest plots with two or more studies we used a random‐effects model for both dichotomous and continuous variables. We adopted the random‐effects model under these circumstances because it has the highest generalisability for empirical examination of summary effect measures in meta‐analyses (Furukawa 2002). However, as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (10.4.4.1), to assess the influence of small‐study effects on the results of a meta‐analysis with between‐study heterogeneity, we routinely examined the robustness by comparing the fixed‐effect model and the random‐effects model. We reported any material differences between the models.

Subgroup analysis and investigation of heterogeneity

As multiple analyses will lead to false‐positive and false‐negative conclusions, subgroup analyses should be performed and interpreted with caution (Brookes 2001; Brookes 2004). We planned the following subgroup analyses, where possible, for the following variables.

  1. Depression severity (severe major depression, moderate or mild major depression): 'Severe major depression' was defined by a threshold baseline severity score for entry of 25 or more for the 17‐item HRSD (Dozois 2004), and 31 or more for MADRS (Muller 2003).

  2. Treatment settings (psychiatric inpatients, psychiatric outpatients, primary care): As depressive disorder in primary care has a different profile than that of psychiatric inpatients or outpatients (Suh 1997), it is possible that results obtained from either of these settings may not be applicable to the other settings (Arroll 2009).

  3. Older people (greater than 65 years of age), separately from other adult participants: Older people may be more vulnerable to adverse effects associated with antidepressants, and a decreased dosage is often recommended. We planned to pool groups whose mean age was more than 65 years.

Sensitivity analysis

We originally planned the following sensitivity analyses for primary outcomes.

  1. Excluding trials with unclear allocation concealment or unclear double blinding.

  2. Excluding studies that included participants with bipolar depression or psychotic features.

  3. Excluding studies that recruited participants with treatment‐resistant depression (defined as inadequate response to at least two antidepressants).

  4. Excluding studies with unfair dose comparisons (Cipriani 2009).

  5. Excluding trials with a dropout rate greater than 20%.

  6. Excluding trials for which the response rates had to be calculated based on an imputation method (Furukawa 2005), and for which the SD had to be borrowed from other trials (Furukawa 2006).

We decided post‐hoc to conduct the following additional sensitivity analyses for primary outcomes.

  1. Excluding trials with add‐on ECT

  2. Excluding multiple doses

Our routine comparisons of random‐effects and fixed‐effect models, as well as our secondary outcomes of remission rates and continuous severity measures, may be considered additional forms of sensitivity analyses.

Summary of findings and assessment of the certainty of the evidence

We constructed a summary of findings table for the main comparisons (ketamine versus placebo, ketamine versus midazolam, and esketamine versus placebo), with regard to the following five outcomes. Where possible, we presented data at all four prespecified time points for the primary outcomes. For secondary outcomes, we selected a primary time point of 24 hours as this was considered the most clinically relevant, and presented the data closest to this time point only.

  1. Efficacy: number of participants who respond to treatment.

  2. Acceptability: total dropouts.

  3. Efficacy: number of participants who achieve remission.

  4. Severity of depression at end of trial.

  5. Acceptability: dropouts due to adverse effects.

In the summary of findings tables, we used GRADEproGDT software (GradePro GDT 2020) and the principles of the GRADE (Schünemann 2013) approach, which assesses the quality of a body of evidence based on the extent to which there can be confidence that the obtained effect estimate reflects the true underlying effect. The quality of a body of evidence is judged on the basis of the included studies’ risks of bias, the directness of the evidence, unexplained heterogeneity, imprecision, and the risk of publication bias. We used the average rate in all the arms of the included trials as the 'assumed risk' for each outcome because we did not expect salient differences in such risks among different agents. We therefore did not target any particularly high‐ or low‐risk populations; all the tables are for medium‐risk populations.

Results

Description of studies

Results of the search

CCMD’s Information Specialist ran update searches using two separate strategies, one for effectiveness (CENTRAL, Ovid MEDLINE, Embase, PsycINFO, Trial Registers 2015 to 30 July 2020) (n = 5075 refs), and one for adverse effects data (Ovid MEDLINE, Embase, PsycINFO, Trial Registers, 2015 to 30 July 2020) (n = 1834). This has been reported in the PRISMA (Moher 2009) diagram (Figure 1).

From a total of 6909 records retrieved from the searches, we removed 3096 duplicate records and excluded a further 3603 on the basis of the title and abstract. We retrieved the full‐text articles for 210 records, yielding 39 new studies.

Included studies

See: Characteristics of included studies; Figure 1.

The initial version of this Cochrane Review (Caddy 2015) identified 25 studies (corresponding to 23 primary references and 61 references overall; 1242 participants) which met the inclusion criteria for this review (Berk 2014; Berman 2000; Ghasemi 2013; Heresco‐Levy 2006; Heresco‐Levy 2013; Huang 2013; Ibrahim 2012a; Ibrahim 2012b; Jarventausta 2013; Lapidus 2014; Loo 2012; Michelson 2007; Murrough 2013; Nations 2012 (part I); Nations 2012 (part II); Omranifard 2014; Preskorn 2008; Sanacora 2014 (a); Sanacora 2014 (b); Smith 2013; Sos 2013; Yoosefi 2014; Zarate 2006a; Zarate 2006b; Zarate 2013). Of these 25 studies, eight RCTs assessed the efficacy of ketamine (Berman 2000; Ghasemi 2013; Lapidus 2014; Loo 2012; Murrough 2013; Sos 2013; Yoosefi 2014; Zarate 2006a); three assessed memantine (Omranifard 2014; Smith 2013; Zarate 2006b); three assessed AZD6765 (Sanacora 2014 (a); Sanacora 2014 (b); Zarate 2013); two assessed D‐cycloserine (Heresco‐Levy 2006; Heresco‐Levy 2013); two assessed Org26576 (Nations 2012 (part I); Nations 2012 (part II)); and one each assessed atomoxetine (Michelson 2007), CP‐101,606 (Preskorn 2008), MK‐0657 (Ibrahim 2012b), N‐acetylcysteine (Berk 2014), riluzole (Ibrahim 2012a), and sarcosine (Huang 2013). One study which was previously included in the ketamine comparison, was re‐evaluated as assessing esketamine (Jarventausta 2013).

Thirty‐nine new studies met the inclusion criteria for this updated review (Abbasinazari 2015; Amidfar 2016; Anderson 2017; Arabzadeh 2018; Canuso 2018; Carspecken 2018; Chen 2017; Chen 2018Correia‐Melo 2020; Daly 2018; Downey 2016; Fava 2018; Fedgchin 2019; Fernie 2017; Fu 2020; Gálvez 2018; Grunebaum 2018; Hu 2016; Ionescu 2018; Ionescu 2020; Jagtiani 2014; Kuşçu 2015; Li 2016; Ochs‐Ross 2020; Preskorn 2015; Popova 2019; Quiroz 2016; Roohi‐Azizi 2017; Salardini 2016; Salehi 2015; Sanacora 2017; Shams Alizadeh 2015; Shiroma 2020; Singh 2016 a; Singh 2016 b; Su 2017; Sumner 2020; Tiger 2020; Umbricht 2020).

The new search identified an additional 22 RCTs for inclusion assessing the efficacy of ketamine (Anderson 2017; Arabzadeh 2018; Carspecken 2018; Chen 2017; Chen 2018; Correia‐Melo 2020; Downey 2016; Fava 2018; Fernie 2017; Gálvez 2018; Grunebaum 2018; Hu 2016; Ionescu 2018; Jagtiani 2014; Kuşçu 2015; Li 2016; Salehi 2015Shams Alizadeh 2015; Shiroma 2020; Singh 2016 a; Su 2017; Sumner 2020; Tiger 2020); eight assessing esketamine (Canuso 2018Correia‐Melo 2020; Daly 2018; Fedgchin 2019; Fu 2020; Ionescu 2020; Ochs‐Ross 2020; Popova 2019; Singh 2016 b); two assessing memantine (Abbasinazari 2015; Amidfar 2016); two assessing lanicemine (Downey 2016; Sanacora 2017), one assessing basimglurant (Quiroz 2016), one assessing citicoline (Roohi‐Azizi 2017); one assessing decoglurant (Umbricht 2020); one assessing rapastinel (Preskorn 2015); one assessing riluzole (Salardini 2016).

The majority of included studies were placebo‐controlled trials (48 out of 64, 75%), with the remaining 16 studies directly comparing a glutamate receptor modulator with an active comparison (citalopram, electroconvulsive therapy (ECT), esketamine, midazolam, methohexital, remifentanil hydrochloride, thiopental). The majority were two‐arm studies (48 out of 64, 75%), whilst nine of the remaining studies (Chen 2018; Fedgchin 2019; Li 2016; Nations 2012 (part II); Quiroz 2016; Sanacora 2014 (b); Sanacora 2017; Singh 2016 b; Su 2017) employed a three‐arm methodology, comparing differing doses of an active drug to placebo. Two studies utilised three‐arm methodologies to compare ketamine with both an active comparator and placebo (Downey 2016; Kuşçu 2015). Four used four‐ and five‐arm methodologies to test differing doses of ketamine versus placebo, respectively (Daly 2018; Fava 2018Preskorn 2015; Umbricht 2020). Another used a four‐arm methodology to test differing treatment regimens (either two or three times weekly) for ketamine against placebo (Singh 2016 a).

Design

All of the studies were double‐blind randomised controlled trials (RCTs), with the exception of Ghasemi 2013, which was single‐blind study, and Kuşçu 2015 in which blinding was at least single‐blind but unclear on double‐blinding (for full details about study blinding, please refer to Characteristics of included studies). Eight of the 64 studies had a cross‐over design (Berman 2000; Heresco‐Levy 2006; Ibrahim 2012b; Lapidus 2014; Sos 2013; Sumner 2020; Zarate 2006a; Zarate 2013). The treatment period ranged from one single administration to 12 weeks.

Sample sizes

The total number of participants from the 64 studies was 5299, with a minimum sample size of five (Ibrahim 2012b; Gálvez 2018) and a maximum of 357 (Umbricht 2020).

Setting

The majority of trials treated patients on an outpatient basis (24 studies), inpatient basis (20 studies), or both (five studies), whilst in the remaining trials the setting was unclear (15 studies). Twenty‐three out of the 64 trials took place in the USA, 16 in Asia, eight in Europe, three in Australia, one in New Zealand one in South America, nine cross‐continental, and in three the study was unclear. Thirty‐one out of the 64 trials were single‐centre studies; 23 were multi‐centre and in the remaining 10 trials it was unclear whether the studies were single‐centred or multi‐centred.

Participants

All studies reported the demographic and/or clinical characteristics of patients, with the exception of Ibrahim 2012b, where no details were reported. The proportion of women ranged from 0% (Gálvez 2018) to 87.5% (Su 2017). Two studies (Omranifard 2014; Ochs‐Ross 2020) recruited older adults above age 60, whilst in the remaining studies mean age ranged from 25.7 to 58.7 years.

The majority of studies defined an inclusion criterion specifying the severity of depression: 29 of these studies specified at least moderate depression; 17 of these studies specified severe depression and five specified mild‐moderate depression. Nineteen studies (Carspecken 2018; Daly 2018; Fava 2018; Fedgchin 2019; Heresco‐Levy 2013; Ibrahim 2012a; Ibrahim 2012b; Jarventausta 2013; Kuşçu 2015; Murrough 2013; Popova 2019; Preskorn 2008; Salehi 2015; Sanacora 2014 (a); Sanacora 2014 (b); Shiroma 2020; Singh 2016 a; Singh 2016 b; Zarate 2006a) recruited only treatment‐resistant patients, which we defined as inadequate response to at least two antidepressants.

In 59 of the 64 studies patients had a diagnosis of unipolar major depression based on the DSM‐IV, DSM‐IV‐TR, or DSM‐V criteria. The remaining five studies (Berman 2000; Ghasemi 2013; Loo 2012; Anderson 2017; Gálvez 2018), recruited mixed samples of major depressive disorder and bipolar depression, with 11.11%, 5.56%, 19.57%, 15.7%, and 25% of the sample diagnosed with bipolar disorder, respectively. One study (Jarventausta 2013) recruited patients with recurrent severe or psychotic major depressive disorder, with 10 out of the 32 participants suffering from psychotic major depressive disorder.

Interventions

A total of 31 studies included ketamine as the experimental intervention; 16 compared ketamine with placebo (Anderson 2017; Arabzadeh 2018; Berman 2000; Chen 2017; Chen 2018; Hu 2016; Ionescu 2018; Lapidus 2014; Li 2016; Loo 2012; Shams Alizadeh 2015; Singh 2016 a; Sos 2013; Su 2017; Tiger 2020; Zarate 2006a); five compared ketamine with midazolam (Fava 2018; Gálvez 2018; Grunebaum 2018; Murrough 2013; Shiroma 2020); four compared ketamine with thiopental (Jagtiani 2014; Kuşçu 2015; Salehi 2015; Yoosefi 2014); one compared ketamine with esketamine (Correia‐Melo 2020); one compared ketamine with lanicemine (Downey 2016); one compared ketamine with methohexital (Carspecken 2018); one compared ketamine with propofol (Fernie 2017); one compared ketamine with remifentanil hydrochloride (Sumner 2020); and one compared ketamine with ECT (Ghasemi 2013).

Fifteen different glutamate receptor modulators were compared with placebo in 32 studies: esketamine (Canuso 2018; Daly 2018; Fedgchin 2019; Fu 2020; Ionescu 2020; Jarventausta 2013; Ochs‐Ross 2020; Popova 2019; Singh 2016 b); memantine (Abbasinazari 2015; Amidfar 2016; Omranifard 2014; Smith 2013; Zarate 2006b); lanicemine (Sanacora 2014 (a); Sanacora 2014 (b); Sanacora 2017; Zarate 2013); D‐cycloserine (Heresco‐Levy 2006; Heresco‐Levy 2013); Org 26576 (Nations 2012 (part I); Nations 2012 (part II)); riluzole (Ibrahim 2012a; Salardini 2016); atomoxetine (Michelson 2007); basimglurant (Quiroz 2016); citicoline (Roohi‐Azizi 2017); CP‐101,606 (Preskorn 2008); decoglurant (Umbricht 2020); MK‐0657 (Ibrahim 2012b); N‐acetylcysteine (Berk 2014); rapastinel (Preskorn 2015). Sarcosine was compared with an active comparator, citalopram, in one study (Huang 2013).

Ketamine was administered intravenously in all studies except three, of which two were administered intranasally (Gálvez 2018; Lapidus 2014), and one was administered orally (Arabzadeh 2018). Esketamine was administered intranasally in all studies except for three in which the drug was administered intravenously (Correia‐Melo 2020; Jarventausta 2013; Singh 2016 b). The majority of the remaining glutamate receptor modulators were administered orally, with the exception of CP‐101,606 (Preskorn 2008) and AZD6765 (Sanacora 2014 (a); Sanacora 2014 (b); Sanacora 2017; Zarate 2013), which were administered intravenously. All comparator interventions matched the administration method of the glutamate receptor modulator, with the exception of ECT versus ketamine (Ghasemi 2013).

In the majority of studies, patients received concomitant medication for their depression alongside the experimental intervention. However, in five studies this information was unclear (Abbasinazari 2015; Chen 2017; Michelson 2007; Sanacora 2014 (a); Yoosefi 2014).

Outcomes

Most studies reported on at least one dichotomous efficacy outcome of response and remission rate. There were eight exceptions (Carspecken 2018; Downey 2016; Fernie 2017; Jagtiani 2014; Salehi 2015; Shams Alizadeh 2015; Singh 2016 b; Sumner 2020).

The continuous efficacy outcome in all included studies was measured on MADRS or HRSD. We imputed missing response and remission rates for 10 studies (Berman 2000; Ghasemi 2013; Loo 2012; Michelson 2007; Murrough 2013; Nations 2012 (part I); Nations 2012 (part II); Sos 2013; Yoosefi 2014; Sanacora 2017) using a validated method reported by Furukawa 2005. We imputed the combined group depression rating scale scores for groups using the same glutamate receptor modulator at different doses (Chen 2018; Fedgchin 2019; Li 2016; Quiroz 2016; Sanacora 2017) using the validated method of Higgins 2011d. We imputed missing SDs for one study (Yoosefi 2014) using P values and a method validated by Altman 1996.

Five comparisons did not include any data about adverse events (namely ketamine versus esketamine, ketamine versus methohexital, ketamine versus propofol, ketamine versus remifentanil hydrochloride, and MK‐0657 versus placebo), while increase in systolic blood pressure and heart rate was the only adverse event with usable information in the comparison ketamine versus ECT. For acceptability outcomes, 23 studies reported data on total dropout rates, six on dropouts due to adverse events, and one on dropouts due to lack of efficacy.

Excluded studies

(See: Characteristics of excluded studies and Figure 1)

We excluded 174 studies. The main reasons for exclusions were study design (44), secondary publications (26), or wrong population (24).

Ongoing studies

(See Characteristics of ongoing studies and Figure 1)

After screening retrieved records and checking full‐texts, we identified 43 ongoing studies.

Studies awaiting classification

(See Characteristics of studies awaiting classification and Figure 1)

We identified 9 studies awaiting classification.

Risk of bias in included studies

See Characteristics of included studies for the risk of bias judgement for each study. A summary of the overall risk of bias is presented in Figure 2 and Figure 3.


Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.


Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

We cannot rule out the potential bias introduced by inadequate blinding procedures. For instance, saline infusion does not necessarily provide adequate blinding for ketamine, as both patients and personnel can probably guess which treatment a patient has received based on differences during the infusion; for example, psychotomimetic side effects. The assessment of bias reported below is based on the adequacy of blinding attempts as described in each papers’ methods, not on the actual degree of blinding achieved. We rated studies as 'low risk' when all measures used to blind study participants and personnel from knowledge of which intervention a participant received was described. We rated studies as 'unclear risk' when there was a lack of information on blinding procedures. Of the 31 included studies assessing the efficacy of ketamine, five tested the blinding and provided information relating to whether the intended blinding was effective (Anderson 2017; Fava 2018; Shiroma 2020; Sumner 2020; Tiger 2020). Blinding was found to be ineffective in all of these studies, with the exception of one study in which participants received concomitant ECT (Anderson 2017).

Allocation

Random sequence generation

The majority of included studies (Abbasinazari 2015; Amidfar 2016; Anderson 2017; Arabzadeh 2018; Canuso 2018; Carspecken 2018; Chen 2017; Chen 2018; Correia‐Melo 2020; Daly 2018; Fava 2018; Fedgchin 2019; Fernie 2017; Fu 2020; Gálvez 2018; Grunebaum 2018; Heresco‐Levy 2013; Huang 2013; Ionescu 2018; Ionescu 2020; Jagtiani 2014; Lapidus 2014; Li 2016; Loo 2012; Michelson 2007; Murrough 2013; Nations 2012 (part I); Ochs‐Ross 2020; Omranifard 2014; Popova 2019; Preskorn 2015; Quiroz 2016; Roohi‐Azizi 2017; Salardini 2016; Salehi 2015; Sanacora 2017; Shams Alizadeh 2015; Shiroma 2020; Singh 2016 a; Singh 2016 b; Smith 2013; Sos 2013; Sumner 2020; Tiger 2020; Umbricht 2020; Yoosefi 2014; Zarate 2006a; Zarate 2013) reported detail on the method of random sequence generation and we classified them as 'low risk'. The remaining 16 studies (Berk 2014; Berman 2000; Downey 2016; Ghasemi 2013; Heresco‐Levy 2006; Hu 2016; Ibrahim 2012a; Ibrahim 2012b; Jarventausta 2013; Kuşçu 2015; Nations 2012 (part II); Preskorn 2008; Sanacora 2014 (a); Sanacora 2014 (b); Su 2017; Zarate 2006b) described the trials as randomised, but gave no details of the methods used to achieve random allocation, so we classified them as 'unclear risk'.

Allocation concealment

Thirty‐eight of the studies (Abbasinazari 2015; Amidfar 2016; Anderson 2017; Arabzadeh 2018; Canuso 2018; Carspecken 2018; Chen 2017; Chen 2018; Correia‐Melo 2020; Downey 2016; Fava 2018; Fedgchin 2019; Fernie 2017; Fu 2020; Huang 2013; Ibrahim 2012a; Ionescu 2018; Ionescu 2020; Jagtiani 2014; Lapidus 2014; Li 2016; Loo 2012; Murrough 2013; Nations 2012 (part I); Ochs‐Ross 2020; Omranifard 2014; Popova 2019; Preskorn 2008; Preskorn 2015; Quiroz 2016; Roohi‐Azizi 2017; Salardini 2016; Sanacora 2017; Shiroma 2020; Singh 2016 a; Smith 2013; Tiger 2020; Umbricht 2020) reported details on allocation concealment and we classified them as 'low risk'. We classified one study (Yoosefi 2014) as 'high risk' due to randomisation being conducted by one of the trial investigators. We classified the remaining 25 studies (Berk 2014; Berman 2000; Daly 2018; Gálvez 2018; Ghasemi 2013; Grunebaum 2018; Heresco‐Levy 2006; Heresco‐Levy 2013; Hu 2016; Ibrahim 2012b; Jarventausta 2013; Kuşçu 2015; Michelson 2007; Nations 2012 (part II); Salehi 2015; Sanacora 2014 (a); Sanacora 2014 (b); Shams Alizadeh 2015; Singh 2016 b; Sos 2013; Su 2017; Sumner 2020; Zarate 2006a; Zarate 2006b; Zarate 2013) as 'unclear risk' as they did not provide details of the methods used to achieve allocation concealment.

Blinding

Blinding of participants and personnel

Twenty‐two out of 64 studies reported detail on the blinding of participants and personnel, and we classified them as 'low risk' (Anderson 2017; Berk 2014; Fernie 2017; Ghasemi 2013; Heresco‐Levy 2006; Heresco‐Levy 2013; Huang 2013; Ibrahim 2012a; Ibrahim 2012b; Jagtiani 2014; Lapidus 2014; Loo 2012; Michelson 2007; Omranifard 2014; Preskorn 2008; Salardini 2016; Sanacora 2017; Smith 2013; Umbricht 2020; Yoosefi 2014; Zarate 2006a; Zarate 2013). Four studies were classified as high risk due to high numbers of participants guessing their treatment allocation, suggesting that blinding was not effective (Fava 2018; Shiroma 2020; Sumner 2020; Tiger 2020). We classified the remaining 38 studies as 'unclear risk' as they did not provide full details of the methods used to blind participants and personnel (Abbasinazari 2015; Amidfar 2016; Arabzadeh 2018; Berman 2000; Canuso 2018; Carspecken 2018; Chen 2017; Chen 2018; Correia‐Melo 2020; Daly 2018; Downey 2016; Fedgchin 2019; Fu 2020; Gálvez 2018; Grunebaum 2018; Hu 2016; Ionescu 2018; Ionescu 2020; Jarventausta 2013; Kuşçu 2015; Li 2016; Murrough 2013; Nations 2012 (part I); Nations 2012 (part II); Ochs‐Ross 2020; Popova 2019; Preskorn 2015; Quiroz 2016; Roohi‐Azizi 2017; Salehi 2015; Sanacora 2014 (a); Sanacora 2014 (b); Shams Alizadeh 2015; Singh 2016 a; Singh 2016 b; Sos 2013; Su 2017; Zarate 2006b).

Blinding of outcome assessment

Twenty‐one studies reported details on the methods used in the blinding of outcome assessment and we classified them as 'low risk' (Anderson 2017; Correia‐Melo 2020; Fernie 2017; Ghasemi 2013; Hu 2016; Huang 2013; Ionescu 2018; Jagtiani 2014; Jarventausta 2013; Lapidus 2014; Murrough 2013; Omranifard 2014; Preskorn 2008; Salardini 2016; Sanacora 2017; Shams Alizadeh 2015; Singh 2016 bSmith 2013; Sumner 2020; Yoosefi 2014; Zarate 2013). Two studies were classified as high risk; one due to the high numbers of correct guesses of treatment assignment, suggesting that blinding of the outcome assessment was not effective (Fava 2018; Tiger 2020), and another due to conflicting information concerning blinding (Salehi 2015). We classified 40 studies as 'unclear risk' as they did not provide full details of the methods used in the blinding of outcome assessment (Abbasinazari 2015; Amidfar 2016; Arabzadeh 2018; Berk 2014; Berman 2000Canuso 2018; Carspecken 2018; Chen 2017; Chen 2018; Daly 2018; Downey 2016; Fedgchin 2019; Fu 2020; Gálvez 2018; Grunebaum 2018; Heresco‐Levy 2006; Heresco‐Levy 2013; Ibrahim 2012a; Ibrahim 2012b; Ionescu 2020; Kuşçu 2015; Li 2016; Loo 2012; Michelson 2007; Nations 2012 (part I); Nations 2012 (part II); Ochs‐Ross 2020; Popova 2019; Preskorn 2015; Quiroz 2016; Roohi‐Azizi 2017; Sanacora 2014 (a); Sanacora 2014 (b); Shiroma 2020; Singh 2016 a; Sos 2013; Su 2017; Umbricht 2020; Zarate 2006a; Zarate 2006b).

Incomplete outcome data

We rated five studies as 'high risk' in terms of attrition bias (Berman 2000; Fedgchin 2019; Fernie 2017; Hu 2016; Loo 2012), and 11 as 'unclear' (Downey 2016; Jarventausta 2013; Michelson 2007; Nations 2012 (part I); Nations 2012 (part II); Salehi 2015; Sanacora 2014 (a); Shiroma 2020; Smith 2013; Yoosefi 2014; Zarate 2006a).

Selective reporting

As no protocol was available for studies or authors could not provide us with supplementary information, we judged 36 trials to have 'unclear' risk of bias (Abbasinazari 2015; Amidfar 2016; Arabzadeh 2018; Berk 2014; Chen 2017; Chen 2018; Downey 2016; Gálvez 2018; Grunebaum 2018; Heresco‐Levy 2006; Heresco‐Levy 2013; Hu 2016; Huang 2013; Ibrahim 2012b; Ionescu 2018; Jagtiani 2014; Jarventausta 2013; Lapidus 2014; Loo 2012; Michelson 2007; Murrough 2013; Nations 2012 (part I); Nations 2012 (part II); Preskorn 2008; Sanacora 2014 (a); Sanacora 2014 (b); Shams Alizadeh 2015; Shiroma 2020; Smith 2013; Sos 2013; Sumner 2020; Tiger 2020; Yoosefi 2014; Zarate 2006a; Zarate 2006b; Zarate 2013). We considered eight trials as having 'high risk' of reporting bias (Berman 2000; Daly 2018; Fernie 2017; Ibrahim 2012a; Kuşçu 2015; Li 2016; Omranifard 2014; Sanacora 2017) because the protocol was unavailable and some outcome measures or time points were not reported.

Other potential sources of bias

We rated 14 studies as high risk due to being funded by pharmaceutical companies and authors having the potential to financially benefit from positive findings (Canuso 2018; Daly 2018; Downey 2016; Fava 2018; Fedgchin 2019; Fu 2020; Ionescu 2018; Ionescu 2020; Ochs‐Ross 2020; Popova 2019; Preskorn 2015; Quiroz 2016; Sanacora 2017; Umbricht 2020).

Effects of interventions

See: Summary of findings 1 Ketamine compared to placebo for adults with unipolar major depressive disorder; Summary of findings 2 Ketamine compared to midazolam for adults with unipolar major depressive disorder; Summary of findings 3 Esketamine compared to placebo for adults with unipolar major depressive disorder

We found data for ketamine versus placebo, ketamine versus pharmacologically active agents, ketamine versus placebo, glutamate receptor modulators versus placebo, and one glutamate receptor modulator (sarcosine) versus a pharmacologically active agent (citalopram). We also found data for ketamine versus another glutamate receptor modulator (esketamine). We did not find any data for glutamate receptor modulators (other than ketamine) versus electroconvulsive therapy (ECT).

From our prespecified time points outlined in the methodology, the majority of comparisons had data provided for up to four weeks, with few studies measuring outcomes at three months. For ketamine versus methohexital data were only provided for 72 hours, and the ketamine versus esketamine and basimglurant versus placebo comparisons only had data up to one week. The ketamine versus ECT and ketamine versus remifentanil hydrochloride comparisons had data up to two weeks. Both CP‐101,606 and MK‐0657 comparisons against placebo had data for two weeks, and citicoline and decoglurant comparisons only had data for four weeks. For the atomoxetine comparison we found data only at the three‐month time point.

For adverse events, we reported all findings in the forest plots, but below we only report findings that were statistically significant. Unless otherwise specified, we report data here below using a fixed‐effect model due to the majority of forest plots including only one study.

A. Ketamine versus placebo

1. Ketamine versus placebo

Ten new studies contributed to this comparison (Anderson 2017; Arabzadeh 2018; Chen 2017; Chen 2018; Hu 2016; Ionescu 2018; Li 2016; Singh 2016 a; Su 2017; Tiger 2020) making a total of 14 including four from the previous review (Berman 2000; Loo 2012; Sos 2013; Zarate 2006a). Outcome data were provided at 24 hours, 72 hours, one week, two weeks, four weeks, and three months. See also summary of findings Table 1.

Thirteen of these studies provided ketamine intravenously, and one administered ketamine orally (Arabzadeh 2018). Nine studies infused a dose of 0.5mg/kg ketamine (Anderson 2017; Berman 2000; Hu 2016; Ionescu 2018; Loo 2012; Singh 2016 a; Sos 2013; Tiger 2020; Zarate 2006a), three studies allocated either 0.2mg/kg or 0.5mg/kg (Chen 2018; Li 2016; Su 2017), and one infused 0.3mg/kg (Chen 2017). The one study that used oral administration routes prescribed doses of 50 mg (Arabzadeh 2018).

In eight studies ketamine was administered intravenously as a single infusion (Berman 2000; Chen 2018; Hu 2016; Li 2016; Sos 2013; Su 2017; Tiger 2020; Zarate 2006a). Two studies infused participants twice weekly (Anderson 2017; Ionescu 2018), two studies infused three times per week (Chen 2017; Loo 2012), and one randomised participants to either two or three infusions weekly (Singh 2016 a). One study using oral administration dosed once daily for six weeks (Arabzadeh 2018).

The majority of studies allowed concomitant medications (Anderson 2017; Chen 2017; Chen 2018; Hu 2016; Ionescu 2018; Li 2016; Loo 2012; Singh 2016 a; Sos 2013; Su 2017). Four studies did not allow concomitant medications (Arabzadeh 2018; Berman 2000; Tiger 2020; Zarate 2006a). In three studies, participants received ECT treatments alongside ketamine (Anderson 2017; Chen 2017; Loo 2012).

1.1 Efficacy: number of participants who respond to treatment

Ketamine was more efficacious than placebo in terms of the number of participants who responded to treatment at 24 hours (random‐effects odds ratio (OR) 3.94, 95% confidence interval (CI )1.54 to 10.10; P = 0.004; participants = 185; studies = 7; I2 = 14%), very low‐certainty evidence,, at 72 hours (random‐effects OR 15.84, 95% CI 3.68 to 68.12; P = 0.0002; participants = 83; studies = 4; I2 = 0%), and at one week (random‐effects OR 3.76, 95% CI 0.98 to 14.42; P = 0.05; participants = 196; studies = 5; I2 = 43%) (Analysis 1.1). Results at two weeks, four weeks, and three months had high levels of heterogeneity, so no conclusions could be made about the response efficacy of ketamine versus placebo at these time points: two weeks (random‐effects OR 2.92, 95% CI 0.48 to 17.78; P = 0.24; participants = 206; studies = 4; I2 = 83%); four weeks (random‐effects OR 1.37, 95% CI 0.50 to 3.77; P = 0.54; participants = 202; studies = 4; I2 = 59%); three months (random‐effects OR 1.95, 95% CI 0.24 to 15.69; P = 0.53; participants = 117; studies = 3; I2 = 80%). Figure 4.


Forest plot of comparison: 1 Ketamine versus Placebo, outcome: 1.1 Response rate.

Forest plot of comparison: 1 Ketamine versus Placebo, outcome: 1.1 Response rate.

1.2 Adverse events

Participants assigned to treatment with ketamine were more likely to report the following adverse events than those who received placebo: agitation/anxiety (random‐effects OR 3.44, 95% CI 1.07 to 11.04; P = 0.04; participants = 143; studies = 3; I2 = 9%; Analysis 1.3), confusion (random‐effects OR 3.76, 95% CI 1.13 to 12.47; P = 0.03; participants = 76; studies = 2; I2 = 4%; Analysis 1.6), dissociative symptoms (random‐effects OR 7.72, 95% CI 1.31 to 45.51; P = 0.02; participants = 145; studies = 3; I2 = 0%; Analysis 1.7).

We found no difference in terms of other adverse events (Analysis 1.2; Analysis 1.4; Analysis 1.5; Analysis 1.8; Analysis 1.9; Analysis 1.10; Analysis 1.11; Analysis 1.12; Analysis 1.13; Analysis 1.14; Analysis 1.15; Analysis 1.16; Analysis 1.17; Analysis 1.18; Analysis 1.19; Analysis 1.20; Analysis 1.21; Analysis 1.22; Analysis 1.23; Analysis 1.24; Analysis 1.25).

1.3 Efficacy: number of participants who achieve remission

Ketamine resulted in increased remission rates over placebo at 24 hours (random‐effects OR 5.60, 95% CI 1.07 to 29.46; P = 0.04; participants = 75; studies = 3; I2 = 0%), very low‐certainty evidence, at 72 hours (random‐effects OR 6.60, 95% CI 1.51 to 28.92; P = 0.01 participants = 83; studies = 4; I2 = 0%), and at one week (random‐effects OR 4.64, 95% CI 1.37 to 15.68; P = 0.01; participants = 196; studies = 5; I2 = 0%) (Analysis 1.26). We found no difference in remission between ketamine and placebo at two weeks (random‐effects OR 1.67, 95% CI 0.38 to 7.27; P = 0.50; participants = 206; studies = 4; I2 = 63%), at four weeks (random‐effects OR 1.46, 95% CI 0.54 to 3.95; P = 0.46; participants = 202; studies = 4; I2 = 35%), or at three months (random‐effects OR 1.09, 95% CI 0.45 to 2.67; participants = 90; studies = 2; I2 = 0%).

1.4 Change scores on depression scale from baseline

We found evidence that ketamine was more effective than placebo at reducing depression rating scale scores from baseline at 24 hours (random‐effects standardised mean difference (SMD) ‐0.87, 95% CI ‐1.26 to ‐0.48; P < 0.0001; participants = 231; studies = 8; I2 = 41%), very low‐certainty evidence, at 72 hours (random‐effects SMD ‐0.68, 95% CI ‐1.28 to ‐0.07; P = 0.03; participants = 148; studies = 6; I2 = 62%), at one week (random‐effects SMD ‐0.72, 95% CI ‐1.10 to ‐0.33; P = 0.0003; participants = 143; studies = 6; I2 = 13%), and at four weeks (random‐effects SMD ‐0.68, 95% CI ‐1.07 to ‐0.29; P = 0.0006; participants = 107; studies = 2; I2 = 0%) (Analysis 1.27). We found no conclusive evidence of reduction in depression rating scale scores between ketamine and placebo at two weeks due to substantial heterogeneity (random‐effects SMD ‐0.43, 95% CI ‐0.90 to 0.04; P = 0.07; participants = 236; studies = 5; I2 = 65%).

1.5 Suicidality

We found no difference in suicidal ideation scores between ketamine and placebo at any time point: at 24 hours (random‐effects mean difference (MD) 0.02, 95% CI ‐0.78 to 0.82; P = 0.96; participants = 48; studies = 1; I2 = 0%), at 72 hours (random‐effects MD 0.34, 95% CI ‐0.25 to 0.93; P = 0.26; participants = 68; studies = 2; I2 = 10%), at one week (random‐effects MD ‐0.30, 95% CI ‐1.56 to 0.96; P = 0.64; participants = 19; studies = 1; I2 = 0%), and at two weeks (random‐effects MD ‐0.20, 95% CI ‐1.46 to 1.06; P = 0.76; participants = 19; studies = 1; I2 = 0%) (Analysis 1.28).

1.6 Cognition

Ketamine was associated with high cognition scores over placebo in immediate‐term memory (random‐effects MD 0.80, 95% CI 0.12 to 1.48; P = 0.02; participants = 127; studies = 1; I2 = 0%), short‐term memory (random‐effects MD 6.90, 95% CI 5.01 to 8.79; P < 0.00001; participants = 127; studies = 1; I2 = 0%), and long‐term memory (random‐effects MD 4.50, 95% CI 2.79 to 6.21; P < 0.00001; participants = 127; studies = 1; I2 = 0%) (Analysis 1.29).

1.7 Quality of life

There were no differences in quality of life between ketamine and placebo (random‐effects MD 0.11, 95% CI ‐0.05 to 0.27; P = 0.19; participants = 64; studies = 1; I2 = 0%) (Analysis 1.30).

1.8 Cost to healthcare services

No data were available for this outcome.

1.9 Acceptability: total dropouts

We found no difference between ketamine and placebo in terms of participants who dropped out due to any cause (random‐effects OR 1.25, 95% CI 0.19 to 8.28; P = 0.81; participants = 201; studies = 6; I2 = 75%), very low‐certainty evidence (Analysis 1.31).

B. Ketamine versus other pharmacologically active agents

2. Ketamine versus midazolam

Five studies contributed data to this comparison, including four newly identified ones (Fava 2018; Gálvez 2018; Grunebaum 2018; Shiroma 2020) and one from the previous review (Murrough 2013). Data were available for 24 hours, 72 hours, one week, two weeks, four weeks, and three months. summary of findings Table 2

2.1 Efficacy: number of participants who respond to treatment

Ketamine had higher response efficacy over midazolam at 24 hours (random‐effects OR 2.48, 95% CI 1.00 to 6.18; P = 0.05; participants = 296; studies = 4; I2 = 58%) very low‐certainty evidence, at one week (random‐effects OR 3.11, 95% CI 1.38 to 7.04; P = 0.006; participants = 126; studies = 2; I2 = 0%), and at two weeks (random‐effects OR 4.89, 95% CI 1.49 to 16.10; P = 0.009; participants = 53; studies = 1; I2 = 0%) (Analysis 2.1)At 72 hours the OR favoured ketamine over midazolam, but wide confidence intervals and heterogeneity created uncertainty about this effect (random‐effects OR 2.20, 95% CI 0.92 to 5.28; P = 0.08; participants = 218; studies = 3; I2 = 46%), No difference was found for response at four weeks (random‐effects OR 0.50, 95% CI 0.01 to 19.56; P = 0.71; participants = 5; studies = 1; I2 = 0%), or three months (random‐effects OR 3.00, 95% CI 0.08 to 115.34; P = 0.56; participants = 5; studies = 1; I2 = 0%). Figure 5.


Forest plot of comparison: 2 Ketamine versus Midazolam, outcome: 2.1 Response rate.

Forest plot of comparison: 2 Ketamine versus Midazolam, outcome: 2.1 Response rate.

2.2 Adverse events

Patients receiving midazolam were less likely to report blurred vision over ketamine 24 hours post‐infusion (random‐effects OR 8.52, 95% CI 1.80 to 40.39; P = 0.007; participants = 72; studies = 1; I2 = 0%), but not at one week (random‐effects OR 1.03, 95% CI 0.23 to 4.70; P = 0.97; participants = 126; studies = 2; I2 = 0%) (Analysis 2.5). Ketamine increased the incidence of dizziness at 24 hours post‐infusion over midazolam (random‐effects OR 3.42, 95% CI 1.44 to 8.14; P = 0.005; participants = 224; studies = 2; I2 = 0%), but not at one week (random‐effects OR 1.05, 95% CI 0.43 to 2.56; P = 0.91; participants = 283; studies = 4; I2 = 0%) (Analysis 2.14). Midazolam was more likely than ketamine to cause general malaise at 24 hours post‐infusion (random‐effects OR 0.18, 95% CI 0.04 to 0.75; P = 0.02; participants = 72; studies = 1; I2 = 0%), however this difference disappeared at one week (random‐effects OR 1.90, 95% CI 0.32 to 11.44; P = 0.48; participants = 131; studies = 3; I2 = 53%) (Analysis 2.18). Ketamine was associated with increased blood pressure or heart rate over midazolam at one week (random‐effects OR 9.37, 95% CI 2.49 to 35.25; P = 0.0009; participants = 54; studies = 1; I2 = 0%), but not at four weeks (random‐effects OR 1.24, 95% CI 0.06 to 26.93; P = 0.89; participants = 99; studies = 1; I2 = 0%) (Analysis 2.21). Nausea/vomiting was more likely to occur on the day of infusion in participants receiving ketamine over midazolam (random‐effects OR 3.62, 95% CI 1.13 to 11.58; P = 0.03; participants = 152; studies = 2; I2 = 0%), but this did not continue at one week (random‐effects OR 2.57, 95% CI 0.78 to 8.52; P = 0.12; participants = 126; studies = 2; I2 = 0%) or four weeks (random‐effects OR 7.12, 95% CI 0.40 to 125.66; P = 0.18; participants = 99; studies = 1; I2 = 0%) (Analysis 2.32). Sleepiness/drowsiness was also more likely with ketamine over midazolam on the day of infusion (random‐effects OR 0.21, 95% CI 0.07 to 0.66; P = 0.008; participants = 80; studies = 1; I2 = 0%), but not at one week (random‐effects OR 2.57, 95% CI 0.43 to 15.41; P = 0.30; participants = 54; studies = 1; I2 = 100%) (Analysis 2.44).

No differences between ketamine and midazolam were found for any other adverse event outcomes (Analysis 2.2; Analysis 2.3; Analysis 2.4; Analysis 2.6; Analysis 2.7; Analysis 2.8; Analysis 2.9; Analysis 2.10; Analysis 2.11; Analysis 2.12; Analysis 2.13; Analysis 2.15; Analysis 2.16; Analysis 2.17; Analysis 2.19; Analysis 2.20; Analysis 2.22; Analysis 2.23; Analysis 2.24; Analysis 2.25; Analysis 2.26; Analysis 2.27; Analysis 2.28; Analysis 2.29; Analysis 2.30; Analysis 2.31; Analysis 2.33; Analysis 2.34; Analysis 2.35; Analysis 2.36; Analysis 2.37; Analysis 2.38; Analysis 2.39; Analysis 2.40; Analysis 2.41; Analysis 2.42; Analysis 2.43; Analysis 2.44; Analysis 2.45; Analysis 2.46; Analysis 2.47; Analysis 2.48; Analysis 2.49; Analysis 2.50; Analysis 2.51; Analysis 2.52).

2.3 Efficacy: number of participants who achieve remission

Effect sizes favoured ketamine over midazolam, however wide confidence intervals affected the certainty of these results at all time points: at 24 hours (random‐effects OR 2.21, 95% CI 0.67 to 7.32; P = 0.19; participants = 122; studies = 2; I2 = 40%), low‐certainty evidence, at 72 hours (random‐effects OR 1.73, 95% CI 0.74 to 4.04; P = 0.20; participants = 118; studies = 2; I2 = 0%), at one week (random‐effects OR 1.86, 95% CI 0.80 to 4.32; P = 0.15; participants = 126; studies = 2; I2 = 0%), at two weeks (random‐effects OR 2.29, 95% CI 0.76 to 6.92; P = 0.14; participants = 53; studies = 1; I2 = 0%), at four weeks (random‐effects OR 0.50, 95% CI 0.01 to 19.56; P = 0.71; participants = 5; studies = 1; I2 = 0%), and at three months (Analysis 2.53).

2.4 Change scores on depression scale from baseline

We found evidence that ketamine was more effective than midazolam at reducing depression scores at 24 hours (random‐effects SMD ‐0.49, 95% CI ‐0.87 to ‐0.10; P = 0.01; participants = 297; studies = 4; I2 = 56%), very low‐certainty evidence, at 72 hours (random‐effects SMD ‐0.39, 95% CI ‐0.70 to ‐0.08; P = 0.01; participants = 207; studies = 3; I2 = 0%), at one week (random‐effects SMD ‐0.38, 95% CI ‐0.69 to ‐0.08; P = 0.01; participants = 212; studies = 3; I2 = 0%), and at four weeks (random‐effects SMD ‐0.57, 95% CI ‐1.10 to ‐0.04; P = 0.03; participants = 86; studies = 1; I2 = 0%) (Analysis 2.54). However there was no effect at two weeks (random‐effects SMD ‐0.37, 95% CI ‐0.84 to 0.10; P = 0.12; participants = 137; studies = 2; I2 = 36%).

2.5 Suicidality

Ketamine was more effective than midazolam in reducing suicidal ideation (random‐effects MD ‐1.32, 95% CI ‐2.52 to ‐0.12; P = 0.03; participants = 57; studies = 1; I2 = 0%) (Analysis 2.55).

2.6 Cognition

No data were available for this outcome.

2.7 Quality of life

No data were available for this outcome.

2.8 Cost to healthcare services

No data were available for this outcome.

2.9 Acceptability: total dropouts

We found no difference between ketamine and midazolam in terms of participants who dropped out due to any cause (random‐effects OR 0.33, 95% CI 0.05 to 2.09; P = 0.24; 1 study, 72 participants), low‐certainty evidence (Analysis 2.56).

3. Ketamine versus thiopental

Two studies contributed to this comparison (Jagtiani 2014; Yoosefi 2014), providing data for 72 hours, two weeks and four weeks. In both studies, ketamine or thiopental was used as an anaesthetic agent for patients undergoing ECT treatment.

3.1 Efficacy: number of participants who respond to treatment

There was no evidence that ketamine was more effective than thiopental in helping participants to achieve response at 72 hours (random‐effects OR 2.64, 95% CI 0.10 to 69.88; P = 0.56; 1 study, 31 participants) or at four weeks (random‐effects OR 0.81, 95% CI 0.05 to 14.28; P = 0.89; 1 study, 31 participants) (Analysis 3.1). There were no participants who met response at two weeks in either the ketamine or thiopental group (1 study, 31 participants).

3.2 Adverse events

Participants receiving thiopental reported more increased secretions than those receiving ketamine (random‐effects OR 3.86, 95% CI 0.93 to 16.05; P = 0.06; participants = 60; studies = 1; I2 = 0%) (Analysis 3.7).

There was no evidence of any difference in the occurrence of any other adverse events Analysis 3.6; Analysis 3.2; Analysis 3.4; Analysis 3.8; Analysis 3.5; Analysis 3.3.

3.3 Efficacy: number of participants who achieve remission

No data were available for this outcome.

3.4 Change scores on depression scale from baseline

We found some evidence that ketamine was more effective than thiopental in improving depression rating scale scores at 72 hours (random‐effects MD ‐3.87, 95% CI ‐6.08 to ‐1.66; P = 0.0006; 1 study, 29 participants), at one week (random‐effects MD ‐6.96, 95% CI ‐9.82 to ‐4.10; P < 0.00001; participants = 60; studies = 1; I2 = 0%); and two weeks (random‐effects MD ‐3.46, 95% CI ‐4.88 to ‐2.04; P < 0.00001; participants = 89; studies = 2; I2 = 97%) (Analysis 3.9). No difference was found between ketamine and thiopental at four weeks (random‐effects MD ‐0.22, 95% CI ‐2.64 to 2.20; P = 0.86; 1 study, 29 participants). However, these findings were based on a very small number of participants.

3.5 Suicidality

No data were available for this outcome.

3.6 Cognition

No data were available for this outcome.

3.7 Quality of life

No data were available for this outcome.

3.8 Cost to healthcare services

No data were available for this outcome.

3.9 Acceptability: total dropouts

We found no difference between ketamine and thiopental in terms of participants who dropped out due to any cause (random‐effects OR 4.68, 95% CI 0.21 to 105.89; P = 0.33; 1 study, 31 participants) (Analysis 3.10).

4. Ketamine versus methohexital

One study contributed to this comparison (Carspecken 2018), providing depression rating scale score data for 72 hours.

4.1 Efficacy: number of participants who respond to treatment

No data were available for this outcome.

4.2 Adverse events

No data were available for this outcome.

4.3 Efficacy: number of participants who achieve remission

No data were available for this outcome.

4.4 Change scores on depression scale from baseline

There was no difference in depression rating scale scores between ketamine and methohexital at 72 hours (random‐effects MD ‐0.80, 95% CI ‐4.45 to 2.85; P = 0.67; participants = 50; studies = 1; I2 = 0%) (Analysis 4.1).

4.5 Suicidality

No data were available for this outcome.

4.6 Cognition

No data were available for this outcome.

4.7 Quality of life

No data were available for this outcome.

4.8 Cost to healthcare services

No data were available for this outcome.

4.9 Acceptability: total dropouts

No data were available for this outcome.

5. Ketamine versus propofol

One study contributed to this comparison (Fernie 2017), providing depression rating scale score data at two weeks and three months.

5.1 Efficacy: number of participants who respond to treatment

No data were available for this outcome.

5.2 Adverse events

No data were available for this outcome.

5.3 Efficacy: number of participants who achieve remission

No data were available for this outcome.

5.4 Change scores on depression scale from baseline

No evidence was found of a difference in depression rating scale scores between ketamine and propofol at two weeks (random‐effects MD 3.67, 95% CI ‐0.84 to 8.18; P = 0.11; participants = 31; studies = 1, or at three months (random‐effects MD 2.00, 95% CI ‐4.93 to 8.93; P = 0.57; participants = 26; studies = 1), based on the small number of participants included in this analysis (Analysis 5.1).

5.5 Suicidality

No data were available for this outcome.

5.6 Cognition

No data were available for this outcome.

5.7 Quality of life

No data were available for this outcome.

5.8 Cost to healthcare services

No data were available for this outcome.

5.9 Acceptability: total dropouts

No data were available for this outcome.

6. Ketamine versus remifentanil hydrochloride

One study contributed to this comparison (Sumner 2020), providing depression rating scale score data at 24 hours, one week and two weeks.

6.1 Efficacy: number of participants who respond to treatment

No data were available for this outcome.

6.2 Adverse events

No data were available for this outcome.

6.3 Efficacy: number of participants who achieve remission

No data were available for this outcome.

6.4 Change scores on depression scale from baseline

There was some evidence that ketamine improved depression rating scale scores over remifentanil hydrochloride at 24 hours (random‐effects MD ‐7.74, 95% CI ‐14.03 to ‐1.45; P = 0.02; participants = 30; studies = 1; I2 = 0%), and at one week (random‐effects MD ‐7.54, 95% CI ‐14.13 to ‐0.95; P = 0.02; participants = 30; studies = 1; I2 = 0%). Results from one small study found no difference at two weeks (random‐effects MD ‐1.00, 95% CI ‐6.98 to 4.98; P = 0.74; participants = 30; studies = 1; I2 = 0%) (Analysis 6.1).

6.5 Suicidality

No data were available for this outcome.

6.6 Cognition

No data were available for this outcome.

6.7 Quality of life

No data were available for this outcome.

6.8 Cost to healthcare services

No data were available for this outcome.

6.9 Acceptability: total dropouts

No data were available for this outcome.

7. Ketamine versus esketamine

One study contributed to this comparison (Correia‐Melo 2020), providing response efficacy data at 24 hours, 72 hours, and one week.

7.1 Efficacy: number of participants who respond to treatment

There was no difference in response between ketamine and esketamine at 24 hours (random‐effects OR 1.07, 95% CI 0.40 to 2.89; P = 0.89; participants = 63; studies = 1; I2 = 0%), at 72 hours (random‐effects OR 1.56, 95% CI 0.58 to 4.22; P = 0.38; participants = 63; studies = 1; I2 = 100%), and at one week (random‐effects OR 2.34, 95% CI 0.85 to 6.45; P = 0.10; participants = 63; studies = 1; I2 = 0%) (Analysis 7.1).

7.2 Adverse events

No data were available for this outcome.

7.3 Efficacy: number of participants who achieve remission

No data were available for this outcome.

7.4 Change scores on depression scale from baseline

No data were available for this outcome.

7.5 Suicidality

No data were available for this outcome.

7.6 Cognition

We found no difference in cognition scores between ketamine and esketamine during infusion (random‐effects MD 3.30, 95% CI ‐4.70 to 11.30; P = 0.42; participants = 63; studies = 1; I2 = 0%) (Analysis 7.2).

7.7 Quality of life

No data were available for this outcome.

7.8 Cost to healthcare services

No data were available for this outcome.

7.9 Acceptability: total dropouts

No data were available for this outcome.

C. Ketamine versus ECT

8. Ketamine versus ECT

One study contributed to this comparison (Ghasemi 2013), providing data for 24 hours, 72 hours, one week and two weeks.

8.1 Efficacy: number of participants who respond to treatment

We found very limited evidence that ketamine was more effective than ECT in terms of response at 24 hours (random‐effects OR 28.00, 95% CI 2.07 to 379.25; P = 0.01; 1 study, 18 participants) and 72 hours (random‐effects OR 12.25, 95% CI 1.33 to 113.06; P = 0.03; 1 study, 18 participants) (Analysis 8.1). Results from one very small study found no difference in response efficacy between ketamine and ECT at one week (random‐effects OR 3.35, 95% CI 0.12 to 93.83; P = 0.48; 1 study, 18 participants) and at two weeks (random‐effects OR 3.35, 95% CI 0.12 to 93.83; P = 0.48; 1 study, 18 participants).

8.2 Adverse events

We found no difference between ketamine and ECT in terms of adverse events. However, the only adverse events reported in this study were blood pressure and heart rate.

8.3 Efficacy: number of participants who achieve remission

Results from one small study found no difference in terms of remission between ECT and ketamine at any time point; at 24 hours (random‐effects OR 3.35, 95% CI 0.12 to 93.83; P = 0.48; 1 study, 18 participants); at 72 hours (random‐effects OR 3.35, 95% CI 0.12 to 93.83; P = 0.48; 1 study, 18 participants); at one week (random‐effects OR 10.23, 95% CI 0.45 to 233.23; P = 0.14; 1 study, 18 participants); and at two weeks (random‐effects OR 4.00, 95% CI 0.33 to 48.66; P = 0.28; 1 study, 18 participants) (Analysis 8.3).

8.4 Change scores on depression scale from baseline

We found some evidence that ketamine may be more effective than ECT at 24 hours (random‐effects MD ‐8.90, 95% CI ‐11.72 to ‐6.08; P < 0.00001; participants = 18; studies = 1; I2 = 0%), at 72 hours (random‐effects MD ‐9.00, 95% CI ‐14.24 to ‐3.76; P = 0.0008; 1 study, 18 participants) and at one week (random‐effects MD ‐6.66, 95% CI ‐11.20 to ‐2.12; P = 0.004; 1 study, 18 participants). No difference in effect of ketamine compared with ECT at two weeks, although this may be impacted by the small sample included in this analysis (random‐effects MD ‐4.45, 95% CI ‐9.01 to 0.11; P = 0.06; 1 study, 18 participants) (Analysis 8.4).

8.5 Suicidality

No data were available for this outcome.

8.6 Cognition

No data were available for this outcome.

8.7 Quality of life

No data were available for this outcome.

8.8 Cost to healthcare services

No data were available for this outcome.

8.9 Acceptability: total dropouts

There were no patients who dropped out of the trial in either the ketamine or ECT group in Ghasemi 2013.

D. Other glutamate receptor modulators versus placebo

9. Esketamine versus placebo

Nine studies contributed to this comparison (Canuso 2018; Daly 2018; Fedgchin 2019; Fu 2020; Ionescu 2020; Jarventausta 2013; Ochs‐Ross 2020; Popova 2019; Singh 2016 b). Data ere available for 24 hours, 72 hours, one week, two weeks, four weeks, and three months. summary of findings Table 3

9.1 Efficacy: number of participants who respond to treatment

Esketamine was more efficacious than placebo in terms of response at 24 hours (random‐effects OR 2.11, 95% CI 1.20 to 3.68; P = 0.009; participants = 1071; studies = 5; I2 = 50%), low‐certainty evidence, at one week (random‐effects OR 1.60, 95% CI 1.09 to 2.34; P = 0.02; participants = 1115; studies = 6; I2 = 20%), at two weeks (random‐effects OR 1.57, 95% CI 1.09 to 2.28; P = 0.02; participants = 451; studies = 2; I2 = 0%), and at four weeks (random‐effects OR 1.84, 95% CI 1.44 to 2.37; P < 0.00001; participants = 1117; studies = 5; I2 = 0%) (Analysis 9.1). There was no difference found at 72 hours (random‐effects OR 1.34, 95% CI 0.92 to 1.96; P = 0.13; participants = 451; studies = 2; I2 = 0%). Figure 6.


Forest plot of comparison: 9 Esketamine versus placebo, outcome: 9.1 Response rate.

Forest plot of comparison: 9 Esketamine versus placebo, outcome: 9.1 Response rate.

9.2 Adverse events

Participants assigned to receive esketamine reported more changes in blood pressure over esketamine (random‐effects OR 2.67, 95% CI 1.52 to 4.70; P = 0.0007; participants = 933; studies = 4; I2 = 0%) (Analysis 9.5). There was an increase in constipation in those receiving esketamine over placebo (random‐effects OR 4.07, 95% CI 1.60 to 10.39; P = 0.003; participants = 452; studies = 2; I2 = 0%) (Analysis 9.6). Dissociative symptoms were also increased for esketamine over placebo (random‐effects OR 8.76, 95% CI 5.19 to 14.77; P < 0.00001; participants = 933; studies = 4; I2 = 0%) (Analysis 9.11), as was dizziness (random‐effects OR 3.67, 95% CI 2.54 to 5.31; P < 0.00001; participants = 933; studies = 4; I2 = 0%) (Analysis 9.12), and dizziness postural (random‐effects OR 4.70, 95% CI 1.06 to 20.80; P = 0.04; participants = 569; studies = 2; I2 = 7%) (Analysis 9.13). Participants receiving esketamine were found to be more likely to feel drunk (random‐effects OR 7.58, 95% CI 1.37 to 41.77; P = 0.02; participants = 571; studies = 2; I2 = 0%) (Analysis 9.17), and experience nausea/vomiting (random‐effects OR 3.24, 95% CI 1.84 to 5.72; P < 0.0001; participants = 933; studies = 4; I2 = 60%) (Analysis 9.26). Paresthesia/neuropathy exacerbation was also increased in participants receiving esketamine compared with placebo (random‐effects OR 3.51, 95% CI 1.62 to 7.62; P = 0.001; participants = 708; studies = 3; I2 = 18%) (Analysis 9.27), as was sensory disturbance (random‐effects OR 7.25, 95% CI 3.55 to 14.78; P < 0.00001; participants = 796; studies = 3; I2 = 0%) (Analysis 9.30). There was a difference in favour of placebo over esketamine for sedation (random‐effects OR 5.31, 95% CI 2.18 to 12.94; P = 0.0002; participants = 796; studies = 3; I2 = 0%) (Analysis 9.31) and sleepiness/drowsiness (random‐effects OR 2.11, 95% CI 1.39 to 3.21; P = 0.0005; participants = 796; studies = 3; I2 = 0%) (Analysis 9.32). We also found that esketamine increased vertigo (random‐effects OR 12.25, 95% CI 4.09 to 36.67; P < 0.00001; participants = 796; studies = 3; I2 = 0%) (Analysis 9.39) and blurred vision (random‐effects OR 3.02, 95% CI 1.37 to 6.66; P = 0.006; participants = 796; studies = 3; I2 = 13%) compared with placebo (Analysis 9.40).

We found no differences between esketamine and placebo for any other adverse events (Analysis 9.2; Analysis 9.3; Analysis 9.4; Analysis 9.7; Analysis 9.8; Analysis 9.9; Analysis 9.10; Analysis 9.14; Analysis 9.15; Analysis 9.16; Analysis 9.18; Analysis 9.19; Analysis 9.20; Analysis 9.21; Analysis 9.22; Analysis 9.23; Analysis 9.24; Analysis 9.25; Analysis 9.28; Analysis 9.29; Analysis 9.33; Analysis 9.34; Analysis 9.35; Analysis 9.36; Analysis 9.37; Analysis 9.38).

9.3 Efficacy: number of participants who achieve remission

Participants assigned esketamine treatment achieved remission more than those receiving placebo at 24 hours (random‐effects OR 2.74, 95% CI 1.71 to 4.40; P < 0.0001; participants = 894; studies = 5; I2 = 0%), moderate‐certainty evidence, at two weeks (random‐effects OR 1.52, 95% CI 1.07 to 2.16; P = 0.02; participants = 832; studies = 4; I2 = 0%), and at four weeks (random‐effects OR 1.57, 95% CI 1.18 to 2.10; P = 0.002; participants = 957; studies = 5; I2 = 0%) (Analysis 9.41). There were no differences found at 72 hours (random‐effects OR 1.55, 95% CI 0.91 to 2.64; P = 0.11; participants = 517; studies = 3; I2 = 24%) or at one week (random‐effects OR 1.54, 95% CI 0.88 to 2.69; P = 0.13; participants = 948; studies = 6; I2 = 30%).

9.4 Change scores on depression scale from baseline

Esketamine reduced depression rating scale scores over placebo at 24 hours (random‐effects SMD ‐0.31, 95% CI ‐0.45 to ‐0.17; P < 0.0001; participants = 824; studies = 4; I2 = 0%), moderate‐certainty evidence, at 72 hours (random‐effects SMD ‐0.30, 95% CI ‐0.50 to ‐0.11; P = 0.002; participants = 517; studies = 3; I2 = 14%), at one week (random‐effects SMD ‐0.23, 95% CI ‐0.37 to ‐0.10; P = 0.0008; participants = 884), at two weeks (random‐effects SMD ‐0.21, 95% CI ‐0.34 to ‐0.07; P = 0.003; participants = 857; studies = 4; I2 = 0%), and at four weeks (random‐effects SMD ‐0.27, 95% CI ‐0.39 to ‐0.16; P < 0.00001; participants = 1182; studies = 6; I2 = 0%) (Analysis 9.42). However, there was no difference at three months (random‐effects SMD ‐0.12, 95% CI ‐0.75 to 0.52; P = 0.72; participants = 38; studies = 1; I2 = 0%).

9.5 Suicidality

There were no differences in suicidal ideation scores at any time point: at 24 hours (random‐effects MD ‐0.15, 95% CI ‐0.44 to 0.15; P = 0.33; participants = 450; studies = 2; I2 = 0%), at 72 hours (random‐effects MD ‐0.20, 95% CI ‐0.49 to 0.08; P = 0.16; participants = 451; studies = 2; I2 = 0%), at one week (random‐effects MD 0.01, 95% CI ‐0.10 to 0.13; P = 0.83; participants = 660; studies = 3; I2 = 0%), at two weeks (random‐effects MD ‐0.10, 95% CI ‐0.22 to 0.02; P = 0.10; participants = 659; studies = 3; I2 = 0%), and at four weeks (random‐effects MD ‐0.04, 95% CI ‐0.12 to 0.05; P = 0.40; participants = 647; studies = 3; I2 = 0%) (Analysis 9.43).

9.6 Cognition

No data were available for this outcome.

9.7 Quality of life

No data were available for this outcome.

9.8 Cost to healthcare services

No data were available for this outcome.

9.9 Acceptability: total dropouts

We found no difference between esketamine and placebo in terms of participants who dropped out due to any cause (random‐effects OR 1.58, 95% CI 0.92 to 2.73; P = 0.10; participants = 773; studies = 5; I2 = 8%) moderate‐certainty evidence (Analysis 9.44).

10. Memantine versus placebo

Four studies contributed to this comparison, including one new study (Amidfar 2016; Omranifard 2014; Smith 2013; Zarate 2006b), providing data at one week, two weeks, four weeks and three months.

10.1 Efficacy: number of participants who respond to treatment

We found no evidence that memantine was more effective than placebo in response at any time point; at one week (random‐effects OR 1.07, 95% CI 0.06 to 18.82; P = 0.96; participants = 63; studies = 2; I2 = 0%) ; two weeks (random‐effects OR 0.31, 95% CI 0.01 to 8.28; P = 0.49; participants = 32; studies = 1; I2 = 0%); four weeks (random‐effects OR 1.22, 95% CI 0.25 to 5.89; P = 0.81; participants = 185; studies = 4; I2 = 57%); and at three months (random‐effects OR 0.48, 95% CI 0.18 to 1.24; P = 0.13; participants = 123; studies = 3; I2 = 0%) (Analysis 10.1).

10.2 Adverse events

We found no difference between memantine and placebo for any adverse events (Analysis 10.2; Analysis 10.3; Analysis 10.4; Analysis 10.5; Analysis 10.6; Analysis 10.7; Analysis 10.8; Analysis 10.9; Analysis 10.10; Analysis 10.11; Analysis 10.12; Analysis 10.13; Analysis 10.14; Analysis 10.15; Analysis 10.16; Analysis 10.17; Analysis 10.18; Analysis 10.19; Analysis 10.20; Analysis 10.21; Analysis 10.22; Analysis 10.23; Analysis 10.24; Analysis 10.25; Analysis 10.26; Analysis 10.27; Analysis 10.28; Analysis 10.29; Analysis 10.30; Analysis 10.31; Analysis 10.32; Analysis 10.33; Analysis 10.34; Analysis 10.35; Analysis 10.36; Analysis 10.37; Analysis 10.38; Analysis 10.39; Analysis 10.40; Analysis 10.41; Analysis 10.42; Analysis 10.43; Analysis 10.44; Analysis 10.45; Analysis 10.46; Analysis 10.47; Analysis 10.48; Analysis 10.49; Analysis 10.50; Analysis 10.51; Analysis 10.52; Analysis 10.53; Analysis 10.54; Analysis 10.55; Analysis 10.56; Analysis 10.57; Analysis 10.58; Analysis 10.59).

10.3 Efficacy: number of participants who achieve remission

We found no evidence that memantine was more effective than placebo in remission at any time point; at one week (random‐effects OR ‐0.11, 95% CI ‐1.10 to 0.89; P = 0.26; participants = 59; studies = 2; I2 = 72%); at four weeks (random‐effects OR 1.39, 95% CI 0.46 to 4.26; P = 0.56; participants = 185; studies = 4; I2 = 0%); or at three months (random‐effects OR 0.76, 95% CI 0.15 to 3.77; P = 0.74; participants = 123; studies = 3; I2 = 0%) (Analysis 10.60).

10.4 Change scores on depression scale from baseline

There was no difference in depression rating scale score changes between memantine and placebo at any of the time points; at one week (random‐effects SMD ‐0.11, 95% CI ‐1.10 to 0.89; P = 0.84; participants = 59; studies = 2; I2 = 72%); at two weeks (random‐effects SMD ‐0.09, 95% CI ‐0.83 to 0.65; P = 0.81; participants = 28; studies = 1; I2 = 100%); at four weeks (random‐effects SMD 0.11, 95% CI ‐0.26 to 0.48; P = 0.56; participants = 112; studies = 3; I2 = 0%); and at three months (random‐effects SMD 0.23, 95% CI ‐0.14 to 0.61; P = 0.22; participants = 110; studies = 3; I2 = 0%) (Analysis 10.61).

10.5 Suicidality

No data were available for this outcome.

10.6 Cognition

No data were available for this outcome.

10.7 Quality of life

We found no difference between memantine and placebo in quality of life at four weeks (random‐effects MD ‐0.70, 95% CI ‐5.04 to 3.64; P = 0.75; 1 study, 57 participants) and at three months (random‐effects MD ‐1.21, 95% CI ‐5.78 to 3.36; P = 0.60; 1 study, 57 participants) (Analysis 10.62).

10.8 Cost to healthcare services

No data were available for this outcome.

10.9 Acceptability: total dropouts

We found no difference between memantine and placebo in terms of participants who dropped out due to any cause (random‐effects OR 0.78, 95% CI 0.23 to 2.66; P = 0.69; I2 = 0%; 3 studies, 123 participants) (Analysis 10.63), nor due to side effects (random‐effects OR 0.68, 95% CI 0.10 to 4.47; P = 0.68; I2= 0%; 2 studies, 63 participants) (Analysis 10.64).

11. Lanicemine (AZD6765) versus placebo

Two studies contributed to this comparison, including one new study (Zarate 2013; Sanacora 2017), providing outcome data at 24 hours, 72 hours, one week and four weeks.

11.1 Efficacy: number of participants who respond to treatment

There was no evidence that lanicemine was more effective than placebo in response at any time point; at 24 hours (random‐effects OR 7.74, 95% CI 0.35 to 170.10; P = 0.19; 1 study, 22 participants); at 72 hours (random‐effects OR 2.74, 95% CI 0.10 to 74.87; P = 0.55; 1 study, 22 participants); at one week (random‐effects OR 2.74, 95% CI 0.10 to 74.87; P = 0.55; 1 study, 22 participants); or at four weeks (random‐effects OR 1.03, 95% CI 0.63 to 1.69; P = 0.92; participants = 298; studies = 1; I2 = 0%) (Analysis 11.1).

11.2 Adverse events

Lanicemine was found to increase the incidence of dizziness over placebo (random‐effects OR 5.02, 95% CI 2.46 to 10.26; P < 0.00001; participants = 301; studies = 1; I2 = 0%) (Analysis 11.6).

There were no other differences between lanicemine and placebo for adverse events (Analysis 11.2; Analysis 11.3; Analysis 11.4; Analysis 11.5; Analysis 11.7; Analysis 11.8; Analysis 11.9; Analysis 11.10; Analysis 11.11; Analysis 11.12; Analysis 11.13; Analysis 11.14; Analysis 11.15; Analysis 11.16).

11.3 Efficacy: number of participants who achieve remission

We found no evidence that lanicemine was more effective than placebo in remission at 24 hours (random‐effects OR 5.00, 95% CI 0.21 to 117.21; P = 0.32; 1 study, 22 participants), 72 hours (random‐effects OR 2.74, 95% CI 0.10 to 74.87; P = 0.55; 1 study, 22 participants); at one week (random‐effects OR 2.74, 95% CI 0.10 to 74.87; P = 0.55; 1 study, 22 participants); or at four weeks (random‐effects OR 1.38, 95% CI 0.75 to 2.52; P = 0.30; participants = 298; studies = 1; I2 = 0%) (Analysis 11.17).

11.4 Change scores on depression scale from baseline

There was no difference between lanicemine and placebo at any time point. The effect of lanicemine compared with placebo at 24 hours was (random‐effects MD ‐8.65, 95% CI ‐17.81 to 0.51; P = 0.06; 1 study, 22 participants), at 72 hours was (random‐effects MD ‐6.27, 95% CI ‐13.93 to 1.39; P = 0.11; 1 study, 21 participants), at one week was (random‐effects MD ‐6.55, 95% CI ‐14.07 to 0.97; P = 0.09; 1 study, 21 participants), at four weeks was (random‐effects MD ‐0.11, 95% CI ‐1.42 to 1.20; P = 0.87; participants = 298; studies = 1; I2 = 0%), and at three months was (random‐effects MD 0.51, 95% CI ‐1.05 to 2.07; P = 0.52; participants = 298; studies = 1; I2 = 0%) (Analysis 11.18).

11.5 Suicidality

No data were available for this outcome.

11.6 Cognition

No data were available for this outcome.

11.7 Quality of life

No data were available for this outcome.

11.8 Cost to healthcare services

No data were available for this outcome.

11.9 Acceptability: total dropouts

We found no difference between lanicemine and placebo in terms of participants who dropped out due to any cause (random‐effects OR 2.74, 95% CI 0.10 to 74.87; P = 0.55, participants = 22, studies = 1) (Analysis 11.19).

12. Org26576 versus placebo

Two studies contributed to this comparison (Nations 2012 (part I); Nations 2012 (part II)), providing data at 24 hours, 72 hours, one week, two weeks and four weeks.

12.1 Efficacy: number of participants who respond to treatment

There was no evidence that Org26576 was more effective than placebo in achieving response at any time point; at 24 hours (random‐effects OR 0.81, 95% CI 0.09 to 7.13; P = 0.85; I2 = 0%; 2 studies, 54 participants); at 72 hours (random‐effects OR 0.80, 95% CI 0.16 to 3.90; P = 0.78; I2 = 0%; 2 studies, 54 participants); at one week (random‐effects OR 1.40, 95% CI 0.31 to 6.28; P = 0.63; I2 = 0%; 2 studies, 54 participants); at two weeks (random‐effects OR 2.24, 95% CI 0.61 to 8.22; P = 0.22; I2 = 0%; 2 studies, 54 participants), and at four weeks (random‐effects OR 0.82, 95% CI 0.18 to 3.74; P = 0.80; 1 study, 30 participants) (Analysis 12.1).

12.2 Adverse events

Org26576 resulted in an increased number of reports of nausea over placebo (random‐effects OR 4.50, 95% CI 1.05 to 19.28; P = 0.04; 2 studies, 54 participants) (Analysis 12.13).

We found no other differences in adverse events for Org26576 and placebo (Analysis 12.2; Analysis 12.3; Analysis 12.4; Analysis 12.5; Analysis 12.6; Analysis 12.7; Analysis 12.8; Analysis 12.9; Analysis 12.10; Analysis 12.11; Analysis 12.12; Analysis 12.13; Analysis 12.14; Analysis 12.15; Analysis 12.16; Analysis 12.17; Analysis 12.18; Analysis 12.19; Analysis 12.20).

12.3 Efficacy: number of participants who achieve remission

We found that there were no participants who met remission at 24 hours in either study, and no participants who met remission at 72 hours in Nations 2012 (part II). There was no evidence that Org26576 was more effective than placebo in remission rates at all other time points; at 72 hours (random‐effects OR 0.47, 95% CI 0.03 to 8.60; P = 0.61; 1 study, 24 participants); at one week (random‐effects OR 1.52, 95% CI 0.21 to 11.06; P = 0.68; I2 = 0%; 2 studies, 54 participants); at two weeks (random‐effects OR 2.29, 95% CI 0.43 to 12.15; P = 0.33; I2 = 0%; 2 studies, 54 participants) and at four weeks (random‐effects OR 0.64, 95% CI 0.13 to 3.14; P = 0.59; 1 study, 30 participants) (Analysis 12.21).

12.4 Change scores on depression scale from baseline

We found no evidence that Org26576 was more effective than placebo at any time point; at 24 hours (random‐effects MD ‐0.51, 95% CI ‐4.14 to 3.13; P = 0.78; I2 = 0%; 2 studies, 54 participants); at 72 hours (random‐effects MD ‐0.88, 95% CI ‐4.67 to 2.91; P = 0.65; I2 = 0%; 2 studies, 54 participants); at one week (random‐effects MD ‐1.43, 95% CI ‐5.31 to 2.44; P = 0.47; I2= 0%; 2 studies, 54 participants); at two weeks (random‐effects MD ‐2.61, 95% CI ‐7.32 to 2.09; P = 0.28; I2 = 0%; 2 studies, 54 participants) and at four weeks (random‐effects MD ‐1.25, 95% CI ‐8.14 to 5.64; P = 0.72; 1 study, 30 participants) (Analysis 12.22).

12.5 Suicidality

No data were available for this outcome.

12.6 Cognition

No data were available for this outcome.

12.7 Quality of life

No data were available for this outcome.

12.8 Cost to healthcare services

No data were available for this outcome.

12.9 Acceptability: dropouts due to adverse effects

We found no difference between Org26576 and placebo in terms of participants who dropped out due to side effects (random‐effects OR 0.50, 95% CI 0.05 to 5.17; P = 0.56; I2 = 0%; 2 studies, 54 participants) (Analysis 12.23). No information about all‐cause dropouts was reported.

13. Riluzole versus placebo

Two studies contributed to this comparison, including one new study (Ibrahim 2012a; Salardini 2016), providing data at 24 hours, 72 hours, one week, two weeks and four weeks.

13.1 Efficacy: number of participants who respond to treatment

There was no evidence that riluzole was more effective than placebo in increasing response rates at any other time point; at 24 hours (random‐effects OR 1.23, 95% CI 0.35 to 4.36; P = 0.75; participants = 42; studies = 1; I2 = 0%); at 72 hours (random‐effects OR 2.62, 95% CI 0.64 to 10.61; P = 0.18; participants = 42; studies = 1; I2 = 0%); or at two weeks (random‐effects OR 1.41, 95% CI 0.27 to 7.26; P = 0.68; participants = 102; studies = 2; I2 = 0%), or at four weeks (random‐effects OR 1.57, 95% CI 0.09 to 28.00; P = 0.76; participants = 102; studies = 2; I2 = 80%) (Analysis 13.1).

13.2 Adverse events

We found no difference between riluzole and placebo in terms of adverse events (Analysis 13.2; Analysis 13.3; Analysis 13.4; Analysis 13.5; Analysis 13.6; Analysis 13.7; Analysis 13.8; Analysis 13.9; Analysis 13.10; Analysis 13.11; Analysis 13.12; Analysis 13.13; Analysis 13.14; Analysis 13.15; Analysis 13.16; Analysis 13.17; Analysis 13.18; Analysis 13.19; Analysis 13.20; Analysis 13.21; Analysis 13.22; Analysis 13.23; Analysis 13.24; Analysis 13.25; Analysis 13.26; Analysis 13.27; Analysis 13.28; Analysis 13.29; Analysis 13.30; Analysis 13.31; Analysis 13.32; Analysis 13.33; Analysis 13.34; Analysis 13.35; Analysis 13.36; Analysis 13.37; Analysis 13.38; Analysis 13.39; Analysis 13.40; Analysis 13.41; Analysis 13.42; Analysis 13.43; Analysis 13.44; Analysis 13.45; Analysis 13.46; Analysis 13.47; Analysis 13.48; Analysis 13.49; Analysis 13.50; Analysis 13.51).

13.3 Efficacy: number of participants who achieve remission

There was no evidence that riluzole was more effective than placebo in remission at any time point; at 24 hours (random‐effects OR 0.71, 95% CI 0.14 to 3.64; P = 0.68; 1 study, 42 participants); at 72 hours (random‐effects OR 1.33, 95% CI 0.30 to 5.84; P = 0.71; 1 study, 42 participants); at one week (random‐effects OR 1.00, 95% CI 0.18 to 5.63; P = 1.00; 1 study, 42 participants); at two weeks (random‐effects OR 1.00, 95% CI 0.13 to 7.85; P = 1.00; 1 study, 42 participants) and at four weeks (random‐effects (OR 1.19, 95% CI 0.12 to 12.13; P = 0.88; participants = 102; studies = 2; I2 = 65%) (Analysis 13.52).

13.4 Change scores on depression scale from baseline

There was no evidence that riluzole was more effective than placebo at any time point; at 24 hours (random‐effects SMD ‐0.26, 95% CI ‐0.87 to 0.35; P 0.40; participants = 42; studies = 1; I2 = 0%); at 72 hours (random‐effects SMD ‐0.25, 95% CI ‐0.86 to 0.37; P = 0.43; participants = 41; studies = 1; I2 = 0%); one week (random‐effects SMD ‐0.06, 95% CI ‐0.70 to 0.58; P = 0.85; participants = 38; studies = 1; I2 = 0%); at two weeks (random‐effects SMD ‐0.36, 95% CI ‐1.20 to 0.47; P = 0.39; participants = 97; studies = 2; I2 = 75%); and at four weeks (random‐effects SMD ‐0.18, 95% CI ‐1.19 to 0.84; P = 0.73; participants = 87; studies = 2; I2 = 79%) (Analysis 13.53).

13.5 Suicidaility

No data were available for this outcome.

13.6 Cognition

No data were available for this outcome.

13.7 Quality of life

No data were available for this outcome.

13.8 Cost to healthcare services

No data were available for this outcome.

13.9 Acceptability: total dropouts

We found no difference between riluzole and placebo in terms of participants who dropped out due to any cause (fixed‐effects OR 0.81, 95% CI 0.23 to 2.88; P = 0.75; 1 study, 42 participants) (Analysis 13.54).

14. Atomoxetine versus placebo

One study contributed to this comparison (Michelson 2007), providing outcome data only at three months.

14.1 Efficacy: number of participants who respond to treatment

We found no evidence that atomoxetine was more effective than placebo in response at three months (OR 1.25, 95% CI 0.63 to 2.47; P = 0.52; 1 study, 146 participants) (Analysis 14.1).

14.2 Adverse events

Atomoxetine treatment was associated with higher incidence of constipation over placebo (OR 17.06, 95% CI 0.96 to 304.51; P = 0.05; 1 study, 146 participants; Analysis 14.3), dry mouth (OR 20.86, 95% CI 2.68 to 162.03; P = 0.004; 1 study, 146 participants ‐ Analysis 14.7) and insomnia (OR 9.13, 95% CI 1.11 to 74.95; P = 0.04; 1 study, 146 participants; Analysis 14.12).

14.3 Efficacy: number of participants who achieve remission

We found no evidence that atomoxetine was more effective than placebo in remission at three months (OR 1.34, 95% CI 0.67 to 2.67; P = 0.41; 1 study, 146 participants) (Analysis 14.16).

14.4 Change scores on depression scale from baseline

There was no difference between atomoxetine and placebo at three months (MD ‐1.60, 95% CI ‐3.88 to 0.68; P = 0.17; 1 study, 141 participants) (Analysis 14.17).

14.5 Suicidality

No data were available for this outcome.

14.6 Cognition

No data were available for this outcome.

14.7 Quality of life

No data were available for this outcome.

14.8 Cost to healthcare services

No data were available for this outcome.

14.9 Acceptability: total dropouts and dropouts due to adverse effects

We found no difference between atomoxetine and placebo in terms of participants who dropped out due to any cause (OR 1.03, 95% CI 0.44 to 2.41; P = 0.94; 1 study; 146 participants; Analysis 14.18), nor in terms of participants who dropped out due to side effects (OR 1.88, 95% CI 0.53 to 6.74; P = 0.33; 1 study; 146 participants; Analysis 14.19).

15. Basimglurant versus placebo

One study contributed to this comparison (Quiroz 2016), providing data at four weeks.

15.1 Efficacy: number of participants who respond to treatment

There was no evidence that basimglurant was more effective than placebo at four weeks (OR 0.98, 95% CI 0.62 to 1.55; P = 0.92; participants = 332; studies = 1; I2 = 0%) (Analysis 15.1).

15.2 Adverse events

Participants assigned to treatment with basimglurant reported more dizziness over placebo (OR 2.77, 95% CI 1.12 to 6.86; P = 0.03; participants = 332; studies = 1; I2 = 0%) (Analysis 15.2).However those receiving basimglurant had lower incidence of nasopharyngitis than those receiving placebo (OR 0.06, 95% CI 0.01 to 0.46; P = 0.007; participants = 332; studies = 1; I2 = 0%) (Analysis 15.7).

15.3 Efficacy: number of participants who achieve remission

We found no evidence of any difference between basimglurant and placebo for remission rates at four weeks (OR 1.05, 95% CI 0.64 to 1.73; P = 0.84; participants = 332; studies = 1; I2 = 0%) (Analysis 15.9).

15.4 Change scores on depression scale from baseline

There was no evidence of a difference between basimglurant and placebo for depression rating scale scores at four weeks (MD ‐0.39, 95% CI ‐1.66 to 0.88; P = 0.55; participants = 332; studies = 1; I2 = 0%) (Analysis 15.10).

15.5 Suicidality

No data were available for this outcome.

15.6 Cognition

No data were available for this outcome.

15.7 Quality of life

No data were available for this outcome.

15.8 Cost to healthcare services

No data were available for this outcome.

15.9 Acceptability: total dropouts

No data were available for this outcome.

16. Citicoline versus placebo

One study contributed to this comparison (Roohi‐Azizi 2017), providing data at four weeks.

16.1 Efficacy: number of participants who respond to treatment

There was no evidence that citicoline was more effective than placebo at four weeks (OR 4.47, 95% CI 0.83 to 24.19; P = 0.08; participants = 50; studies = 1; I2 = 0%) (Analysis 16.1).

16.2 Adverse events

There were no differences in adverse events between citicoline and placebo (Analysis 16.2; Analysis 16.3; Analysis 16.4; Analysis 16.5; Analysis 16.6; Analysis 16.7; Analysis 16.8; Analysis 16.9; Analysis 16.10).

16.3 Efficacy: number of participants who achieve remission

Citicoline was more efficacious in achieving remission than placebo at four weeks (OR 3.27, 95% CI 1.01 to 10.62; P = 0.05; participants = 50; studies = 1; I2 = 0%) (Analysis 16.11)

16.4 Change scores on depression scale from baseline

No data were available for this outcome.

16.5 Suicidality

No data were available for this outcome.

16.6 Cognition

No data were available for this outcome.

16.7 Quality of life

No data were available for this outcome.

16.8 Cost to healthcare services

No data were available for this outcome.

16.9 Acceptability: total dropouts

No data were available for this outcome.

17. CP‐101,606 versus placebo

One study contributed to this comparison (Preskorn 2008), providing continuous outcome data at 24 hours, one week and two weeks.

17.1 Efficacy: number of participants who respond to treatment

No data were available for this outcome

17.2 Adverse events

We found no difference between CP‐101, 606 and placebo in terms of adverse events (1 study, 30 participants) (Analysis 17.1; Analysis 17.2).

17.3 Efficacy: number of participants who achieve remission

No data were available for this outcome.

17.4 Change scores on depression scale from baseline

We found no difference between CP‐101,606 and placebo at 24 hours (MD ‐0.40, 95% CI ‐6.75 to 5.95; P = 0.90; 1 study, 30 participants) (Analysis 17.3). CP‐101,606 was more effective in reducing depression rating scale scores at one week over placebo (MD ‐7.10, 95% CI ‐13.42 to ‐0.78; P = 0.03; 1 study, 26 participants). At two weeks we observed no difference between CP‐101,606 and placebo (MD ‐2.90, 95% CI ‐12.06 to 6.26; P = 0.53; 1 study, 20 participants).

17.5 Suicidality

No data were available for this outcome.

17.6 Cognition

No data were available for this outcome.

17.7 Quality of life

No data were available for this outcome.

17.8 Cost to healthcare services

No data were available for this outcome.

17.9 Acceptability: total dropouts and dropouts due to adverse effects

We found no difference between CP‐101,606 and placebo in terms of participants who dropped out due to any cause (OR 0.29, 95% CI 0.06 to 1.45; P = 0.13; 1 study, 30 participants) (Analysis 17.4). No participants dropped out due to side effects.

18. D‐cycloserine versus placebo

One study contributed to this comparison (Heresco‐Levy 2013), providing data only at two and four weeks.

18.1 Efficacy: number of participants who respond to treatment

We found no difference between D‐cycloserine and placebo in terms of response at two weeks (OR 5.33, 95% CI 0.51 to 56.24; P = 0.16; 1 study, 26 participants), or at four weeks (OR 3.44, 95% CI 0.53 to 22.43; P = 0.20; 1 study, 26 participants) (Analysis 18.1).

18.2 Adverse events

We found no difference between D‐cycloserine and placebo in terms of any adverse event (Analysis 18.2; Analysis 18.3; Analysis 18.4; Analysis 18.5; Analysis 18.6; Analysis 18.7; Analysis 18.8; Analysis 18.9; Analysis 18.10; Analysis 18.11; Analysis 18.12; Analysis 18.13; Analysis 18.14).

18.3 Efficacy: number of participants who achieve remission

There were no participants who met remission in either the D‐cycloserine or placebo group at two weeks and there was no difference in terms of remission between D‐cycloserine and placebo at four weeks (OR 9.00, 95% CI 0.42 to 194.07; P = 0.16; 1 study, 26 participants) (Analysis 18.15).

18.4 Change scores on depression scale from baseline

There was no evidence of a difference between D‐cycloserine and placebo at two weeks (MD ‐5.00, 95% CI ‐11.08 to 1.08; P = 0.11; 1 study, 25 participants), or at four weeks (MD ‐7.00, 95% CI ‐14.53 to 0.53; P = 0.07; 1 study, 23 participants) (Analysis 18.16).

18.5 Suicidality

No data were available for this outcome.

18.6 Cognition

No data were available for this outcome.

18.7 Quality of life

No data were available for this outcome.

18.8 Cost to healthcare services

No data were available for this outcome.

18.9 Acceptability: total dropouts

We found no difference between D‐cycloserine and placebo in terms of participants who dropped out due to any cause (OR 3.60, 95% CI 0.32 to 40.23; P = 0.30; 1 study, 26 participants) (Analysis 18.17).

19. Decoglurant versus placebo

One study contributed to this comparison (Umbricht 2020), providing data only at four weeks.

19.1 Efficacy: number of participants who respond to treatment

Participants assigned to treatment with decoglurant were more likely to respond to treatment than those receiving a placebo at four weeks (OR 2.04, 95% CI 1.23 to 3.38; P = 0.006; participants = 309; studies = 1; I2 = 0%) (Analysis 19.1).

19.2 Adverse events

Decoglurant was associated with more reports of dizziness than placebo (OR 2.01, 95% CI 1.03 to 3.94; P = 0.04; participants = 357; studies = 1; I2 = 0%) (Analysis 19.3).

There were no other differences in adverse events between decoglurant and placebo (Analysis 19.2; Analysis 19.4; Analysis 19.5; Analysis 19.6; Analysis 19.7).

19.3 Efficacy: number of participants who achieve remission

We found no evidence of any differences between decoglurant and placebo for remission rates at four weeks (OR 1.60, 95% CI 0.95 to 2.69; P = 0.08; participants = 309; studies = 1; I2 = 0%) (Analysis 19.8).

19.4 Change scores on depression scale from baseline

No data were available for this outcome.

19.5 Suicidality

No data were available for this outcome.

19.6 Cognition

No data were available for this outcome.

19.7 Quality of life

No data were available for this outcome.

19.8 Cost to healthcare services

No data were available for this outcome.

19.9 Acceptability: total dropouts

No data were available for this outcome.

20. MK‐0657 versus placebo

Only one cross‐over study (five patients overall) contributed to this comparison (Ibrahim 2012b), providing data at 24 hours, 72 hours, one week and two weeks.

20.1 Efficacy: number of participants who respond to treatment

There were no responders in the MK‐0657 or placebo group in any of the time points measured: 24 hours; 72 hours; one week and two weeks.

20.2 Adverse events

No data were available for this outcome.

20.3 Efficacy: number of participants who achieve remission

No patients met remission in the MK‐0657 or placebo group at any of the time points measures: 24 hours; 72 hours; one week and two weeks.

20.4 Change scores on depression scale from baseline

We found no difference between MK‐0657 and placebo at 24 hours (MD 4.17, 95% CI ‐7.21 to 15.55; P = 0.47; 1 study, 5 participants), 72 hours (MD ‐2.83, 95% CI ‐14.21 to 8.55; P = 0.63; 1 study, 5 participants), one week (MD 0.67, 95% CI ‐13.16 to 14.50; P = 0.92; 1 study, 5 participants) and at two weeks (MD 3.50, 95% CI ‐8.67 to 15.67; P = 0.57; 1 study, 5 participants) (Analysis 20.1).

20.5 Suicidality

No data were available for this outcome.

20.6 Cognition

No data were available for this outcome.

20.7 Quality of life

No data were available for this outcome.

20.8 Cost to healthcare services

No data were available for this outcome.

20.9 Acceptability: total dropouts

No patients dropped out of the trial in either the MK‐0657 or placebo group.

21. N‐acetylcysteine versus placebo

One study contributed to this comparison (Berk 2014), providing data at two weeks, four weeks and three months.

21.1 Efficacy: number of participants who respond to treatment

There was no evidence that N‐acetylcysteine was more effective than placebo in response at any time point; at two weeks (OR 0.77, 95% CI 0.38 to 1.55; P = 0.46; 1 study, 269 participants); at four weeks (OR 0.91, 95% CI 0.52 to 1.61; P = 0.75; 1 study, 269 participants) and at three months (OR 1.38, 95% CI 0.83 to 2.30; P = 0.21; 1 study, 269 participants) (Analysis 21.1).

21.2 Adverse events

Participants receiving N‐acetylcysteine were more likely to report gastrointestinal problems than those receiving placebo (OR 2.26, 95% CI 1.27 to 4.02; P = 0.006; 1 study, 169 participants) (Analysis 21.3).

No other differences in adverse events were found (Analysis 21.2; Analysis 21.4; Analysis 21.5).

21.3 Efficacy: number of participants who achieve remission

We found no difference in remission between N‐acetylcysteine and placebo at two weeks (OR 0.48, 95% CI 0.12 to 1.98; P = 0.31; 1 study, 269 participants) or at three months (OR 1.45, 95% CI 0.79 to 2.68; P = 0.23; 1 study, 269 participants) (Analysis 21.6). However, N‐acetylcysteine produced higher remission rates over placebo at four weeks (OR 0.41, 95% CI 0.17 to 0.97; P = 0.04; 1 study, 269 participants).

21.4 Change scores on depression scale from baseline

We found no difference between N‐acetylcysteine and placebo at two weeks (MD ‐0.40, 95% CI ‐2.06 to 1.26; P = 0.64; 1 study, 252 participants), at four weeks (MD ‐1.20, 95% CI ‐3.28 to 0.88; P = 0.26; 1 study, 252 participants) and at three months (MD ‐1.50, 95% CI ‐4.14 to 1.14; P = 0.26; 1 study, 207 participants) (Analysis 21.7).

21.5 Suicidality

No data were available for this outcome.

21.6 Cognition

No data were available for this outcome.

21.7 Quality of life

We found no difference between N‐acetylcysteine and placebo at three months (MD ‐0.10, 95% CI ‐2.74 to 2.54; P = 0.94; 1 study, 207 participants) (Analysis 21.8).

21.8 Cost to healthcare services

No data were available for this outcome.

21.9 Acceptability: total dropouts and dropouts due to adverse events

We found no difference between N‐acetylcysteine and placebo in terms of participants who dropped out due to any cause (OR 0.67, 95% CI 0.36 to 1.24; P = 0.20; 1 study, 269 participants; Analysis 21.9), nor due to side effects (OR 0.49, 95% CI 0.04 to 5.50; P = 0.57; 1 study, 269 participants; Analysis 21.10).

E. Other glutamate receptor modulators versus other pharmacologically active agents

22. Sarcosine versus citalopram

One study contributed to this comparison (Huang 2013), providing data only at two and four weeks.

22.1 Efficacy: number of participants who respond to treatment

We found no difference in terms of response between sarcosine and citalopram at two weeks (OR 8.14, 95% CI 0.88 to 75.48; P = 0.06; 1 study, 40 participants). A difference in favour of sarcosine was found at four weeks (OR 6.93, 95% CI 1.53 to 31.38; P = 0.01; 1 study, 40 participants) (Analysis 22.1).

22.2 Adverse events

A higher number of participants receiving sarcosine treatment experienced adverse events over citalopram (OR 0.04, 95% CI 0.00 to 0.68; P = 0.03; 1 study, 40 participants) (Analysis 22.2).

22.3 Efficacy: number of participants who achieve remission

We found no difference in terms of remission between sarcosine and citalopram at two weeks (OR 14.55, 95% CI 0.75 to 283.37; P = 0.08; 1 study, 40 participants). Sarcosine treatment resulted in more frequent remission over citalopram at four weeks (OR 27.88, 95% CI 1.48 to 526.12; P = 0.03; 1 study, 40 participants) (Analysis 22.20).

22.4 Change scores on depression scale from baseline

We found evidence that sarcosine was more effective than citalopram at two weeks (MD ‐5.50, 95% CI ‐10.12 to ‐0.88; P = 0.02; 1 study, 40 participants). The effect of sarcosine compared with citalopram at four weeks was MD ‐4.00, 95% CI ‐8.30 to 0.30; P = 0.07; 1 study, 31 participants (Analysis 22.21).

22.5 Suicidality

No data were available for this outcome.

22.6 Cognition

No data were available for this outcome.

22.7 Quality of life

No data were available for this outcome.

22.8 Cost to healthcare services

No data were available for this outcome.

22.9 Acceptability: total dropouts and dropouts due to adverse events

We found no difference between sarcosine and citalopram in terms of participants who dropped out due to any cause (OR 0.52, 95% CI 0.14 to 1.92; P = 0.33; 1 study, 40 participants) (Analysis 22.22). In Huang 2013 no participants dropped out due to side effects.

Subgroup analyses

Two comparisons had enough data to complete the pre‐planned subgroup analyses (ketamine versus placebo and esketamine versus placebo).

23. Ketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting)

Four studies contributed to this subgroup analysis (Arabzadeh 2018; Hu 2016; Ionescu 2018; Su 2017), providing data at 24 hours, 72 hours, one week, two weeks, four weeks, and three months.

23.1 Efficacy: number of participants who respond to treatment

Ketamine treatment in outpatient settings resulted in increased response efficacy at 72 hours over placebo (random‐effects OR 33.46, 95% CI 1.65 to 677.83; P = 0.02; participants = 27; studies = 1; I2 = 0%), one week (random‐effects OR 33.46, 95% CI 1.65 to 677.83; P = 0.02; participants = 27; studies = 1; I2 = 0%), and two weeks (random‐effects OR 20.80, 95% CI 2.04 to 211.79; P = 0.01; participants = 27; studies = 1; I2 = 0%) (Analysis 23.1). There was no difference at 24 hours (random‐effects OR 18.76, 95% CI 0.92 to 383.10; P = 0.06; participants = 27; studies = 1; I2 = 0%), four weeks (random‐effects OR 2.00, 95% CI 0.68 to 5.85; P = 0.21; participants = 132; studies = 3; I2 = 41%), or three months (random‐effects OR 3.95, 95% CI 0.16 to 97.23; P = 0.40; participants = 47; studies = 2; I2 = 80%).

23.2 Efficacy: number of participants who achieve remission

We found no differences in terms of remission between ketamine and placebo in outpatient treatment settings at any time points: at 24 hours (random‐effects OR 3.48, 95% CI 0.13 to 93.30; P = 0.46; participants = 27; studies = 1; I2 = 0%), at 72 hours (random‐effects OR 6.30, 95% CI 0.27 to 144.70; P = 0.25; participants = 27; studies = 1; I2 = 0%), at one week (random‐effects OR 6.30, 95% CI 0.27 to 144.70; P = 0.25; participants = 27; studies = 1; I2 = 0%), at two weeks (random‐effects OR 3.90, 95% CI 0.35 to 43.36; P = 0.27; participants = 27; studies = 1; I2 = 0%), at four weeks (random‐effects OR 2.19, 95% CI 0.85 to 5.66; P = 0.11; participants = 132; studies = 3; I2 = 0%), and at three months (random‐effects OR 1.09, 95% CI 0.45 to 2.67; P = 0.85; participants = 90; studies = 2; I2 = 0%) (Analysis 23.2).

23.3 Change scores on depression scale from baseline

We found evidence that ketamine was more effective at reducing depression rating scale scores than placebo in outpatient treatment settings at two weeks (random‐effects SMD ‐0.73, 95% CI ‐1.31 to ‐0.15; P = 0.01; participants = 126; studies = 3; I2 = 50%) and at four weeks (random‐effects SMD ‐0.68, 95% CI ‐1.07 to ‐0.29; P = 0.0006; participants = 107; studies = 2; I2 = 0%) (Analysis 23.3). There were no differences observed between ketamine and placebo at 24 hours (random‐effects SMD ‐0.47, 95% CI ‐1.11 to 0.18; P = 0.16; participants = 75; studies = 2; I2 = 42%), at 72 hours (random‐effects SMD ‐0.28, 95% CI ‐1.18 to 0.62; P = 0.54; participants = 94; studies = 3; I2 = 75%), or at one week (random‐effects SMD ‐0.52, 95% CI ‐1.69 to 0.65; P = 0.38; participants = 45; studies = 2; I2 = 72%).

23.4 Suicidality

There were no differences in suicidality between ketamine and placebo in outpatient settings at any time point: at 24 hours (random‐effects MD 0.02, 95% CI ‐0.78 to 0.82; P = 0.96; participants = 48; studies = 1; I2 = 0%); at 72 hours (random‐effects MD 0.34, 95% CI ‐0.25 to 0.93; P = 0.26; participants = 68; studies = 2; I2 = 10%), at one week (random‐effects MD ‐0.30, 95% CI ‐1.56 to 0.96; P = 0.64; participants = 19; studies = 1; I2 = 0%), at two weeks (random‐effects MD ‐0.20, 95% CI ‐1.46 to 1.06; P = 0.76; participants = 19; studies = 1; I2 = 0%) (Analysis 23.4).

24. Ketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting)

Three studies contributed to this subgroup analysis (Loo 2012; Sos 2013; Zarate 2006a), providing data at 24 hours, 72 hours, one week, and two weeks.

24.1 Efficacy: number of participants who respond to treatment

Ketamine was more efficacious than placebo in achieving response in inpatient treatment settings at 24 hours (random‐effects OR 15.11, 95% CI 1.97 to 115.92; P = 0.009; participants = 48; studies = 2; I2 = 10%) and 72 hours (random‐effects OR 14.00, 95% CI 2.07 to 94.75; P = 0.007; participants = 48; studies = 2; I2 = 0%) (Analysis 24.1). There was no difference in response between ketamine and placebo at one week (random‐effects OR 3.41, 95% CI 0.95 to 12.27; P = 0.06; participants = 99; studies = 3; I2 = 21%) and two weeks (random‐effects OR 0.93, 95% CI 0.31 to 2.83; P = 0.90; participants = 51; studies = 1; I2 = 0%).

24.2 Efficacy: number of participants who achieve remission

Ketamine had higher efficacy for remission over placebo when administered in an inpatient setting at 24 hours (random‐effects OR 6.60, 95% CI 0.96 to 45.09; P = 0.05; participants = 48; studies = 2; I2 = 0%), at 72 hours (random‐effects OR 7.88, 95% CI 1.17 to 53.21; P = 0.03; participants = 48; studies = 2; I2 = 0%), and at one week (random‐effects OR 7.24, 95% CI 1.70 to 30.81; P = 0.007; participants = 99; studies = 3; I2 = 0%) (Analysis 24.2). There was no difference in remission at two weeks (random‐effects OR 0.95, 95% CI 0.28 to 3.24; P = 0.93; participants = 51; studies = 1; I2 = 100%).

24.3 Change scores on depression scale from baseline

There was evidence suggesting a decrease in depression rating scale scores for ketamine over placebo in inpatient treatment settings at 24 hours (random‐effects SMD ‐1.63, 95% CI ‐2.86 to ‐0.39; P = 0.010; participants = 46; studies = 2; I2 = 62%) , at 72 hours (random‐effects SMD ‐1.21, 95% CI ‐1.87 to ‐0.55; P = 0.0003; participants = 46; studies = 2; I2 = 0%) , and at one week (random‐effects SMD ‐0.75, 95% CI ‐1.19 to ‐0.31; P = 0.0008; participants = 91; studies = 3; I2 = 0%) (Analysis 24.3). There was no difference in change on depression rating scale scores between ketamine and placebo at two weeks (random‐effects SMD ‐0.10, 95% CI ‐0.68 to 0.48; P = 0.74; participants = 46; studies = 1; I2 = 0%).

24.4 Suicidality

No data were available for this outcome.

25. Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting)

Three studies contributed to this subgroup analysis (Daly 2018; Fedgchin 2019; Popova 2019), contributing data at 24 hours, one week, two weeks, four week, and three months.

25.1 Efficacy: number of participants who respond to treatment

We found a difference in response rates favouring esketamine over placebo in outpatient treatment settings at 24 hours (random‐effects OR 4.33, 95% CI 1.08 to 17.31; P = 0.04; participants = 620; studies = 3; I2 = 66%), one week (random‐effects OR 2.73, 95% CI 1.41 to 5.28; P = 0.003; participants = 632; studies = 3; I2 = 0%), and four weeks (random‐effects OR 1.92, 95% CI 1.34 to 2.75; P = 0.0004; participants = 543; studies = 2; I2 = 0%) (Analysis 25.1).

25.2 Efficacy: number of participants who achieve remission

There was an increased likelihood of remission in those receiving esketamine in outpatient treatment settings over placebo at 24 hours (random‐effects OR 6.51, 95% CI 1.93 to 21.92; P = 0.002; participants = 377; studies = 2; I2 = 0%), one week (random‐effects OR 7.76, 95% CI 1.75 to 34.48; P = 0.007; participants = 399; studies = 2; I2 = 0%), and at two weeks (random‐effects OR 2.30, 95% CI 1.02 to 5.17; P = 0.04; participants = 315; studies = 1; I2 = 0%) (Analysis 25.2). We found no difference between esketamine and placebo in outpatient settings at four weeks (random‐effects OR 1.39, 95% CI 0.84 to 2.30; P = 0.20; participants = 317; studies = 1; I2 = 0%).

25.3 Change scores on depression scale from baseline

We found a decrease in depression scores from baseline in participants allocated to esketamine over placebo in outpatient treatment settings at 24 hours (random‐effects SMD ‐0.25, 95% CI ‐0.49 to ‐0.01; P = 0.04; participants = 310; studies = 1; I2 = 100%), at one week (random‐effects SMD ‐0.28, 95% CI ‐0.51 to ‐0.06; P = 0.01; participants = 340; studies = 1; I2 = 0%), at two weeks (random‐effects SMD ‐0.32, 95% CI ‐0.54 to ‐0.09; P = 0.006; participants = 340; studies = 1; I2 = 0%), and at four weeks (random‐effects SMD ‐0.28, 95% CI ‐0.45 to ‐0.10; P = 0.002; participants = 213; studies = 2; I2 = 0%) (Analysis 25.3). No difference was found at three months (random‐effects SMD ‐0.12, 95% CI ‐0.75 to 0.52; P = 0.72; participants = 38; studies = 1; I2 = 0%).

25.4 Suicidality

There were no differences in suicidality between esketamine and placebo in outpatient treatment settings at any time point: at one week (random‐effects MD 0.05, 95% CI ‐0.08 to 0.18; P = 0.43; participants = 209; studies = 1; I2 = 0%), at two weeks (random‐effects MD ‐0.07, 95% CI ‐0.21 to 0.07; P = 0.31; participants = 208; studies = 1; I2 = 0%), or at four weeks (random‐effects MD ‐0.02, 95% CI ‐0.11 to 0.07; P = 0.65; participants = 196; studies = 1; I2 = 0%) (Analysis 25.4).

26. Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting)

Two studies contributed data to this subgroup analysis (Canuso 2018; Fu 2020), providing data at 24 hours, 72 hours, one week, two weeks, and four weeks.

26.1 Efficacy: number of participants who respond to treatment

Esketamine had higher response efficacy over placebo in inpatient treatment settings at two weeks (random‐effects OR 1.71, 95% CI 1.01 to 2.91; P = 0.05; participants = 224; studies = 1; I2 = 0%) and four weeks (random‐effects OR 1.85, 95% CI 1.09 to 3.14; P = 0.02; participants = 224; studies = 1; I2 = 100%) only (Analysis 26.1). No difference was found between esketamine and placebo at 24 hours (random‐effects OR 1.40, 95% CI 0.79 to 2.49; P = 0.25; participants = 224; studies = 1; I2 = 0%), at 72 hours (random‐effects OR 1.52, 95% CI 0.88 to 2.62; P = 0.13; participants = 224; studies = 1; I2 = 0%), or at one week (random‐effects OR 1.29, 95% CI 0.76 to 2.18; P = 0.35; participants = 224; studies = 1; I2 = 0%).

26.2 Efficacy: number of participants who achieve remission

Esketamine had increased remission rates over placebo in inpatient treatment settings at 24 hours only (random‐effects OR 2.25, 95% CI 1.13 to 4.49; P = 0.02; participants = 290; studies = 2; I2 = 0%) (Analysis 26.2). There was no difference at any other time point: at 72 hours (random‐effects OR 1.61, 95% CI 0.59 to 4.34; P = 0.35; participants = 290; studies = 2; I2 = 54%), at one week (random‐effects OR 1.22, 95% CI 0.70 to 2.13; P = 0.49; participants = 290; studies = 2; I2 = 0%), at two weeks (random‐effects OR 1.39, 95% CI 0.83 to 2.32; P = 0.21; participants = 290; studies = 2; I2 = 0%), or at four weeks (random‐effects OR 1.48, 95% CI 0.91 to 2.42; P = 0.11; participants = 290; studies = 2; I2 = 0%).

26.3 Change scores on depression scale from baseline

We found that esketamine decreased depression rating scale scores over placebo in inpatient treatment settings at 24 hours (random‐effects SMD ‐0.35, 95% CI ‐0.58 to ‐0.12; P = 0.003; participants = 290; studies = 2; I2 = 0%), at 72 hours (random‐effects SMD ‐0.41, 95% CI ‐0.64 to ‐0.17; P = 0.0006; participants = 290; studies = 2; I2 = 0%), and at four weeks (random‐effects SMD ‐0.25, 95% CI ‐0.48 to ‐0.02; P = 0.03; participants = 290; studies = 2; I2 = 0%) (Analysis 26.3). No difference was found between esketamine and placebo at one week (random‐effects SMD ‐0.20, 95% CI ‐0.43 to 0.04; P = 0.10; participants = 290; studies = 2; I2 = 0%) or at two weeks (random‐effects SMD ‐0.14, 95% CI ‐0.37 to 0.09; P = 0.23; participants = 290; studies = 2; I2 = 0%).

26.4 Suicidality

We found no difference in suicidality between esketamine and placebo at any time point: at 24 hours (random‐effects MD ‐0.20, 95% CI ‐0.63 to 0.23; P = 0.36; participants = 224; studies = 1; I2 = 0%), at 72 hours (random‐effects MD ‐0.30, 95% CI ‐0.69 to 0.09; P = 0.14; participants = 224; studies = 1; I2 = 0%), at one week (random‐effects MD ‐0.20, 95% CI ‐0.56 to 0.16; P = 0.28; participants = 224; studies = 1; I2 = 0%), at two weeks (random‐effects MD ‐0.10, 95% CI ‐0.43 to 0.23; P = 0.55; participants = 224; studies = 1; I2 = 0%), and at four weeks (random‐effects MD ‐0.20, 95% CI ‐0.53 to 0.13; P = 0.25; participants = 224; studies = 1; I2 = 0%; Analysis 26.4).

27. Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years)

Eight studies contributed to this subgroup analysis (Canuso 2018; Daly 2018; Fedgchin 2019; Fu 2020; Ionescu 2020; Jarventausta 2013; Popova 2019; Singh 2016 b), with one study excluded as it recruited solely older adults aged 65 and over (Ochs‐Ross 2020). Data were provided at 24 hours, 72 hours, one week, two weeks, four weeks, and three months.

27.1 Efficacy: number of participants who respond to treatment

Participants receiving esketamine (excluding elderly populations) were more likely to achieve response than those receiving placebo at 24 hours (random‐effects OR 2.11, 95% CI 1.20 to 3.68; P = 0.009; participants = 1071; studies = 5; I2 = 50%), at one week, (random‐effects OR 1.64, 95% CI 1.05 to 2.54; P = 0.03; participants = 1083; studies = 5; I2 = 35%), at two weeks (random‐effects OR 1.57, 95% CI 1.09 to 2.28; P = 0.02; participants = 451; studies = 2; I2 = 0%), and at four weeks (random‐effects OR 1.81, 95% CI 1.40 to 2.34; P < 0.00001; participants = 994; studies = 4; I2 = 0%) (Analysis 27.1). However there was no difference found between esketamine and placebo at 72 hours (random‐effects OR 1.34, 95% CI 0.92 to 1.96; P = 0.13; participants = 451; studies = 2; I2 = 0%).

27.2 Efficacy: number of participants who achieve remission

Esketamine treatment led to higher remission rates over placebo excluding elderly populations at 24 hours (random‐effects OR 2.74, 95% CI 1.71 to 4.40; P < 0.0001; participants = 894; studies = 5; I2 = 0%), two weeks (random‐effects OR 1.52, 95% CI 1.07 to 2.16; P = 0.02; participants = 832; studies = 4; I2 = 0%), and at four weeks (random‐effects OR 1.51, 95% CI 1.12 to 2.04; P = 0.006; participants = 834; studies = 4; I2 = 0%) (Analysis 27.2). No difference was found at 72 hours (random‐effects OR 1.55, 95% CI 0.91 to 2.64; P = 0.11; participants = 517; studies = 3; I2 = 24%), or at one week (random‐effects OR 1.62, 95% CI 0.91 to 2.89; P = 0.10; participants = 916; studies = 5; I2 = 36%).

27.3 Change scores on depression scale from baseline

A decrease in depression rating scale scores was found in esketamine over placebo when excluding elderly populations at 24 hours (random‐effects SMD ‐0.31, 95% CI ‐0.45 to ‐0.17; P < 0.0001; participants = 824; studies = 4; I2 = 0%), at 72 hours (random‐effects SMD ‐0.30, 95% CI ‐0.50 to ‐0.11; P = 0.002; participants = 517; studies = 3; I2 = 14%), at one week (random‐effects SMD ‐0.24, 95% CI ‐0.37 to ‐0.10; P = 0.0007; participants = 857; studies = 4; I2 = 0%), at two weeks (random‐effects SMD ‐0.21, 95% CI ‐0.34 to ‐0.07; P = 0.003; participants = 857; studies = 4; I2 = 0%), and at four weeks (random‐effects SMD ‐0.27, 95% CI ‐0.40 to ‐0.15; P < 0.0001; participants = 1059; studies = 5; I2 = 0%) (Analysis 27.3). No difference was found between esketamine and placebo was found at three months (random‐effects SMD ‐0.12, 95% CI ‐0.75 to 0.52; P = 0.72; participants = 38; studies = 1; I2 = 0%).

27.4 Suicidality

We found no differences in suicidality between esketamine and placebo in the excluding elderly populations subgroup at any time point: at 24 hours (random‐effects MD ‐0.15, 95% CI ‐0.44 to 0.15; P = 0.33; participants = 450; studies = 2; I2 = 0%), at 72 hours (random‐effects MD ‐0.20, 95% CI ‐0.49 to 0.08; P = 0.16; participants = 451; studies = 2; I2 = 0%), at one week (random‐effects MD 0.01, 95% CI ‐0.10 to 0.13; P = 83; participants = 660; studies = 3; I2 = 0%), at two weeks (random‐effects MD ‐0.10, 95% CI ‐0.22 to 0.02; P = 0.10; participants = 659; studies = 3; I2 = 0%), or at four weeks (random‐effects MD ‐0.04, 95% CI ‐0.12 to 0.05; P = 0.40; participants = 647; studies = 3; I2 = 0%) (Analysis 27.4).

Sensitivity analyses

Two comparisons had enough data to complete sensitivity analyses (ketamine versus placebo and esketamine versus placebo).

28. Ketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features)

Eleven studies contributed to this sensitivity analysis (Arabzadeh 2018; Chen 2017; Chen 2018; Hu 2016; Ionescu 2018; Li 2016; Singh 2016 a; Sos 2013; Su 2017; Tiger 2020; Zarate 2006a). Data were provided at 24 hours, 72 hours, one week, two weeks, four weeks, and three months.

28.1 Efficacy: number of participants who respond to treatment

Ketamine had higher efficacy in terms of response over placebo in studies excluding participants with bipolar disorder or psychotic features at 24 hours (random‐effects OR 4.33, 95% CI 1.47 to 12.80; P = 0.008; participants = 177; studies = 6; I2 = 28%), at 72 hours (random‐effects OR 17.99, 95% CI 3.58 to 90.34; P = 0.0004; participants = 75; studies = 3; I2 = 0%), at one week (random‐effects OR 14.32, 95% CI 2.90 to 70.64; P = 0.001; participants = 75; studies = 3; I2 = 0%), at two weeks (random‐effects OR 15.73, 95% CI 4.71 to 52.51; P < 0.00001; participants = 85; studies = 2; I2 = 0%) (Analysis 28.1). No difference was found between ketamine and placebo at four weeks (random‐effects OR 2.00, 95% CI 0.68 to 5.85; participants = 132; P = 0.21; studies = 3; I2 = 41%), and at three months (random‐effects OR 3.95, 95% CI 0.16 to 97.23; P = 0.40; participants = 47; studies = 2; I2 = 80%).

28.2 Efficacy: number of participants who achieve remission

Participants assigned to ketamine treatment achieved remission at a higher rather than those assigned to placebo treatment in studies that did not include participants with bipolar disorder or psychotic features at 24 hours (random‐effects OR 5.60, 95% CI 1.07 to 29.46; P = 0.04; participants = 75; studies = 3; I2 = 0%), very low‐certainty evidence, at 72 hours (random‐effects OR 7.42, 95% CI 1.45 to 37.89; P = 0.02; participants = 75; studies = 3; I2 = 0%), at one week (random‐effects OR 9.02, 95% CI 1.80 to 45.31; P = 0.008; participants = 75; studies = 3; I2 = 0%), and at two weeks (random‐effects OR 7.50, 95% CI 1.51 to 37.22; P = 0.01; participants = 85; studies = 2; I2 = 0%) (Analysis 28.2). No difference was found at four weeks (random‐effects OR 2.19, 95% CI 0.85 to 5.66; P = 0.11; participants = 132; studies = 3; I2 = 0%) or three months (random‐effects OR 1.29, 95% CI 0.14 to 11.54; P = 0.82; participants = 20; studies = 1; I2 = 0%).

28.3 Change scores on depression scale from baseline

We found a reduction in depression rating scale scores in ketamine over placebo for studies that excluded participants with bipolar disorder or psychotic features at all time points: at 24 hours (random‐effects SMD ‐0.88, 95% CI ‐1.31 to ‐0.46; P < 0.0001; participants = 223; studies = 7; I2 = 50%), at 72 hours (random‐effects SMD ‐0.63, 95% CI ‐1.29 to 0.04; P = 0.06; participants = 140; studies = 5; I2 = 69%), at one week (random‐effects SMD ‐0.76, 95% CI ‐1.34 to ‐0.19; P = 0.010; participants = 90; studies = 4; I2 = 40%), at two weeks (random‐effects SMD ‐0.73, 95% CI ‐1.31 to ‐0.15; P = 0.01; participants = 126; studies = 3; I2 = 50%), and at four weeks (random‐effects SMD ‐0.68, 95% CI ‐1.07 to ‐0.29; P = 0.0006; participants = 107; studies = 2; I2 = 0%) (Analysis 28.3).

28.4 Suicidality

No differences in suicidality were found between ketamine and placebo in studies excluding participants with bipolar or psychotic features at any time point: at 24 hours (random‐effects MD 0.02, 95% CI ‐0.78 to 0.82; P = 0.96; participants = 48; studies = 1; I2 = 0%), at 72 hours (random‐effects MD 0.34, 95% CI ‐0.25 to 0.93; P = 0.26; participants = 68; studies = 2; I2 = 10%), at one week (random‐effects MD ‐0.30, 95% CI ‐1.56 to 0.96; P = 0.64 participants = 19; studies = 1; I2 = 0%), or at two weeks (random‐effects MD ‐0.20, 95% CI ‐1.46 to 1.06; P = 0.76; participants = 19; studies = 1; I2 = 0%) (Analysis 28.4).

29. Ketamine versus placebo (pre‐planned sensitivity analysis: excluding treatment resistant populations)

Four studies contributed to this sensitivity analysis (Arabzadeh 2018; Berman 2000; Sos 2013; Tiger 2020). Data were provided at 24 hours, 72 hours, one week, two weeks, and four weeks.

29.1 Efficacy: number of participants who respond to treatment

Ketamine produced higher response rates over placebo in studies excluding treatment resistant populations was found at 72 hours (random‐effects OR 15.32, 95% CI 1.58 to 148.09; P = 0.02; participants = 38; studies = 2; I2 = 0%), one week (random‐effects OR 10.29, 95% CI 0.97 to 108.81; P = 0.05; participants = 30; studies = 1; I2 = 0%), and at four weeks (random‐effects OR 4.31, 95% CI 1.48 to 12.56; P = 0.007; participants = 81; studies = 1; I2 = 0%) (Analysis 29.1). No differences were found at 24 hours (random‐effects OR 2.31, 95% CI 0.65 to 8.14; P = 0.19; participants = 68; studies = 3; I2 = 0%).

29.2 Efficacy: number of participants who achieve remission

Remission was achieved more frequently in participants receiving ketamine over placebo in studies excluding treatment resistant populations was found at one week (random‐effects OR 10.29, 95% CI 0.97 to 108.81; P = 0.05; participants = 30; studies = 1; I2 = 0%) (Analysis 29.2). However, no differences were found at any other time point: at 24 hours (random‐effects OR 6.75, 95% CI 0.61 to 75.27; P = 0.12; participants = 30; studies = 1; I2 = 0%), at 72 hours (random‐effects OR 5.63, 95% CI 0.77 to 40.99; P = 0.09; participants = 38; studies = 2; I2 = 0%), or at four weeks (random‐effects OR 1.59, 95% CI 0.51 to 4.98; P = 0.42; participants = 81; studies = 1; I2 = 0%).

29.3 Change scores on depression scale from baseline

We found a decrease in depression scores in participants allocated to receive ketamine over placebo within studies that excluded treatment resistant patients at all time points: at 24 hours (random‐effects SMD ‐1.06, 95% CI ‐1.61 to ‐0.52; P = 0.0001; participants = 66; studies = 3; I2 = 0%), at 72 hours (random‐effects SMD ‐1.20, 95% CI ‐1.96 to ‐0.44; P = 0.002; participants = 36; studies = 2; I2 = 0%), at one week (random‐effects SMD ‐1.19, 95% CI ‐1.97 to ‐0.42; P = 0.003; participants = 35; studies = 2; I2 = 0%), at two weeks (random‐effects SMD ‐0.90, 95% CI ‐1.36 to ‐0.45; P = 0.0001; participants = 81; studies = 1; I2 = 0%), and at four weeks (random‐effects SMD ‐0.77, 95% CI ‐1.22 to ‐0.31; P = 0.0009; participants = 81; studies = 1; I2 = 0%) (Analysis 29.3).

29.4 Suicidality

No data were available for this outcome.

30. Ketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%)

Eleven studies contributed to this sensitivity analysis (Arabzadeh 2018; Berman 2000; Chen 2017; Chen 2018; Hu 2016; Li 2016; Loo 2012; Sos 2013; Su 2017; Tiger 2020; Zarate 2006a). Data were provided at 24 hours, 72 hours, one week, two weeks, four weeks, and three months.

30.1 Efficacy: number of participants who respond to treatment

Ketamine was more efficacious than placebo in creating response when excluding trials with a dropout rate greater than 20% at 24 hours (random‐effects OR 3.94, 95% CI 1.54 to 10.10; P = 0.004; participants = 185; studies = 7; I2 = 14%), at 72 hours (random‐effects OR 15.84, 95% CI 3.68 to 68.12; P = 0.0002; participants = 83; studies = 4; I2 = 0%), at one week (random‐effects OR 5.69, 95% CI 1.34 to 24.11; P = 0.02; participants = 126; studies = 4; I2 = 39%), and at three months (random‐effects OR 20.00, 95% CI 2.77 to 144.31; P = 0.003; participants = 27; studies = 1; I2 = 100%) (Analysis 30.1). No difference was found at two weeks (random‐effects OR 3.72, 95% CI 0.17 to 79.32; P = 0.40; participants = 78; studies = 2; I2 = 83%) or at four weeks (random‐effects OR 2.00, 95% CI 0.68 to 5.85; P = 0.21; participants = 132; studies = 3; I2 = 41%).

30.2 Efficacy: number of participants who achieve remission

Ketamine treatment was associated with higher remission rates over placebo when trials with a dropout rate greater than 20% were excluded at 24 hours (random‐effects OR 5.60, 95% CI 1.07 to 29.46; P 0.04; participants = 75; studies = 3; I2 = 0%), at 72 hours (random‐effects OR 6.60, 95% CI 1.51 to 28.92; P = 0.01; participants = 83; studies = 4; I2 = 0%), and at one week (OR 7.06, 95% CI 1.90 to 26.31; P = 0.004; participants = 126; studies = 4; I2 = 0%) (Analysis 30.2). No difference was found at two weeks (random‐effects OR 1.30, 95% CI 0.41 to 4.12; P = 0.66; participants = 78; studies = 2; I2 = 5%) or at four weeks (random‐effects OR 2.60, 95% CI 0.60 to 11.33; P = 0.20; participants = 108; studies = 2; I2 = 35%).

30.3 Change scores on depression scale from baseline

A decrease in depression rating scale scores was found for ketamine over placebo when excluding trials with a dropout rate greater than 20% at all time points: at 24 hours (random‐effects SMD ‐0.87, 95% CI ‐1.26 to ‐0.48; P < 0.0001; participants = 231; studies = 8; I2 = 41%), very low‐certainty evidence, at 72 hours (random‐effects SMD ‐0.86, 95% CI ‐1.24 to ‐0.48; P < 0.00001; participants = 128; studies = 5; I2 = 0%), at one week (random‐effects SMD ‐0.85, 95% CI ‐1.23 to ‐0.47; P < 0.0001; participants = 124; studies = 5; I2 = 0%), at two weeks (random‐effects SMD ‐0.68, 95% CI ‐1.29 to ‐0.08; P = 0.03; participants = 153; studies = 3; I2 = 66%), and at four weeks (random‐effects SMD ‐0.68, 95% CI ‐1.07 to ‐0.29; P = 0.0006; participants = 107; studies = 2; I2 = 0%) (Analysis 30.3).

30.4 Suicidality

No differences were found for suicidality between ketamine and placebo when trials with a dropout rate greater than 20% were excluded at 24 hours (random‐effects MD 0.02, 95% CI ‐0.78 to 0.82; P = 0.96; participants = 48; studies = 1; I2 = 0%) or at 72 hours (random‐effects MD 0.09, 95% CI ‐0.63 to 0.81; P = 0.81; participants = 48; studies = 1; I2 = 0%) (Analysis 30.4).

31. Ketamine versus placebo (post‐hoc sensitivity analysis: excluding multiple doses)

Eight studies contributed to this sensitivity analysis (Berman 2000; Chen 2018; Hu 2016; Li 2016; Sos 2013; Su 2017; Tiger 2020; Zarate 2006a). Data were provided at 24 hours, 72 hours, one week, two weeks, four weeks, and three months.

31.1 Efficacy: number of participants who respond to treatment

Ketamine treatment resulted in larger numbers of participants responding to treatment over placebo when excluding studies that administered multiple doses of study drugs at 24 hours (random‐effects OR 3.94, 95% CI 1.54 to 10.10; P 0.004; participants = 185; studies = 7; I2 = 14%), at 72 hours (random‐effects OR 15.84, 95% CI 3.68 to 68.12; P = 0.0002; participants = 83; studies = 4; I2 = 0%), at one week (random‐effects OR 14.32, 95% CI 2.90 to 70.64; P = 0.001; participants = 75; studies = 3; I2 = 0%), at two weeks (random‐effects OR 20.80, 95% CI 2.04 to 211.79; P = 0.01; participants = 27; studies = 1; I2 = 0%), and at three months (random‐effects OR 20.00, 95% CI 2.77 to 144.31; P = 0.003; participants = 27; studies = 1; I2 = 100%) (Analysis 31.1). No difference was found between ketamine and placebo at four weeks (random‐effects OR 1.60, 95% CI 0.35 to 7.40; P = 0.55; participants = 27; studies = 1; I2 = 100%).

31.2 Efficacy: number of participants who achieve remission

More participants receiving ketamine achieved remission than those receiving placebo in single dose administration studies at 24 hours (random‐effects OR 5.60, 95% CI 1.07 to 29.46; P 0.04; participants = 75; studies = 3; I2 = 0%), at 72 hours (random‐effects OR 6.60, 95% CI 1.51 to 28.92; P = 0.01; participants = 83; studies = 4; I2 = 0%), at one week (random‐effects OR 9.02, 95% CI 1.80 to 45.31; P = 0.008; participants = 75; studies = 3; I2 = 0%), and at four weeks (random‐effects OR 8.12, 95% CI 0.80 to 82.73; P = 0.08; participants = 27; studies = 1; I2 = 0%) (Analysis 31.2). No difference in remission was found at two weeks (random‐effects OR 1.30, 95% CI 0.41 to 4.12; P = 0.66; participants = 78; studies = 2; I2 = 5%)

31.3 Change scores on depression scale from baseline

A decrease in depression rating scale scores was found in participants randomised to receive ketamine over placebo when excluding multiple dose trials at 24 hours (random‐effects SMD ‐0.87, 95% CI ‐1.26 to ‐0.48; P < 0.0001; participants = 231; studies = 8; I2 = 41%), at 72 hours (random‐effects SMD ‐0.68, 95% CI ‐1.28 to ‐0.07; P = 0.03; participants = 148; studies = 6; I2 = 62%), at one week (random‐effects SMD ‐1.07, 95% CI ‐1.57 to ‐0.58; P < 0.0001; participants = 78; studies = 4; I2 = 0%), and at two weeks (random‐effects SMD ‐1.14, 95% CI ‐1.98 to ‐0.30; P = 0.08; participants = 26; studies = 1; I2 = 0%) (Analysis 31.3). No difference was found at four weeks (random‐effects SMD ‐0.43, 95% CI ‐1.21 to 0.35; P = 0.28; participants = 26; studies = 1; I2 = 0%).

31.4 Suicidality

No differences in suicidality were found between ketamine and placebo in single dose trials at 24 hours (MD 0.02, 95% CI ‐0.78 to 0.82; P = 0.96; participants = 48; studies = 1; I2 = 0%) or at 72 hours (MD 0.09, 95% CI ‐0.63 to 0.81; P = 0.81; participants = 48; studies = 1; I2 = 0%) (Analysis 31.4).

32. Ketamine versus placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies)

Eleven studies contributed to this sensitivity analysis (Arabzadeh 2018; Berman 2000; Chen 2018; Hu 2016; Ionescu 2018; Li 2016; Singh 2016 a; Sos 2013; Su 2017; Tiger 2020; Zarate 2006a). Data were provided at 24 hours, 72 hours, one week, two weeks, four weeks, and three months.

32.1 Efficacy: number of participants who respond to treatment

Ketamine was more efficacious than placebo for response when excluding add‐on ECT studies at 24 hours (random‐effects OR 3.94, 95% CI 1.54 to 10.10; P = 0.004; participants = 185; studies = 7; I2 = 14%), at 72 hours (random‐effects OR 15.84, 95% CI 3.68 to 68.12; P = 0.0002; participants = 83; studies = 4; I2 = 0%), at one week (random‐effects OR 14.32, 95% CI 2.90 to 70.64; P = 0.001; participants = 75; studies = 3; I2 = 0%), and at two weeks (random‐effects OR 15.73, 95% CI 4.71 to 52.51; P < 0.00001; participants = 85; studies = 2; I2 = 0%) (Analysis 32.1). No difference was found between ketamine and placebo at four weeks (random‐effects OR 2.00, 95% CI 0.68 to 5.85; P = 0.21; participants = 132; studies = 3; I2 = 41%) or at three months (random‐effects OR 3.95, 95% CI 0.16 to 97.23; P = 0.40; participants = 47; studies = 2; I2 = 80%).

32.2 Efficacy: number of participants who achieve remission

Remission rates were increased in participants assigned to receive ketamine over placebo in studies administering study medications without ECT at 24 hours (random‐effects OR 5.60, 95% CI 1.07 to 29.46; P = 0.04; participants = 75; studies = 3; I2 = 0%), at 72 hours (random‐effects OR 6.60, 95% CI 1.51 to 28.92; P = 0.01; participants = 83; studies = 4; I2 = 0%), at one week (random‐effects OR 9.02, 95% CI 1.80 to 45.31; P = 0.008; participants = 75; studies = 3; I2 = 0%), and at two weeks (random‐effects OR 7.50, 95% CI 1.51 to 37.22; P = 0.01; participants = 85; studies = 2; I2 = 0%) (Analysis 32.2). No difference was found at four weeks (random‐effects OR 2.19. 95% CI 0.85 to 5.66, participants‐ 132, studies = 3; I2 = 0%), or at three months (random‐effects OR 1.29, 95% CI 0.14 to 11.54; P = 0.82; participants = 20; studies = 1; I2 = 0%).

32.3 Change scores on depression scale from baseline

We found a decrease in depression rating scale scores in those allocated ketamine over placebo when excluding add‐on ECT trials at all time points: at 24 hours (random‐effects SMD ‐0.87, 95% CI ‐1.26 to ‐0.48; P < 0.0001; participants = 231; studies = 8; I2 = 41%), at 72 hours (random‐effects SMD ‐0.68, 95% CI ‐1.28 to ‐0.07; P = 0.03; participants = 148; studies = 6; I2 = 62%), at one week (random‐effects SMD ‐0.80, 95% CI ‐1.31 to ‐0.30; P = 0.002; participants = 97; studies = 5; I2 = 24%), at two weeks (random‐effects SMD ‐0.73, 95% CI ‐1.31 to ‐0.15; P = 0.01; participants = 126; studies = 3; I2 = 50%), and at four weeks (random‐effects SMD ‐0.68, 95% CI ‐1.07 to ‐0.29; P = 0.0006; participants = 107; studies = 2; I2 = 0%) (Analysis 32.3).

32.4 Suicidality

No differences were found in suicidality between ketamine and placebo excluding trials using add‐on ECT at any time point: at 24 hours (random‐effects MD 0.02, 95% CI ‐0.78 to 0.82; P = 0.96; participants = 48; studies = 1; I2 = 0%), at 72 hours (random‐effects MD 0.34, 95% CI ‐0.25 to 0.93; P = 0.26; participants = 68; studies = 2; I2 = 10%), at one week (random‐effects MD ‐0.30, 95% CI ‐1.56 to 0.96; P = 0.64; participants = 19; studies = 1; I2 = 0%), and at two weeks (random‐effects MD ‐0.20, 95% CI ‐1.46 to 1.06; P = 0.76; participants = 19; studies = 1; I2 = 0%) (Analysis 32.4).

33. Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features)

Eight studies contributed to this sensitivity analysis (Canuso 2018; Daly 2018; Fedgchin 2019; Fu 2020; Ionescu 2020; Ochs‐Ross 2020; Popova 2019; Singh 2016 b). Data were provided at 24 hours, 72 hours, one week, two weeks, four weeks, and three months.

33.1 Efficacy: number of participants who respond to treatment

Esketamine treatment increased response rates compared with placebo at 24 hours when excluding studies that included participants with bipolar disorder or psychotic features (random‐effects OR 2.11, 95% CI 1.20 to 3.68; P = 0.009; participants = 1071; studies = 5; I2 = 50%), at one week (random‐effects OR 1.64, 95% CI 1.05 to 2.54; P = 0.03; participants = 1083; studies = 5; I2 = 35%), at two weeks (random‐effects OR 1.57, 95% CI 1.09 to 2.28; P = 0.02; participants = 451; studies = 2; I2 = 0%), and at four weeks (random‐effects OR 1.84, 95% CI 1.44 to 2.37; P<0.00001; participants = 1117; studies = 5; I2 = 0%) (Analysis 33.1). No difference was found between esketamine and placebo at 72 hours (random‐effects OR 1.34, 95% CI 0.92 to 1.96; P = 0.13; P < 0.13; participants = 451; studies = 2; I2 = 0%).

33.2 Efficacy: number of participants who achieve remission

Remission was higher in participants receiving esketamine over placebo in studies that did not include participants with bipolar disorder or psychotic features at 24 hours (random‐effects OR 2.74, 95% CI 1.71 to 4.40; P < 0.0001; participants = 894; studies = 5; I2 = 0%), at two weeks (random‐effects OR 1.52, 95% CI 1.07 to 2.16; P = 0.02; participants = 832; studies = 4; I2 = 0%), and at four weeks (random‐effects OR 1.57, 95% CI 1.18 to 2.10; P = 0.002; participants = 957; studies = 5; I2 = 0%) (Analysis 33.2). No difference was found at 72 hours (random‐effects OR 1.55, 95% CI 0.91 to 2.64; P = 0.11; participants = 517; studies = 3; I2 = 24%), at one week (random‐effects OR 1.62, 95% CI 0.91 to 2.89; P = 0.10; participants = 916; studies = 5; I2 = 36%).

33.3 Change scores on depression scale from baseline

Esketamine was associated with a decrease in depression rating scale scores over placebo when studies including participants with bipolar disorder or psychotic features were excluded at 24 hours (random‐effects SMD ‐0.31, 95% CI ‐0.45 to ‐0.17; P < 0.0001; participants = 824; studies = 4; I2 = 0%), at 72 hours (random‐effects SMD ‐0.30, 95% CI ‐0.50 to ‐0.11; P = 0.002; participants = 517; studies = 3; I2 = 14%), at one week (random‐effects SMD ‐0.24, 95% CI ‐0.37 to ‐0.10; P = 0.0007; participants = 857; studies = 4; I2 = 0%), at two weeks (random‐effects SMD ‐0.21, 95% CI ‐0.34 to ‐0.07; P = 0.003; participants = 857; studies = 4; I2 = 0%), and at four weeks (random‐effects SMD ‐0.27, 95% CI ‐0.39 to ‐0.16; P < 0.00001; participants = 1182; studies = 6; I2 = 0%) (Analysis 33.3). No difference between esketamine and placebo was found at three months (random‐effects SMD ‐0.12, 95% CI ‐0.75 to 0.52; P = 0.72; participants = 38; studies = 1; I2 = 0%).

33.4 Suicidality

No differences in suicidality were found between esketamine and placebo when excluding studies that included participants with bipolar disorder or psychotic features at any time points: at 24 hours (random‐effects MD ‐0.15, 95% CI ‐0.44 to 0.15; P = 0.33; participants = 450; studies = 2; I2 = 0%), at 72 hours (random‐effects MD ‐0.20, 95% CI ‐0.49 to 0.08; P = 0.16; participants = 451; studies = 2; I2 = 0%), at one week (random‐effects MD 0.01, 95% CI ‐0.10 to 0.13; P = 0.83; participants = 660; studies = 3; I2 = 0%), at two weeks (random‐effects MD ‐0.10, 95% CI ‐0.22 to 0.02; P = 0.10; participants = 659; studies = 3; I2 = 0%), and at four weeks (random‐effects MD ‐0.04, 95% CI ‐0.12 to 0.05; P = 0.40; participants = 647; studies = 3; I2 = 0%) (Analysis 33.4).

34. Esketamine versus placebo (pre‐planned sensitivity analysis: excluding treatment resistant populations)

Three studies contributed to this sensitivity analysis (Canuso 2018; Fu 2020; Ionescu 2020). Data were provided at 24 hours, 72 hours, one week, two weeks, and four weeks.

34.1 Efficacy: number of participants who respond to treatment

Esketamine had higher response efficacy over placebo when excluding treatment resistant populations at 24 hours (random‐effects OR 1.55, 95% CI 1.03 to 2.33; P = 0.03; participants = 451; studies = 2; I2 = 0%), two weeks (random‐effects OR 1.57, 95% CI 1.09 to 2.28; P = 0.02; participants = 451; studies = 2; I2 = 0%), and at four weeks (random‐effects OR 1.70, 95% CI 1.17 to 2.46; P = 0.006; participants = 451; studies = 2; I2 = 0%) (Analysis 34.1). There was no difference found between esketamine and placebo at 72 hours (random‐effects OR 1.34, 95% CI 0.92 to 1.96; P = 0.13; participants = 451; studies = 2; I2 = 0%), and at one week (random‐effects OR 1.23, 95% CI 0.85 to 1.78; P = 0.28; participants = 451; studies = 2; I2 = 0%).

34.2 Efficacy: number of participants who achieve remission

Remission rates were greater in participants receiving esketamine over placebo when excluding treatment resistant populations at 24 hours (random‐effects OR 2.35, 95% CI 1.40 to 3.92; P = 0.001; participants = 517; studies = 3; I2 = 0%), and at four weeks (random‐effects OR 1.58, 95% CI 1.10 to 2.29; P = 0.01; participants = 517; studies = 3; I2 = 0%) (Analysis 34.2). No difference was found at 72 hours (random‐effects OR 1.55, 95% CI 0.91 to 2.64; P = 0.11; participants = 517; studies = 3; I2 = 24%), at one week (random‐effects OR 1.31, 95% CI 0.86 to 2.01; P = 0.21; participants = 517; studies = 3; I2 = 0%), or at two weeks (random‐effects OR 1.38, 95% CI 0.93 to 2.04; P = 0.11; participants = 517; studies = 3; I2 = 0%).

34.3 Change scores on depression scale from baseline

There was a decrease in depression rating scale scores found in esketamine over placebo when treatment resistant populations were excluded at 24 hours (random‐effects SMD ‐0.34, 95% CI ‐0.52 to ‐0.17; P = 0.0001; participants = 514; studies = 3; I2 = 0%), at 72 hours (random‐effects SMD ‐0.30, 95% CI ‐0.50 to ‐0.11; P = 0.002; participants = 517; studies = 3; I2 = 14%), at one week (random‐effects SMD ‐0.21, 95% CI ‐0.38 to ‐0.04; P = 0.02; participants = 517; studies = 3; I2 = 0%), and at four weeks (random‐effects SMD ‐0.27, 95% CI ‐0.44 to ‐0.10; P = 0.002; participants = 517; studies = 3; I2 = 0%) (Analysis 34.3). No difference was found between esketamine and placebo at two weeks (random‐effects SMD ‐0.14, 95% CI ‐0.32 to 0.03; P = 0.10; participants = 517; studies = 3; I2 = 0%).

34.4 Suicidality

No differences in suicidality were found between esketamine and placebo when excluding treatment resistant populations at any time point: at 24 hours (random‐effects MD ‐0.15, 95% CI ‐0.44 to 0.15; P = 0.33; participants = 450; studies = 2; I2 = 0%), at 72 hours (random‐effects MD ‐0.20, 95% CI ‐0.49 to 0.08; P = 0.16; participants = 451; studies = 2; I2 = 0%), at one week (random‐effects MD ‐0.15, 95% CI ‐0.41 to 0.11; P = 0.26; participants = 451; studies = 2; I2 = 0%), at two weeks (random‐effects MD ‐0.19, 95% CI ‐0.43 to 0.05; P = 0.12; participants = 451; studies = 2; I2 = 0%), and at four weeks (random‐effects MD ‐0.15, 95% CI ‐0.39 to 0.09; P = 0.22; participants = 451; studies = 2; I2 = 0%) (Analysis 34.4).

35. Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%)

Eight studies contributed to this sensitivity analysis (Daly 2018; Fedgchin 2019; Fu 2020; Ionescu 2020; Jarventausta 2013; Ochs‐Ross 2020; Popova 2019; Singh 2016 b). Data were provided at 24 hours, 72 hours, one week, two weeks, four weeks, and three months.

35.1 Efficacy: number of participants who respond to treatment

Esketamine administration increased response rates over placebo when excluding trials with a dropout rate greater than 20% at 24 hours (random‐effects OR 2.11, 95% CI 1.20 to 3.68; P = 0.009; participants = 1071; studies = 5; I2 = 50%), at one week (random‐effects OR 1.60, 95% CI 1.09 to 2.34; P = 0.02; participants = 1115; studies = 6; I2 = 20%), at two weeks (random‐effects OR 1.57, 95% CI 1.09 to 2.28; P = 0.02; participants = 451; studies = 2; I2 = 0%), and at four weeks (random‐effects OR 1.84, 95% CI 1.44 to 2.37; P < 0.00001; participants = 1117; studies = 5; I2 = 0%) (Analysis 35.1). No differences in response were found between esketamine and placebo at 72 hours (random‐effects OR 1.34, 95% CI 0.92 to 1.96; P = 0.13; participants = 451; studies = 2; I2 = 0%).

35.2 Efficacy: number of participants who achieve remission

Esketamine was associated with higher remission numbers of participants achieving remission over placebo in trials with a dropout rate less than 20% at 24 hours (random‐effects OR 2.88, 95% CI 1.72 to 4.81; P < 0.0001; participants = 828; studies = 4; I2 = 0%), at two weeks (random‐effects OR 1.51, 95% CI 1.04 to 2.19; P = 0.03; participants = 766; studies = 3; I2 = 0%), and at four weeks (random‐effects OR 1.60, 95% CI 1.19 to 2.16; P = 0.002; participants = 891; studies = 4; I2 = 0%) (Analysis 35.2). No differences were found at 72 hours (random‐effects OR 1.76, 95% CI 0.97 to 3.18; P = 0.06; participants = 451; studies = 2; I2 = 31%), or at one week (random‐effects OR 1.79, 95% CI 0.93 to 3.42; P = 0.08; participants = 882; studies = 5; I2 = 33%)

35.3 Change scores on depression scale from baseline

We found a decrease in depression rating scale scores in esketamine over placebo when excluding trials with a dropout rate greater than 20% at 24 hours (random‐effects SMD ‐0.29, 95% CI ‐0.43 to ‐0.14; P = 0.0001; participants = 758; studies = 3; I2 = 0%), at 72 hours (random‐effects SMD ‐0.26, 95% CI ‐0.45 to ‐0.07; P = 0.007; participants = 451; studies = 2; I2 = 4%), at one week (random‐effects SMD ‐0.23, 95% CI ‐0.37 to ‐0.09; P = 0.001; participants = 818; studies = 4; I2 = 0%), at two weeks (random‐effects SMD ‐0.21, 95% CI ‐0.36 to ‐0.07; P = 0.004; participants = 791; studies = 3; I2 = 0%), and at four weeks (random‐effects SMD ‐0.27, 95% CI ‐0.39 to ‐0.15; P < 0.0001; participants = 1116; studies = 5; I2 = 0%) (Analysis 35.3). No differences were found at three months (random‐effects SMD ‐0.12, 95% CI ‐0.75 to 0.52; P = 0.72; participants = 38; studies = 1; I2 = 0%).

35.4 Suicidality

No differences in suicidality were found between esketamine and placebo when excluding trials with a dropout rate greater than 20% at any time point: at 24 hours (random‐effects MD ‐0.15, 95% CI ‐0.44 to 0.15; P = 0.33; participants = 450; studies = 2; I2 = 0%), at 72 hours (random‐effects MD ‐0.20, 95% CI ‐0.49 to 0.08; P = 0.16; participants = 451; studies = 2; I2 = 0%), at one week (random‐effects MD 0.01, 95% CI ‐0.10 to 0.13; P = 0.83; participants = 660; studies = 3; I2 = 0%), at two weeks (random‐effects MD ‐0.10, 95% CI ‐0.22 to 0.02; P = 0.10; participants = 659; studies = 3; I2 = 0%), and at four weeks (random‐effects MD ‐0.04, 95% CI ‐0.12 to 0.05; P = 0.40; participants = 647; studies = 3; I2 = 0%) (Analysis 35.4).

Discussion

Summary of main results

This updated systematic review assessed the efficacy and acceptability of ketamine and other glutamate receptor modulators for the treatment of unipolar depression. We identified a total of 64 randomised controlled trials, involving 5299 participants and 16 glutamate receptor modulators (of which data were available for 15). It is important to note that the included studies in the present review had, on average, small to very small sample sizes, and furthermore there was a lack of data available on important pre‐defined outcomes, including side effects.

Efficacy: Ketamine versus placebo

Overall, we found potential evidence of efficacy of ketamine over placebo up to one week, in terms of response, remission and change in depressive symptoms. Not all the included studies reported data at all the time points prespecified in this review, so we cannot rule out the possibility that results would have been different if all studies contributed to all outcomes at every time point. The updated review included new studies with longer‐term data, with three studies providing data for up to three months (Anderson 2017Hu 2016Ionescu 2018), which found a lack of efficacy of ketamine over placebo at this time point for response and remission. This indicates that although ketamine may be an effective treatment compared to placebo in the short term, this effect could be lost after treatment ends. No differences were found in suicidality at any time point, suggesting that ketamine is not an effective treatment for suicidality over placebo. However, this was based on only two studies.

We were able to conduct a number of subgroup analyses for the ketamine versus placebo comparison. Inpatients appeared to have a faster response to ketamine than outpatients, with higher response rates at 24 hours over placebo, and both inpatients and outpatients observing higher response with ketamine at 72 hours.  This seemed to be sustained for longer in outpatients (at one week and two weeks), which was not seen in inpatients. We found no evidence of a difference in remission between ketamine and placebo in outpatients, although this was based on extremely small participant numbers. Ketamine was likely more effective than placebo at 24 hours, 72 hours, and one week for inpatients. For depression scores on rating scales there were decreases for inpatients administered ketamine over placebo at 24 hours, 72 hours, and one week, whereas depression scores for outpatients only saw decreases for ketamine over placebo at two weeks and four weeks. Limited data identified no differences in suicidality at any time point for outpatients, and no data were available for inpatients. These subgroup analyses suggest that the effects of ketamine may be experienced differently depending on the setting in which the drug is administered. However, this finding could also reflect differences in the clinical characteristics of the patients treated in inpatient versus outpatient settings. Additionally, the sample sizes in these analyses are too small to be conclusive.

We consistently found possible increased response and remission rates favouring ketamine over placebo up to one week in all sensitivity analyses. Depression rating scale scores may have been decreased for those administered ketamine over placebo for up to two weeks in all sensitivity analyses, and up to four weeks in all but one analysis (excluding multiple doses). No differences were found in all sensitivity analyses about suicidality, but data were limited.

Efficacy: ketamine versus other pharmacologically active agents and: electroconvulsive therapy (ECT)

Ketamine appeared to be more effective than midazolam in the short term. Only one study provided data at three months for response and remission (Gálvez 2018), with ketamine not being more effective than midazolam for either outcome. This is in line with other evidence supporting the notion that ketamine can be an effective drug in treating depressive symptoms in the short term, but this effect is not sustained when treatment ends. Results from ketamine versus thiopental, remifentanil hydrochloride and ECT comparisons also supported this conclusion, although very limited data were available. Comparisons with methohexital and propofol showed no differences. However, data were only available for one study in each comparison and only for depression rating scale score outcomes. Also these comparisons occurred in the context of ECT treatment which complicates interpretation.

Efficacy: esketamine

There was also evidence of esketamine being efficacious over placebo at 24 hours, two weeks, and four weeks for response, remission, and depression rating scale scores. Evidence was mixed at other time points. Only one study provided data at three months, and only for depression rating scale scores, showing uncertain evidence of no difference between esketamine and placebo (Fedgchin 2019). This suggests short‐term effectiveness of esketamine for treatment of depression, but further studies exploring long‐term outcomes are needed. There were no differences in suicidality between esketamine over placebo at any time point.

Several subgroup and sensitivity analyses were able to be conducted for the esketamine versus placebo comparison. In the subgroup analyses we found that outpatients may have a very quick increased response to esketamine, whilst inpatients could take longer to respond. No differences in suicidality between esketamine and placebo were found in any subgroups.

Sensitivity analyses for esketamine versus placebo did not materially change the results from the primary analysis. No differences were found between esketamine and placebo at any time point for suicidality, suggesting that esketamine is not effective in reducing suicidal ideation.

When compared head‐to‐head, one study showed no difference in depression rating scale scores between ketamine and esketamine at any time point (Correia‐Melo 2020). However, data were only provided up to one week, and minimal data were available for other outcomes in this study.

Adverse events

In terms of adverse events, ketamine increased the incidence of agitation/anxiety, confusion, and dissociative symptoms over placebo. When compared to midazolam, ketamine was more likely to be associated with blurred vision, dizziness, general malaise, increased blood pressure or heart rate, nausea/vomiting, sleepiness/drowsiness. However, the majority of these effects were short‐lived on the day of infusion, and were not observed at one to seven days post‐infusion. Esketamine was more likely than placebo to be associated with change in blood pressure, constipation, dissociative symptoms, dizziness, dizziness postural, feeling drunk, nausea/vomiting, paresthesia/neuropathy exacerbation, sensory disturbance, sedation, sleepiness/drowsiness, vertigo, and vision blurred.

Efficacy: other glutamate receptor modulators

We found very limited evidence for the antidepressant efficacy of the remaining 13 glutamate receptor modulators, with the only effects found being citicoline over placebo remission rate at four weeks, decoglurant over placebo response at four weeks, and response rate of sarcosine over citalopram at two weeks.

Overall completeness and applicability of evidence

The overall completeness of the evidence was found to be limited. We set out nine outcomes in the protocol and found that many trials did not provide data on all of these outcomes. The primary outcomes of response rate and adverse events were not reported in all studies, but response was imputed where possible. However, adverse events data were not accessible in some trials. We found no data, or very limited data, on certain prespecified outcomes, namely: suicidality, cognition, quality of life, costs to healthcare services and dropouts due to lack of efficacy. The great majority of the included trials in this review were placebo‐controlled, with only 16 studies comparing a glutamate receptor modulator with an active comparison. This limits the completeness of the comparative evidence (Cipriani 2020; Naci 2020). The literature search for this review identified a large number of ongoing studies. These trials could contribute key data and of course will be included in future updates of the review.

In terms of applicability of evidence, all participants in the included studies of the present review met standardised diagnostic criteria of a depressive episode according to the DSM‐IV, DSM‐IV‐TR, or DSM‐5. However, there was variation in regards to the severity of depression in the recruited participants, with severities including moderate, severe and treatment resistant, which may impact the intervention effect (Deeks 2021). There was also disparity among the studies in terms of how the interventions were administered. In many of the trials, participants received concomitant psychotropic medications (for example, continuing the pre‐existing antidepressant), some received concomitant ECT, and the length and route of administration also varied.

Quality of the evidence

It was difficult to judge the overall quality of the retrieved evidence, as the most important items of the risk of bias tool (random sequence generation, allocation concealment and blinding of outcome assessment) were deemed ''unclear'' in many studies. This might be due to problems in the reporting of the included studies; however this could potentially bias our results and limit the reliability of the findings of the review.

The vast majority of studies in this review included small sample sizes (50 out of the 64 studies had an overall study sample size below 100). This is not unusual in psychiatry; however, in certain comparisons there were too few participants to be able to draw any meaningful conclusion. For example, in the MK‐0657 versus placebo comparison, there were only five participants in total.

An important factor to take into consideration is the bias that may have occurred in blinding procedures. Given the profile of ketamine and its psychotomimetic side effects, participants and personnel, particularly in comparisons with inactive placebo, would probably not have remained unaware of treatment arm allocation, despite attempts to blind them. Of the included studies assessing the efficacy of ketamine, most did not test the blinding or provide any information relating to whether the intended blinding was effective. This should be considered a major limitation, which is likely to result in a biased assessment of the intervention effect.

The certainty of evidence according to GRADE (Atkins 2004) was very low to moderate in the comparison between ketamine and placebo (summary of findings Table 1), and also for ketamine versus midazolam (summary of findings Table 2). The GRADE certainty of evidence the comparison between esketamine and placebo was very low to high (summary of findings Table 3).

Potential biases in the review process

We identified 64 studies, but we could only include 54 of them in the meta‐analysis due to the unavailability of data despite contacting the authors. We cannot rule out that this may have had an impact on the pooled results, as these 10 studies may have contributed additional important data (Mavridis 2014).

We could not evaluate study publication bias or outcome reporting bias due to the small number of included studies in each comparison and due to the unavailability of the study protocols. Although we searched extensively for relevant trials, it is possible that unpublished trials remain unknown to us.

In order to generate as much data as possible, according to the review protocol we imputed response and remission rates, as we did previously in other Cochrane Reviews (Furukawa 2005Magni 2013Watanabe 2011). In addition, in one case we imputed standard deviations (SDs) (Yoosefi 2014) using a validated method (Furukawa 2006). Imputation of SDs might affect the results, by widening the confidence interval and reducing its weight in the analysis, underestimating the overall treatment effect (Aitken 2019). Due to limited data in the ketamine versus thiopental comparison, however, Yoosefi 2014 was frequently the only study contributing to outcomes, so a reduction in weighting would not significantly impact our results and interpretation.

In this review, we used the following definition of treatment‐resistant definition: inadequate response to at least two antidepressants. This definition can limit the interpretation of our findings, as it enables inclusion of patients who have merely failed treatment with two selective serotonin reuptake inhibitors and no other classes of antidepressants or psychotherapy. Some definitions of treatment‐resistant depression demand that a trial of an antidepressant can only be regarded as adequate if the drug is take for a minimum duration and dose. Other definitions will count a trial of an antidepressant which was not tolerated. A majority of surveyed clinicians indicated that they would define treatment resistant depression as an adequate trial of two to three antidepressant medications plus a 10‐ to 12‐week trial of evidence‐based psychotherapy (Brown 2019). While recognising that this definition may limit generalisability of this review to real‐world clinical practice (Turner 2019), it is also used by the majority of depression treatment studies, so a pragmatic decision was made to use it.

There is also some discussion in the scientific literature about the classification of drugs (Malhi 2019). Unlike ketamine and memantine which have well‐characterised primary effects on glutamate receptors, some of the treatments included in this review (for instance, atomoxetine) have an action on glutamate receptors, but have other pharmacological properties that are thought more important in their mode of action. However, these complex pharmacological properties are not always recognised in drug descriptions. For example, a publication on neuroscience‐based drug nomenclature described atomoxetine as a norepinephrine reuptake inhibitor only, without mention of its action on glutamate receptors (Zohar 2014). However, in the present review we wished to adopt a more pragmatic approach to better inform clinical practice. We therefore decided to run a very comprehensive search of the scientific literature, and compared individual drugs in order to avoid the clustering of different interventions into non‐homogeneous drug classes.

Agreements and disagreements with other studies or reviews

In line with findings of previous reviews (Caddy 2015; McGirr 2015; Naughton 2014; Marcantoni 2020; Memon 2020), the present review demonstrated a rapid onset of antidepressant effect for ketamine, which lasts up to one week. However, the majority of these reviews have not adopted the same strict inclusion criteria as in the present review. Most previously conducted reviews have included data from non‐randomised studies and from both phases of cross‐over trials (Marcantoni 2020), which may have overestimated the efficacy of ketamine due to selection bias and carry‐over effect. In order to be clinically informative and rely only on the most robust results, in the present review we only included data from the first phase of cross‐over trials and included only double blind or single blind randomised controlled trials |9RCTs).

We also found a rapid onset of antidepressant effect for esketamine, which was consistent with a systematic review by Zheng 2020. Zheng concluded that an antidepressant effect lasted for at least 28 days; however we were unable to find an effect at 72 hours and one week. This may be because Zheng only compared data between baseline and endpoint (which ranged between 8 to 28 days), whilst we examined data for all available time points.

Of further note is that previous reviews included studies of patients diagnosed with unipolar and bipolar depression in the same analyses (Caddy 2014; Coyle 2015; Marcantoni 2020). By contrast, in this review we have focused specifically on unipolar depression because of the specific clinical features that differentiate this disorder from bipolar depression.

Study flow diagram.

Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 Ketamine versus Placebo, outcome: 1.1 Response rate.

Figures and Tables -
Figure 4

Forest plot of comparison: 1 Ketamine versus Placebo, outcome: 1.1 Response rate.

Forest plot of comparison: 2 Ketamine versus Midazolam, outcome: 2.1 Response rate.

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Figure 5

Forest plot of comparison: 2 Ketamine versus Midazolam, outcome: 2.1 Response rate.

Forest plot of comparison: 9 Esketamine versus placebo, outcome: 9.1 Response rate.

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Figure 6

Forest plot of comparison: 9 Esketamine versus placebo, outcome: 9.1 Response rate.

Comparison 1: Ketamine versus Placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 1.1

Comparison 1: Ketamine versus Placebo, Outcome 1: Response rate

Comparison 1: Ketamine versus Placebo, Outcome 2: AE Abdominal Pain

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Analysis 1.2

Comparison 1: Ketamine versus Placebo, Outcome 2: AE Abdominal Pain

Comparison 1: Ketamine versus Placebo, Outcome 3: AE Agitation/anxiety

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Analysis 1.3

Comparison 1: Ketamine versus Placebo, Outcome 3: AE Agitation/anxiety

Comparison 1: Ketamine versus Placebo, Outcome 4: AE Blurred vision

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Analysis 1.4

Comparison 1: Ketamine versus Placebo, Outcome 4: AE Blurred vision

Comparison 1: Ketamine versus Placebo, Outcome 5: AE Change in blood pressure

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Analysis 1.5

Comparison 1: Ketamine versus Placebo, Outcome 5: AE Change in blood pressure

Comparison 1: Ketamine versus Placebo, Outcome 6: AE Confusion

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Analysis 1.6

Comparison 1: Ketamine versus Placebo, Outcome 6: AE Confusion

Comparison 1: Ketamine versus Placebo, Outcome 7: AE Dissociative symptoms

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Analysis 1.7

Comparison 1: Ketamine versus Placebo, Outcome 7: AE Dissociative symptoms

Comparison 1: Ketamine versus Placebo, Outcome 8: AE Dizziness

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Analysis 1.8

Comparison 1: Ketamine versus Placebo, Outcome 8: AE Dizziness

Comparison 1: Ketamine versus Placebo, Outcome 9: AE Emotional blunting

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Analysis 1.9

Comparison 1: Ketamine versus Placebo, Outcome 9: AE Emotional blunting

Comparison 1: Ketamine versus Placebo, Outcome 10: AE Euphoria

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Analysis 1.10

Comparison 1: Ketamine versus Placebo, Outcome 10: AE Euphoria

Comparison 1: Ketamine versus Placebo, Outcome 11: AE Hallucinations

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Analysis 1.11

Comparison 1: Ketamine versus Placebo, Outcome 11: AE Hallucinations

Comparison 1: Ketamine versus Placebo, Outcome 12: AE Headache

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Analysis 1.12

Comparison 1: Ketamine versus Placebo, Outcome 12: AE Headache

Comparison 1: Ketamine versus Placebo, Outcome 13: AE Infections and Infestations

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Analysis 1.13

Comparison 1: Ketamine versus Placebo, Outcome 13: AE Infections and Infestations

Comparison 1: Ketamine versus Placebo, Outcome 14: AE Loss of Appetite

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Analysis 1.14

Comparison 1: Ketamine versus Placebo, Outcome 14: AE Loss of Appetite

Comparison 1: Ketamine versus Placebo, Outcome 15: AE Mania/hypomania

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Analysis 1.15

Comparison 1: Ketamine versus Placebo, Outcome 15: AE Mania/hypomania

Comparison 1: Ketamine versus Placebo, Outcome 16: AE Musculoskeletal and connective tissue disorders

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Analysis 1.16

Comparison 1: Ketamine versus Placebo, Outcome 16: AE Musculoskeletal and connective tissue disorders

Comparison 1: Ketamine versus Placebo, Outcome 17: AE Nausea/vomiting

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Analysis 1.17

Comparison 1: Ketamine versus Placebo, Outcome 17: AE Nausea/vomiting

Comparison 1: Ketamine versus Placebo, Outcome 18: AE Nervousness

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Analysis 1.18

Comparison 1: Ketamine versus Placebo, Outcome 18: AE Nervousness

Comparison 1: Ketamine versus Placebo, Outcome 19: AE Nervous system disorders

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Analysis 1.19

Comparison 1: Ketamine versus Placebo, Outcome 19: AE Nervous system disorders

Comparison 1: Ketamine versus Placebo, Outcome 20: AE Palpitations

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Analysis 1.20

Comparison 1: Ketamine versus Placebo, Outcome 20: AE Palpitations

Comparison 1: Ketamine versus Placebo, Outcome 21: AE Psychiatric disorders

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Analysis 1.21

Comparison 1: Ketamine versus Placebo, Outcome 21: AE Psychiatric disorders

Comparison 1: Ketamine versus Placebo, Outcome 22: AE Restlessness

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Analysis 1.22

Comparison 1: Ketamine versus Placebo, Outcome 22: AE Restlessness

Comparison 1: Ketamine versus Placebo, Outcome 23: AE Skin and subcutaneous tissue disorders

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Analysis 1.23

Comparison 1: Ketamine versus Placebo, Outcome 23: AE Skin and subcutaneous tissue disorders

Comparison 1: Ketamine versus Placebo, Outcome 24: AE Suicidal Ideas

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Analysis 1.24

Comparison 1: Ketamine versus Placebo, Outcome 24: AE Suicidal Ideas

Comparison 1: Ketamine versus Placebo, Outcome 25: AE Tremor

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Analysis 1.25

Comparison 1: Ketamine versus Placebo, Outcome 25: AE Tremor

Comparison 1: Ketamine versus Placebo, Outcome 26: Remission rate

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Analysis 1.26

Comparison 1: Ketamine versus Placebo, Outcome 26: Remission rate

Comparison 1: Ketamine versus Placebo, Outcome 27: Depression rating scale score

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Analysis 1.27

Comparison 1: Ketamine versus Placebo, Outcome 27: Depression rating scale score

Comparison 1: Ketamine versus Placebo, Outcome 28: Suicidal ideation composite

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Analysis 1.28

Comparison 1: Ketamine versus Placebo, Outcome 28: Suicidal ideation composite

Comparison 1: Ketamine versus Placebo, Outcome 29: Cognition scores

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Analysis 1.29

Comparison 1: Ketamine versus Placebo, Outcome 29: Cognition scores

Comparison 1: Ketamine versus Placebo, Outcome 30: Quality of Life

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Analysis 1.30

Comparison 1: Ketamine versus Placebo, Outcome 30: Quality of Life

Comparison 1: Ketamine versus Placebo, Outcome 31: Acceptability

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Analysis 1.31

Comparison 1: Ketamine versus Placebo, Outcome 31: Acceptability

Comparison 2: Ketamine versus Midazolam, Outcome 1: Response rate

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Analysis 2.1

Comparison 2: Ketamine versus Midazolam, Outcome 1: Response rate

Comparison 2: Ketamine versus Midazolam, Outcome 2: AE Abnormal dreams

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Analysis 2.2

Comparison 2: Ketamine versus Midazolam, Outcome 2: AE Abnormal dreams

Comparison 2: Ketamine versus Midazolam, Outcome 3: AE Agitation/anxiety

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Analysis 2.3

Comparison 2: Ketamine versus Midazolam, Outcome 3: AE Agitation/anxiety

Comparison 2: Ketamine versus Midazolam, Outcome 4: AE Back pain

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Analysis 2.4

Comparison 2: Ketamine versus Midazolam, Outcome 4: AE Back pain

Comparison 2: Ketamine versus Midazolam, Outcome 5: AE Blurred vision

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Analysis 2.5

Comparison 2: Ketamine versus Midazolam, Outcome 5: AE Blurred vision

Comparison 2: Ketamine versus Midazolam, Outcome 6: AE Chest pain

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Analysis 2.6

Comparison 2: Ketamine versus Midazolam, Outcome 6: AE Chest pain

Comparison 2: Ketamine versus Midazolam, Outcome 7: AE Chills

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Analysis 2.7

Comparison 2: Ketamine versus Midazolam, Outcome 7: AE Chills

Comparison 2: Ketamine versus Midazolam, Outcome 8: AE Constipation

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Analysis 2.8

Comparison 2: Ketamine versus Midazolam, Outcome 8: AE Constipation

Comparison 2: Ketamine versus Midazolam, Outcome 9: AE Decreased energy

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Analysis 2.9

Comparison 2: Ketamine versus Midazolam, Outcome 9: AE Decreased energy

Comparison 2: Ketamine versus Midazolam, Outcome 10: AE Decreased libido

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Analysis 2.10

Comparison 2: Ketamine versus Midazolam, Outcome 10: AE Decreased libido

Comparison 2: Ketamine versus Midazolam, Outcome 11: AE Depression

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Analysis 2.11

Comparison 2: Ketamine versus Midazolam, Outcome 11: AE Depression

Comparison 2: Ketamine versus Midazolam, Outcome 12: AE Diarrhea

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Analysis 2.12

Comparison 2: Ketamine versus Midazolam, Outcome 12: AE Diarrhea

Comparison 2: Ketamine versus Midazolam, Outcome 13: AE Difficulty swallowing

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Analysis 2.13

Comparison 2: Ketamine versus Midazolam, Outcome 13: AE Difficulty swallowing

Comparison 2: Ketamine versus Midazolam, Outcome 14: AE Dizziness

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Analysis 2.14

Comparison 2: Ketamine versus Midazolam, Outcome 14: AE Dizziness

Comparison 2: Ketamine versus Midazolam, Outcome 15: AE Dry mouth

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Analysis 2.15

Comparison 2: Ketamine versus Midazolam, Outcome 15: AE Dry mouth

Comparison 2: Ketamine versus Midazolam, Outcome 16: AE Dry skin

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Analysis 2.16

Comparison 2: Ketamine versus Midazolam, Outcome 16: AE Dry skin

Comparison 2: Ketamine versus Midazolam, Outcome 17: AE Fatigue

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Analysis 2.17

Comparison 2: Ketamine versus Midazolam, Outcome 17: AE Fatigue

Comparison 2: Ketamine versus Midazolam, Outcome 18: AE General malaise

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Analysis 2.18

Comparison 2: Ketamine versus Midazolam, Outcome 18: AE General malaise

Comparison 2: Ketamine versus Midazolam, Outcome 19: AE Insomnia

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Analysis 2.19

Comparison 2: Ketamine versus Midazolam, Outcome 19: AE Insomnia

Comparison 2: Ketamine versus Midazolam, Outcome 20: AE Headache

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Analysis 2.20

Comparison 2: Ketamine versus Midazolam, Outcome 20: AE Headache

Comparison 2: Ketamine versus Midazolam, Outcome 21: AE Increased blood pressure or heart rate

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Analysis 2.21

Comparison 2: Ketamine versus Midazolam, Outcome 21: AE Increased blood pressure or heart rate

Comparison 2: Ketamine versus Midazolam, Outcome 22: AE Increase in systolic blood pressure and heart rate

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Analysis 2.22

Comparison 2: Ketamine versus Midazolam, Outcome 22: AE Increase in systolic blood pressure and heart rate

Comparison 2: Ketamine versus Midazolam, Outcome 23: AE Increased perspiration

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Analysis 2.23

Comparison 2: Ketamine versus Midazolam, Outcome 23: AE Increased perspiration

Comparison 2: Ketamine versus Midazolam, Outcome 24: AE Indigestion

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Analysis 2.24

Comparison 2: Ketamine versus Midazolam, Outcome 24: AE Indigestion

Comparison 2: Ketamine versus Midazolam, Outcome 25: AE Insomnia

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Analysis 2.25

Comparison 2: Ketamine versus Midazolam, Outcome 25: AE Insomnia

Comparison 2: Ketamine versus Midazolam, Outcome 26: AE Irritability

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Analysis 2.26

Comparison 2: Ketamine versus Midazolam, Outcome 26: AE Irritability

Comparison 2: Ketamine versus Midazolam, Outcome 27: AE Itching

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Analysis 2.27

Comparison 2: Ketamine versus Midazolam, Outcome 27: AE Itching

Comparison 2: Ketamine versus Midazolam, Outcome 28: AE Loss of consciousness

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Analysis 2.28

Comparison 2: Ketamine versus Midazolam, Outcome 28: AE Loss of consciousness

Comparison 2: Ketamine versus Midazolam, Outcome 29: AE Memory problems

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Analysis 2.29

Comparison 2: Ketamine versus Midazolam, Outcome 29: AE Memory problems

Comparison 2: Ketamine versus Midazolam, Outcome 30: AE Muscle/bone/joint pain

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Analysis 2.30

Comparison 2: Ketamine versus Midazolam, Outcome 30: AE Muscle/bone/joint pain

Comparison 2: Ketamine versus Midazolam, Outcome 31: AE Nasal congestion

Figures and Tables -
Analysis 2.31

Comparison 2: Ketamine versus Midazolam, Outcome 31: AE Nasal congestion

Comparison 2: Ketamine versus Midazolam, Outcome 32: AE Nausea/vomiting

Figures and Tables -
Analysis 2.32

Comparison 2: Ketamine versus Midazolam, Outcome 32: AE Nausea/vomiting

Comparison 2: Ketamine versus Midazolam, Outcome 33: AE Numbness

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Analysis 2.33

Comparison 2: Ketamine versus Midazolam, Outcome 33: AE Numbness

Comparison 2: Ketamine versus Midazolam, Outcome 34: AE Pain in extremities

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Analysis 2.34

Comparison 2: Ketamine versus Midazolam, Outcome 34: AE Pain in extremities

Comparison 2: Ketamine versus Midazolam, Outcome 35: AE Palpitations

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Analysis 2.35

Comparison 2: Ketamine versus Midazolam, Outcome 35: AE Palpitations

Comparison 2: Ketamine versus Midazolam, Outcome 36: AE Poor concentration

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Analysis 2.36

Comparison 2: Ketamine versus Midazolam, Outcome 36: AE Poor concentration

Comparison 2: Ketamine versus Midazolam, Outcome 37: AE Poor co‐ordination

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Analysis 2.37

Comparison 2: Ketamine versus Midazolam, Outcome 37: AE Poor co‐ordination

Comparison 2: Ketamine versus Midazolam, Outcome 38: AE Poor quality sleep

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Analysis 2.38

Comparison 2: Ketamine versus Midazolam, Outcome 38: AE Poor quality sleep

Comparison 2: Ketamine versus Midazolam, Outcome 39: AE Rash

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Analysis 2.39

Comparison 2: Ketamine versus Midazolam, Outcome 39: AE Rash

Comparison 2: Ketamine versus Midazolam, Outcome 40: AE Reduced duration of sleep

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Analysis 2.40

Comparison 2: Ketamine versus Midazolam, Outcome 40: AE Reduced duration of sleep

Comparison 2: Ketamine versus Midazolam, Outcome 41: AE Restlessness

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Analysis 2.41

Comparison 2: Ketamine versus Midazolam, Outcome 41: AE Restlessness

Comparison 2: Ketamine versus Midazolam, Outcome 42: AE Sensory disturbance

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Analysis 2.42

Comparison 2: Ketamine versus Midazolam, Outcome 42: AE Sensory disturbance

Comparison 2: Ketamine versus Midazolam, Outcome 43: AE Sexual dysfunction

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Analysis 2.43

Comparison 2: Ketamine versus Midazolam, Outcome 43: AE Sexual dysfunction

Comparison 2: Ketamine versus Midazolam, Outcome 44: AE Sleepiness/drowsiness

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Analysis 2.44

Comparison 2: Ketamine versus Midazolam, Outcome 44: AE Sleepiness/drowsiness

Comparison 2: Ketamine versus Midazolam, Outcome 45: AE Stomach or abdominal discomfort

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Analysis 2.45

Comparison 2: Ketamine versus Midazolam, Outcome 45: AE Stomach or abdominal discomfort

Comparison 2: Ketamine versus Midazolam, Outcome 46: AE Suicide attempt

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Analysis 2.46

Comparison 2: Ketamine versus Midazolam, Outcome 46: AE Suicide attempt

Comparison 2: Ketamine versus Midazolam, Outcome 47: AE Suicidal ideas

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Analysis 2.47

Comparison 2: Ketamine versus Midazolam, Outcome 47: AE Suicidal ideas

Comparison 2: Ketamine versus Midazolam, Outcome 48: AE Tachycardia

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Analysis 2.48

Comparison 2: Ketamine versus Midazolam, Outcome 48: AE Tachycardia

Comparison 2: Ketamine versus Midazolam, Outcome 49: AE Tinnitus

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Analysis 2.49

Comparison 2: Ketamine versus Midazolam, Outcome 49: AE Tinnitus

Comparison 2: Ketamine versus Midazolam, Outcome 50: AE Tooth Abscess

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Analysis 2.50

Comparison 2: Ketamine versus Midazolam, Outcome 50: AE Tooth Abscess

Comparison 2: Ketamine versus Midazolam, Outcome 51: AE Tremor

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Analysis 2.51

Comparison 2: Ketamine versus Midazolam, Outcome 51: AE Tremor

Comparison 2: Ketamine versus Midazolam, Outcome 52: AE Urination issues

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Analysis 2.52

Comparison 2: Ketamine versus Midazolam, Outcome 52: AE Urination issues

Comparison 2: Ketamine versus Midazolam, Outcome 53: Remission rate

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Analysis 2.53

Comparison 2: Ketamine versus Midazolam, Outcome 53: Remission rate

Comparison 2: Ketamine versus Midazolam, Outcome 54: Depression rating scale score

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Analysis 2.54

Comparison 2: Ketamine versus Midazolam, Outcome 54: Depression rating scale score

Comparison 2: Ketamine versus Midazolam, Outcome 55: Suicidal ideation composite

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Analysis 2.55

Comparison 2: Ketamine versus Midazolam, Outcome 55: Suicidal ideation composite

Comparison 2: Ketamine versus Midazolam, Outcome 56: Acceptability

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Analysis 2.56

Comparison 2: Ketamine versus Midazolam, Outcome 56: Acceptability

Comparison 3: Ketamine versus Thiopental, Outcome 1: Response rate

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Analysis 3.1

Comparison 3: Ketamine versus Thiopental, Outcome 1: Response rate

Comparison 3: Ketamine versus Thiopental, Outcome 2: AE Blood Pressure Rise

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Analysis 3.2

Comparison 3: Ketamine versus Thiopental, Outcome 2: AE Blood Pressure Rise

Comparison 3: Ketamine versus Thiopental, Outcome 3: AE Delirium

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Analysis 3.3

Comparison 3: Ketamine versus Thiopental, Outcome 3: AE Delirium

Comparison 3: Ketamine versus Thiopental, Outcome 4: AE Emergence reactions

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Analysis 3.4

Comparison 3: Ketamine versus Thiopental, Outcome 4: AE Emergence reactions

Comparison 3: Ketamine versus Thiopental, Outcome 5: AE Headache

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Analysis 3.5

Comparison 3: Ketamine versus Thiopental, Outcome 5: AE Headache

Comparison 3: Ketamine versus Thiopental, Outcome 6: AE Heart Rate Rise

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Analysis 3.6

Comparison 3: Ketamine versus Thiopental, Outcome 6: AE Heart Rate Rise

Comparison 3: Ketamine versus Thiopental, Outcome 7: AE Increased secretions

Figures and Tables -
Analysis 3.7

Comparison 3: Ketamine versus Thiopental, Outcome 7: AE Increased secretions

Comparison 3: Ketamine versus Thiopental, Outcome 8: AE Nausea/vomiting

Figures and Tables -
Analysis 3.8

Comparison 3: Ketamine versus Thiopental, Outcome 8: AE Nausea/vomiting

Comparison 3: Ketamine versus Thiopental, Outcome 9: Depression rating scale score

Figures and Tables -
Analysis 3.9

Comparison 3: Ketamine versus Thiopental, Outcome 9: Depression rating scale score

Comparison 3: Ketamine versus Thiopental, Outcome 10: Acceptability

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Analysis 3.10

Comparison 3: Ketamine versus Thiopental, Outcome 10: Acceptability

Comparison 4: Ketamine versus Methohexital, Outcome 1: Depression rating scale score

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Analysis 4.1

Comparison 4: Ketamine versus Methohexital, Outcome 1: Depression rating scale score

Comparison 5: Ketamine versus Propofol, Outcome 1: Depression rating scale score

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Analysis 5.1

Comparison 5: Ketamine versus Propofol, Outcome 1: Depression rating scale score

Comparison 6: Ketamine versus Remifentanil hydrochloride, Outcome 1: Depression rating scale score

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Analysis 6.1

Comparison 6: Ketamine versus Remifentanil hydrochloride, Outcome 1: Depression rating scale score

Comparison 7: Ketamine versus Esketamine, Outcome 1: Response Rate

Figures and Tables -
Analysis 7.1

Comparison 7: Ketamine versus Esketamine, Outcome 1: Response Rate

Comparison 7: Ketamine versus Esketamine, Outcome 2: Cognition

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Analysis 7.2

Comparison 7: Ketamine versus Esketamine, Outcome 2: Cognition

Comparison 8: Ketamine versus ECT, Outcome 1: Response rate

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Analysis 8.1

Comparison 8: Ketamine versus ECT, Outcome 1: Response rate

Comparison 8: Ketamine versus ECT, Outcome 2: AE Increase in systolic blood pressure and heart rate

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Analysis 8.2

Comparison 8: Ketamine versus ECT, Outcome 2: AE Increase in systolic blood pressure and heart rate

Comparison 8: Ketamine versus ECT, Outcome 3: Remission rate

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Analysis 8.3

Comparison 8: Ketamine versus ECT, Outcome 3: Remission rate

Comparison 8: Ketamine versus ECT, Outcome 4: Depression rating scale score

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Analysis 8.4

Comparison 8: Ketamine versus ECT, Outcome 4: Depression rating scale score

Comparison 9: Esketamine versus placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 9.1

Comparison 9: Esketamine versus placebo, Outcome 1: Response rate

Comparison 9: Esketamine versus placebo, Outcome 2: AE Aggression

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Analysis 9.2

Comparison 9: Esketamine versus placebo, Outcome 2: AE Aggression

Comparison 9: Esketamine versus placebo, Outcome 3: AE Agitation/anxiety

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Analysis 9.3

Comparison 9: Esketamine versus placebo, Outcome 3: AE Agitation/anxiety

Comparison 9: Esketamine versus placebo, Outcome 4: AE Arrhythmia

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Analysis 9.4

Comparison 9: Esketamine versus placebo, Outcome 4: AE Arrhythmia

Comparison 9: Esketamine versus placebo, Outcome 5: AE Change in blood pressure

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Analysis 9.5

Comparison 9: Esketamine versus placebo, Outcome 5: AE Change in blood pressure

Comparison 9: Esketamine versus placebo, Outcome 6: AE Constipation

Figures and Tables -
Analysis 9.6

Comparison 9: Esketamine versus placebo, Outcome 6: AE Constipation

Comparison 9: Esketamine versus placebo, Outcome 7: AE Depersonalisation/derealization

Figures and Tables -
Analysis 9.7

Comparison 9: Esketamine versus placebo, Outcome 7: AE Depersonalisation/derealization

Comparison 9: Esketamine versus placebo, Outcome 8: AE Depression

Figures and Tables -
Analysis 9.8

Comparison 9: Esketamine versus placebo, Outcome 8: AE Depression

Comparison 9: Esketamine versus placebo, Outcome 9: AE Diabetic ketoacidosis

Figures and Tables -
Analysis 9.9

Comparison 9: Esketamine versus placebo, Outcome 9: AE Diabetic ketoacidosis

Comparison 9: Esketamine versus placebo, Outcome 10: AE Diarrhoea

Figures and Tables -
Analysis 9.10

Comparison 9: Esketamine versus placebo, Outcome 10: AE Diarrhoea

Comparison 9: Esketamine versus placebo, Outcome 11: AE Dissociative symptoms

Figures and Tables -
Analysis 9.11

Comparison 9: Esketamine versus placebo, Outcome 11: AE Dissociative symptoms

Comparison 9: Esketamine versus placebo, Outcome 12: AE Dizziness

Figures and Tables -
Analysis 9.12

Comparison 9: Esketamine versus placebo, Outcome 12: AE Dizziness

Comparison 9: Esketamine versus placebo, Outcome 13: AE Dizziness postural

Figures and Tables -
Analysis 9.13

Comparison 9: Esketamine versus placebo, Outcome 13: AE Dizziness postural

Comparison 9: Esketamine versus placebo, Outcome 14: AE Double vision

Figures and Tables -
Analysis 9.14

Comparison 9: Esketamine versus placebo, Outcome 14: AE Double vision

Comparison 9: Esketamine versus placebo, Outcome 15: AE Euphoria

Figures and Tables -
Analysis 9.15

Comparison 9: Esketamine versus placebo, Outcome 15: AE Euphoria

Comparison 9: Esketamine versus placebo, Outcome 16: AE Fatigue

Figures and Tables -
Analysis 9.16

Comparison 9: Esketamine versus placebo, Outcome 16: AE Fatigue

Comparison 9: Esketamine versus placebo, Outcome 17: AE Feeling drunk

Figures and Tables -
Analysis 9.17

Comparison 9: Esketamine versus placebo, Outcome 17: AE Feeling drunk

Comparison 9: Esketamine versus placebo, Outcome 18: AE Headache

Figures and Tables -
Analysis 9.18

Comparison 9: Esketamine versus placebo, Outcome 18: AE Headache

Comparison 9: Esketamine versus placebo, Outcome 19: AE Hypertransaminasemia

Figures and Tables -
Analysis 9.19

Comparison 9: Esketamine versus placebo, Outcome 19: AE Hypertransaminasemia

Comparison 9: Esketamine versus placebo, Outcome 20: AE Increased sweating

Figures and Tables -
Analysis 9.20

Comparison 9: Esketamine versus placebo, Outcome 20: AE Increased sweating

Comparison 9: Esketamine versus placebo, Outcome 21: AE Infections and Infestations

Figures and Tables -
Analysis 9.21

Comparison 9: Esketamine versus placebo, Outcome 21: AE Infections and Infestations

Comparison 9: Esketamine versus placebo, Outcome 22: AE Insomnia

Figures and Tables -
Analysis 9.22

Comparison 9: Esketamine versus placebo, Outcome 22: AE Insomnia

Comparison 9: Esketamine versus placebo, Outcome 23: AE Lethargy

Figures and Tables -
Analysis 9.23

Comparison 9: Esketamine versus placebo, Outcome 23: AE Lethargy

Comparison 9: Esketamine versus placebo, Outcome 24: AE Mental impairment

Figures and Tables -
Analysis 9.24

Comparison 9: Esketamine versus placebo, Outcome 24: AE Mental impairment

Comparison 9: Esketamine versus placebo, Outcome 25: AE Nasal discomfort

Figures and Tables -
Analysis 9.25

Comparison 9: Esketamine versus placebo, Outcome 25: AE Nasal discomfort

Comparison 9: Esketamine versus placebo, Outcome 26: AE Nausea/vomiting

Figures and Tables -
Analysis 9.26

Comparison 9: Esketamine versus placebo, Outcome 26: AE Nausea/vomiting

Comparison 9: Esketamine versus placebo, Outcome 27: AE Paresthesia/neuropathy exacerbation

Figures and Tables -
Analysis 9.27

Comparison 9: Esketamine versus placebo, Outcome 27: AE Paresthesia/neuropathy exacerbation

Comparison 9: Esketamine versus placebo, Outcome 28: AE Pericardial effusion

Figures and Tables -
Analysis 9.28

Comparison 9: Esketamine versus placebo, Outcome 28: AE Pericardial effusion

Comparison 9: Esketamine versus placebo, Outcome 29: AE Pneumothorax

Figures and Tables -
Analysis 9.29

Comparison 9: Esketamine versus placebo, Outcome 29: AE Pneumothorax

Comparison 9: Esketamine versus placebo, Outcome 30: AE Sensory disturbance

Figures and Tables -
Analysis 9.30

Comparison 9: Esketamine versus placebo, Outcome 30: AE Sensory disturbance

Comparison 9: Esketamine versus placebo, Outcome 31: AE Sedation

Figures and Tables -
Analysis 9.31

Comparison 9: Esketamine versus placebo, Outcome 31: AE Sedation

Comparison 9: Esketamine versus placebo, Outcome 32: AE Sleepiness/drowsiness

Figures and Tables -
Analysis 9.32

Comparison 9: Esketamine versus placebo, Outcome 32: AE Sleepiness/drowsiness

Comparison 9: Esketamine versus placebo, Outcome 33: AE Sore throat

Figures and Tables -
Analysis 9.33

Comparison 9: Esketamine versus placebo, Outcome 33: AE Sore throat

Comparison 9: Esketamine versus placebo, Outcome 34: AE Suicide attempt

Figures and Tables -
Analysis 9.34

Comparison 9: Esketamine versus placebo, Outcome 34: AE Suicide attempt

Comparison 9: Esketamine versus placebo, Outcome 35: AE Suicidal ideas

Figures and Tables -
Analysis 9.35

Comparison 9: Esketamine versus placebo, Outcome 35: AE Suicidal ideas

Comparison 9: Esketamine versus placebo, Outcome 36: AE Taste perversion

Figures and Tables -
Analysis 9.36

Comparison 9: Esketamine versus placebo, Outcome 36: AE Taste perversion

Comparison 9: Esketamine versus placebo, Outcome 37: AE Tremor

Figures and Tables -
Analysis 9.37

Comparison 9: Esketamine versus placebo, Outcome 37: AE Tremor

Comparison 9: Esketamine versus placebo, Outcome 38: AE Urination issues

Figures and Tables -
Analysis 9.38

Comparison 9: Esketamine versus placebo, Outcome 38: AE Urination issues

Comparison 9: Esketamine versus placebo, Outcome 39: AE Vertigo

Figures and Tables -
Analysis 9.39

Comparison 9: Esketamine versus placebo, Outcome 39: AE Vertigo

Comparison 9: Esketamine versus placebo, Outcome 40: AE Vision blurred

Figures and Tables -
Analysis 9.40

Comparison 9: Esketamine versus placebo, Outcome 40: AE Vision blurred

Comparison 9: Esketamine versus placebo, Outcome 41: Remission rate

Figures and Tables -
Analysis 9.41

Comparison 9: Esketamine versus placebo, Outcome 41: Remission rate

Comparison 9: Esketamine versus placebo, Outcome 42: Depression rating scale score

Figures and Tables -
Analysis 9.42

Comparison 9: Esketamine versus placebo, Outcome 42: Depression rating scale score

Comparison 9: Esketamine versus placebo, Outcome 43: Suicidal ideation composite

Figures and Tables -
Analysis 9.43

Comparison 9: Esketamine versus placebo, Outcome 43: Suicidal ideation composite

Comparison 9: Esketamine versus placebo, Outcome 44: Acceptability

Figures and Tables -
Analysis 9.44

Comparison 9: Esketamine versus placebo, Outcome 44: Acceptability

Comparison 10: Memantine versus Placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 10.1

Comparison 10: Memantine versus Placebo, Outcome 1: Response rate

Comparison 10: Memantine versus Placebo, Outcome 2: AE Abdominal Pain

Figures and Tables -
Analysis 10.2

Comparison 10: Memantine versus Placebo, Outcome 2: AE Abdominal Pain

Comparison 10: Memantine versus Placebo, Outcome 3: AE Active suicidal ideation

Figures and Tables -
Analysis 10.3

Comparison 10: Memantine versus Placebo, Outcome 3: AE Active suicidal ideation

Comparison 10: Memantine versus Placebo, Outcome 4: AE Agitation/anxiety

Figures and Tables -
Analysis 10.4

Comparison 10: Memantine versus Placebo, Outcome 4: AE Agitation/anxiety

Comparison 10: Memantine versus Placebo, Outcome 5: AE Appetite increase

Figures and Tables -
Analysis 10.5

Comparison 10: Memantine versus Placebo, Outcome 5: AE Appetite increase

Comparison 10: Memantine versus Placebo, Outcome 6: AE Back pain

Figures and Tables -
Analysis 10.6

Comparison 10: Memantine versus Placebo, Outcome 6: AE Back pain

Comparison 10: Memantine versus Placebo, Outcome 7: AE Balance or gait problems

Figures and Tables -
Analysis 10.7

Comparison 10: Memantine versus Placebo, Outcome 7: AE Balance or gait problems

Comparison 10: Memantine versus Placebo, Outcome 8: AE Carbohydrate craving

Figures and Tables -
Analysis 10.8

Comparison 10: Memantine versus Placebo, Outcome 8: AE Carbohydrate craving

Comparison 10: Memantine versus Placebo, Outcome 9: AE Chest pain

Figures and Tables -
Analysis 10.9

Comparison 10: Memantine versus Placebo, Outcome 9: AE Chest pain

Comparison 10: Memantine versus Placebo, Outcome 10: AE Chills

Figures and Tables -
Analysis 10.10

Comparison 10: Memantine versus Placebo, Outcome 10: AE Chills

Comparison 10: Memantine versus Placebo, Outcome 11: AE Clammy hands

Figures and Tables -
Analysis 10.11

Comparison 10: Memantine versus Placebo, Outcome 11: AE Clammy hands

Comparison 10: Memantine versus Placebo, Outcome 12: AE Confusion/decreased mental clarity

Figures and Tables -
Analysis 10.12

Comparison 10: Memantine versus Placebo, Outcome 12: AE Confusion/decreased mental clarity

Comparison 10: Memantine versus Placebo, Outcome 13: AE Conjunctival swelling

Figures and Tables -
Analysis 10.13

Comparison 10: Memantine versus Placebo, Outcome 13: AE Conjunctival swelling

Comparison 10: Memantine versus Placebo, Outcome 14: AE Constipation

Figures and Tables -
Analysis 10.14

Comparison 10: Memantine versus Placebo, Outcome 14: AE Constipation

Comparison 10: Memantine versus Placebo, Outcome 15: AE Decreased appetite

Figures and Tables -
Analysis 10.15

Comparison 10: Memantine versus Placebo, Outcome 15: AE Decreased appetite

Comparison 10: Memantine versus Placebo, Outcome 16: AE Delusions

Figures and Tables -
Analysis 10.16

Comparison 10: Memantine versus Placebo, Outcome 16: AE Delusions

Comparison 10: Memantine versus Placebo, Outcome 17: AE Diaphoresis

Figures and Tables -
Analysis 10.17

Comparison 10: Memantine versus Placebo, Outcome 17: AE Diaphoresis

Comparison 10: Memantine versus Placebo, Outcome 18: AE Difficulty breathing

Figures and Tables -
Analysis 10.18

Comparison 10: Memantine versus Placebo, Outcome 18: AE Difficulty breathing

Comparison 10: Memantine versus Placebo, Outcome 19: AE Dissociative symptoms

Figures and Tables -
Analysis 10.19

Comparison 10: Memantine versus Placebo, Outcome 19: AE Dissociative symptoms

Comparison 10: Memantine versus Placebo, Outcome 20: AE Dizziness

Figures and Tables -
Analysis 10.20

Comparison 10: Memantine versus Placebo, Outcome 20: AE Dizziness

Comparison 10: Memantine versus Placebo, Outcome 21: AE Dry mouth

Figures and Tables -
Analysis 10.21

Comparison 10: Memantine versus Placebo, Outcome 21: AE Dry mouth

Comparison 10: Memantine versus Placebo, Outcome 22: AE Dyskinesia

Figures and Tables -
Analysis 10.22

Comparison 10: Memantine versus Placebo, Outcome 22: AE Dyskinesia

Comparison 10: Memantine versus Placebo, Outcome 23: AE Dyspepsia

Figures and Tables -
Analysis 10.23

Comparison 10: Memantine versus Placebo, Outcome 23: AE Dyspepsia

Comparison 10: Memantine versus Placebo, Outcome 24: AE Ear pain/jaw pain

Figures and Tables -
Analysis 10.24

Comparison 10: Memantine versus Placebo, Outcome 24: AE Ear pain/jaw pain

Comparison 10: Memantine versus Placebo, Outcome 25: AE Emotional lability

Figures and Tables -
Analysis 10.25

Comparison 10: Memantine versus Placebo, Outcome 25: AE Emotional lability

Comparison 10: Memantine versus Placebo, Outcome 26: AE Eye photosensitivity

Figures and Tables -
Analysis 10.26

Comparison 10: Memantine versus Placebo, Outcome 26: AE Eye photosensitivity

Comparison 10: Memantine versus Placebo, Outcome 27: AE Facial twitching

Figures and Tables -
Analysis 10.27

Comparison 10: Memantine versus Placebo, Outcome 27: AE Facial twitching

Comparison 10: Memantine versus Placebo, Outcome 28: AE Falls

Figures and Tables -
Analysis 10.28

Comparison 10: Memantine versus Placebo, Outcome 28: AE Falls

Comparison 10: Memantine versus Placebo, Outcome 29: AE Fatigue

Figures and Tables -
Analysis 10.29

Comparison 10: Memantine versus Placebo, Outcome 29: AE Fatigue

Comparison 10: Memantine versus Placebo, Outcome 30: AE Feeling flushed/hot

Figures and Tables -
Analysis 10.30

Comparison 10: Memantine versus Placebo, Outcome 30: AE Feeling flushed/hot

Comparison 10: Memantine versus Placebo, Outcome 31: AE Generalised aches

Figures and Tables -
Analysis 10.31

Comparison 10: Memantine versus Placebo, Outcome 31: AE Generalised aches

Comparison 10: Memantine versus Placebo, Outcome 32: AE Head pressure/ear pressure

Figures and Tables -
Analysis 10.32

Comparison 10: Memantine versus Placebo, Outcome 32: AE Head pressure/ear pressure

Comparison 10: Memantine versus Placebo, Outcome 33: AE Headache

Figures and Tables -
Analysis 10.33

Comparison 10: Memantine versus Placebo, Outcome 33: AE Headache

Comparison 10: Memantine versus Placebo, Outcome 34: AE Heart palpitations

Figures and Tables -
Analysis 10.34

Comparison 10: Memantine versus Placebo, Outcome 34: AE Heart palpitations

Comparison 10: Memantine versus Placebo, Outcome 35: AE Hypomania/mania

Figures and Tables -
Analysis 10.35

Comparison 10: Memantine versus Placebo, Outcome 35: AE Hypomania/mania

Comparison 10: Memantine versus Placebo, Outcome 36: AE Increased menstrual pain

Figures and Tables -
Analysis 10.36

Comparison 10: Memantine versus Placebo, Outcome 36: AE Increased menstrual pain

Comparison 10: Memantine versus Placebo, Outcome 37: AE Insomnia

Figures and Tables -
Analysis 10.37

Comparison 10: Memantine versus Placebo, Outcome 37: AE Insomnia

Comparison 10: Memantine versus Placebo, Outcome 38: AE Internal sensation of speed or rapid thoughts

Figures and Tables -
Analysis 10.38

Comparison 10: Memantine versus Placebo, Outcome 38: AE Internal sensation of speed or rapid thoughts

Comparison 10: Memantine versus Placebo, Outcome 39: AE Irritability

Figures and Tables -
Analysis 10.39

Comparison 10: Memantine versus Placebo, Outcome 39: AE Irritability

Comparison 10: Memantine versus Placebo, Outcome 40: AE Leg weakness

Figures and Tables -
Analysis 10.40

Comparison 10: Memantine versus Placebo, Outcome 40: AE Leg weakness

Comparison 10: Memantine versus Placebo, Outcome 41: AE Nausea

Figures and Tables -
Analysis 10.41

Comparison 10: Memantine versus Placebo, Outcome 41: AE Nausea

Comparison 10: Memantine versus Placebo, Outcome 42: AE Nightmares

Figures and Tables -
Analysis 10.42

Comparison 10: Memantine versus Placebo, Outcome 42: AE Nightmares

Comparison 10: Memantine versus Placebo, Outcome 43: AE Paresthesia/neuropathy exacerbation

Figures and Tables -
Analysis 10.43

Comparison 10: Memantine versus Placebo, Outcome 43: AE Paresthesia/neuropathy exacerbation

Comparison 10: Memantine versus Placebo, Outcome 44: AE Passive suicidal ideation

Figures and Tables -
Analysis 10.44

Comparison 10: Memantine versus Placebo, Outcome 44: AE Passive suicidal ideation

Comparison 10: Memantine versus Placebo, Outcome 45: AE Perceived weight gain

Figures and Tables -
Analysis 10.45

Comparison 10: Memantine versus Placebo, Outcome 45: AE Perceived weight gain

Comparison 10: Memantine versus Placebo, Outcome 46: AE Perceived weight loss

Figures and Tables -
Analysis 10.46

Comparison 10: Memantine versus Placebo, Outcome 46: AE Perceived weight loss

Comparison 10: Memantine versus Placebo, Outcome 47: AE Pruritus

Figures and Tables -
Analysis 10.47

Comparison 10: Memantine versus Placebo, Outcome 47: AE Pruritus

Comparison 10: Memantine versus Placebo, Outcome 48: AE Rash

Figures and Tables -
Analysis 10.48

Comparison 10: Memantine versus Placebo, Outcome 48: AE Rash

Comparison 10: Memantine versus Placebo, Outcome 49: AE Sedation

Figures and Tables -
Analysis 10.49

Comparison 10: Memantine versus Placebo, Outcome 49: AE Sedation

Comparison 10: Memantine versus Placebo, Outcome 50: AE Skin lesion

Figures and Tables -
Analysis 10.50

Comparison 10: Memantine versus Placebo, Outcome 50: AE Skin lesion

Comparison 10: Memantine versus Placebo, Outcome 51: AE Sleepiness/drowsiness

Figures and Tables -
Analysis 10.51

Comparison 10: Memantine versus Placebo, Outcome 51: AE Sleepiness/drowsiness

Comparison 10: Memantine versus Placebo, Outcome 52: AE Sleepwalking

Figures and Tables -
Analysis 10.52

Comparison 10: Memantine versus Placebo, Outcome 52: AE Sleepwalking

Comparison 10: Memantine versus Placebo, Outcome 53: AE Sore throat

Figures and Tables -
Analysis 10.53

Comparison 10: Memantine versus Placebo, Outcome 53: AE Sore throat

Comparison 10: Memantine versus Placebo, Outcome 54: AE Taste perversion

Figures and Tables -
Analysis 10.54

Comparison 10: Memantine versus Placebo, Outcome 54: AE Taste perversion

Comparison 10: Memantine versus Placebo, Outcome 55: AE Tinnitus

Figures and Tables -
Analysis 10.55

Comparison 10: Memantine versus Placebo, Outcome 55: AE Tinnitus

Comparison 10: Memantine versus Placebo, Outcome 56: AE Upper respiratory infection symptoms

Figures and Tables -
Analysis 10.56

Comparison 10: Memantine versus Placebo, Outcome 56: AE Upper respiratory infection symptoms

Comparison 10: Memantine versus Placebo, Outcome 57: AE Vomiting

Figures and Tables -
Analysis 10.57

Comparison 10: Memantine versus Placebo, Outcome 57: AE Vomiting

Comparison 10: Memantine versus Placebo, Outcome 58: AE Worsened acne

Figures and Tables -
Analysis 10.58

Comparison 10: Memantine versus Placebo, Outcome 58: AE Worsened acne

Comparison 10: Memantine versus Placebo, Outcome 59: AE Worsened sleep apnoea

Figures and Tables -
Analysis 10.59

Comparison 10: Memantine versus Placebo, Outcome 59: AE Worsened sleep apnoea

Comparison 10: Memantine versus Placebo, Outcome 60: Remission rate

Figures and Tables -
Analysis 10.60

Comparison 10: Memantine versus Placebo, Outcome 60: Remission rate

Comparison 10: Memantine versus Placebo, Outcome 61: Depression scale rating score

Figures and Tables -
Analysis 10.61

Comparison 10: Memantine versus Placebo, Outcome 61: Depression scale rating score

Comparison 10: Memantine versus Placebo, Outcome 62: Quality of life

Figures and Tables -
Analysis 10.62

Comparison 10: Memantine versus Placebo, Outcome 62: Quality of life

Comparison 10: Memantine versus Placebo, Outcome 63: Acceptability

Figures and Tables -
Analysis 10.63

Comparison 10: Memantine versus Placebo, Outcome 63: Acceptability

Comparison 10: Memantine versus Placebo, Outcome 64: Acceptability ‐ adverse events

Figures and Tables -
Analysis 10.64

Comparison 10: Memantine versus Placebo, Outcome 64: Acceptability ‐ adverse events

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 11.1

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 1: Response rate

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 2: AE Agitation/anxiety

Figures and Tables -
Analysis 11.2

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 2: AE Agitation/anxiety

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 3: AE Back pain

Figures and Tables -
Analysis 11.3

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 3: AE Back pain

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 4: AE Blood Pressure Rise

Figures and Tables -
Analysis 11.4

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 4: AE Blood Pressure Rise

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 5: AE Dissociative symptoms

Figures and Tables -
Analysis 11.5

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 5: AE Dissociative symptoms

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 6: AE Dizziness

Figures and Tables -
Analysis 11.6

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 6: AE Dizziness

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 7: AE Dry mouth

Figures and Tables -
Analysis 11.7

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 7: AE Dry mouth

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 8: AE Feeling drunk

Figures and Tables -
Analysis 11.8

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 8: AE Feeling drunk

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 9: AE Insomnia

Figures and Tables -
Analysis 11.9

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 9: AE Insomnia

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 10: AE Muscle/bone/joint pain

Figures and Tables -
Analysis 11.10

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 10: AE Muscle/bone/joint pain

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 11: AE Nausea

Figures and Tables -
Analysis 11.11

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 11: AE Nausea

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 12: AE Rash

Figures and Tables -
Analysis 11.12

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 12: AE Rash

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 13: AE Sedation

Figures and Tables -
Analysis 11.13

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 13: AE Sedation

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 14: AE Upper respiratory infection symptoms

Figures and Tables -
Analysis 11.14

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 14: AE Upper respiratory infection symptoms

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 15: AE Vomiting

Figures and Tables -
Analysis 11.15

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 15: AE Vomiting

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 16: AE Weight gain

Figures and Tables -
Analysis 11.16

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 16: AE Weight gain

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 17: Remission rate

Figures and Tables -
Analysis 11.17

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 17: Remission rate

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 18: Depression rating scale score

Figures and Tables -
Analysis 11.18

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 18: Depression rating scale score

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 19: Acceptability

Figures and Tables -
Analysis 11.19

Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 19: Acceptability

Comparison 12: Org 26576 versus Placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 12.1

Comparison 12: Org 26576 versus Placebo, Outcome 1: Response rate

Comparison 12: Org 26576 versus Placebo, Outcome 2: AE Abnormal dreams

Figures and Tables -
Analysis 12.2

Comparison 12: Org 26576 versus Placebo, Outcome 2: AE Abnormal dreams

Comparison 12: Org 26576 versus Placebo, Outcome 3: AE Back pain

Figures and Tables -
Analysis 12.3

Comparison 12: Org 26576 versus Placebo, Outcome 3: AE Back pain

Comparison 12: Org 26576 versus Placebo, Outcome 4: AE Disturbance in attention

Figures and Tables -
Analysis 12.4

Comparison 12: Org 26576 versus Placebo, Outcome 4: AE Disturbance in attention

Comparison 12: Org 26576 versus Placebo, Outcome 5: AE Dizziness

Figures and Tables -
Analysis 12.5

Comparison 12: Org 26576 versus Placebo, Outcome 5: AE Dizziness

Comparison 12: Org 26576 versus Placebo, Outcome 6: AE Fatigue

Figures and Tables -
Analysis 12.6

Comparison 12: Org 26576 versus Placebo, Outcome 6: AE Fatigue

Comparison 12: Org 26576 versus Placebo, Outcome 7: AE Feeling drunk

Figures and Tables -
Analysis 12.7

Comparison 12: Org 26576 versus Placebo, Outcome 7: AE Feeling drunk

Comparison 12: Org 26576 versus Placebo, Outcome 8: AE Headache

Figures and Tables -
Analysis 12.8

Comparison 12: Org 26576 versus Placebo, Outcome 8: AE Headache

Comparison 12: Org 26576 versus Placebo, Outcome 9: AE Insomnia

Figures and Tables -
Analysis 12.9

Comparison 12: Org 26576 versus Placebo, Outcome 9: AE Insomnia

Comparison 12: Org 26576 versus Placebo, Outcome 10: AE Irritability

Figures and Tables -
Analysis 12.10

Comparison 12: Org 26576 versus Placebo, Outcome 10: AE Irritability

Comparison 12: Org 26576 versus Placebo, Outcome 11: AE Muscle twitching

Figures and Tables -
Analysis 12.11

Comparison 12: Org 26576 versus Placebo, Outcome 11: AE Muscle twitching

Comparison 12: Org 26576 versus Placebo, Outcome 12: AE Nasal congestion

Figures and Tables -
Analysis 12.12

Comparison 12: Org 26576 versus Placebo, Outcome 12: AE Nasal congestion

Comparison 12: Org 26576 versus Placebo, Outcome 13: AE Nausea

Figures and Tables -
Analysis 12.13

Comparison 12: Org 26576 versus Placebo, Outcome 13: AE Nausea

Comparison 12: Org 26576 versus Placebo, Outcome 14: AE Palpitations

Figures and Tables -
Analysis 12.14

Comparison 12: Org 26576 versus Placebo, Outcome 14: AE Palpitations

Comparison 12: Org 26576 versus Placebo, Outcome 15: AE Post‐lumbar puncture syndrome

Figures and Tables -
Analysis 12.15

Comparison 12: Org 26576 versus Placebo, Outcome 15: AE Post‐lumbar puncture syndrome

Comparison 12: Org 26576 versus Placebo, Outcome 16: AE Rash

Figures and Tables -
Analysis 12.16

Comparison 12: Org 26576 versus Placebo, Outcome 16: AE Rash

Comparison 12: Org 26576 versus Placebo, Outcome 17: AE Sedation

Figures and Tables -
Analysis 12.17

Comparison 12: Org 26576 versus Placebo, Outcome 17: AE Sedation

Comparison 12: Org 26576 versus Placebo, Outcome 18: AE Sensory disturbance

Figures and Tables -
Analysis 12.18

Comparison 12: Org 26576 versus Placebo, Outcome 18: AE Sensory disturbance

Comparison 12: Org 26576 versus Placebo, Outcome 19: AE Sleepiness/drowsiness

Figures and Tables -
Analysis 12.19

Comparison 12: Org 26576 versus Placebo, Outcome 19: AE Sleepiness/drowsiness

Comparison 12: Org 26576 versus Placebo, Outcome 20: AE Total

Figures and Tables -
Analysis 12.20

Comparison 12: Org 26576 versus Placebo, Outcome 20: AE Total

Comparison 12: Org 26576 versus Placebo, Outcome 21: Remission rate

Figures and Tables -
Analysis 12.21

Comparison 12: Org 26576 versus Placebo, Outcome 21: Remission rate

Comparison 12: Org 26576 versus Placebo, Outcome 22: Depression rating scale score

Figures and Tables -
Analysis 12.22

Comparison 12: Org 26576 versus Placebo, Outcome 22: Depression rating scale score

Comparison 12: Org 26576 versus Placebo, Outcome 23: Acceptability ‐ adverse events

Figures and Tables -
Analysis 12.23

Comparison 12: Org 26576 versus Placebo, Outcome 23: Acceptability ‐ adverse events

Comparison 13: Riluzole versus Placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 13.1

Comparison 13: Riluzole versus Placebo, Outcome 1: Response rate

Comparison 13: Riluzole versus Placebo, Outcome 2: AE Abdominal Pain

Figures and Tables -
Analysis 13.2

Comparison 13: Riluzole versus Placebo, Outcome 2: AE Abdominal Pain

Comparison 13: Riluzole versus Placebo, Outcome 3: AE Appetite decrease

Figures and Tables -
Analysis 13.3

Comparison 13: Riluzole versus Placebo, Outcome 3: AE Appetite decrease

Comparison 13: Riluzole versus Placebo, Outcome 4: AE Appetite increase

Figures and Tables -
Analysis 13.4

Comparison 13: Riluzole versus Placebo, Outcome 4: AE Appetite increase

Comparison 13: Riluzole versus Placebo, Outcome 5: AE Agitation/anxiety

Figures and Tables -
Analysis 13.5

Comparison 13: Riluzole versus Placebo, Outcome 5: AE Agitation/anxiety

Comparison 13: Riluzole versus Placebo, Outcome 6: AE Blurred vision

Figures and Tables -
Analysis 13.6

Comparison 13: Riluzole versus Placebo, Outcome 6: AE Blurred vision

Comparison 13: Riluzole versus Placebo, Outcome 7: AE Chest pain

Figures and Tables -
Analysis 13.7

Comparison 13: Riluzole versus Placebo, Outcome 7: AE Chest pain

Comparison 13: Riluzole versus Placebo, Outcome 8: AE Concentration difficulty

Figures and Tables -
Analysis 13.8

Comparison 13: Riluzole versus Placebo, Outcome 8: AE Concentration difficulty

Comparison 13: Riluzole versus Placebo, Outcome 9: AE Confusion

Figures and Tables -
Analysis 13.9

Comparison 13: Riluzole versus Placebo, Outcome 9: AE Confusion

Comparison 13: Riluzole versus Placebo, Outcome 10: AE Constipation

Figures and Tables -
Analysis 13.10

Comparison 13: Riluzole versus Placebo, Outcome 10: AE Constipation

Comparison 13: Riluzole versus Placebo, Outcome 11: AE Coughing

Figures and Tables -
Analysis 13.11

Comparison 13: Riluzole versus Placebo, Outcome 11: AE Coughing

Comparison 13: Riluzole versus Placebo, Outcome 12: AE Cramps

Figures and Tables -
Analysis 13.12

Comparison 13: Riluzole versus Placebo, Outcome 12: AE Cramps

Comparison 13: Riluzole versus Placebo, Outcome 13: AE Decreased appetite

Figures and Tables -
Analysis 13.13

Comparison 13: Riluzole versus Placebo, Outcome 13: AE Decreased appetite

Comparison 13: Riluzole versus Placebo, Outcome 14: AE Decreased motor activity

Figures and Tables -
Analysis 13.14

Comparison 13: Riluzole versus Placebo, Outcome 14: AE Decreased motor activity

Comparison 13: Riluzole versus Placebo, Outcome 15: AE Decreased libido

Figures and Tables -
Analysis 13.15

Comparison 13: Riluzole versus Placebo, Outcome 15: AE Decreased libido

Comparison 13: Riluzole versus Placebo, Outcome 16: AE Dental problems

Figures and Tables -
Analysis 13.16

Comparison 13: Riluzole versus Placebo, Outcome 16: AE Dental problems

Comparison 13: Riluzole versus Placebo, Outcome 17: AE Depression

Figures and Tables -
Analysis 13.17

Comparison 13: Riluzole versus Placebo, Outcome 17: AE Depression

Comparison 13: Riluzole versus Placebo, Outcome 18: AE Dermatologic/skin irritation/lesions

Figures and Tables -
Analysis 13.18

Comparison 13: Riluzole versus Placebo, Outcome 18: AE Dermatologic/skin irritation/lesions

Comparison 13: Riluzole versus Placebo, Outcome 19: AE Diarrhoea

Figures and Tables -
Analysis 13.19

Comparison 13: Riluzole versus Placebo, Outcome 19: AE Diarrhoea

Comparison 13: Riluzole versus Placebo, Outcome 20: AE Dizziness

Figures and Tables -
Analysis 13.20

Comparison 13: Riluzole versus Placebo, Outcome 20: AE Dizziness

Comparison 13: Riluzole versus Placebo, Outcome 21: AE Dry mouth

Figures and Tables -
Analysis 13.21

Comparison 13: Riluzole versus Placebo, Outcome 21: AE Dry mouth

Comparison 13: Riluzole versus Placebo, Outcome 22: AE Eye irritation

Figures and Tables -
Analysis 13.22

Comparison 13: Riluzole versus Placebo, Outcome 22: AE Eye irritation

Comparison 13: Riluzole versus Placebo, Outcome 23: AE Flatulence

Figures and Tables -
Analysis 13.23

Comparison 13: Riluzole versus Placebo, Outcome 23: AE Flatulence

Comparison 13: Riluzole versus Placebo, Outcome 24: AE Flu/upper respiratory infection

Figures and Tables -
Analysis 13.24

Comparison 13: Riluzole versus Placebo, Outcome 24: AE Flu/upper respiratory infection

Comparison 13: Riluzole versus Placebo, Outcome 25: AE Genital discomfort

Figures and Tables -
Analysis 13.25

Comparison 13: Riluzole versus Placebo, Outcome 25: AE Genital discomfort

Comparison 13: Riluzole versus Placebo, Outcome 26: AE Gum problems

Figures and Tables -
Analysis 13.26

Comparison 13: Riluzole versus Placebo, Outcome 26: AE Gum problems

Comparison 13: Riluzole versus Placebo, Outcome 27: AE Headache

Figures and Tables -
Analysis 13.27

Comparison 13: Riluzole versus Placebo, Outcome 27: AE Headache

Comparison 13: Riluzole versus Placebo, Outcome 28: AE Increased libido

Figures and Tables -
Analysis 13.28

Comparison 13: Riluzole versus Placebo, Outcome 28: AE Increased libido

Comparison 13: Riluzole versus Placebo, Outcome 29: AE Increased thirst

Figures and Tables -
Analysis 13.29

Comparison 13: Riluzole versus Placebo, Outcome 29: AE Increased thirst

Comparison 13: Riluzole versus Placebo, Outcome 30: AE Insomnia

Figures and Tables -
Analysis 13.30

Comparison 13: Riluzole versus Placebo, Outcome 30: AE Insomnia

Comparison 13: Riluzole versus Placebo, Outcome 31: AE Irritability

Figures and Tables -
Analysis 13.31

Comparison 13: Riluzole versus Placebo, Outcome 31: AE Irritability

Comparison 13: Riluzole versus Placebo, Outcome 32: AE Memory problems

Figures and Tables -
Analysis 13.32

Comparison 13: Riluzole versus Placebo, Outcome 32: AE Memory problems

Comparison 13: Riluzole versus Placebo, Outcome 33: AE Mouth ulcer

Figures and Tables -
Analysis 13.33

Comparison 13: Riluzole versus Placebo, Outcome 33: AE Mouth ulcer

Comparison 13: Riluzole versus Placebo, Outcome 34: AE Muscle/bone/joint pain

Figures and Tables -
Analysis 13.34

Comparison 13: Riluzole versus Placebo, Outcome 34: AE Muscle/bone/joint pain

Comparison 13: Riluzole versus Placebo, Outcome 35: AE Nasal congestion

Figures and Tables -
Analysis 13.35

Comparison 13: Riluzole versus Placebo, Outcome 35: AE Nasal congestion

Comparison 13: Riluzole versus Placebo, Outcome 36: AE Nausea

Figures and Tables -
Analysis 13.36

Comparison 13: Riluzole versus Placebo, Outcome 36: AE Nausea

Comparison 13: Riluzole versus Placebo, Outcome 37: AE Oedema

Figures and Tables -
Analysis 13.37

Comparison 13: Riluzole versus Placebo, Outcome 37: AE Oedema

Comparison 13: Riluzole versus Placebo, Outcome 38: AE Sexual dysfunction

Figures and Tables -
Analysis 13.38

Comparison 13: Riluzole versus Placebo, Outcome 38: AE Sexual dysfunction

Comparison 13: Riluzole versus Placebo, Outcome 39: AE Shortness of breath

Figures and Tables -
Analysis 13.39

Comparison 13: Riluzole versus Placebo, Outcome 39: AE Shortness of breath

Comparison 13: Riluzole versus Placebo, Outcome 40: AE Sleepiness/drowsiness

Figures and Tables -
Analysis 13.40

Comparison 13: Riluzole versus Placebo, Outcome 40: AE Sleepiness/drowsiness

Comparison 13: Riluzole versus Placebo, Outcome 41: AE Sore throat

Figures and Tables -
Analysis 13.41

Comparison 13: Riluzole versus Placebo, Outcome 41: AE Sore throat

Comparison 13: Riluzole versus Placebo, Outcome 42: AE Sore tongue

Figures and Tables -
Analysis 13.42

Comparison 13: Riluzole versus Placebo, Outcome 42: AE Sore tongue

Comparison 13: Riluzole versus Placebo, Outcome 43: AE Stomach or abdominal discomfort

Figures and Tables -
Analysis 13.43

Comparison 13: Riluzole versus Placebo, Outcome 43: AE Stomach or abdominal discomfort

Comparison 13: Riluzole versus Placebo, Outcome 44: AE Suicidal ideas

Figures and Tables -
Analysis 13.44

Comparison 13: Riluzole versus Placebo, Outcome 44: AE Suicidal ideas

Comparison 13: Riluzole versus Placebo, Outcome 45: AE Sweating

Figures and Tables -
Analysis 13.45

Comparison 13: Riluzole versus Placebo, Outcome 45: AE Sweating

Comparison 13: Riluzole versus Placebo, Outcome 46: AE Tachycardia

Figures and Tables -
Analysis 13.46

Comparison 13: Riluzole versus Placebo, Outcome 46: AE Tachycardia

Comparison 13: Riluzole versus Placebo, Outcome 47: AE Tinnitus

Figures and Tables -
Analysis 13.47

Comparison 13: Riluzole versus Placebo, Outcome 47: AE Tinnitus

Comparison 13: Riluzole versus Placebo, Outcome 48: AE Tiredness/fatigue

Figures and Tables -
Analysis 13.48

Comparison 13: Riluzole versus Placebo, Outcome 48: AE Tiredness/fatigue

Comparison 13: Riluzole versus Placebo, Outcome 49: AE Urination problems

Figures and Tables -
Analysis 13.49

Comparison 13: Riluzole versus Placebo, Outcome 49: AE Urination problems

Comparison 13: Riluzole versus Placebo, Outcome 50: AE Weight gain

Figures and Tables -
Analysis 13.50

Comparison 13: Riluzole versus Placebo, Outcome 50: AE Weight gain

Comparison 13: Riluzole versus Placebo, Outcome 51: AE Weight loss

Figures and Tables -
Analysis 13.51

Comparison 13: Riluzole versus Placebo, Outcome 51: AE Weight loss

Comparison 13: Riluzole versus Placebo, Outcome 52: Remission rate

Figures and Tables -
Analysis 13.52

Comparison 13: Riluzole versus Placebo, Outcome 52: Remission rate

Comparison 13: Riluzole versus Placebo, Outcome 53: Depression rating scale score

Figures and Tables -
Analysis 13.53

Comparison 13: Riluzole versus Placebo, Outcome 53: Depression rating scale score

Comparison 13: Riluzole versus Placebo, Outcome 54: Acceptability

Figures and Tables -
Analysis 13.54

Comparison 13: Riluzole versus Placebo, Outcome 54: Acceptability

Comparison 14: Atomoxetine versus Placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 14.1

Comparison 14: Atomoxetine versus Placebo, Outcome 1: Response rate

Comparison 14: Atomoxetine versus Placebo, Outcome 2: AE Agitation/anxiety

Figures and Tables -
Analysis 14.2

Comparison 14: Atomoxetine versus Placebo, Outcome 2: AE Agitation/anxiety

Comparison 14: Atomoxetine versus Placebo, Outcome 3: AE Constipation

Figures and Tables -
Analysis 14.3

Comparison 14: Atomoxetine versus Placebo, Outcome 3: AE Constipation

Comparison 14: Atomoxetine versus Placebo, Outcome 4: AE Depressed mood

Figures and Tables -
Analysis 14.4

Comparison 14: Atomoxetine versus Placebo, Outcome 4: AE Depressed mood

Comparison 14: Atomoxetine versus Placebo, Outcome 5: AE Diarrhea

Figures and Tables -
Analysis 14.5

Comparison 14: Atomoxetine versus Placebo, Outcome 5: AE Diarrhea

Comparison 14: Atomoxetine versus Placebo, Outcome 6: AE Dizziness

Figures and Tables -
Analysis 14.6

Comparison 14: Atomoxetine versus Placebo, Outcome 6: AE Dizziness

Comparison 14: Atomoxetine versus Placebo, Outcome 7: AE Dry mouth

Figures and Tables -
Analysis 14.7

Comparison 14: Atomoxetine versus Placebo, Outcome 7: AE Dry mouth

Comparison 14: Atomoxetine versus Placebo, Outcome 8: AE Fatigue

Figures and Tables -
Analysis 14.8

Comparison 14: Atomoxetine versus Placebo, Outcome 8: AE Fatigue

Comparison 14: Atomoxetine versus Placebo, Outcome 9: AE Flatulence

Figures and Tables -
Analysis 14.9

Comparison 14: Atomoxetine versus Placebo, Outcome 9: AE Flatulence

Comparison 14: Atomoxetine versus Placebo, Outcome 10: AE Headache

Figures and Tables -
Analysis 14.10

Comparison 14: Atomoxetine versus Placebo, Outcome 10: AE Headache

Comparison 14: Atomoxetine versus Placebo, Outcome 11: AE Increased sweating

Figures and Tables -
Analysis 14.11

Comparison 14: Atomoxetine versus Placebo, Outcome 11: AE Increased sweating

Comparison 14: Atomoxetine versus Placebo, Outcome 12: AE Insomnia

Figures and Tables -
Analysis 14.12

Comparison 14: Atomoxetine versus Placebo, Outcome 12: AE Insomnia

Comparison 14: Atomoxetine versus Placebo, Outcome 13: AE Nasopharyngitis

Figures and Tables -
Analysis 14.13

Comparison 14: Atomoxetine versus Placebo, Outcome 13: AE Nasopharyngitis

Comparison 14: Atomoxetine versus Placebo, Outcome 14: AE Nausea

Figures and Tables -
Analysis 14.14

Comparison 14: Atomoxetine versus Placebo, Outcome 14: AE Nausea

Comparison 14: Atomoxetine versus Placebo, Outcome 15: AE Tremor

Figures and Tables -
Analysis 14.15

Comparison 14: Atomoxetine versus Placebo, Outcome 15: AE Tremor

Comparison 14: Atomoxetine versus Placebo, Outcome 16: Remission rate

Figures and Tables -
Analysis 14.16

Comparison 14: Atomoxetine versus Placebo, Outcome 16: Remission rate

Comparison 14: Atomoxetine versus Placebo, Outcome 17: Depression rating scale score

Figures and Tables -
Analysis 14.17

Comparison 14: Atomoxetine versus Placebo, Outcome 17: Depression rating scale score

Comparison 14: Atomoxetine versus Placebo, Outcome 18: Acceptability

Figures and Tables -
Analysis 14.18

Comparison 14: Atomoxetine versus Placebo, Outcome 18: Acceptability

Comparison 14: Atomoxetine versus Placebo, Outcome 19: Acceptability ‐ adverse events

Figures and Tables -
Analysis 14.19

Comparison 14: Atomoxetine versus Placebo, Outcome 19: Acceptability ‐ adverse events

Comparison 14: Atomoxetine versus Placebo, Outcome 20: Acceptability ‐ lack of efficacy

Figures and Tables -
Analysis 14.20

Comparison 14: Atomoxetine versus Placebo, Outcome 20: Acceptability ‐ lack of efficacy

Comparison 15: Basimglurant versus Placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 15.1

Comparison 15: Basimglurant versus Placebo, Outcome 1: Response rate

Comparison 15: Basimglurant versus Placebo, Outcome 2: AE Dizziness

Figures and Tables -
Analysis 15.2

Comparison 15: Basimglurant versus Placebo, Outcome 2: AE Dizziness

Comparison 15: Basimglurant versus Placebo, Outcome 3: AE Dry mouth

Figures and Tables -
Analysis 15.3

Comparison 15: Basimglurant versus Placebo, Outcome 3: AE Dry mouth

Comparison 15: Basimglurant versus Placebo, Outcome 4: AE Fatigue

Figures and Tables -
Analysis 15.4

Comparison 15: Basimglurant versus Placebo, Outcome 4: AE Fatigue

Comparison 15: Basimglurant versus Placebo, Outcome 5: AE Headache

Figures and Tables -
Analysis 15.5

Comparison 15: Basimglurant versus Placebo, Outcome 5: AE Headache

Comparison 15: Basimglurant versus Placebo, Outcome 6: AE Insomnia

Figures and Tables -
Analysis 15.6

Comparison 15: Basimglurant versus Placebo, Outcome 6: AE Insomnia

Comparison 15: Basimglurant versus Placebo, Outcome 7: AE Nasopharyngitis

Figures and Tables -
Analysis 15.7

Comparison 15: Basimglurant versus Placebo, Outcome 7: AE Nasopharyngitis

Comparison 15: Basimglurant versus Placebo, Outcome 8: AE Nausea

Figures and Tables -
Analysis 15.8

Comparison 15: Basimglurant versus Placebo, Outcome 8: AE Nausea

Comparison 15: Basimglurant versus Placebo, Outcome 9: Remission rate

Figures and Tables -
Analysis 15.9

Comparison 15: Basimglurant versus Placebo, Outcome 9: Remission rate

Comparison 15: Basimglurant versus Placebo, Outcome 10: Depression rating scale score

Figures and Tables -
Analysis 15.10

Comparison 15: Basimglurant versus Placebo, Outcome 10: Depression rating scale score

Comparison 16: Citicoline versus Placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 16.1

Comparison 16: Citicoline versus Placebo, Outcome 1: Response rate

Comparison 16: Citicoline versus Placebo, Outcome 2: AE Abdominal Pain

Figures and Tables -
Analysis 16.2

Comparison 16: Citicoline versus Placebo, Outcome 2: AE Abdominal Pain

Comparison 16: Citicoline versus Placebo, Outcome 3: AE Appetite decrease

Figures and Tables -
Analysis 16.3

Comparison 16: Citicoline versus Placebo, Outcome 3: AE Appetite decrease

Comparison 16: Citicoline versus Placebo, Outcome 4: AE Appetite increase

Figures and Tables -
Analysis 16.4

Comparison 16: Citicoline versus Placebo, Outcome 4: AE Appetite increase

Comparison 16: Citicoline versus Placebo, Outcome 5: AE Dizziness

Figures and Tables -
Analysis 16.5

Comparison 16: Citicoline versus Placebo, Outcome 5: AE Dizziness

Comparison 16: Citicoline versus Placebo, Outcome 6: AE Diarrhoea

Figures and Tables -
Analysis 16.6

Comparison 16: Citicoline versus Placebo, Outcome 6: AE Diarrhoea

Comparison 16: Citicoline versus Placebo, Outcome 7: AE Headache

Figures and Tables -
Analysis 16.7

Comparison 16: Citicoline versus Placebo, Outcome 7: AE Headache

Comparison 16: Citicoline versus Placebo, Outcome 8: AE Insomnia

Figures and Tables -
Analysis 16.8

Comparison 16: Citicoline versus Placebo, Outcome 8: AE Insomnia

Comparison 16: Citicoline versus Placebo, Outcome 9: AE Nausea

Figures and Tables -
Analysis 16.9

Comparison 16: Citicoline versus Placebo, Outcome 9: AE Nausea

Comparison 16: Citicoline versus Placebo, Outcome 10: AE Sedation

Figures and Tables -
Analysis 16.10

Comparison 16: Citicoline versus Placebo, Outcome 10: AE Sedation

Comparison 16: Citicoline versus Placebo, Outcome 11: Remission rate

Figures and Tables -
Analysis 16.11

Comparison 16: Citicoline versus Placebo, Outcome 11: Remission rate

Comparison 17: CP‐101,606 versus Placebo, Outcome 1: AE Change in blood pressure

Figures and Tables -
Analysis 17.1

Comparison 17: CP‐101,606 versus Placebo, Outcome 1: AE Change in blood pressure

Comparison 17: CP‐101,606 versus Placebo, Outcome 2: AE Dissociative reaction

Figures and Tables -
Analysis 17.2

Comparison 17: CP‐101,606 versus Placebo, Outcome 2: AE Dissociative reaction

Comparison 17: CP‐101,606 versus Placebo, Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 17.3

Comparison 17: CP‐101,606 versus Placebo, Outcome 3: Depression rating scale score

Comparison 17: CP‐101,606 versus Placebo, Outcome 4: Acceptability

Figures and Tables -
Analysis 17.4

Comparison 17: CP‐101,606 versus Placebo, Outcome 4: Acceptability

Comparison 18: D‐cycloserine versus Placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 18.1

Comparison 18: D‐cycloserine versus Placebo, Outcome 1: Response rate

Comparison 18: D‐cycloserine versus Placebo, Outcome 2: AE Agitation/anxiety

Figures and Tables -
Analysis 18.2

Comparison 18: D‐cycloserine versus Placebo, Outcome 2: AE Agitation/anxiety

Comparison 18: D‐cycloserine versus Placebo, Outcome 3: AE Concentration difficulties

Figures and Tables -
Analysis 18.3

Comparison 18: D‐cycloserine versus Placebo, Outcome 3: AE Concentration difficulties

Comparison 18: D‐cycloserine versus Placebo, Outcome 4: AE Constipation

Figures and Tables -
Analysis 18.4

Comparison 18: D‐cycloserine versus Placebo, Outcome 4: AE Constipation

Comparison 18: D‐cycloserine versus Placebo, Outcome 5: AE Failing memory

Figures and Tables -
Analysis 18.5

Comparison 18: D‐cycloserine versus Placebo, Outcome 5: AE Failing memory

Comparison 18: D‐cycloserine versus Placebo, Outcome 6: AE Headache

Figures and Tables -
Analysis 18.6

Comparison 18: D‐cycloserine versus Placebo, Outcome 6: AE Headache

Comparison 18: D‐cycloserine versus Placebo, Outcome 7: AE Increased dream activity

Figures and Tables -
Analysis 18.7

Comparison 18: D‐cycloserine versus Placebo, Outcome 7: AE Increased dream activity

Comparison 18: D‐cycloserine versus Placebo, Outcome 8: AE Increased duration of sleep

Figures and Tables -
Analysis 18.8

Comparison 18: D‐cycloserine versus Placebo, Outcome 8: AE Increased duration of sleep

Comparison 18: D‐cycloserine versus Placebo, Outcome 9: AE Increased sexual desire

Figures and Tables -
Analysis 18.9

Comparison 18: D‐cycloserine versus Placebo, Outcome 9: AE Increased sexual desire

Comparison 18: D‐cycloserine versus Placebo, Outcome 10: AE Increased tendency to sweat

Figures and Tables -
Analysis 18.10

Comparison 18: D‐cycloserine versus Placebo, Outcome 10: AE Increased tendency to sweat

Comparison 18: D‐cycloserine versus Placebo, Outcome 11: AE Nausea/vomiting

Figures and Tables -
Analysis 18.11

Comparison 18: D‐cycloserine versus Placebo, Outcome 11: AE Nausea/vomiting

Comparison 18: D‐cycloserine versus Placebo, Outcome 12: AE Palpitation/tachycardia

Figures and Tables -
Analysis 18.12

Comparison 18: D‐cycloserine versus Placebo, Outcome 12: AE Palpitation/tachycardia

Comparison 18: D‐cycloserine versus Placebo, Outcome 13: AE Sleepiness/drowsiness

Figures and Tables -
Analysis 18.13

Comparison 18: D‐cycloserine versus Placebo, Outcome 13: AE Sleepiness/drowsiness

Comparison 18: D‐cycloserine versus Placebo, Outcome 14: AE Urination issues

Figures and Tables -
Analysis 18.14

Comparison 18: D‐cycloserine versus Placebo, Outcome 14: AE Urination issues

Comparison 18: D‐cycloserine versus Placebo, Outcome 15: Remission rate

Figures and Tables -
Analysis 18.15

Comparison 18: D‐cycloserine versus Placebo, Outcome 15: Remission rate

Comparison 18: D‐cycloserine versus Placebo, Outcome 16: Depression rating scale score

Figures and Tables -
Analysis 18.16

Comparison 18: D‐cycloserine versus Placebo, Outcome 16: Depression rating scale score

Comparison 18: D‐cycloserine versus Placebo, Outcome 17: Acceptability

Figures and Tables -
Analysis 18.17

Comparison 18: D‐cycloserine versus Placebo, Outcome 17: Acceptability

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 1: Response Rate

Figures and Tables -
Analysis 19.1

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 1: Response Rate

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 2: AE Diarrhea

Figures and Tables -
Analysis 19.2

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 2: AE Diarrhea

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 3: AE Dizziness

Figures and Tables -
Analysis 19.3

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 3: AE Dizziness

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 4: AE Headache

Figures and Tables -
Analysis 19.4

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 4: AE Headache

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 5: AE Nausea

Figures and Tables -
Analysis 19.5

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 5: AE Nausea

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 6: AE Sleepiness/drowsiness

Figures and Tables -
Analysis 19.6

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 6: AE Sleepiness/drowsiness

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 7: AE Vomiting

Figures and Tables -
Analysis 19.7

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 7: AE Vomiting

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 8: Remission rate

Figures and Tables -
Analysis 19.8

Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 8: Remission rate

Comparison 20: MK‐0657 versus Placebo, Outcome 1: Depression rating scale score

Figures and Tables -
Analysis 20.1

Comparison 20: MK‐0657 versus Placebo, Outcome 1: Depression rating scale score

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 1: Response rate

Figures and Tables -
Analysis 21.1

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 1: Response rate

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 2: AE Back pain

Figures and Tables -
Analysis 21.2

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 2: AE Back pain

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 3: AE Gastrointestinal problems

Figures and Tables -
Analysis 21.3

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 3: AE Gastrointestinal problems

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 4: AE Joint pain

Figures and Tables -
Analysis 21.4

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 4: AE Joint pain

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 5: AE Muscle spasms

Figures and Tables -
Analysis 21.5

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 5: AE Muscle spasms

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 6: Remission rate

Figures and Tables -
Analysis 21.6

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 6: Remission rate

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 7: Depression rating scale score

Figures and Tables -
Analysis 21.7

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 7: Depression rating scale score

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 8: Quality of life

Figures and Tables -
Analysis 21.8

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 8: Quality of life

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 9: Acceptability

Figures and Tables -
Analysis 21.9

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 9: Acceptability

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 10: Acceptability ‐ adverse events

Figures and Tables -
Analysis 21.10

Comparison 21: N‐acetylcysteine versus Placebo, Outcome 10: Acceptability ‐ adverse events

Comparison 22: Sarcosine versus Citalopram, Outcome 1: Response rate

Figures and Tables -
Analysis 22.1

Comparison 22: Sarcosine versus Citalopram, Outcome 1: Response rate

Comparison 22: Sarcosine versus Citalopram, Outcome 2: AE Total

Figures and Tables -
Analysis 22.2

Comparison 22: Sarcosine versus Citalopram, Outcome 2: AE Total

Comparison 22: Sarcosine versus Citalopram, Outcome 3: AE Agitation/anxiety

Figures and Tables -
Analysis 22.3

Comparison 22: Sarcosine versus Citalopram, Outcome 3: AE Agitation/anxiety

Comparison 22: Sarcosine versus Citalopram, Outcome 4: AE Asthenia/increased fatigability

Figures and Tables -
Analysis 22.4

Comparison 22: Sarcosine versus Citalopram, Outcome 4: AE Asthenia/increased fatigability

Comparison 22: Sarcosine versus Citalopram, Outcome 5: AE Constipation

Figures and Tables -
Analysis 22.5

Comparison 22: Sarcosine versus Citalopram, Outcome 5: AE Constipation

Comparison 22: Sarcosine versus Citalopram, Outcome 6: AE Concentration difficulties

Figures and Tables -
Analysis 22.6

Comparison 22: Sarcosine versus Citalopram, Outcome 6: AE Concentration difficulties

Comparison 22: Sarcosine versus Citalopram, Outcome 7: AE Depression

Figures and Tables -
Analysis 22.7

Comparison 22: Sarcosine versus Citalopram, Outcome 7: AE Depression

Comparison 22: Sarcosine versus Citalopram, Outcome 8: AE Dizziness

Figures and Tables -
Analysis 22.8

Comparison 22: Sarcosine versus Citalopram, Outcome 8: AE Dizziness

Comparison 22: Sarcosine versus Citalopram, Outcome 9: AE Dystonia

Figures and Tables -
Analysis 22.9

Comparison 22: Sarcosine versus Citalopram, Outcome 9: AE Dystonia

Comparison 22: Sarcosine versus Citalopram, Outcome 10: AE Headache/migraine

Figures and Tables -
Analysis 22.10

Comparison 22: Sarcosine versus Citalopram, Outcome 10: AE Headache/migraine

Comparison 22: Sarcosine versus Citalopram, Outcome 11: AE Increased dream activity

Figures and Tables -
Analysis 22.11

Comparison 22: Sarcosine versus Citalopram, Outcome 11: AE Increased dream activity

Comparison 22: Sarcosine versus Citalopram, Outcome 12: AE Increased duration of sleep

Figures and Tables -
Analysis 22.12

Comparison 22: Sarcosine versus Citalopram, Outcome 12: AE Increased duration of sleep

Comparison 22: Sarcosine versus Citalopram, Outcome 13: AE Nausea/vomiting

Figures and Tables -
Analysis 22.13

Comparison 22: Sarcosine versus Citalopram, Outcome 13: AE Nausea/vomiting

Comparison 22: Sarcosine versus Citalopram, Outcome 14: AE Palpitations/tachycardia

Figures and Tables -
Analysis 22.14

Comparison 22: Sarcosine versus Citalopram, Outcome 14: AE Palpitations/tachycardia

Comparison 22: Sarcosine versus Citalopram, Outcome 15: AE Reduced duration of sleep

Figures and Tables -
Analysis 22.15

Comparison 22: Sarcosine versus Citalopram, Outcome 15: AE Reduced duration of sleep

Comparison 22: Sarcosine versus Citalopram, Outcome 16: AE Sleepiness/drowsiness

Figures and Tables -
Analysis 22.16

Comparison 22: Sarcosine versus Citalopram, Outcome 16: AE Sleepiness/drowsiness

Comparison 22: Sarcosine versus Citalopram, Outcome 17: AE Tremor

Figures and Tables -
Analysis 22.17

Comparison 22: Sarcosine versus Citalopram, Outcome 17: AE Tremor

Comparison 22: Sarcosine versus Citalopram, Outcome 18: AE Weight gain

Figures and Tables -
Analysis 22.18

Comparison 22: Sarcosine versus Citalopram, Outcome 18: AE Weight gain

Comparison 22: Sarcosine versus Citalopram, Outcome 19: AE Weight loss

Figures and Tables -
Analysis 22.19

Comparison 22: Sarcosine versus Citalopram, Outcome 19: AE Weight loss

Comparison 22: Sarcosine versus Citalopram, Outcome 20: Remission rate

Figures and Tables -
Analysis 22.20

Comparison 22: Sarcosine versus Citalopram, Outcome 20: Remission rate

Comparison 22: Sarcosine versus Citalopram, Outcome 21: Depression rating scale score

Figures and Tables -
Analysis 22.21

Comparison 22: Sarcosine versus Citalopram, Outcome 21: Depression rating scale score

Comparison 22: Sarcosine versus Citalopram, Outcome 22: Acceptability

Figures and Tables -
Analysis 22.22

Comparison 22: Sarcosine versus Citalopram, Outcome 22: Acceptability

Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 1: Response rate

Figures and Tables -
Analysis 23.1

Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 1: Response rate

Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 2: Remission rate

Figures and Tables -
Analysis 23.2

Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 2: Remission rate

Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 23.3

Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 3: Depression rating scale score

Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 23.4

Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 4: Suicidal ideation composite

Comparison 24: Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 1: Response rate

Figures and Tables -
Analysis 24.1

Comparison 24: Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 1: Response rate

Comparison 24: Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 2: Remission rate

Figures and Tables -
Analysis 24.2

Comparison 24: Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 2: Remission rate

Comparison 24: Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 24.3

Comparison 24: Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 3: Depression rating scale score

Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 1: Response rate

Figures and Tables -
Analysis 25.1

Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 1: Response rate

Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 2: Remission rate

Figures and Tables -
Analysis 25.2

Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 2: Remission rate

Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 25.3

Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 3: Depression rating scale score

Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 25.4

Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 4: Suicidal ideation composite

Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 1: Response rate

Figures and Tables -
Analysis 26.1

Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 1: Response rate

Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 2: Remission rate

Figures and Tables -
Analysis 26.2

Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 2: Remission rate

Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 26.3

Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 3: Depression rating scale score

Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 26.4

Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 4: Suicidal ideation composite

Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 1: Response rate

Figures and Tables -
Analysis 27.1

Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 1: Response rate

Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 2: Remission rate

Figures and Tables -
Analysis 27.2

Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 2: Remission rate

Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 27.3

Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 3: Depression rating scale score

Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 27.4

Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 4: Suicidal ideation composite

Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 1: Response rate

Figures and Tables -
Analysis 28.1

Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 1: Response rate

Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 2: Remission rate

Figures and Tables -
Analysis 28.2

Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 2: Remission rate

Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 28.3

Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 3: Depression rating scale score

Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 28.4

Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 4: Suicidal ideation composite

Comparison 29: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 1: Response rate

Figures and Tables -
Analysis 29.1

Comparison 29: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 1: Response rate

Comparison 29: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 2: Remission rate

Figures and Tables -
Analysis 29.2

Comparison 29: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 2: Remission rate

Comparison 29: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 29.3

Comparison 29: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 3: Depression rating scale score

Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 1: Response rate

Figures and Tables -
Analysis 30.1

Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 1: Response rate

Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 2: Remission rate

Figures and Tables -
Analysis 30.2

Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 2: Remission rate

Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 30.3

Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 3: Depression rating scale score

Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 30.4

Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 4: Suicidal ideation composite

Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 1: Response rate

Figures and Tables -
Analysis 31.1

Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 1: Response rate

Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 2: Remission rate

Figures and Tables -
Analysis 31.2

Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 2: Remission rate

Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 31.3

Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 3: Depression rating scale score

Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 31.4

Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 4: Suicidal ideation composite

Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 1: Response rate

Figures and Tables -
Analysis 32.1

Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 1: Response rate

Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 2: Remission rate

Figures and Tables -
Analysis 32.2

Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 2: Remission rate

Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 32.3

Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 3: Depression rating scale score

Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 32.4

Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 4: Suicidal ideation composite

Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 1: Response rate

Figures and Tables -
Analysis 33.1

Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 1: Response rate

Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 2: Remission rate

Figures and Tables -
Analysis 33.2

Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 2: Remission rate

Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 33.3

Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 3: Depression rating scale score

Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 33.4

Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 4: Suicidal ideation composite

Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 1: Response rate

Figures and Tables -
Analysis 34.1

Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 1: Response rate

Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 2: Remission rate

Figures and Tables -
Analysis 34.2

Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 2: Remission rate

Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 34.3

Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 3: Depression rating scale score

Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 34.4

Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 4: Suicidal ideation composite

Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 1: Response rate

Figures and Tables -
Analysis 35.1

Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 1: Response rate

Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 2: Remission rate

Figures and Tables -
Analysis 35.2

Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 2: Remission rate

Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 3: Depression rating scale score

Figures and Tables -
Analysis 35.3

Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 3: Depression rating scale score

Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 4: Suicidal ideation composite

Figures and Tables -
Analysis 35.4

Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 4: Suicidal ideation composite

Summary of findings 1. Ketamine compared to placebo for adults with unipolar major depressive disorder

Ketamine compared to Placebo for adults with unipolar major depressive disorder

Patient or population: adults (aged 18 years+) with unipolar major depressive disorder 
Setting: any setting (outpatient, inpatient, or both) 
Intervention: ketamine 
Comparison: placebo

Outcomes

Relative effect
(95% CI)

Anticipated absolute effects* (95% CI)

Certainty of the evidence
(GRADE)

What happens

Without ketamine

With ketamine

Difference

Efficacy: number of participants who respond to treatment ‐ at 24 hours (Response)
assessed with: HDRS, HDRS‐17, MADRS
№ of participants: 185
(7 RCTs)

OR 3.94
(1.54 to 10.10)

Study population

⊕⊝⊝⊝
VERY LOW 1 2

 

8.8%

27.4%
(12.9 to 49.2)

18.7% more
(4.1 more to 40.4 more)

Efficacy: number of participants who achieve remission ‐ at 24 hours (Remission)
assessed with: MADRS, HDRS
№ of participants: 75
(3 RCTs)

OR 5.60
(1.07 to 29.46)

Study population

⊕⊝⊝⊝
VERY LOW 3 4

 

2.4%

12.0%
(2.5 to 41.8)

9.6% more
(0.2 more to 39.4 more)

Depression rating scale score ‐ at 24 hours
assessed with: HDRS, HDRS‐17, MADRS
№ of participants: 231
(8 RCTs)

SMD 0.87 lower
(1.26 lower to 0.48 lower)

⊕⊝⊝⊝
VERY LOW 1 2 5

 

Acceptability: total dropouts
№ of participants: 201
(6 RCTs)

OR 1.25
(0.19 to 8.28)

Study population

⊕⊝⊝⊝
VERY LOW 1 2 6

 

34.0%

39.1%
(8.9 to 81)

5.2% more
(25.1 fewer to 47 more)

Acceptability: dropouts due to adverse effects ‐ not reported

 

 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 

CI: Confidence interval; HDRS: Hamilton Depression Rating Scale; MADRS: Montgomery‐Asberg Depression Rating Scale; OR: Odds ratio;RCT: randomised controlled trial;SMD: standardised mean difference.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1 Downgraded by one point due to the low number of participants available for this outcome and the associated width of the confidence intervals.

2 Downgraded by two points due to the majority of trials being unclear or high risk regarding the blinding of outcome assessments.

3 Downgraded by two points due to the very low number of participants available for this outcome and the associated width of the confidence intervals.

4 Downgraded by one point due to the majority of trials being unclear regarding blinding of outcome assessments.

5 Downgraded by one point due to moderately large heterogeneity (I2 value = 30% to 60%).

6 Downgraded by two points due to substantially large heterogeneity (I2 value = 50% to 90%).

Figures and Tables -
Summary of findings 1. Ketamine compared to placebo for adults with unipolar major depressive disorder
Summary of findings 2. Ketamine compared to midazolam for adults with unipolar major depressive disorder

Ketamine compared to Midazolam for adults with unipolar major depressive disorder

Patient or population: adults (aged 18 years+) with unipolar major depressive disorder 
Setting: any setting (outpatient, inpatient, or both) 
Intervention: ketamine 
Comparison: midazolam

Outcomes

Relative effect
(95% CI)

Anticipated absolute effects* (95% CI)

Certainty of the evidence
(GRADE)

What happens

Without ketamine

With ketamine

Difference

Efficacy: number of participants who respond to treatment ‐ at 24 hours
assessed with: HAM‐D‐6, HAM‐D‐17, MADRS
№ of participants: 296
(4 RCTs)

OR 2.48
(1.00 to 6.18)

Study population

⊕⊝⊝⊝
VERY LOW 1 2 3

 

25.9%

46.5%
(25.9 to 68.4)

20.5% more
(0 fewer to 42.5 more)

Efficacy: number of participants who achieve remission ‐ at 24 hours
assessed with: MADRS
№ of participants: 122
(2 RCTs)

OR 2.21
(0.67 to 7.32)

Study population

⊕⊕⊝⊝
LOW 2 3

 

18.0%

32.7%
(12.8 to 61.6)

14.7% more
(5.2 fewer to 43.6 more)

Depression rating scale score ‐ at 24 hours
assessed with: MADRS
№ of participants: 297
(4 RCTs)

SMD 0.49 lower
(0.87 lower to 0.1 lower)

⊕⊝⊝⊝
VERY LOW 1 2 3

 

Acceptability: total dropouts
№ of participants: 72
(1 RCT)

OR 0.33
(0.05 to 2.09)

Study population

⊕⊕⊝⊝
LOW 4

 

12.0%

4.3%
(0.7 to 22.2)

7.7% fewer
(11.3 fewer to 10.2 more)

Acceptability: dropouts due to adverse effects ‐ not reported

 

 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 

CI: Confidence interval;HAM‐D: Hamilton Depression Rating Scale; MADRS: Montgomery‐Asberg Depression Rating Scale;OR: Odds ratio; RCT: randomised controlled trial; SMD: standardised mean difference.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1 Downgraded by two points due to the majority of trials being unclear or high risk regarding the blinding of outcome assessments.

2 Downgraded by one point due to moderately large heterogeneity (I2 value = 30% to 60%).

3 Downgraded by one point due to the low number of participants available for this outcome and the associated width of the confidence intervals.

4 Downgraded by two points due to the very low number of participants available for this outcome and the associated width of the confidence intervals.

Figures and Tables -
Summary of findings 2. Ketamine compared to midazolam for adults with unipolar major depressive disorder
Summary of findings 3. Esketamine compared to placebo for adults with unipolar major depressive disorder

Esketamine compared to Placebo for adults with unipolar major depressive disorder

Patient or population: adults (aged 18 years+) with unipolar major depressive disorder 
Setting: any setting (outpatient, inpatient, or both) 
Intervention: esketamine 
Comparison: placebo

Outcomes

Relative effect
(95% CI)

Anticipated absolute effects* (95% CI)

Certainty of the evidence
(GRADE)

What happens

Without esketamine

With esketamine

Difference

Efficacy: number of participants who respond to treatment ‐ at 24 hours (Response)
assessed with: MADRS
№ of participants: 1071
(5 RCTs)

OR 2.11
(1.20 to 3.68)

Study population

⊕⊕⊝⊝
LOW 1 2

 

15.0%

27.1%
(17.5 to 39.4)

12.1% more
(2.5 more to 24.4 more)

Efficacy: number of participants who achieve remission ‐ at 24 hours (Remission)
assessed with: MADRS
№ of participants: 894
(5 RCTs)

OR 2.74
(1.71 to 4.40)

Study population

⊕⊕⊕⊝
MODERATE 1

 

7.2%

17.5%
(11.7 to 25.4)

10.3% more
(4.5 more to 18.2 more)

Depression rating scale score ‐ at 24 hours
assessed with: MADRS
№ of participants: 824
(4 RCTs)

SMD 0.31 lower
(0.45 lower to 0.17 lower)

⊕⊕⊕⊝
MODERATE 1

 

Acceptability: total dropouts
№ of participants: 773
(5 RCTs)

OR 1.58
(0.92 to 2.73)

Study population

⊕⊕⊕⊝
MODERATE 1

 

8.5%

12.9%
(7.9 to 20.3)

4.3% more
(0.6 fewer to 11.8 more)

Acceptability: dropouts due to adverse effects ‐ not reported

 

 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 

CI: Confidence interval; MADRS: Montgomery‐Asberg Depression Rating Scale; OR: Odds ratio; RCT: randomised controlled trial; SMD: standardised mean difference.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1 Downgraded by one point due to the majority of trials being unclear regarding blinding of outcome assessments.

2 Downgraded by one point due to moderately large heterogeneity (I2 value = 30% to 60%).

Figures and Tables -
Summary of findings 3. Esketamine compared to placebo for adults with unipolar major depressive disorder
Comparison 1. Ketamine versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Response rate Show forest plot

12

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1.1 at 24 hours

7

185

Odds Ratio (M‐H, Random, 95% CI)

3.94 [1.54, 10.10]

1.1.2 at 72 hours

4

83

Odds Ratio (M‐H, Random, 95% CI)

15.84 [3.68, 68.12]

1.1.3 at 1 week

5

196

Odds Ratio (M‐H, Random, 95% CI)

3.76 [0.98, 14.42]

1.1.4 at 2 weeks

4

206

Odds Ratio (M‐H, Random, 95% CI)

2.92 [0.48, 17.78]

1.1.5 at 4 weeks

4

202

Odds Ratio (M‐H, Random, 95% CI)

1.37 [0.50, 3.77]

1.1.6 at 3 months

3

117

Odds Ratio (M‐H, Random, 95% CI)

1.95 [0.24, 15.69]

1.2 AE Abdominal Pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.3 AE Agitation/anxiety Show forest plot

3

143

Odds Ratio (M‐H, Random, 95% CI)

3.44 [1.07, 11.04]

1.4 AE Blurred vision Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.5 AE Change in blood pressure Show forest plot

2

157

Odds Ratio (M‐H, Random, 95% CI)

3.23 [0.49, 21.31]

1.6 AE Confusion Show forest plot

2

76

Odds Ratio (M‐H, Random, 95% CI)

3.76 [1.13, 12.47]

1.7 AE Dissociative symptoms Show forest plot

3

145

Odds Ratio (M‐H, Random, 95% CI)

7.72 [1.31, 45.51]

1.8 AE Dizziness Show forest plot

3

196

Odds Ratio (M‐H, Random, 95% CI)

1.74 [0.52, 5.81]

1.9 AE Emotional blunting Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.10 AE Euphoria Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.11 AE Hallucinations Show forest plot

3

203

Odds Ratio (M‐H, Random, 95% CI)

2.19 [0.45, 10.78]

1.12 AE Headache Show forest plot

2

194

Odds Ratio (M‐H, Random, 95% CI)

1.23 [0.62, 2.45]

1.13 AE Infections and Infestations Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.14 AE Loss of Appetite Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.15 AE Mania/hypomania Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.16 AE Musculoskeletal and connective tissue disorders Show forest plot

2

137

Odds Ratio (M‐H, Random, 95% CI)

1.39 [0.07, 26.35]

1.17 AE Nausea/vomiting Show forest plot

5

353

Odds Ratio (M‐H, Random, 95% CI)

1.83 [0.81, 4.13]

1.18 AE Nervousness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.19 AE Nervous system disorders Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.20 AE Palpitations Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.21 AE Psychiatric disorders Show forest plot

2

137

Odds Ratio (M‐H, Fixed, 95% CI)

0.93 [0.30, 2.93]

1.22 AE Restlessness Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.23 AE Skin and subcutaneous tissue disorders Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.24 AE Suicidal Ideas Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.25 AE Tremor Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.26 Remission rate Show forest plot

9

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

1.26.1 at 24 hours

3

75

Odds Ratio (M‐H, Random, 95% CI)

5.60 [1.07, 29.46]

1.26.2 at 72 hours

4

83

Odds Ratio (M‐H, Random, 95% CI)

6.60 [1.51, 28.92]

1.26.3 at 1 week

5

196

Odds Ratio (M‐H, Random, 95% CI)

4.64 [1.37, 15.68]

1.26.4 at 2 weeks

4

206

Odds Ratio (M‐H, Random, 95% CI)

1.67 [0.38, 7.27]

1.26.5 at 4 weeks

4

202

Odds Ratio (M‐H, Random, 95% CI)

1.46 [0.54, 3.95]

1.26.6 at 3 months

2

90

Odds Ratio (M‐H, Random, 95% CI)

1.09 [0.45, 2.67]

1.27 Depression rating scale score Show forest plot

12

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

1.27.1 at 24 hours

8

231

Std. Mean Difference (IV, Random, 95% CI)

‐0.87 [‐1.26, ‐0.48]

1.27.2 at 72 hours

6

148

Std. Mean Difference (IV, Random, 95% CI)

‐0.68 [‐1.28, ‐0.07]

1.27.3 at 1 week

6

143

Std. Mean Difference (IV, Random, 95% CI)

‐0.72 [‐1.10, ‐0.33]

1.27.4 at 2 weeks

5

236

Std. Mean Difference (IV, Random, 95% CI)

‐0.43 [‐0.90, 0.04]

1.27.5 at 4 weeks

2

107

Std. Mean Difference (IV, Random, 95% CI)

‐0.68 [‐1.07, ‐0.29]

1.28 Suicidal ideation composite Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.28.1 at 24 hours

1

48

Mean Difference (IV, Random, 95% CI)

0.02 [‐0.78, 0.82]

1.28.2 at 72 hours

2

68

Mean Difference (IV, Random, 95% CI)

0.34 [‐0.25, 0.93]

1.28.3 at 1 week

1

19

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐1.56, 0.96]

1.28.4 at 2 weeks

1

19

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐1.46, 1.06]

1.29 Cognition scores Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.29.1 Immediate‐term Memory

1

127

Mean Difference (IV, Random, 95% CI)

0.80 [0.12, 1.48]

1.29.2 Short‐term Memory

1

127

Mean Difference (IV, Random, 95% CI)

6.90 [5.01, 8.79]

1.29.3 Long‐term Memory

1

127

Mean Difference (IV, Random, 95% CI)

4.50 [2.79, 6.21]

1.30 Quality of Life Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.30.1 EQ‐5D‐3L INDEX at 2 weeks

1

64

Mean Difference (IV, Random, 95% CI)

0.11 [‐0.05, 0.27]

1.31 Acceptability Show forest plot

6

201

Odds Ratio (M‐H, Random, 95% CI)

1.25 [0.19, 8.28]

Figures and Tables -
Comparison 1. Ketamine versus Placebo
Comparison 2. Ketamine versus Midazolam

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Response rate Show forest plot

5

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1.1 at 24 hours

4

296

Odds Ratio (M‐H, Random, 95% CI)

2.48 [1.00, 6.18]

2.1.2 at 72 hours

3

218

Odds Ratio (M‐H, Random, 95% CI)

2.20 [0.92, 5.28]

2.1.3 at 1 week

2

126

Odds Ratio (M‐H, Random, 95% CI)

3.11 [1.38, 7.04]

2.1.4 at 2 weeks

1

53

Odds Ratio (M‐H, Random, 95% CI)

4.89 [1.49, 16.10]

2.1.5 at 4 weeks

1

5

Odds Ratio (M‐H, Random, 95% CI)

0.50 [0.01, 19.56]

2.1.6 at 3 months

1

5

Odds Ratio (M‐H, Random, 95% CI)

3.00 [0.08, 115.34]

2.2 AE Abnormal dreams Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.2.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.3 AE Agitation/anxiety Show forest plot

4

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.3.1 Infusion day

1

144

Odds Ratio (M‐H, Random, 95% CI)

1.99 [0.69, 5.75]

2.3.2 at 1 week

3

278

Odds Ratio (M‐H, Random, 95% CI)

1.32 [0.69, 2.50]

2.3.3 48‐72 hours after last treatment

1

5

Odds Ratio (M‐H, Random, 95% CI)

0.50 [0.01, 19.56]

2.4 AE Back pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.4.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.5 AE Blurred vision Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.5.1 Infusion day

1

72

Odds Ratio (M‐H, Random, 95% CI)

8.52 [1.80, 40.39]

2.5.2 at 1 week

2

126

Odds Ratio (M‐H, Random, 95% CI)

1.03 [0.23, 4.70]

2.6 AE Chest pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.6.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.6.2 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.7 AE Chills Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.7.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.8 AE Constipation Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.8.1 Infusion day

1

72

Odds Ratio (M‐H, Random, 95% CI)

2.80 [0.13, 60.66]

2.8.2 at 1 week

3

206

Odds Ratio (M‐H, Random, 95% CI)

1.98 [0.42, 9.27]

2.9 AE Decreased energy Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.9.1 Infusion day

1

72

Odds Ratio (M‐H, Random, 95% CI)

1.28 [0.30, 5.47]

2.9.2 at 1 week

2

126

Odds Ratio (M‐H, Random, 95% CI)

1.17 [0.44, 3.13]

2.10 AE Decreased libido Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.10.1 48‐72 hours after last treatment

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.11 AE Depression Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.11.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.12 AE Diarrhea Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.12.1 Infusion day

1

72

Odds Ratio (M‐H, Random, 95% CI)

1.07 [0.09, 12.37]

2.12.2 at 1 week

2

152

Odds Ratio (M‐H, Random, 95% CI)

0.82 [0.18, 3.83]

2.12.3 at 4 weeks

1

99

Odds Ratio (M‐H, Random, 95% CI)

1.24 [0.06, 26.93]

2.13 AE Difficulty swallowing Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.13.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.14 AE Dizziness Show forest plot

4

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.14.1 Infusion day

2

224

Odds Ratio (M‐H, Random, 95% CI)

3.42 [1.44, 8.14]

2.14.2 at 1 week

4

283

Odds Ratio (M‐H, Random, 95% CI)

1.05 [0.43, 2.56]

2.15 AE Dry mouth Show forest plot

4

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.15.1 Infusion day

2

152

Odds Ratio (M‐H, Random, 95% CI)

2.10 [0.66, 6.70]

2.15.2 at 1 week

3

206

Odds Ratio (M‐H, Random, 95% CI)

0.79 [0.22, 2.91]

2.15.3 48‐72 hours after last treatment

1

5

Odds Ratio (M‐H, Random, 95% CI)

3.00 [0.08, 115.34]

2.16 AE Dry skin Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.16.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.16.2 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.17 AE Fatigue Show forest plot

4

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.17.1 Infusion day

2

152

Odds Ratio (M‐H, Random, 95% CI)

0.29 [0.00, 22.84]

2.17.2 at 1 week

4

211

Odds Ratio (M‐H, Random, 95% CI)

1.42 [0.62, 3.27]

2.18 AE General malaise Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.18.1 Infusion day

1

72

Odds Ratio (M‐H, Random, 95% CI)

0.18 [0.04, 0.75]

2.18.2 at 1 week

3

131

Odds Ratio (M‐H, Random, 95% CI)

1.90 [0.32, 11.44]

2.19 AE Insomnia Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.19.1 at 1 week

1

54

Odds Ratio (M‐H, Random, 95% CI)

2.57 [0.43, 15.41]

2.19.2 at 4 weeks

1

99

Odds Ratio (M‐H, Random, 95% CI)

1.24 [0.06, 26.93]

2.20 AE Headache Show forest plot

4

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.20.1 Infusion day

2

152

Odds Ratio (M‐H, Random, 95% CI)

0.94 [0.19, 4.56]

2.20.2 at 1 week

3

206

Odds Ratio (M‐H, Random, 95% CI)

0.85 [0.32, 2.29]

2.20.3 at 4 weeks

1

99

Odds Ratio (M‐H, Random, 95% CI)

5.18 [0.29, 93.01]

2.21 AE Increased blood pressure or heart rate Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.21.1 at 1 week

1

54

Odds Ratio (M‐H, Random, 95% CI)

9.37 [2.49, 35.25]

2.21.2 at 4 weeks

1

99

Odds Ratio (M‐H, Random, 95% CI)

1.24 [0.06, 26.93]

2.22 AE Increase in systolic blood pressure and heart rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.22.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.23 AE Increased perspiration Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.23.1 Infusion day

1

72

Odds Ratio (M‐H, Random, 95% CI)

2.86 [0.32, 25.91]

2.23.2 at 1 week

2

126

Odds Ratio (M‐H, Random, 95% CI)

1.48 [0.23, 9.58]

2.24 AE Indigestion Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.24.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.25 AE Insomnia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.25.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.26 AE Irritability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.26.1 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.27 AE Itching Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.27.1 Infusion day

1

72

Odds Ratio (M‐H, Random, 95% CI)

1.07 [0.09, 12.37]

2.27.2 at 1 week

2

126

Odds Ratio (M‐H, Random, 95% CI)

3.54 [0.58, 21.59]

2.27.3 48‐72 hours after last treatment

1

5

Odds Ratio (M‐H, Random, 95% CI)

8.33 [0.22, 320.38]

2.28 AE Loss of consciousness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.28.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.29 AE Memory problems Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.29.1 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.30 AE Muscle/bone/joint pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.30.1 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.31 AE Nasal congestion Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.31.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.32 AE Nausea/vomiting Show forest plot

4

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.32.1 Infusion day

2

152

Odds Ratio (M‐H, Random, 95% CI)

3.62 [1.13, 11.58]

2.32.2 at 1 week

2

126

Odds Ratio (M‐H, Random, 95% CI)

2.57 [0.78, 8.52]

2.32.3 at 4 weeks

1

99

Odds Ratio (M‐H, Random, 95% CI)

7.12 [0.40, 125.66]

2.33 AE Numbness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.33.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.34 AE Pain in extremities Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.34.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.35 AE Palpitations Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.35.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.35.2 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.36 AE Poor concentration Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.36.1 Infusion day

1

72

Odds Ratio (M‐H, Random, 95% CI)

3.94 [0.81, 19.27]

2.36.2 at 1 week

3

131

Odds Ratio (M‐H, Random, 95% CI)

1.51 [0.18, 12.31]

2.37 AE Poor co‐ordination Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.37.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.37.2 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.38 AE Poor quality sleep Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.38.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.39 AE Rash Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.39.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.39.2 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.40 AE Reduced duration of sleep Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.40.1 48‐72 hours after last treatment

1

5

Odds Ratio (M‐H, Random, 95% CI)

0.50 [0.01, 19.56]

2.40.2 at 1 week

1

80

Odds Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 8.22]

2.41 AE Restlessness Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.41.1 48‐72 hours after last treatment

1

5

Odds Ratio (M‐H, Random, 95% CI)

3.00 [0.08, 115.34]

2.41.2 at 1 week

1

54

Odds Ratio (M‐H, Random, 95% CI)

6.28 [0.29, 137.16]

2.42 AE Sensory disturbance Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.42.1 Infusion day

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.42.2 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.43 AE Sexual dysfunction Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.43.1 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.44 AE Sleepiness/drowsiness Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.44.1 Infusion day

1

80

Odds Ratio (M‐H, Random, 95% CI)

0.21 [0.07, 0.66]

2.44.2 at 1 week

1

54

Odds Ratio (M‐H, Random, 95% CI)

2.57 [0.43, 15.41]

2.45 AE Stomach or abdominal discomfort Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.45.1 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.46 AE Suicide attempt Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.46.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.47 AE Suicidal ideas Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.47.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.48 AE Tachycardia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.48.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.49 AE Tinnitus Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.49.1 Infusion day

1

72

Odds Ratio (M‐H, Random, 95% CI)

1.07 [0.09, 12.37]

2.49.2 at 1 week

2

126

Odds Ratio (M‐H, Random, 95% CI)

0.99 [0.26, 3.73]

2.49.3 48‐72 hours after last treatment

1

5

Odds Ratio (M‐H, Random, 95% CI)

2.00 [0.05, 78.25]

2.50 AE Tooth Abscess Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.50.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.51 AE Tremor Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.51.1 Infusion day

1

72

Odds Ratio (M‐H, Random, 95% CI)

7.99 [0.43, 147.87]

2.51.2 at 1 week

2

126

Odds Ratio (M‐H, Random, 95% CI)

1.14 [0.23, 5.74]

2.52 AE Urination issues Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.52.1 Infusion day

1

216

Odds Ratio (M‐H, Random, 95% CI)

Not estimable

2.52.2 at 1 week

2

126

Odds Ratio (M‐H, Random, 95% CI)

2.19 [0.08, 63.59]

2.53 Remission rate Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.53.1 at 24 hours

2

122

Odds Ratio (M‐H, Random, 95% CI)

2.21 [0.67, 7.32]

2.53.2 at 72 hours

2

118

Odds Ratio (M‐H, Random, 95% CI)

1.73 [0.74, 4.04]

2.53.3 at 1 week

2

126

Odds Ratio (M‐H, Random, 95% CI)

1.86 [0.80, 4.32]

2.53.4 at 2 weeks

1

53

Odds Ratio (M‐H, Random, 95% CI)

2.29 [0.76, 6.92]

2.53.5 at 4 weeks

1

5

Odds Ratio (M‐H, Random, 95% CI)

0.50 [0.01, 19.56]

2.53.6 at 3 months

1

5

Odds Ratio (M‐H, Random, 95% CI)

Not estimable

2.54 Depression rating scale score Show forest plot

4

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

2.54.1 at 24 hours

4

297

Std. Mean Difference (IV, Random, 95% CI)

‐0.49 [‐0.87, ‐0.10]

2.54.2 at 72 hours

3

207

Std. Mean Difference (IV, Random, 95% CI)

‐0.39 [‐0.70, ‐0.08]

2.54.3 at 1 week

3

212

Std. Mean Difference (IV, Random, 95% CI)

‐0.38 [‐0.69, ‐0.08]

2.54.4 at 2 weeks

2

137

Std. Mean Difference (IV, Random, 95% CI)

‐0.37 [‐0.84, 0.10]

2.54.5 at 4 weeks

1

86

Std. Mean Difference (IV, Random, 95% CI)

‐0.57 [‐1.10, ‐0.04]

2.55 Suicidal ideation composite Show forest plot

1

57

Mean Difference (IV, Random, 95% CI)

‐1.32 [‐2.52, ‐0.12]

2.56 Acceptability Show forest plot

1

72

Odds Ratio (M‐H, Random, 95% CI)

0.33 [0.05, 2.09]

Figures and Tables -
Comparison 2. Ketamine versus Midazolam
Comparison 3. Ketamine versus Thiopental

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Response rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1.1 at 3 days

1

31

Odds Ratio (M‐H, Random, 95% CI)

2.64 [0.10, 69.88]

3.1.2 at 4 weeks

1

31

Odds Ratio (M‐H, Random, 95% CI)

0.81 [0.05, 14.28]

3.2 AE Blood Pressure Rise Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

3.3 AE Delirium Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

3.4 AE Emergence reactions Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

3.5 AE Headache Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

3.6 AE Heart Rate Rise Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

3.7 AE Increased secretions Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

3.8 AE Nausea/vomiting Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

3.9 Depression rating scale score Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

3.9.1 at 72 hours

1

29

Mean Difference (IV, Random, 95% CI)

‐3.87 [‐6.08, ‐1.66]

3.9.2 at 1 week

1

60

Mean Difference (IV, Random, 95% CI)

‐6.96 [‐9.82, ‐4.10]

3.9.3 at 2 weeks

2

89

Mean Difference (IV, Random, 95% CI)

‐4.84 [‐13.42, 3.73]

3.9.4 at 4 weeks

1

29

Mean Difference (IV, Random, 95% CI)

‐0.22 [‐2.64, 2.20]

3.10 Acceptability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 3. Ketamine versus Thiopental
Comparison 4. Ketamine versus Methohexital

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Depression rating scale score Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

4.1.1 At 72 hours

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 4. Ketamine versus Methohexital
Comparison 5. Ketamine versus Propofol

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

5.1 Depression rating scale score Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

5.1.1 At 2 weeks

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

5.1.2 At 3 months

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 5. Ketamine versus Propofol
Comparison 6. Ketamine versus Remifentanil hydrochloride

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

6.1 Depression rating scale score Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

6.1.1 at 24 hours

1

30

Mean Difference (IV, Random, 95% CI)

‐7.74 [‐14.03, ‐1.45]

6.1.2 at 1 week

1

30

Mean Difference (IV, Random, 95% CI)

‐7.54 [‐14.13, ‐0.95]

6.1.3 at 2 weeks

1

30

Mean Difference (IV, Random, 95% CI)

‐1.00 [‐6.98, 4.98]

Figures and Tables -
Comparison 6. Ketamine versus Remifentanil hydrochloride
Comparison 7. Ketamine versus Esketamine

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

7.1 Response Rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1.1 at 24 hours

1

63

Odds Ratio (M‐H, Random, 95% CI)

1.07 [0.40, 2.89]

7.1.2 at 72 hours

1

63

Odds Ratio (M‐H, Random, 95% CI)

1.56 [0.58, 4.22]

7.1.3 at 1 week

1

63

Odds Ratio (M‐H, Random, 95% CI)

2.34 [0.85, 6.45]

7.2 Cognition Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

7.2.1 CADSS scores during infusion

1

63

Mean Difference (IV, Random, 95% CI)

3.30 [‐4.70, 11.30]

Figures and Tables -
Comparison 7. Ketamine versus Esketamine
Comparison 8. Ketamine versus ECT

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

8.1 Response rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.1.1 at 24 hours

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.1.2 at 72 hours

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.1.3 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.1.4 at 2 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.2 AE Increase in systolic blood pressure and heart rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.3 Remission rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.3.1 at 24 hours

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.3.2 at 72 hours

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.3.3 at 1 week

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.3.4 at 2 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

8.4 Depression rating scale score Show forest plot

1

72

Mean Difference (IV, Random, 95% CI)

‐2.98 [‐7.07, 1.12]

8.4.1 at 24 hours

1

18

Mean Difference (IV, Random, 95% CI)

‐8.90 [‐11.72, ‐6.08]

8.4.2 at 72 hours

1

18

Mean Difference (IV, Random, 95% CI)

‐3.40 [‐5.99, ‐0.81]

8.4.3 at 1 week

1

18

Mean Difference (IV, Random, 95% CI)

‐1.00 [‐3.45, 1.45]

8.4.4 at 2 weeks

1

18

Mean Difference (IV, Random, 95% CI)

1.20 [‐1.20, 3.60]

Figures and Tables -
Comparison 8. Ketamine versus ECT
Comparison 9. Esketamine versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

9.1 Response rate Show forest plot

7

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

9.1.1 at 24 hours

5

1071

Odds Ratio (M‐H, Random, 95% CI)

2.11 [1.20, 3.68]

9.1.2 at 72 hours

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.34 [0.92, 1.96]

9.1.3 at 1 week

6

1115

Odds Ratio (M‐H, Random, 95% CI)

1.60 [1.09, 2.34]

9.1.4 at 2 weeks

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.57 [1.09, 2.28]

9.1.5 at 4 weeks

5

1117

Odds Ratio (M‐H, Random, 95% CI)

1.84 [1.44, 2.37]

9.2 AE Aggression Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.3 AE Agitation/anxiety Show forest plot

4

933

Odds Ratio (M‐H, Random, 95% CI)

1.06 [0.46, 2.42]

9.4 AE Arrhythmia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.5 AE Change in blood pressure Show forest plot

4

933

Odds Ratio (M‐H, Random, 95% CI)

2.67 [1.52, 4.70]

9.6 AE Constipation Show forest plot

2

452

Odds Ratio (M‐H, Random, 95% CI)

4.07 [1.60, 10.39]

9.7 AE Depersonalisation/derealization Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.8 AE Depression Show forest plot

2

452

Odds Ratio (M‐H, Random, 95% CI)

0.62 [0.08, 5.05]

9.9 AE Diabetic ketoacidosis Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.10 AE Diarrhoea Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.11 AE Dissociative symptoms Show forest plot

4

933

Odds Ratio (M‐H, Random, 95% CI)

8.76 [5.19, 14.77]

9.12 AE Dizziness Show forest plot

4

933

Odds Ratio (M‐H, Random, 95% CI)

3.67 [2.54, 5.31]

9.13 AE Dizziness postural Show forest plot

2

569

Odds Ratio (M‐H, Random, 95% CI)

4.70 [1.06, 20.80]

9.14 AE Double vision Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.15 AE Euphoria Show forest plot

2

571

Odds Ratio (M‐H, Random, 95% CI)

5.27 [0.94, 29.64]

9.16 AE Fatigue Show forest plot

2

481

Odds Ratio (M‐H, Random, 95% CI)

1.90 [0.89, 4.04]

9.17 AE Feeling drunk Show forest plot

2

571

Odds Ratio (M‐H, Random, 95% CI)

7.58 [1.37, 41.77]

9.18 AE Headache Show forest plot

4

933

Odds Ratio (M‐H, Random, 95% CI)

1.18 [0.80, 1.74]

9.19 AE Hypertransaminasemia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.20 AE Increased sweating Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.21 AE Infections and Infestations Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.22 AE Insomnia Show forest plot

4

933

Odds Ratio (M‐H, Random, 95% CI)

0.87 [0.53, 1.42]

9.23 AE Lethargy Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.24 AE Mental impairment Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.25 AE Nasal discomfort Show forest plot

2

571

Odds Ratio (M‐H, Random, 95% CI)

0.84 [0.42, 1.68]

9.26 AE Nausea/vomiting Show forest plot

4

933

Odds Ratio (M‐H, Random, 95% CI)

3.24 [1.84, 5.72]

9.27 AE Paresthesia/neuropathy exacerbation Show forest plot

3

708

Odds Ratio (M‐H, Random, 95% CI)

3.51 [1.62, 7.62]

9.28 AE Pericardial effusion Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.29 AE Pneumothorax Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.30 AE Sensory disturbance Show forest plot

3

796

Odds Ratio (M‐H, Random, 95% CI)

7.25 [3.55, 14.78]

9.31 AE Sedation Show forest plot

3

796

Odds Ratio (M‐H, Random, 95% CI)

5.31 [2.18, 12.94]

9.32 AE Sleepiness/drowsiness Show forest plot

3

796

Odds Ratio (M‐H, Random, 95% CI)

2.11 [1.39, 3.21]

9.33 AE Sore throat Show forest plot

2

571

Odds Ratio (M‐H, Random, 95% CI)

1.65 [0.70, 3.87]

9.34 AE Suicide attempt Show forest plot

2

452

Odds Ratio (M‐H, Random, 95% CI)

0.99 [0.24, 4.02]

9.35 AE Suicidal ideas Show forest plot

3

796

Odds Ratio (M‐H, Random, 95% CI)

0.69 [0.38, 1.26]

9.36 AE Taste perversion Show forest plot

4

933

Odds Ratio (M‐H, Random, 95% CI)

1.39 [0.95, 2.04]

9.37 AE Tremor Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.38 AE Urination issues Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

9.39 AE Vertigo Show forest plot

3

796

Odds Ratio (M‐H, Random, 95% CI)

12.25 [4.09, 36.67]

9.40 AE Vision blurred Show forest plot

3

796

Odds Ratio (M‐H, Random, 95% CI)

3.02 [1.37, 6.66]

9.41 Remission rate Show forest plot

7

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

9.41.1 at 24 hours

5

894

Odds Ratio (M‐H, Random, 95% CI)

2.74 [1.71, 4.40]

9.41.2 at 72 hours

3

517

Odds Ratio (M‐H, Random, 95% CI)

1.55 [0.91, 2.64]

9.41.3 at 1 week

6

948

Odds Ratio (M‐H, Random, 95% CI)

1.54 [0.88, 2.69]

9.41.4 at 2 weeks

4

832

Odds Ratio (M‐H, Random, 95% CI)

1.52 [1.07, 2.16]

9.41.5 at 4 weeks

5

957

Odds Ratio (M‐H, Random, 95% CI)

1.57 [1.18, 2.10]

9.42 Depression rating scale score Show forest plot

7

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

9.42.1 at 24 hours

4

824

Std. Mean Difference (IV, Random, 95% CI)

‐0.31 [‐0.45, ‐0.17]

9.42.2 at 72 hours

3

517

Std. Mean Difference (IV, Random, 95% CI)

‐0.30 [‐0.50, ‐0.11]

9.42.3 at 1 week

5

884

Std. Mean Difference (IV, Random, 95% CI)

‐0.23 [‐0.37, ‐0.10]

9.42.4 at 2 weeks

4

857

Std. Mean Difference (IV, Random, 95% CI)

‐0.21 [‐0.34, ‐0.07]

9.42.5 at 4 weeks

6

1182

Std. Mean Difference (IV, Random, 95% CI)

‐0.27 [‐0.39, ‐0.16]

9.42.6 at 3 months

1

38

Std. Mean Difference (IV, Random, 95% CI)

‐0.12 [‐0.75, 0.52]

9.43 Suicidal ideation composite Show forest plot

3

Mean Difference (IV, Random, 95% CI)

Subtotals only

9.43.1 at 24 hours

2

450

Mean Difference (IV, Random, 95% CI)

‐0.15 [‐0.44, 0.15]

9.43.2 at 72 hours

2

451

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐0.49, 0.08]

9.43.3 at 1 week

3

660

Mean Difference (IV, Random, 95% CI)

0.01 [‐0.10, 0.13]

9.43.4 at 2 weeks

3

659

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.22, 0.02]

9.43.5 at 4 weeks

3

647

Mean Difference (IV, Random, 95% CI)

‐0.04 [‐0.12, 0.05]

9.44 Acceptability Show forest plot

5

773

Odds Ratio (M‐H, Random, 95% CI)

1.58 [0.92, 2.73]

Figures and Tables -
Comparison 9. Esketamine versus placebo
Comparison 10. Memantine versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

10.1 Response rate Show forest plot

4

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

10.1.1 at 1 week

2

63

Odds Ratio (M‐H, Random, 95% CI)

1.07 [0.06, 18.82]

10.1.2 at 2 weeks

1

32

Odds Ratio (M‐H, Random, 95% CI)

0.31 [0.01, 8.28]

10.1.3 at 4 weeks

4

185

Odds Ratio (M‐H, Random, 95% CI)

1.22 [0.25, 5.89]

10.1.4 at 3 months

3

123

Odds Ratio (M‐H, Random, 95% CI)

0.48 [0.18, 1.24]

10.2 AE Abdominal Pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.3 AE Active suicidal ideation Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.4 AE Agitation/anxiety Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.5 AE Appetite increase Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.6 AE Back pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.7 AE Balance or gait problems Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.8 AE Carbohydrate craving Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.9 AE Chest pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.10 AE Chills Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.11 AE Clammy hands Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.12 AE Confusion/decreased mental clarity Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.13 AE Conjunctival swelling Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.14 AE Constipation Show forest plot

2

88

Odds Ratio (M‐H, Random, 95% CI)

0.82 [0.20, 3.29]

10.15 AE Decreased appetite Show forest plot

2

93

Odds Ratio (M‐H, Random, 95% CI)

1.57 [0.24, 10.10]

10.16 AE Delusions Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.17 AE Diaphoresis Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.18 AE Difficulty breathing Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.19 AE Dissociative symptoms Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.20 AE Dizziness Show forest plot

3

181

Odds Ratio (M‐H, Random, 95% CI)

0.83 [0.33, 2.13]

10.21 AE Dry mouth Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.22 AE Dyskinesia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.23 AE Dyspepsia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.24 AE Ear pain/jaw pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.25 AE Emotional lability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.26 AE Eye photosensitivity Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.27 AE Facial twitching Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.28 AE Falls Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.29 AE Fatigue Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.30 AE Feeling flushed/hot Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.31 AE Generalised aches Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.32 AE Head pressure/ear pressure Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.33 AE Headache Show forest plot

3

150

Odds Ratio (M‐H, Random, 95% CI)

1.44 [0.56, 3.72]

10.34 AE Heart palpitations Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

10.35 AE Hypomania/mania Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.36 AE Increased menstrual pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.37 AE Insomnia Show forest plot

2

93

Odds Ratio (M‐H, Random, 95% CI)

0.69 [0.19, 2.58]

10.38 AE Internal sensation of speed or rapid thoughts Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.39 AE Irritability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.40 AE Leg weakness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.41 AE Nausea Show forest plot

3

150

Odds Ratio (M‐H, Random, 95% CI)

0.75 [0.17, 3.38]

10.42 AE Nightmares Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.43 AE Paresthesia/neuropathy exacerbation Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.44 AE Passive suicidal ideation Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.45 AE Perceived weight gain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.46 AE Perceived weight loss Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.47 AE Pruritus Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.48 AE Rash Show forest plot

3

150

Odds Ratio (M‐H, Random, 95% CI)

1.45 [0.25, 8.55]

10.49 AE Sedation Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.50 AE Skin lesion Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.51 AE Sleepiness/drowsiness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.52 AE Sleepwalking Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.53 AE Sore throat Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.54 AE Taste perversion Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.55 AE Tinnitus Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.56 AE Upper respiratory infection symptoms Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.57 AE Vomiting Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.58 AE Worsened acne Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.59 AE Worsened sleep apnoea Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

10.60 Remission rate Show forest plot

4

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

10.60.1 at 1 week

2

63

Odds Ratio (M‐H, Random, 95% CI)

6.11 [0.27, 138.45]

10.60.2 at 4 weeks

4

185

Odds Ratio (M‐H, Random, 95% CI)

1.39 [0.46, 4.26]

10.60.3 at 3 months

3

123

Odds Ratio (M‐H, Random, 95% CI)

0.76 [0.15, 3.77]

10.61 Depression scale rating score Show forest plot

3

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

10.61.1 at 1 week

2

59

Std. Mean Difference (IV, Random, 95% CI)

‐0.11 [‐1.10, 0.89]

10.61.2 at 2 weeks

1

28

Std. Mean Difference (IV, Random, 95% CI)

‐0.09 [‐0.83, 0.65]

10.61.3 at 4 weeks

3

112

Std. Mean Difference (IV, Random, 95% CI)

0.11 [‐0.26, 0.48]

10.61.4 at 3 months

3

110

Std. Mean Difference (IV, Random, 95% CI)

0.23 [‐0.14, 0.61]

10.62 Quality of life Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

10.62.1 at 4 weeks

1

57

Mean Difference (IV, Random, 95% CI)

‐0.70 [‐5.04, 3.64]

10.62.2 at 3 months

1

57

Mean Difference (IV, Random, 95% CI)

‐1.21 [‐5.78, 3.36]

10.63 Acceptability Show forest plot

3

123

Odds Ratio (M‐H, Random, 95% CI)

0.78 [0.23, 2.66]

10.64 Acceptability ‐ adverse events Show forest plot

2

63

Odds Ratio (M‐H, Random, 95% CI)

0.68 [0.10, 4.47]

Figures and Tables -
Comparison 10. Memantine versus Placebo
Comparison 11. Lanicemine (AZD6765) versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

11.1 Response rate Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

11.1.1 at 24 hours

1

22

Odds Ratio (M‐H, Random, 95% CI)

7.74 [0.35, 170.10]

11.1.2 at 72 hours

1

22

Odds Ratio (M‐H, Random, 95% CI)

2.74 [0.10, 74.87]

11.1.3 at 1 week

1

22

Odds Ratio (M‐H, Random, 95% CI)

2.74 [0.10, 74.87]

11.1.4 at 4 weeks

1

298

Odds Ratio (M‐H, Random, 95% CI)

1.03 [0.63, 1.69]

11.2 AE Agitation/anxiety Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.3 AE Back pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.4 AE Blood Pressure Rise Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.5 AE Dissociative symptoms Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.6 AE Dizziness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.7 AE Dry mouth Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.8 AE Feeling drunk Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.9 AE Insomnia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.10 AE Muscle/bone/joint pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.11 AE Nausea Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.12 AE Rash Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.13 AE Sedation Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.14 AE Upper respiratory infection symptoms Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.15 AE Vomiting Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.16 AE Weight gain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

11.17 Remission rate Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

11.17.1 at 24 hours

1

22

Odds Ratio (M‐H, Random, 95% CI)

5.00 [0.21, 117.21]

11.17.2 at 72 hours

1

22

Odds Ratio (M‐H, Random, 95% CI)

2.74 [0.10, 74.87]

11.17.3 at 1 week

1

22

Odds Ratio (M‐H, Random, 95% CI)

2.74 [0.10, 74.87]

11.17.4 at 4 weeks

1

298

Odds Ratio (M‐H, Random, 95% CI)

1.38 [0.75, 2.52]

11.18 Depression rating scale score Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

11.18.1 at 24 hours

1

22

Mean Difference (IV, Random, 95% CI)

‐8.65 [‐17.81, 0.51]

11.18.2 at 72 hours

1

21

Mean Difference (IV, Random, 95% CI)

‐6.27 [‐13.93, 1.39]

11.18.3 at 1 week

1

21

Mean Difference (IV, Random, 95% CI)

‐6.55 [‐14.07, 0.97]

11.18.4 at 4 weeks

1

298

Mean Difference (IV, Random, 95% CI)

‐0.11 [‐1.42, 1.20]

11.18.5 at 3 months

1

298

Mean Difference (IV, Random, 95% CI)

0.51 [‐1.05, 2.07]

11.19 Acceptability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 11. Lanicemine (AZD6765) versus Placebo
Comparison 12. Org 26576 versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

12.1 Response rate Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.1.1 at 24 hours

2

54

Odds Ratio (M‐H, Random, 95% CI)

0.81 [0.09, 7.13]

12.1.2 at 72 hours

2

54

Odds Ratio (M‐H, Random, 95% CI)

0.80 [0.16, 3.90]

12.1.3 at 1 week

2

54

Odds Ratio (M‐H, Random, 95% CI)

1.40 [0.31, 6.28]

12.1.4 at 2 weeks

2

54

Odds Ratio (M‐H, Random, 95% CI)

2.24 [0.61, 8.22]

12.1.5 at 4 weeks

1

30

Odds Ratio (M‐H, Random, 95% CI)

0.82 [0.18, 3.74]

12.2 AE Abnormal dreams Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.3 AE Back pain Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.4 AE Disturbance in attention Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

12.5 AE Dizziness Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.6 AE Fatigue Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

12.7 AE Feeling drunk Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.8 AE Headache Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.9 AE Insomnia Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.10 AE Irritability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

12.11 AE Muscle twitching Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.12 AE Nasal congestion Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

12.13 AE Nausea Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.14 AE Palpitations Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.15 AE Post‐lumbar puncture syndrome Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

12.16 AE Rash Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

12.17 AE Sedation Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.18 AE Sensory disturbance Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.19 AE Sleepiness/drowsiness Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.20 AE Total Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.21 Remission rate Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

12.21.1 at 72 hours

2

54

Odds Ratio (M‐H, Random, 95% CI)

0.47 [0.03, 8.60]

12.21.2 at 1 week

2

54

Odds Ratio (M‐H, Random, 95% CI)

1.52 [0.21, 11.06]

12.21.3 at 2 weeks

2

54

Odds Ratio (M‐H, Random, 95% CI)

2.29 [0.43, 12.15]

12.21.4 at 4 weeks

1

30

Odds Ratio (M‐H, Random, 95% CI)

0.64 [0.13, 3.14]

12.22 Depression rating scale score Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

12.22.1 at 24 hours

2

54

Mean Difference (IV, Random, 95% CI)

‐0.51 [‐4.14, 3.13]

12.22.2 at 72 hours

2

54

Mean Difference (IV, Random, 95% CI)

‐0.88 [‐4.67, 2.91]

12.22.3 at 1 week

2

54

Mean Difference (IV, Random, 95% CI)

‐1.43 [‐5.31, 2.44]

12.22.4 at 2 weeks

2

54

Mean Difference (IV, Random, 95% CI)

‐2.61 [‐7.32, 2.09]

12.22.5 at 4 weeks

1

30

Mean Difference (IV, Random, 95% CI)

‐1.25 [‐8.14, 5.64]

12.23 Acceptability ‐ adverse events Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

Figures and Tables -
Comparison 12. Org 26576 versus Placebo
Comparison 13. Riluzole versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

13.1 Response rate Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.1.1 at 24 hours

1

42

Odds Ratio (M‐H, Random, 95% CI)

1.23 [0.35, 4.36]

13.1.2 at 72 hours

1

42

Odds Ratio (M‐H, Random, 95% CI)

2.62 [0.64, 10.61]

13.1.3 at 1 week

1

42

Odds Ratio (M‐H, Random, 95% CI)

2.40 [0.51, 11.26]

13.1.4 at 2 weeks

2

102

Odds Ratio (M‐H, Random, 95% CI)

1.41 [0.27, 7.26]

13.1.5 at 4 weeks

2

102

Odds Ratio (M‐H, Random, 95% CI)

1.57 [0.09, 28.00]

13.2 AE Abdominal Pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.3 AE Appetite decrease Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.4 AE Appetite increase Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.5 AE Agitation/anxiety Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.6 AE Blurred vision Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.7 AE Chest pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.8 AE Concentration difficulty Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.9 AE Confusion Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.10 AE Constipation Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.11 AE Coughing Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.12 AE Cramps Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.13 AE Decreased appetite Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.14 AE Decreased motor activity Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.15 AE Decreased libido Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.16 AE Dental problems Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.17 AE Depression Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.18 AE Dermatologic/skin irritation/lesions Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.19 AE Diarrhoea Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.20 AE Dizziness Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.21 AE Dry mouth Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.22 AE Eye irritation Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.23 AE Flatulence Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.24 AE Flu/upper respiratory infection Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.25 AE Genital discomfort Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.26 AE Gum problems Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.27 AE Headache Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.28 AE Increased libido Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.29 AE Increased thirst Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.30 AE Insomnia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.31 AE Irritability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.32 AE Memory problems Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.33 AE Mouth ulcer Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.34 AE Muscle/bone/joint pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.35 AE Nasal congestion Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.36 AE Nausea Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.37 AE Oedema Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.38 AE Sexual dysfunction Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.39 AE Shortness of breath Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.40 AE Sleepiness/drowsiness Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.41 AE Sore throat Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.42 AE Sore tongue Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.43 AE Stomach or abdominal discomfort Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.44 AE Suicidal ideas Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.45 AE Sweating Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.46 AE Tachycardia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.47 AE Tinnitus Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.48 AE Tiredness/fatigue Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.49 AE Urination problems Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.50 AE Weight gain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.51 AE Weight loss Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

13.52 Remission rate Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.52.1 at 24 hours

1

42

Odds Ratio (M‐H, Random, 95% CI)

0.71 [0.14, 3.64]

13.52.2 at 72 hours

1

42

Odds Ratio (M‐H, Random, 95% CI)

1.33 [0.30, 5.84]

13.52.3 at 1 week

1

42

Odds Ratio (M‐H, Random, 95% CI)

1.00 [0.18, 5.63]

13.52.4 at 2 weeks

1

42

Odds Ratio (M‐H, Random, 95% CI)

1.00 [0.13, 7.85]

13.52.5 at 4 weeks

2

102

Odds Ratio (M‐H, Random, 95% CI)

1.19 [0.12, 12.13]

13.53 Depression rating scale score Show forest plot

2

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

13.53.1 at 24 hours

1

42

Std. Mean Difference (IV, Random, 95% CI)

‐0.26 [‐0.87, 0.35]

13.53.2 at 72 hours

1

41

Std. Mean Difference (IV, Random, 95% CI)

‐0.25 [‐0.86, 0.37]

13.53.3 at 1 week

1

38

Std. Mean Difference (IV, Random, 95% CI)

‐0.06 [‐0.70, 0.58]

13.53.4 at 2 weeks

2

97

Std. Mean Difference (IV, Random, 95% CI)

‐0.36 [‐1.20, 0.47]

13.53.5 at 4 weeks

2

87

Std. Mean Difference (IV, Random, 95% CI)

‐0.18 [‐1.19, 0.84]

13.54 Acceptability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 13. Riluzole versus Placebo
Comparison 14. Atomoxetine versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

14.1 Response rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.1.1 at 3 months

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.2 AE Agitation/anxiety Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.3 AE Constipation Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.4 AE Depressed mood Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.5 AE Diarrhea Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.6 AE Dizziness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.7 AE Dry mouth Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.8 AE Fatigue Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.9 AE Flatulence Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.10 AE Headache Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.11 AE Increased sweating Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.12 AE Insomnia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.13 AE Nasopharyngitis Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.14 AE Nausea Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.15 AE Tremor Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.16 Remission rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.16.1 at 3 months

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.17 Depression rating scale score Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

14.17.1 at 3 months

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

14.18 Acceptability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.19 Acceptability ‐ adverse events Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

14.20 Acceptability ‐ lack of efficacy Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 14. Atomoxetine versus Placebo
Comparison 15. Basimglurant versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

15.1 Response rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.1.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.2 AE Dizziness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.3 AE Dry mouth Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.4 AE Fatigue Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.5 AE Headache Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.6 AE Insomnia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.7 AE Nasopharyngitis Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.8 AE Nausea Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.9 Remission rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.9.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

15.10 Depression rating scale score Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

15.10.1 at 4 weeks

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 15. Basimglurant versus Placebo
Comparison 16. Citicoline versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

16.1 Response rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.1.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.2 AE Abdominal Pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.3 AE Appetite decrease Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.4 AE Appetite increase Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.5 AE Dizziness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.6 AE Diarrhoea Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.7 AE Headache Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.8 AE Insomnia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.9 AE Nausea Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.10 AE Sedation Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.11 Remission rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

16.11.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 16. Citicoline versus Placebo
Comparison 17. CP‐101,606 versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

17.1 AE Change in blood pressure Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

17.2 AE Dissociative reaction Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

17.3 Depression rating scale score Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

17.3.1 at 24 hours

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

17.3.2 at 1 week

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

17.3.3 at 2 weeks

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

17.4 Acceptability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 17. CP‐101,606 versus Placebo
Comparison 18. D‐cycloserine versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

18.1 Response rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.1.1 at 2 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.1.2 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.2 AE Agitation/anxiety Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.3 AE Concentration difficulties Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.4 AE Constipation Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.5 AE Failing memory Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.6 AE Headache Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.7 AE Increased dream activity Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.8 AE Increased duration of sleep Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.9 AE Increased sexual desire Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.10 AE Increased tendency to sweat Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.11 AE Nausea/vomiting Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.12 AE Palpitation/tachycardia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.13 AE Sleepiness/drowsiness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.14 AE Urination issues Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.15 Remission rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.15.1 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

18.16 Depression rating scale score Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

18.16.1 at 2 weeks

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

18.16.2 at 4 weeks

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

18.17 Acceptability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 18. D‐cycloserine versus Placebo
Comparison 19. Decoglurant (mGlu2/3) versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

19.1 Response Rate Show forest plot

1

309

Odds Ratio (M‐H, Random, 95% CI)

2.04 [1.23, 3.38]

19.1.1 at 4 weeks

1

309

Odds Ratio (M‐H, Random, 95% CI)

2.04 [1.23, 3.38]

19.2 AE Diarrhea Show forest plot

1

357

Odds Ratio (M‐H, Random, 95% CI)

0.91 [0.42, 1.99]

19.3 AE Dizziness Show forest plot

1

357

Odds Ratio (M‐H, Random, 95% CI)

2.01 [1.03, 3.94]

19.4 AE Headache Show forest plot

1

357

Odds Ratio (M‐H, Random, 95% CI)

1.02 [0.61, 1.70]

19.5 AE Nausea Show forest plot

1

357

Odds Ratio (M‐H, Random, 95% CI)

1.38 [0.74, 2.59]

19.6 AE Sleepiness/drowsiness Show forest plot

1

357

Odds Ratio (M‐H, Random, 95% CI)

4.78 [0.61, 37.26]

19.7 AE Vomiting Show forest plot

1

357

Odds Ratio (M‐H, Random, 95% CI)

2.11 [0.79, 5.65]

19.8 Remission rate Show forest plot

1

309

Odds Ratio (M‐H, Random, 95% CI)

1.60 [0.95, 2.69]

19.8.1 at 4 weeks

1

309

Odds Ratio (M‐H, Random, 95% CI)

1.60 [0.95, 2.69]

Figures and Tables -
Comparison 19. Decoglurant (mGlu2/3) versus placebo
Comparison 20. MK‐0657 versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

20.1 Depression rating scale score Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

20.1.1 at 24 hours

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

20.1.2 at 72 hours

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

20.1.3 at 1 week

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

20.1.4 at 2 weeks

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 20. MK‐0657 versus Placebo
Comparison 21. N‐acetylcysteine versus Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

21.1 Response rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.1.1 at 2 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.1.2 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.1.3 at 3 months

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.2 AE Back pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.3 AE Gastrointestinal problems Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.4 AE Joint pain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.5 AE Muscle spasms Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.6 Remission rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.6.1 at 2 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.6.2 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.6.3 at 3 months

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.7 Depression rating scale score Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

21.7.1 at 2 weeks

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

21.7.2 at 4 weeks

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

21.7.3 at 3 months

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

21.8 Quality of life Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

21.8.1 at 3 months

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

21.9 Acceptability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

21.10 Acceptability ‐ adverse events Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 21. N‐acetylcysteine versus Placebo
Comparison 22. Sarcosine versus Citalopram

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

22.1 Response rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.1.1 at 2 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.1.2 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.2 AE Total Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.3 AE Agitation/anxiety Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.4 AE Asthenia/increased fatigability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.5 AE Constipation Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.6 AE Concentration difficulties Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.7 AE Depression Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.8 AE Dizziness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.9 AE Dystonia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.10 AE Headache/migraine Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.11 AE Increased dream activity Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.12 AE Increased duration of sleep Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.13 AE Nausea/vomiting Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.14 AE Palpitations/tachycardia Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.15 AE Reduced duration of sleep Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.16 AE Sleepiness/drowsiness Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.17 AE Tremor Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.18 AE Weight gain Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.19 AE Weight loss Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.20 Remission rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.20.1 at 2 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.20.2 at 4 weeks

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

22.21 Depression rating scale score Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

22.21.1 at 2 weeks

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

22.21.2 at 4 weeks

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

22.22 Acceptability Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

Figures and Tables -
Comparison 22. Sarcosine versus Citalopram
Comparison 23. Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

23.1 Response rate Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

23.1.1 at 24 hours

1

27

Odds Ratio (M‐H, Random, 95% CI)

18.76 [0.92, 383.10]

23.1.2 at 72 hours

1

27

Odds Ratio (M‐H, Random, 95% CI)

33.46 [1.65, 677.83]

23.1.3 at 1 week

1

27

Odds Ratio (M‐H, Random, 95% CI)

33.46 [1.65, 677.83]

23.1.4 at 2 weeks

1

27

Odds Ratio (M‐H, Random, 95% CI)

20.80 [2.04, 211.79]

23.1.5 at 4 weeks

3

132

Odds Ratio (M‐H, Random, 95% CI)

2.00 [0.68, 5.85]

23.1.6 at 3 months

2

47

Odds Ratio (M‐H, Random, 95% CI)

3.95 [0.16, 97.23]

23.2 Remission rate Show forest plot

4

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

23.2.1 at 24 hours

1

27

Odds Ratio (M‐H, Random, 95% CI)

3.48 [0.13, 93.30]

23.2.2 at 72 hours

1

27

Odds Ratio (M‐H, Random, 95% CI)

6.30 [0.27, 144.70]

23.2.3 at 1 week

1

27

Odds Ratio (M‐H, Random, 95% CI)

6.30 [0.27, 144.70]

23.2.4 at 2 weeks

1

27

Odds Ratio (M‐H, Random, 95% CI)

3.90 [0.35, 43.36]

23.2.5 at 4 weeks

3

132

Odds Ratio (M‐H, Random, 95% CI)

2.19 [0.85, 5.66]

23.2.6 at 3 months

2

90

Odds Ratio (M‐H, Random, 95% CI)

1.09 [0.45, 2.67]

23.3 Depression rating scale score Show forest plot

4

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

23.3.1 at 24 hours

2

75

Std. Mean Difference (IV, Random, 95% CI)

‐0.47 [‐1.11, 0.18]

23.3.2 at 72 hours

3

94

Std. Mean Difference (IV, Random, 95% CI)

‐0.28 [‐1.18, 0.62]

23.3.3 at 1 week

2

45

Std. Mean Difference (IV, Random, 95% CI)

‐0.52 [‐1.69, 0.65]

23.3.4 at 2 weeks

3

126

Std. Mean Difference (IV, Random, 95% CI)

‐0.73 [‐1.31, ‐0.15]

23.3.5 at 4 weeks

2

107

Std. Mean Difference (IV, Random, 95% CI)

‐0.68 [‐1.07, ‐0.29]

23.4 Suicidal ideation composite Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

23.4.1 at 24 hours

1

48

Mean Difference (IV, Random, 95% CI)

0.02 [‐0.78, 0.82]

23.4.2 at 72 hours

2

68

Mean Difference (IV, Random, 95% CI)

0.34 [‐0.25, 0.93]

23.4.3 at 1 week

1

19

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐1.56, 0.96]

23.4.4 at 2 weeks

1

19

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐1.46, 1.06]

Figures and Tables -
Comparison 23. Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting)
Comparison 24. Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

24.1 Response rate Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

24.1.1 at 24 hours

2

48

Odds Ratio (M‐H, Random, 95% CI)

15.11 [1.97, 115.92]

24.1.2 at 72 hours

2

48

Odds Ratio (M‐H, Random, 95% CI)

14.00 [2.07, 94.75]

24.1.3 at 1 week

3

99

Odds Ratio (M‐H, Random, 95% CI)

3.41 [0.95, 12.27]

24.1.4 at 2 weeks

1

51

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.31, 2.83]

24.2 Remission rate Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

24.2.1 at 24 hours

2

48

Odds Ratio (M‐H, Random, 95% CI)

6.60 [0.96, 45.09]

24.2.2 at 72 hours

2

48

Odds Ratio (M‐H, Random, 95% CI)

7.88 [1.17, 53.21]

24.2.3 at 1 week

3

99

Odds Ratio (M‐H, Random, 95% CI)

7.24 [1.70, 30.81]

24.2.4 at 2 weeks

1

51

Odds Ratio (M‐H, Random, 95% CI)

0.95 [0.28, 3.24]

24.3 Depression rating scale score Show forest plot

3

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

24.3.1 at 24 hours

2

46

Std. Mean Difference (IV, Random, 95% CI)

‐1.63 [‐2.86, ‐0.39]

24.3.2 at 72 hours

2

46

Std. Mean Difference (IV, Random, 95% CI)

‐1.21 [‐1.87, ‐0.55]

24.3.3 at 1 week

3

91

Std. Mean Difference (IV, Random, 95% CI)

‐0.75 [‐1.19, ‐0.31]

24.3.4 at 2 weeks

1

46

Std. Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.68, 0.48]

Figures and Tables -
Comparison 24. Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting)
Comparison 25. Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

25.1 Response rate Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

25.1.1 at 24 hours

3

620

Odds Ratio (M‐H, Random, 95% CI)

4.33 [1.08, 17.31]

25.1.2 at 1 week

3

632

Odds Ratio (M‐H, Random, 95% CI)

2.73 [1.41, 5.28]

25.1.3 at 4 weeks

2

543

Odds Ratio (M‐H, Random, 95% CI)

1.92 [1.34, 2.75]

25.2 Remission rate Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

25.2.1 at 24 hours

2

377

Odds Ratio (M‐H, Random, 95% CI)

6.51 [1.93, 21.92]

25.2.2 at 1 week

2

399

Odds Ratio (M‐H, Random, 95% CI)

7.76 [1.75, 34.48]

25.2.3 at 2 weeks

1

315

Odds Ratio (M‐H, Random, 95% CI)

2.30 [1.02, 5.17]

25.2.4 at 4 weeks

1

317

Odds Ratio (M‐H, Random, 95% CI)

1.39 [0.84, 2.30]

25.3 Depression rating scale score Show forest plot

2

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

25.3.1 at 24 hours

1

310

Std. Mean Difference (IV, Random, 95% CI)

‐0.25 [‐0.49, ‐0.01]

25.3.2 at 1 week

1

340

Std. Mean Difference (IV, Random, 95% CI)

‐0.28 [‐0.51, ‐0.06]

25.3.3 at 2 weeks

1

340

Std. Mean Difference (IV, Random, 95% CI)

‐0.32 [‐0.54, ‐0.09]

25.3.4 at 4 weeks

2

542

Std. Mean Difference (IV, Random, 95% CI)

‐0.28 [‐0.45, ‐0.10]

25.3.5 at 3 months

1

38

Std. Mean Difference (IV, Random, 95% CI)

‐0.12 [‐0.75, 0.52]

25.4 Suicidal ideation composite Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

25.4.1 at 1 week

1

209

Mean Difference (IV, Random, 95% CI)

0.05 [‐0.08, 0.18]

25.4.2 at 2 weeks

1

208

Mean Difference (IV, Random, 95% CI)

‐0.07 [‐0.21, 0.07]

25.4.3 at 4 weeks

1

196

Mean Difference (IV, Random, 95% CI)

‐0.02 [‐0.11, 0.07]

Figures and Tables -
Comparison 25. Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting)
Comparison 26. Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

26.1 Response rate Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

26.1.1 at 24 hours

1

224

Odds Ratio (M‐H, Random, 95% CI)

1.40 [0.79, 2.49]

26.1.2 at 72 hours

1

224

Odds Ratio (M‐H, Random, 95% CI)

1.52 [0.88, 2.62]

26.1.3 at 1 week

1

224

Odds Ratio (M‐H, Random, 95% CI)

1.29 [0.76, 2.18]

26.1.4 at 2 weeks

1

224

Odds Ratio (M‐H, Random, 95% CI)

1.71 [1.01, 2.91]

26.1.5 at 4 weeks

1

224

Odds Ratio (M‐H, Random, 95% CI)

1.85 [1.09, 3.14]

26.2 Remission rate Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

26.2.1 at 24 hours

2

290

Odds Ratio (M‐H, Random, 95% CI)

2.25 [1.13, 4.49]

26.2.2 at 72 hours

2

290

Odds Ratio (M‐H, Random, 95% CI)

1.61 [0.59, 4.34]

26.2.3 at 1 week

2

290

Odds Ratio (M‐H, Random, 95% CI)

1.22 [0.70, 2.13]

26.2.4 at 2 weeks

2

290

Odds Ratio (M‐H, Random, 95% CI)

1.39 [0.83, 2.32]

26.2.5 at 4 weeks

2

290

Odds Ratio (M‐H, Random, 95% CI)

1.48 [0.91, 2.42]

26.3 Depression rating scale score Show forest plot

2

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

26.3.1 at 24 hours

2

290

Std. Mean Difference (IV, Random, 95% CI)

‐0.35 [‐0.58, ‐0.12]

26.3.2 at 72 hours

2

290

Std. Mean Difference (IV, Random, 95% CI)

‐0.41 [‐0.64, ‐0.17]

26.3.3 at 1 week

2

290

Std. Mean Difference (IV, Random, 95% CI)

‐0.20 [‐0.43, 0.04]

26.3.4 at 2 weeks

2

290

Std. Mean Difference (IV, Random, 95% CI)

‐0.14 [‐0.37, 0.09]

26.3.5 at 4 weeks

2

290

Std. Mean Difference (IV, Random, 95% CI)

‐0.25 [‐0.48, ‐0.02]

26.4 Suicidal ideation composite Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

26.4.1 at 24 hours

1

224

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐0.63, 0.23]

26.4.2 at 72 hours

1

224

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐0.69, 0.09]

26.4.3 at 1 week

1

224

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐0.56, 0.16]

26.4.4 at 2 weeks

1

224

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.43, 0.23]

26.4.5 at 4 weeks

1

224

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐0.53, 0.13]

Figures and Tables -
Comparison 26. Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting)
Comparison 27. Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

27.1 Response rate Show forest plot

5

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

27.1.1 at 24 hours

5

1071

Odds Ratio (M‐H, Random, 95% CI)

2.11 [1.20, 3.68]

27.1.2 at 72 hours

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.34 [0.92, 1.96]

27.1.3 at 1 week

5

1083

Odds Ratio (M‐H, Random, 95% CI)

1.64 [1.05, 2.54]

27.1.4 at 2 weeks

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.57 [1.09, 2.28]

27.1.5 at 4 weeks

4

994

Odds Ratio (M‐H, Random, 95% CI)

1.81 [1.40, 2.34]

27.2 Remission rate Show forest plot

5

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

27.2.1 at 24 hours

5

894

Odds Ratio (M‐H, Random, 95% CI)

2.74 [1.71, 4.40]

27.2.2 at 72 hours

3

517

Odds Ratio (M‐H, Random, 95% CI)

1.55 [0.91, 2.64]

27.2.3 at 1 week

5

916

Odds Ratio (M‐H, Random, 95% CI)

1.62 [0.91, 2.89]

27.2.4 at 2 weeks

4

832

Odds Ratio (M‐H, Random, 95% CI)

1.52 [1.07, 2.16]

27.2.5 at 4 weeks

4

834

Odds Ratio (M‐H, Random, 95% CI)

1.51 [1.12, 2.04]

27.3 Depression rating scale score Show forest plot

5

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

27.3.1 at 24 hours

4

824

Std. Mean Difference (IV, Random, 95% CI)

‐0.31 [‐0.45, ‐0.17]

27.3.2 at 72 hours

3

517

Std. Mean Difference (IV, Random, 95% CI)

‐0.30 [‐0.50, ‐0.11]

27.3.3 at 1 week

4

857

Std. Mean Difference (IV, Random, 95% CI)

‐0.24 [‐0.37, ‐0.10]

27.3.4 at 2 weeks

4

857

Std. Mean Difference (IV, Random, 95% CI)

‐0.21 [‐0.34, ‐0.07]

27.3.5 at 4 weeks

5

1059

Std. Mean Difference (IV, Random, 95% CI)

‐0.27 [‐0.40, ‐0.15]

27.3.6 at 3 months

1

38

Std. Mean Difference (IV, Random, 95% CI)

‐0.12 [‐0.75, 0.52]

27.4 Suicidal ideation composite Show forest plot

3

Mean Difference (IV, Random, 95% CI)

Subtotals only

27.4.1 at 24 hours

2

450

Mean Difference (IV, Random, 95% CI)

‐0.15 [‐0.44, 0.15]

27.4.2 at 72 hours

2

451

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐0.49, 0.08]

27.4.3 at 1 week

3

660

Mean Difference (IV, Random, 95% CI)

0.01 [‐0.10, 0.13]

27.4.4 at 2 weeks

3

659

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.22, 0.02]

27.4.5 at 4 weeks

3

647

Mean Difference (IV, Random, 95% CI)

‐0.04 [‐0.12, 0.05]

Figures and Tables -
Comparison 27. Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years)
Comparison 28. Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

28.1 Response rate Show forest plot

9

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

28.1.1 at 24 hours

6

177

Odds Ratio (M‐H, Random, 95% CI)

4.33 [1.47, 12.80]

28.1.2 at 72 hours

3

75

Odds Ratio (M‐H, Random, 95% CI)

17.99 [3.58, 90.34]

28.1.3 at 1 week

3

75

Odds Ratio (M‐H, Random, 95% CI)

14.32 [2.90, 70.64]

28.1.4 at 2 weeks

2

85

Odds Ratio (M‐H, Random, 95% CI)

15.73 [4.71, 52.51]

28.1.5 at 4 weeks

3

132

Odds Ratio (M‐H, Random, 95% CI)

2.00 [0.68, 5.85]

28.1.6 at 3 months

2

47

Odds Ratio (M‐H, Random, 95% CI)

3.95 [0.16, 97.23]

28.2 Remission rate Show forest plot

6

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

28.2.1 at 24 hours

3

75

Odds Ratio (M‐H, Random, 95% CI)

5.60 [1.07, 29.46]

28.2.2 at 72 hours

3

75

Odds Ratio (M‐H, Random, 95% CI)

7.42 [1.45, 37.89]

28.2.3 at 1 week

3

75

Odds Ratio (M‐H, Random, 95% CI)

9.02 [1.80, 45.31]

28.2.4 at 2 weeks

2

85

Odds Ratio (M‐H, Random, 95% CI)

7.50 [1.51, 37.22]

28.2.5 at 4 weeks

3

132

Odds Ratio (M‐H, Random, 95% CI)

2.19 [0.85, 5.66]

28.2.6 at 3 months

1

20

Odds Ratio (M‐H, Random, 95% CI)

1.29 [0.14, 11.54]

28.3 Depression rating scale score Show forest plot

9

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

28.3.1 at 24 hours

7

223

Std. Mean Difference (IV, Random, 95% CI)

‐0.88 [‐1.31, ‐0.46]

28.3.2 at 72 hours

5

140

Std. Mean Difference (IV, Random, 95% CI)

‐0.63 [‐1.29, 0.04]

28.3.3 at 1 week

4

90

Std. Mean Difference (IV, Random, 95% CI)

‐0.76 [‐1.34, ‐0.19]

28.3.4 at 2 weeks

3

126

Std. Mean Difference (IV, Random, 95% CI)

‐0.73 [‐1.31, ‐0.15]

28.3.5 at 4 weeks

2

107

Std. Mean Difference (IV, Random, 95% CI)

‐0.68 [‐1.07, ‐0.29]

28.4 Suicidal ideation composite Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

28.4.1 at 24 hours

1

48

Mean Difference (IV, Random, 95% CI)

0.02 [‐0.78, 0.82]

28.4.2 at 72 hours

2

68

Mean Difference (IV, Random, 95% CI)

0.34 [‐0.25, 0.93]

28.4.3 at 1 week

1

19

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐1.56, 0.96]

28.4.4 at 2 weeks

1

19

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐1.46, 1.06]

Figures and Tables -
Comparison 28. Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features)
Comparison 29. Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

29.1 Response rate Show forest plot

4

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

29.1.1 at 24 hours

3

68

Odds Ratio (M‐H, Random, 95% CI)

2.31 [0.65, 8.14]

29.1.2 at 72 hours

2

38

Odds Ratio (M‐H, Random, 95% CI)

15.32 [1.58, 148.09]

29.1.3 at 1 week

1

30

Odds Ratio (M‐H, Random, 95% CI)

10.29 [0.97, 108.81]

29.1.4 at 4 weeks

1

81

Odds Ratio (M‐H, Random, 95% CI)

4.31 [1.48, 12.56]

29.2 Remission rate Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

29.2.1 at 24 hours

1

30

Odds Ratio (M‐H, Random, 95% CI)

6.75 [0.61, 75.27]

29.2.2 at 72 hours

2

38

Odds Ratio (M‐H, Random, 95% CI)

5.63 [0.77, 40.99]

29.2.3 at 1 week

1

30

Odds Ratio (M‐H, Random, 95% CI)

10.29 [0.97, 108.81]

29.2.4 at 4 weeks

1

81

Odds Ratio (M‐H, Random, 95% CI)

1.59 [0.51, 4.98]

29.3 Depression rating scale score Show forest plot

4

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

29.3.1 at 24 hours

3

66

Std. Mean Difference (IV, Random, 95% CI)

‐1.06 [‐1.61, ‐0.52]

29.3.2 at 72 hours

2

36

Std. Mean Difference (IV, Random, 95% CI)

‐1.20 [‐1.96, ‐0.44]

29.3.3 at 1 week

2

35

Std. Mean Difference (IV, Random, 95% CI)

‐1.19 [‐1.97, ‐0.42]

29.3.4 at 2 weeks

1

81

Std. Mean Difference (IV, Random, 95% CI)

‐0.90 [‐1.36, ‐0.45]

29.3.5 at 4 weeks

1

81

Std. Mean Difference (IV, Random, 95% CI)

‐0.77 [‐1.22, ‐0.31]

Figures and Tables -
Comparison 29. Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations)
Comparison 30. Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

30.1 Response rate Show forest plot

10

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

30.1.1 at 24 hours

7

185

Odds Ratio (M‐H, Random, 95% CI)

3.94 [1.54, 10.10]

30.1.2 at 72 hours

4

83

Odds Ratio (M‐H, Random, 95% CI)

15.84 [3.68, 68.12]

30.1.3 at 1 week

4

126

Odds Ratio (M‐H, Random, 95% CI)

5.69 [1.34, 24.11]

30.1.4 at 2 weeks

2

78

Odds Ratio (M‐H, Random, 95% CI)

3.72 [0.17, 79.32]

30.1.5 at 4 weeks

3

132

Odds Ratio (M‐H, Random, 95% CI)

2.00 [0.68, 5.85]

30.1.6 at 3 months

1

27

Odds Ratio (M‐H, Random, 95% CI)

20.00 [2.77, 144.31]

30.2 Remission rate Show forest plot

6

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

30.2.1 at 24 hours

3

75

Odds Ratio (M‐H, Random, 95% CI)

5.60 [1.07, 29.46]

30.2.2 at 72 hours

4

83

Odds Ratio (M‐H, Random, 95% CI)

6.60 [1.51, 28.92]

30.2.3 at 1 week

4

126

Odds Ratio (M‐H, Random, 95% CI)

7.06 [1.90, 26.31]

30.2.4 at 2 weeks

2

78

Odds Ratio (M‐H, Random, 95% CI)

1.30 [0.41, 4.12]

30.2.5 at 4 weeks

2

108

Odds Ratio (M‐H, Random, 95% CI)

2.60 [0.60, 11.33]

30.3 Depression rating scale score Show forest plot

10

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

30.3.1 at 24 hours

8

231

Std. Mean Difference (IV, Random, 95% CI)

‐0.87 [‐1.26, ‐0.48]

30.3.2 at 72 hours

5

128

Std. Mean Difference (IV, Random, 95% CI)

‐0.86 [‐1.24, ‐0.48]

30.3.3 at 1 week

5

124

Std. Mean Difference (IV, Random, 95% CI)

‐0.85 [‐1.23, ‐0.47]

30.3.4 at 2 weeks

3

153

Std. Mean Difference (IV, Random, 95% CI)

‐0.68 [‐1.29, ‐0.08]

30.3.5 at 4 weeks

2

107

Std. Mean Difference (IV, Random, 95% CI)

‐0.68 [‐1.07, ‐0.29]

30.4 Suicidal ideation composite Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

30.4.1 at 24 hours

1

48

Mean Difference (IV, Random, 95% CI)

0.02 [‐0.78, 0.82]

30.4.2 at 72 hours

1

48

Mean Difference (IV, Random, 95% CI)

0.09 [‐0.63, 0.81]

Figures and Tables -
Comparison 30. Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%
Comparison 31. Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

31.1 Response rate Show forest plot

7

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

31.1.1 at 24 hours

7

185

Odds Ratio (M‐H, Random, 95% CI)

3.94 [1.54, 10.10]

31.1.2 at 72 hours

4

83

Odds Ratio (M‐H, Random, 95% CI)

15.84 [3.68, 68.12]

31.1.3 at 1 week

3

75

Odds Ratio (M‐H, Random, 95% CI)

14.32 [2.90, 70.64]

31.1.4 at 2 weeks

1

27

Odds Ratio (M‐H, Random, 95% CI)

20.80 [2.04, 211.79]

31.1.5 at 4 weeks

1

27

Odds Ratio (M‐H, Random, 95% CI)

1.60 [0.35, 7.40]

31.1.6 at 3 months

1

27

Odds Ratio (M‐H, Random, 95% CI)

20.00 [2.77, 144.31]

31.2 Remission rate Show forest plot

5

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

31.2.1 at 24 hours

3

75

Odds Ratio (M‐H, Random, 95% CI)

5.60 [1.07, 29.46]

31.2.2 at 72 hours

4

83

Odds Ratio (M‐H, Random, 95% CI)

6.60 [1.51, 28.92]

31.2.3 at 1 week

3

75

Odds Ratio (M‐H, Random, 95% CI)

9.02 [1.80, 45.31]

31.2.4 at 2 weeks

2

78

Odds Ratio (M‐H, Random, 95% CI)

1.30 [0.41, 4.12]

31.2.5 at 4 weeks

1

27

Odds Ratio (M‐H, Random, 95% CI)

8.12 [0.80, 82.73]

31.3 Depression rating scale score Show forest plot

9

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

31.3.1 at 24 hours

8

231

Std. Mean Difference (IV, Random, 95% CI)

‐0.87 [‐1.26, ‐0.48]

31.3.2 at 72 hours

6

148

Std. Mean Difference (IV, Random, 95% CI)

‐0.68 [‐1.28, ‐0.07]

31.3.3 at 1 week

4

78

Std. Mean Difference (IV, Random, 95% CI)

‐1.07 [‐1.57, ‐0.58]

31.3.4 at 2 weeks

1

26

Std. Mean Difference (IV, Random, 95% CI)

‐1.14 [‐1.98, ‐0.30]

31.3.5 at 4 weeks

1

26

Std. Mean Difference (IV, Random, 95% CI)

‐0.43 [‐1.21, 0.35]

31.4 Suicidal ideation composite Show forest plot

1

96

Mean Difference (IV, Random, 95% CI)

0.06 [‐0.48, 0.59]

31.4.1 at 24 hours

1

48

Mean Difference (IV, Random, 95% CI)

0.02 [‐0.78, 0.82]

31.4.2 at 72 hours

1

48

Mean Difference (IV, Random, 95% CI)

0.09 [‐0.63, 0.81]

Figures and Tables -
Comparison 31. Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses)
Comparison 32. Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

32.1 Response rate Show forest plot

10

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

32.1.1 at 24 hours

7

185

Odds Ratio (M‐H, Random, 95% CI)

3.94 [1.54, 10.10]

32.1.2 at 72 hours

4

83

Odds Ratio (M‐H, Random, 95% CI)

15.84 [3.68, 68.12]

32.1.3 at 1 week

3

75

Odds Ratio (M‐H, Random, 95% CI)

14.32 [2.90, 70.64]

32.1.4 at 2 weeks

2

85

Odds Ratio (M‐H, Random, 95% CI)

15.73 [4.71, 52.51]

32.1.5 at 4 weeks

3

132

Odds Ratio (M‐H, Random, 95% CI)

2.00 [0.68, 5.85]

32.1.6 at 3 months

2

47

Odds Ratio (M‐H, Random, 95% CI)

3.95 [0.16, 97.23]

32.2 Remission rate Show forest plot

7

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

32.2.1 at 24 hours

3

75

Odds Ratio (M‐H, Random, 95% CI)

5.60 [1.07, 29.46]

32.2.2 at 72 hours

4

83

Odds Ratio (M‐H, Random, 95% CI)

6.60 [1.51, 28.92]

32.2.3 at 1 week

3

75

Odds Ratio (M‐H, Random, 95% CI)

9.02 [1.80, 45.31]

32.2.4 at 2 weeks

2

85

Odds Ratio (M‐H, Random, 95% CI)

7.50 [1.51, 37.22]

32.2.5 at 4 weeks

3

132

Odds Ratio (M‐H, Random, 95% CI)

2.19 [0.85, 5.66]

32.2.6 at 3 months

1

20

Odds Ratio (M‐H, Random, 95% CI)

1.29 [0.14, 11.54]

32.3 Depression rating scale score Show forest plot

10

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

32.3.1 at 24 hours

8

231

Std. Mean Difference (IV, Random, 95% CI)

‐0.87 [‐1.26, ‐0.48]

32.3.2 at 72 hours

6

148

Std. Mean Difference (IV, Random, 95% CI)

‐0.68 [‐1.28, ‐0.07]

32.3.3 at 1 week

5

97

Std. Mean Difference (IV, Random, 95% CI)

‐0.80 [‐1.31, ‐0.30]

32.3.4 at 2 weeks

3

126

Std. Mean Difference (IV, Random, 95% CI)

‐0.73 [‐1.31, ‐0.15]

32.3.5 at 4 weeks

2

107

Std. Mean Difference (IV, Random, 95% CI)

‐0.68 [‐1.07, ‐0.29]

32.4 Suicidal ideation composite Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

32.4.1 at 24 hours

1

48

Mean Difference (IV, Random, 95% CI)

0.02 [‐0.78, 0.82]

32.4.2 at 72 hours

2

68

Mean Difference (IV, Random, 95% CI)

0.34 [‐0.25, 0.93]

32.4.3 at 1 week

1

19

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐1.56, 0.96]

32.4.4 at 2 weeks

1

19

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐1.46, 1.06]

Figures and Tables -
Comparison 32. Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies)
Comparison 33. Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

33.1 Response rate Show forest plot

6

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

33.1.1 at 24 hours

5

1071

Odds Ratio (M‐H, Random, 95% CI)

2.11 [1.20, 3.68]

33.1.2 at 72 hours

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.34 [0.92, 1.96]

33.1.3 at 1 week

5

1083

Odds Ratio (M‐H, Random, 95% CI)

1.64 [1.05, 2.54]

33.1.4 at 2 weeks

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.57 [1.09, 2.28]

33.1.5 at 4 weeks

5

1117

Odds Ratio (M‐H, Random, 95% CI)

1.84 [1.44, 2.37]

33.2 Remission rate Show forest plot

6

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

33.2.1 at 24 hours

5

894

Odds Ratio (M‐H, Random, 95% CI)

2.74 [1.71, 4.40]

33.2.2 at 72 hours

3

517

Odds Ratio (M‐H, Random, 95% CI)

1.55 [0.91, 2.64]

33.2.3 at 1 week

5

916

Odds Ratio (M‐H, Random, 95% CI)

1.62 [0.91, 2.89]

33.2.4 at 2 weeks

4

832

Odds Ratio (M‐H, Random, 95% CI)

1.52 [1.07, 2.16]

33.2.5 at 4 weeks

5

957

Odds Ratio (M‐H, Random, 95% CI)

1.57 [1.18, 2.10]

33.3 Depression rating scale score Show forest plot

6

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

33.3.1 at 24 hours

4

824

Std. Mean Difference (IV, Random, 95% CI)

‐0.31 [‐0.45, ‐0.17]

33.3.2 at 72 hours

3

517

Std. Mean Difference (IV, Random, 95% CI)

‐0.30 [‐0.50, ‐0.11]

33.3.3 at 1 week

4

857

Std. Mean Difference (IV, Random, 95% CI)

‐0.24 [‐0.37, ‐0.10]

33.3.4 at 2 weeks

4

857

Std. Mean Difference (IV, Random, 95% CI)

‐0.21 [‐0.34, ‐0.07]

33.3.5 at 4 weeks

6

1182

Std. Mean Difference (IV, Random, 95% CI)

‐0.27 [‐0.39, ‐0.16]

33.3.6 at 3 months

1

38

Std. Mean Difference (IV, Random, 95% CI)

‐0.12 [‐0.75, 0.52]

33.4 Suicidal ideation composite Show forest plot

3

Mean Difference (IV, Random, 95% CI)

Subtotals only

33.4.1 at 24 hours

2

450

Mean Difference (IV, Random, 95% CI)

‐0.15 [‐0.44, 0.15]

33.4.2 at 72 hours

2

451

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐0.49, 0.08]

33.4.3 at 1 week

3

660

Mean Difference (IV, Random, 95% CI)

0.01 [‐0.10, 0.13]

33.4.4 at 2 weeks

3

659

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.22, 0.02]

33.4.5 at 4 weeks

3

647

Mean Difference (IV, Random, 95% CI)

‐0.04 [‐0.12, 0.05]

Figures and Tables -
Comparison 33. Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features)
Comparison 34. Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

34.1 Response rate Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

34.1.1 at 24 hours

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.55 [1.03, 2.33]

34.1.2 at 72 hours

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.34 [0.92, 1.96]

34.1.3 at 1 week

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.23 [0.85, 1.78]

34.1.4 at 2 weeks

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.57 [1.09, 2.28]

34.1.5 at 4 weeks

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.70 [1.17, 2.46]

34.2 Remission rate Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

34.2.1 at 24 hours

3

517

Odds Ratio (M‐H, Random, 95% CI)

2.35 [1.40, 3.92]

34.2.2 at 72 hours

3

517

Odds Ratio (M‐H, Random, 95% CI)

1.55 [0.91, 2.64]

34.2.3 at 1 week

3

517

Odds Ratio (M‐H, Random, 95% CI)

1.31 [0.86, 2.01]

34.2.4 at 2 weeks

3

517

Odds Ratio (M‐H, Random, 95% CI)

1.38 [0.93, 2.04]

34.2.5 at 4 weeks

3

517

Odds Ratio (M‐H, Random, 95% CI)

1.58 [1.10, 2.29]

34.3 Depression rating scale score Show forest plot

3

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

34.3.1 at 24 hours

3

514

Std. Mean Difference (IV, Random, 95% CI)

‐0.34 [‐0.52, ‐0.17]

34.3.2 at 72 hours

3

517

Std. Mean Difference (IV, Random, 95% CI)

‐0.30 [‐0.50, ‐0.11]

34.3.3 at 1 week

3

517

Std. Mean Difference (IV, Random, 95% CI)

‐0.21 [‐0.38, ‐0.04]

34.3.4 at 2 weeks

3

517

Std. Mean Difference (IV, Random, 95% CI)

‐0.14 [‐0.32, 0.03]

34.3.5 at 4 weeks

3

517

Std. Mean Difference (IV, Random, 95% CI)

‐0.27 [‐0.44, ‐0.10]

34.4 Suicidal ideation composite Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

34.4.1 at 24 hours

2

450

Mean Difference (IV, Random, 95% CI)

‐0.15 [‐0.44, 0.15]

34.4.2 at 72 hours

2

451

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐0.49, 0.08]

34.4.3 at 1 week

2

451

Mean Difference (IV, Random, 95% CI)

‐0.15 [‐0.41, 0.11]

34.4.4 at 2 weeks

2

451

Mean Difference (IV, Random, 95% CI)

‐0.19 [‐0.43, 0.05]

34.4.5 at 4 weeks

2

451

Mean Difference (IV, Random, 95% CI)

‐0.15 [‐0.39, 0.09]

Figures and Tables -
Comparison 34. Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations)
Comparison 35. Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

35.1 Response rate Show forest plot

7

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

35.1.1 at 24 hours

5

1071

Odds Ratio (M‐H, Random, 95% CI)

2.11 [1.20, 3.68]

35.1.2 at 72 hours

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.34 [0.92, 1.96]

35.1.3 at 1 week

6

1115

Odds Ratio (M‐H, Random, 95% CI)

1.60 [1.09, 2.34]

35.1.4 at 2 weeks

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.57 [1.09, 2.28]

35.1.5 at 4 weeks

5

1117

Odds Ratio (M‐H, Random, 95% CI)

1.84 [1.44, 2.37]

35.2 Remission rate Show forest plot

6

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

35.2.1 at 24 hours

4

828

Odds Ratio (M‐H, Random, 95% CI)

2.88 [1.72, 4.81]

35.2.2 at 72 hours

2

451

Odds Ratio (M‐H, Random, 95% CI)

1.76 [0.97, 3.18]

35.2.3 at 1 week

5

882

Odds Ratio (M‐H, Random, 95% CI)

1.79 [0.93, 3.42]

35.2.4 at 2 weeks

3

766

Odds Ratio (M‐H, Random, 95% CI)

1.51 [1.04, 2.19]

35.2.5 at 4 weeks

4

891

Odds Ratio (M‐H, Random, 95% CI)

1.60 [1.19, 2.16]

35.3 Depression rating scale score Show forest plot

6

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

35.3.1 at 24 hours

3

758

Std. Mean Difference (IV, Random, 95% CI)

‐0.29 [‐0.43, ‐0.14]

35.3.2 at 72 hours

2

451

Std. Mean Difference (IV, Random, 95% CI)

‐0.26 [‐0.45, ‐0.07]

35.3.3 at 1 week

4

818

Std. Mean Difference (IV, Random, 95% CI)

‐0.23 [‐0.37, ‐0.09]

35.3.4 at 2 weeks

3

791

Std. Mean Difference (IV, Random, 95% CI)

‐0.21 [‐0.36, ‐0.07]

35.3.5 at 4 weeks

5

1116

Std. Mean Difference (IV, Random, 95% CI)

‐0.27 [‐0.39, ‐0.15]

35.3.6 at 3 months

1

38

Std. Mean Difference (IV, Random, 95% CI)

‐0.12 [‐0.75, 0.52]

35.4 Suicidal ideation composite Show forest plot

3

Mean Difference (IV, Random, 95% CI)

Subtotals only

35.4.1 at 24 hours

2

450

Mean Difference (IV, Random, 95% CI)

‐0.15 [‐0.44, 0.15]

35.4.2 at 72 hours

2

451

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐0.49, 0.08]

35.4.3 at 1 week

3

660

Mean Difference (IV, Random, 95% CI)

0.01 [‐0.10, 0.13]

35.4.4 at 2 weeks

3

659

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.22, 0.02]

35.4.5 at 4 weeks

3

647

Mean Difference (IV, Random, 95% CI)

‐0.04 [‐0.12, 0.05]

Figures and Tables -
Comparison 35. Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%