Efficacy of amisulpride for depressive symptoms in individuals with mental disorders: A systematic review and meta‐analysis

Abstract Background Depressive symptoms occur in several psychiatric disorders, often in the absence of a formal diagnosis of depression. We aimed to evaluate the efficacy and the tolerability of amisulpride, both alone and as augmentation therapy, in the treatment of depressive symptoms in individuals with any major psychiatric disorder. Methods We searched PubMed, Embase, PsycINFO, GreyLit, OpenGrey and ProQuest up to March 2020 for randomised controlled trials focussing on the treatment of an acute depressive episode in any major psychiatric disorder. A random‐effect meta‐analysis was performed to synthesize the findings on depressive symptoms (primary outcome), response rate and tolerability. Results We retrieved 11 studies including 2065 patients with a diagnosis of dysthymia (eight studies), major depression (one study) or schizophrenia (two studies). Amisulpride 50 mg/day was associated with a larger reduction of depressive symptoms compared to placebo (standardised mean difference [SMD] = −0.70, CI 95% −0.92, −0.49; I 2 = 0.0%), and was found to be comparable to selective serotonin reuptake inhibitors (SSRIs; SMD = −0.08, CI 95% −0.23, 0.06, I 2 = 0.0%), amineptine, imipramine and amitriptyline in the treatment of dysthymia (three studies, not pooled). In individuals with schizophrenia, amisulpride administered at higher doses (>400 mg/day) was comparable to olanzapine and risperidone (two studies, not pooled). In terms of tolerability, amisulpride was superior to placebo for dysthymia (odds ratio [OR] = 3.94, CI 95% 1.07, 14.48; I 2 = 0.0) and comparable with SSRIs (OR = 0.94, CI 95% 0.55, 1.62; I 2 = 0.0%). Conclusion Treatment with amisulpride could be a valid choice for selected individuals with dysthymia or depressive symptoms in the context of schizophrenia. More studies on the efficacy and tolerability of amisulpride are needed to draw firm conclusions on its potential benefits in other psychiatric disorders.


| BACKGROUND
The term 'depression' is widely used to describe a clinical spectrum, ranging from subsyndromal isolated depressive symptoms to major depressive disorder (Busch et al., 2013;Vos et al., 2012). It is a major public health problem, considering its high prevalence and severe consequences for individuals and society (Cuijpers & Smit, 2008;Henderson & Pollard, 1992;Judd et al., 1996;Kessler et al., 2011;Murray et al., 2012Murray et al., , 2013. In a recent community cohort study, 54.4% of the sample met lifetime criteria for any DSM-5 depressive disorder (APA, 2013;Vandeleur et al., 2017). Clinically, depression could present alone or in the context of other diagnoses. Indeed, depressive symptoms and depression co-occurrence have been reported to be very common in other psychiatric disorders, such as anxiety disorders (Nordahl et al., 2018;Ratnani et al., 2017), post-traumatic stress disorder (PTSD; Armenta et al., 2019;Campbell et al., 2007), and schizophrenia (SCZ), especially during the first psychotic episode (Häfner et al., 2015).
Although many antidepressant medications are available (Cipriani et al., 2018), a significant proportion of individuals with a depressive episode do not respond to the first treatment (Rush et al., 2006), with up to one-third eventually classified as having treatment-resistant depression (Al-Harbi, 2012). Among the antidepressant drugs, agomelatine has attracted interest due to its efficacy via an alternative mechanism of action (Pompili et al. 2013).
Besides conventional first-line treatment with antidepressants, second-generation antipsychotics (SGA), and in particular amisulpride (AMS), have been used in clinical practice, alone or as augmentation, to treat depressive symptoms (Ravindran et al., 2007;Simons et al., 2017).
AMS is a substituted benzamide derivative with a higher affinity for dopamine D2/D3 receptors in limbic rather than in nigrostriatal structures, which has been related to the low incidence of extrapyramidal side effects, especially at low doses (Lecrubier, 2004). It shows a double mechanism of action. At low dosages it blocks the D2/D3 autoreceptors enhancing dopamine transmission, while high dosages reduce the transmission by antagonising the postsynaptic receptors (McKeage & Plosker, 2004). For this reason, AMS is considered different to other SGA, such as olanzapine and risperidone, which are pure antagonist, but also to partial agonists, such as aripiprazole.
Several authors suggested this double mechanism might explain the beneficial effect of AMS on positive symptoms of SCZ at high doses and on negative and depressive symptoms at low doses (McKeage & Plosker, 2004;Stahl, 2013Stahl, , 2018. AMS might also be a partial agonist of dopamine 2 receptors (Stahl, 2013(Stahl, , 2018 and, unlike other atypical antipsychotics, does not have potent actions at 5-HT2A or 5-HT1A receptors but at 5-HT2B and 5-HT7 receptors (Abbas et al., 2009;Stahl, 2013Stahl, , 2018. Finally, AMS has a renal metabolism, with 25%-50% of the dose eliminated unchanged with urine (Rosenzweig et al., 2002). Some evidence reported the antidepressant properties of AMS in the treatment of dysthymia, SCZ with co-occurrence of a depressive episode and depressive symptoms in chronic diseases, such as fibromyalgia and cancer (Calandre & Rico-Villademoros, 2013;Kim et al., 2007;Montgomery, 2002;Torta et al., 2007). Moreover, AMS is approved for treating dysthymia in Italy and other European countries (Table 1; Pani & Gessa, 2002;Rittmannsberger, 2019).
Notwithstanding its use in clinical practice, few high-quality data on the use of AMS in dysthymia are available (Komossa et al., 2010;Kriston et al., 2014). Furthermore, evidence is still required to establish the efficacy and safety of this molecule across a broader spectrum of diagnoses, including acute depressive episodes (Rittmannsberger, 2019).
The current systematic review and meta-analysis aimed to assess the efficacy and tolerability profiles of AMS, both as monotherapy and augmentation therapy, in the treatment of acute depressive episodes in individuals with a major mental health disorder.

| METHOD
The systematic review was conducted following the recommendations of the MOOSE and PRISMA statements (see Appendix S1; Moher et al., 2009;Stroup et al., 2000). The protocol is available on PROSPERO with the number CRD42020177918.

| Search methods
We searched PubMed, Embase, PsycINFO, GreyLit, OpenGrey and ProQuest from inception until 21st March 2020 for published and unpublished records using relevant keywords and thesauri (see Appendix S2 for the full search strategy). We inspected the reference lists of the records identified from our search to retrieve any additional relevant study.

| Study types
We included only randomised controlled trials (RCTs). No time or language restriction was applied.

| Population
We included studies recruiting adult individuals with any primary psychiatric diagnosis (i.e., mood disorders, SCZ spectrum diagnosis, T A B L E 1 Availability of AMS in different countries

Country Availability (psychiatric indication)
Europe AMS is indicated for the treatment of acute or chronic schizophrenic disorders in the following countries:

| Intervention
AMS, administered alone or as augmentation of the usual treatment.
Augmentation studies were only considered if usual treatment was stable prior to randomisation and balanced between the randomised groups. We considered eligible any dosage within the therapeutic range (25-1200 mg; fixed and flexible dosages) and any route of administration.

| Comparison
Placebo or any other drug. We excluded studies comparing AMS with non-pharmacological interventions unless there was one or more pharmacological comparison.

| Outcome
Our primary outcome was the reduction of the acute depressive symptomatology assessed by validated scales, as a measure of the efficacy.
-3 of 11 Our secondary outcomes were: -Response rate, as defined by the original authors -Tolerability, defined as the number of dropout due to an adverse effect

| Selection of studies, data extraction and assessment of study quality
At least two authors (BG, CZ, HCS, SB) independently performed both the abstract screening and the full-text screening phases. Any disagreement was resolved by consensus or by consultation with another member of the review team (ADA, EGO).
At least two team members (BG, CZ, HCS, SB) independently extracted data and study characteristics according to a pre-planned data extraction form. Any difference in the extracted data was discussed and resolved by consensus. Articles referring to the same trial were merged to avoid double-counting.
We attempted to contact the original authors where further information or data were missing and deemed potentially relevant (Appendix S3).
We assessed the quality of the included studies using the Risk Of Bias 2 (ROB2) tool (Sterne et al., 2019).

| Statistical analysis
For continuous data, we performed a random-effects meta-analysis of the endpoint or change mean depressive symptoms scores. We extracted data for both endpoint and change scores, prioritising the first when both were available. Should different scales be employed, we aim at providing the quantitative synthesis employing the Hedge's g standardised effect size. Dichotomous data were pooled using a random-effects meta-analysis of the event rate of interest.
Consistency between studies was measured with I 2 statistics, following the Cochrane Handbook thresholds for the interpretation (Deeks et al., 2020). All the statistical analyses were performed using Stata (StataCorp, 2015). The full code is available upon request to the contact author.
We evaluated the transdiagnostic potential of AMS following the TRANSD criteria, as it has been recently done for aripiprazole (Solmi et al. 2020).

| RESULTS
Our search identified 862 records for the screening (Figure 1). After the duplication check and the screening processes, a total of 57 potentially eligible studies were kept for further examination. Ten full-text articles could not be retrieved, so 47 papers were examined in full-text. Of them, 31 were excluded and three remained in 'awaiting assessment' since no sufficient information for the inclusion could be obtained (Appendix S4). We contacted a total of five authors, but no further data was acquired (Appendix S3  (Amore & Jori, 2001;Bellino et al., 1997;Boyer et al., 1999;Lecrubier et al., 1997;Ravizza, 1999;Rocca et al., 2002aRocca et al., , 2002bSmeraldi, 1998

| AMS versus placebo
Two double-blind RCTs (n = 358) contributed to this outcome (Boyer et al., 1999;Lecrubier et al., 1997). In both studies AMS was administered at the fixed dose of 50 mg/day.

T A B L E 2 Studies included in this review (by first author surname)
Author ( The only study evaluating AMS as augmentation to paroxetine compared to paroxetine alone found a difference in terms of mean change between treatments no statistically significant (p = 0.6149 for the HAMD, p = 0.3375 for the MADRS). The percentages of responders were 54% with paroxetine and 56% in the combined treatment group (p = 0.9585), while two percentage per group withdrew because of an adverse event.

| AMS and MDD
Only one study examined the efficacy of AMS in MDD (Cassano & Jori, 2002). This was an 8-week multicentric, double-blind, parallelgroup RCT comparing monotherapies of AMS 50 mg per day to paroxetine 20 mg per day in 277 adult outpatients with MDD (mean age 51.2 years, F/M ratio 72.6%). This study found no significant differences between the two drugs either in the reduction in HAMD, MADRS and CGI scores at endpoint (p = 0.37, p = 0.56 and p = 0.51 respectively), or in the response rate, defined as the reduction of at least 50% in the HAMD score (AMS 76% vs. paroxetine 84%, p = 0.13). The

F I G U R E 2 Amisulpride versus placebo in dysthymia (primary outcome)
F I G U R E 3 Amisulpride versus selective serotonin reuptake inhibitor in dysthymia (primary outcome) ZANGANI ET AL.

| AMS and SCZ
The efficacy of AMS in reducing acute depressive symptoms in patients with SCZ was examined in two studies (n = 172; Kim et al., 2007;Vanelle & Douki, 2006). One study compared AMS 400 mg to olanzapine 10 mg in an 8-week, multicentric, double-blind, parallel-group trial conducted on 85 patients (

| DISCUSSION
In the present review, we assessed available studies of AMS for depressive episodes across several mental health conditions. Overall, available evidence suggests AMS might potentially be effective and tolerable as a treatment alternative for individuals with depressive symptoms and an underlying diagnosis of dysthymia, MDD and SCZ.
Although depressive features are frequently co-morbid with other diagnoses (e.g., anxiety disorder, obsessive-compulsive disorder), AMS was evaluated only for a restricted number of mental health disorders.
Hence, a systematic evaluation of the transdiagnostic potential of AMS across and beyond diagnoses using the TRANS-D criteria (Solmi et al., 2020) could not be assessed due to a limited number of studies.
Most of the included studies focussed on individuals with a dysthymic disorder. The efficacy and tolerability profiles of AMS was overall comparable to both SSRI and TCA antidepressants. The only study evaluating AMS as augmentation to paroxetine compared to paroxetine alone found no difference in terms of response and remission rates, although the group receiving the combined intervention had a significantly greater psychosocial improvement (Rocca et al., 2002b). Despite these findings, its use in the clinical practice is limited. Rittmannsberger (2019) suggested that AMS not being licensed for the treatment of dysthymia in the majority of the Western countries could have contributed its relatively low use.
Leveraging the available-albeit limited-evidence, our findings together with peculiar pharmacodynamic properties (e.g., tolerability profile and renal excretion) may support the use of AMS for selected individuals with dysthymia, for instance with significant physical and hepatic comorbidities. More studies are needed to draw a firm conclusion on the clinical role of AMS in dysthymia.
Only one RCT, rated as 'some concerns' at RoB2, on the treatment of Major Depression was retrieved. It showed that AMS could be a valid alternative for the treatment of MDD (Cassano & Jori, 2002). Indeed, several authors suggested how MDD and dysthymia may lie on the same continuum, with some evidence that the two may intertwine through the clinical history of some patients (Angst et al., 2000;Horwath et al., 1992;Kovacs et al., 1994). Hence, treatment efficacy might be comparable. In a study comparing olanzapine and AMS as augmentation of SSRIs (fluoxetine and sertraline, respectively) for individuals with recurrent depressive disorder, both groups showed a significant reduction of depressive symptoms since report of AMS as an effective and rapid augmentation agent for the treatment of depression, although the efficacy rate might vary between patients (Rittmannsberger, 2019).
In SCZ, the impact of AMS on depressive symptoms is uncertain.
Notably, the administered mean dose of AMS was higher than 400 mg/die in both included studies. It has been suggested that lower doses of AMS (<400 mg/die) might be more effective on depressive and negative symptoms, whilst higher dosages for positive symptoms (McKeage & Plosker, 2004). This apparent discrepancy should be considered in light of the individual response to AMS and the gradual activating-to-inhibiting transition linked to the pharmacological properties of the drug (Stahl, 2013). Notwithstanding the dosage of AMS administered in the included studies, olanzapine and risperidone did not perform better. The differences in receptor affinities between AMS, olanzapine and risperidone (see the introduction for a comprehensive discussion on AMS pharmacodynamic) highlight the level of complexity of the multi-receptor networks underlying depressive symptoms (Leggio et al., 2013).
Our findings on the tolerability in patients with SCZ are consistent with the overall low incidence of extrapyramidal symptoms and limited impact on cognitive function on healthy individuals (Rosenzweig et al., 2002). Commonly reported side effects are weight gain and endocrine dysfunctions due to increase in prolactin levels (e.g., galactorrhoea, libido reduction, amenorrhea; Meister et al., 2016;Stahl, 2013Stahl, , 2018. Its tolerability profile and the renal excretion make AMS suitable as augmentation in patients with complex multipharmacological regimens, or in individuals with significant physical and hepatic comorbidities (Stahl, 2018).
No RCT investigated the potential use of AMS for depressive symptoms in individuals with other psychiatric disorders (e.g., bipolar disorder, anxiety disorder, obsessive-compulsive disorder), in contrast with the high prevalence of depressive symptoms and depression cooccurrence in individuals with mental health problems (Armenta et al., 2019;Häfner et al., 2005;Nordahl et al., 2018;Ratnani et al., 2017). Hence, AMS could be further studied as a treatment over the depressive symptoms spectra, also in light of the role of the dopaminergic system in the pathogenesis of depression (Leggio et al., 2013). The activity of AMS as a partial D2 agonist at low doses and as a full D2 antagonist at higher doses (Stahl, 2018) may represent the rationale for its effectiveness in the treatment of depressive symptoms across diagnoses and spectra (Leggio et al., 2013;Stahl, 2018).
The present review presents some limitations. First, eight potentially eligible articles could not be retrieved for a full text assessment. To overcome this limitation, we contacted the original authors. Two original investigators replied but could not provide us with the full text of the publication.
Second, the included studies had overall a moderate to high risk of bias, especially related to missing outcome data and absence of an available protocol. This may be due to the year of publication and the significant changes in the standard for conducting and reporting a trial over time (Schulz et al., 2010). Indeed, the majority of the included studies were published before the 2000.

| CONCLUSION
In summary, we found that AMS might be an effective and tolerable treatment for depression and depressive symptoms. In particular, its use could be evaluated in selected individuals, such as when prioritising renal excretion over hepatic metabolism. This evidence is stronger for dysthymia, and less conclusive for other depressive disorders and depressive episodes in SCZ. Novel high-quality studies are needed to assess effectiveness and tolerability of AMS as a transdiagnostic agent for the treatment of depressive symptoms.