Treatments in the pipeline for attention-deficit/hyperactivity disorder (ADHD) in adults

To provide an overview of treatments in the pipeline for adults with attention-deficit/hyperactivity disorder (ADHD), we searched https://clinicaltrials.gov/and and https://www.clinicaltrialsregister.eu


Introduction
Attention-deficit/hyperactivity disorder (ADHD) is characterised by developmentally inappropriate and impairing inattention plus hyperactivity and/or impulsivity (Faraone et al., 2024).ADHD is the most common neurodevelopmental disorder, affecting around 5 % of school-aged children worldwide according to a re-analysis of the Global Burden of Disease (GBD) data (Cortese et al., 2023) and 8 %, with an uneven gender distribution of 10 % for males and 5 % for females, based on an umbrella review including five systematic reviews and meta-analyses (57 unique primary studies) (Ayano et al., 2023).
Impairing symptoms of ADHD persist into adulthood in up to 75 % of the cases (Sibley et al., 2016), with an estimated prevalence of ADHD in adults at around 2.5 % (Song et al., 2021).ADHD is often comorbid with other disorders, including mood, anxiety, and substance use disorders, or dysfunctions, such as emotional dysregulation and executive dysfunction (Faraone et al., 2021), as well as physical disorders, including obesity and asthma (Arrondo et al., 2022).
Treatment options proposed for ADHD include pharmacologicalencompassing stimulant and non-stimulant medications -and nonpharmacological interventions (Cortese, 2020).In currently available guidelines, pharmacotherapy plays an important role in the management of ADHD in adults.For instance, the 2018 (updated in 2019) National Institute for Healthcare and Excellence (NICE) guidelines (National Institute For Health and Care Excellence (NICE), 2019) suggested that medication (stimulants as first line, followed by the non-stimulant atomoxetine) should be offered after environmental modifications (such as reducing noise or distractions) have been implemented but ADHD symptoms are still impairing.Current medications for ADHD in adults are efficacious, albeit with lower effect sizes compared to children, especially in relation to stimulants for which effects sizes have been found to be high in children and medium in adults (Cortese et al., 2018).However, there are concerns around the safety of currently available ADHD medications, including their possible cardiovascular effects (Cortese and Fava, 2024) and limited abuse potential -even though the risk-benefit profile in general favours the use of medications, as recently highlighted by the ADDUCE project, a naturalistic, longitudinal, controlled study in 27 European child and adolescent mental health centres (e.g., Buitelaar et al., 2022).Therefore, there is a need for additional efficacious and safer medications for adults with ADHD.
In addition to pharmacological treatments, current guidelines include also non-pharmacological options.For instance, the NICE guidelines recommend considering non-pharmacological treatments if they are the preferred choice by the patient, medications are not well tolerated or ineffective, or regular adherence to medication is difficult.It remains unclear to what extent non-pharmacological options are efficacious and effective to tackle ADHD core symptoms or associated problems, such as emotional dysregulation.Of note, an increasing number of randomised controlled trials (RCTs) are testing the efficacy of non-pharmacological treatments, including psychotherapy, diet changes, cognitive training, and neurostimulation, for adult ADHD.Therefore, gaining insight into promising pharmacological and nonpharmacological treatment for adults with ADHD is crucial to inform future guidelines.
A previous study systematically reviewed 939 phase 2 or 3 RCTs testing medications for adults with mental health conditions, but ADHD was outside the scope of that work (Correll et al., 2023).Another study (Cortese et al., 2023b) systematically reviewed 234 phase 2 or 3 RCTs of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics, as well as phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders, including ADHD, but was limited to children and to pharmacological treatments.The present review builds on those two previous studies and complements them by systematically searching for phase 2, 3, 4 RCTs of non-approved pharmacological and non-pharmacological interventions for adults with ADHD.The present review is expected to provide a comprehensive overview of treatments in the pipeline for adult ADHD inform future research priorities in the field.

Search strategy
We searched https://clinicaltrials.gov/and and https://www.clinicaltrialsregister.eu/from 01/01/2010-10/18/2023.The time frame is very similar to the one considered in a recent similar review on phase 2/ 3 RCTs of psychopharmacological agents in adults (Correll et al., 2023).We also conducted an additional systematic targeted search in PubMed to check if identified RCTs for which results were not available in the clinical trials platforms had been published.The following filters were used for the search in clinicaltrials.gov: 1) study type: interventional studies (Clinical Trials); 2) recruitment: any available option (not yet recruiting/recruiting/enrolling by invitation/active, not recruiting/terminated/completed/unknown status); 3) age group: "adults"; 4) phase: phase 2/phase 3 or 4; 5) study start: From 01/01/2010 (assuming that if studies initiated ≥13 years ago and results had not been published or no additional studies were ongoing that this trial program had been discontinued).Likewise, the following filters were used for the search in https://www.clinicaltrialsregister.eu/: 1) select trial status: completed/ongoing/restarted; 2) age range: adults; 3) select trial phase: phase two/phase three/phase four; and 4) select date range: 01/01/2010-10/18/2023 (with the same reasoning for the cut-off date as mentioned for clinicaltrials.gov).

Inclusion and exclusion criteria
We included ongoing or completed phase 2 or 3 RCTs, regardless of their level of blinding, assessing pharmacological or nonpharmacological interventions for adults with ADHD that had to the best of our knowledge no regulatory approval in the US, Europe (through EMA licensing procedures, not those approved by individual countries through national licensing procedures) or Asia as of 10/18/ 2023.We also aimed to include any phase 4 RCTs of nonpharmacological treatments and, for pharmacological treatments, of medications, if any, already approved for adults with ADHD but targeting a currently unapproved indication (e.g., emotional dysregulation as primary outcome).

Classification of the mechanisms of action of the tested medications
To describe the possible mechanisms of action of the tested medications, we referred, whenever possible to the Neuroscience based Nomenclature (NbN) website (https://nbn2r.com/).

Evaluation of the chances of success
After summarizing the search results, we highlighted those interventions that were considered to be most promising based on the current level of evidence with regard to i) positive phase 2 and/or phase 3 or 4 clinical trials indicating superiority vs. placebo/other control.In particular, we assessed i) whether there were treatments with at least two positive RCTs (on the primary outcomes) without any negative RCTs (on the primary outcomes); ii) magnitude of the observed effect, with reference to the benchmarks suggested by Cohen (Cohen, 1988): 0.2: small; 0.5: medium; 0,8: large effect size; iii) demonstration of minimum requirements for safety/tolerability, in terms of lack of severe adverse events as defined by the Food and Drug Administration (FDA), i.e., those: resulting in death, or life threatening, or requiring inpatient hospitalisation or causing prolongation of existing hospitalisation, or resulting in persistent or significant disability/incapacity, or contributing to a congenital anomaly/birth defect, or requiring intervention to prevent permanent impairment or damage.

Overview of included RCTs
We initially identified 115 potentially eligible RCTs (Table S1).However, 25 of the RCTs of pharmacological treatments tested medications already approved for adults with ADHD for core symptoms of ADHD (Table S2), which will not be discussed further in the present article.Of the remaining 90 RCTs, around 27 % (n = 24) reported results with statistical analysis for primary efficacy endpoints; in the rest (73 %, n = 66), results with statistical analysis of significance were not reported/available (ongoing trials: 38 %, completed trials: 38 %, unknown status: 14 %, terminated: 4 %, not yet recruiting: 6 %).
Completed RCTs with positive results on at least one primary outcome (n = 26) and those with negative results on every primary outcome (n = 8) are reported in Table 1 (pharmacological treatment) and Table 2 (non-pharmacological treatment).When available, Tables 1-2 report also data on tolerability, in terms of percentage of participants who dropped out due to adverse events or those who experienced adverse events defined as serious by the study authors, in line with the above-mentioned FDA classification.

Pharmacological treatments
Agents for which results of statistical analysis were available are descried below, in alphabetical order.
The second trial (NCT03605836) utilised the same design and had a total of 440 participants (47 % females) randomised to treatment.Measurement of change from baseline in AISRS total score at the end of week six also showed superiority of centanafadine SR over placebo for both 200 mg/day and 400 mg/day dose groups.Respectively, LS mean differences were reported as − 4.01 ([-6.55, − 1.46]; p = 0.0021; effect size = − 0.37) and − 4.47 ([-7.02,− 1.82]; p = 0.0009; effect size = − 0.40).
In both studies, adverse effects (AEs) were more frequent in the active groups (200 mg/day = 25.2 %; 400 mg/day = 31.8%) than in controls (17.6 %), although most were mild or moderate in severity.Of the AEs deemed to be possibly related to centanafadine, the most common AEs were decreased appetite, headache, dry mouth, and nausea.Discontinuation due to treatment-emergent AEs (TEAEs) was also higher in the active (200 mg/day = 4.8 %; 400 mg/day = 6.2 %) than in the placebo arm (1.4 %).
An earlier, phase IIb study (NCT02547428), reported in Wigal et al. (2020), had previously evaluated the efficacy of centanafadine SR in 85 adults (44 % females) with ADHD utilising a crossover design.Patients were allocated to either placebo or centanafadine SR (400-800 mg/day) and received three weeks of treatment before crossing over to the opposite treatment assignment.Change in ADHD Rating Scale-IV (ADHD-RS-IV) score from baseline to week 3 showed superiority of centanafadine SR against placebo (LS mean difference [CI 95 %]: − 8.1 [-11.0,− 5.1]; p < 0.001; effect size = 0.66).Eighty percent of patients receiving centanafadine SR experienced an AE, compared with 68 % in the placebo group.In the centanafadine SR group, TEAEs were, in descending order of occurrence, decreased appetite, headache, and nausea.Out of the twelve patients that discontinued treatment due to a TEAE (centanafadine: n = 11; placebo: n = 1), ten had received 600 mg or more of centanafadine SR within one day of AE onset.

Dasotraline
A multicentre RCT including 636 adults (39.6 % females) with ADHD (NCT02276209) (Adler et al., 2021) investigated the efficacy of dasotraline, a pharmacologic agent that potently inhibits dopamine and norepinephrine transporters presynaptically (Adler et al., 2021).Subjects were allocated on a 1:1:1 ratio to treatment with dasotraline 4 or 6 mg/day, or placebo.At the end of week 8, change in severity of ADHD symptoms as measured by the ADHD Rating Scale, Version IV, total score showed no significant improvement in the active groups when compared to placebo when corrected using Hochberg's procedure ([dasotraline 4 mg/day vs. placebo: − 15.0 vs. − 13.9; p = n.s.; effect size: 0.09]; [dasotraline 6 mg/day vs. placebo: − 16.5 vs. − 13.9; P = 0.074; effect size: 0.23]).For non-adjusted p-values, dasotraline 6 mg/day was significantly better than placebo (p = 0.037).AEs were more common in the combined dasotraline dose group (80.1 %) than in the placebo arm (62.6 %).The most common AEs in the former group were insomnia, decreased appetite, dry mouth, and anxiety.Psychosis and mania-related events happened in two patients in the dasotraline 4 mg/day group, four patients in the Dasotraline 6 mg/day group and two in those taking placebo.

L-methylfolate supplementation
L-methylfolate is a folate derivative which is transported across the blood brain barrier and acts as an important factor in the synthesis of monoaminergic neurotransmitters such as norepinephrine and dopamine (Lam et al., 2022).A pilot study (NCT01853280) evaluated the effect of L-methylfolate supplementation to OROS-methylphenidate pharmacotherapy in adults with ADHD.Following randomisation, 44 patients (61.4 % females) received treatment with either 15 mg/day of L-methylfolate plus OROS methylphenidate or OROS methylphenidate with matched placebo comparator, for a period of twelve weeks.The mean change in score from baseline in the AISRS at week 12 was slightly greater in the treatment (-22.9, with a standard deviation of 10.4) than in the control arm (-20.8, with a standard deviation of 11.3); however, no additional statistical analyses were reported.No serious adverse events were reported.Other (not serious) adverse events that included headache, insomnia, mucosal dryness, decreased appetite and nausea, vomiting and diarrhoea were reported in 20/22 and 19/22 of the participants in the active and control group, respectively.

Mazindol
One study (NCT02808104) (Wigal et al., 2018) investigated the efficacy of a controlled-release (CR) formulation of mazindol, a drug previously marketed for short-term treatment of obesity which acts by blocking the reuptake of dopamine and noradrenaline, for adult ADHD.Seventy-five patients (57 % females) completed six weeks of treatment with either placebo or 1-3 mg/day of mazindol CR.At the end of week 6, a significant decrease in the ADHD-RS-DSM5 score was seen in the intervention group when compared to placebo (-18.9 vs. − 5.7; LS mean difference [95 % CI]: − 13.2 [-18.7, − 7.6]; p < 0.001), with an overall placebo-corrected effect size of 1.09 in the intention-to-treat population.The group taking mazindol CR experienced more dry mouth, nausea, fatigue, increased heart rate, decreased appetite and constipation than the one allocated to placebo, with no serious treatment-emergent adverse events.

Metadoxine
The efficacy of metadoxine -a selective antagonist of the serotonin receptor subtype 5-HT 2b -in decreasing ADHD symptoms in G.F. Veronesi et al.

Table 1
Completed RCTs of pharmacological treatments with positive results on at least one primary outcome and those with negative results on every primary outcome.comparison to placebo was investigated in an RCT (NCT02059642) with 249 adults (53 % females).Groups were randomly assigned to receive either a once-daily dose of metadoxine 1400 mg or placebo, for six weeks.At the end of week 6, no statistically significant change in total ADHD symptom score with adult prompts of the Conners Adult ADHD Rating Scale was seen in the two groups (Metadoxine vs. Placebo: − 12.0 vs. − 9.9; LS mean difference [95 % CI]: − 2.1 [-4.87-0.66];p = 0.1358).

Sativex
One study (NCT02249299) (Cooper et al., 2017) evaluated the efficacy of cannabinoids in 30 adults (50 % females) with ADHD.Following a six-week period of treatment with either placebo or Sativex, an oromucosal spray containing 2.7 mg delta-9-tetrahydrocannabinol and 2.5 mg cannabidiol per 100 microlitres, measurement of cognitive performance and activity level were carried out utilising the Quantitative Behavioural Test (QbTest).Each participant followed a dosing schedule comprised of a 14-day titration period to find the optimal dose (up to maximum of 14 sprays per day), followed by another 28 days of daily administration of the titrated dose.However, no statistically significant changes in QbTest performance from baseline to day 42 were found between the two groups (estimated reduction in scores = − 0.17 [95 % CI − 0.40-0.07];p = 0.16).Mild adverse events were experienced by three patients on the sativex group, including two reports of light-headedness and one of diarrhoea, all of whom were able to resume and complete treatment.One active group participant reported sudden onset of muscular seizures/spasms and stopped Sativex.

Solriamfetol
Solriamfetol, a dopamine and norepinephrine reuptake inhibitor most commonly used for treatment of sleep disorders, was evaluated in a study with 60 adults (48.3 % females) with ADHD (NCT04839562) (Surman et al., 2023).Subjects were randomised to receive placebo or Solriamfetol (75-150 mg/day) for six weeks.Following treatment, patients in the active group had greater improvement in total scores in the ADHD Investigator Symptom Rating Scale (AISRS), starting from week 3 through week 6 (p = 0.0012; week 6 effect size = 1.09).Adverse effects reported by the solriamfetol group with a minimum 10 % difference when compared to placebo included decreased appetite, headache, gastrointestinal, insomnia, increased energy, cardiovascular, and neurologic symptoms.

Vortioxetine
Vortioxetine, a multimodal antidepressant, which acts as a serotonin reuptake inhibitor, receptor agonist (5-HT 1A ), receptor partial agonist (5-HT 1B ), and a receptor antagonist (5-HT 3 ), was investigated as a potential treatment for ADHD in a twelve week, two-stage study (NCT02327013) (Biederman et al., 2019).Stage I, completed by 181 adults, comprised of six weeks of treatment with vortioxetine 10 or 20 mg/day, or placebo (randomised in a 1:1:3 ratio).Placebo non-responders (n = 59) were then re-allocated in stage II to another six weeks of vortioxetine 10 or 20 mg/day, or placebo (randomised in a 1:1:1 ratio).A total of 151 subjects completed the study.The primary efficacy endpoint, measured as mean scores on Adult ADHD Investigator Symptom Rating Scale (AISRS), did not reveal any significant differences between the groups (vortioxetine 10 mg vs. placebo = − 0.1 [SE = 1.4; p = 0.972]; vortioxetine 20 mg vs placebo = 1.0 [SE = 1.9; p = 0.601).TEAEs were more common in the vortioxetine 20 mg group, with nausea and fatigue being the most frequently reported ones in either active group.Suicidal ideation reported by one patient was the only serious adverse event in the active groups.

Compounds in RCTs with results of statistical analysis not reported
Non-FDA approved compounds for ADHD core symptoms or other outcomes in RCTs with results of statistical analysis not reported included: TAK-137 (AMPA receptor potentiator) (note: RCT terminated), vayarin (which acts on restoring brain lipid imbalance), metadoxine (a selective antagonist of the serotonin receptor subtype 5-HT 2b, in addition to the RCT above-in a RCT that was terminated), centanafadine (inhibitor of norepinephrine, dopamine, and serotonin reuptake, in addition to the two positive RCTs above-in a RCT that was terminated), probiotic, melatonin, oxytocin, tolcapone (specific inhibitor of cathechol-O-methyltransferase), contrave (combination of naltrexone, an opioid antagonist, and bupropion, an inhibitor of the neuronal reuptake of dopamine and norepinephrine in a study that was withdrawn), solriamfetol (dopamine and norepinephrine reuptake inhibitor, in addition to a study with positive results reported above), MM-120 (a tartrate salt form of lysergide, which is a partial 5-HT2A agonist), PDC-1421 (inhibitor of the norepinephrine plasma membrane transport protein), cannabis oil (note: RCT terminated), zantiva (selective inhibition of presynaptic norepinephrine reuptake), and NRCT-101SR (adrenergic receptor agonist).

Non-pharmacological interventions
Interventions for which results with statistical analysis were available are descried below, grouped by type and presented in alphabetical order.

Dietary interventions
A study (NCT03342469) investigated the effects of artificial food colours (AFCs) on ADHD symptoms in 29 students with ADHD (aged 18-24 years, 21 females), following a stable medication dose and frequency (ADHD medication or otherwise) for at least 3 months.The dietary intervention consisted of ingesting six of the most common AFCs (Red 40, Red 3, Yellow 5, Yellow 6, Blue 1 and Blue 2) mixed in chocolate biscuits or a placebo of chocolate biscuits.The participants underwent an electroencephalogram (EEG) and a cognitive test (Adult ADHD Self-Report Scale-V1).Exposure to AFC did not result in any significant changes in ADHD symptoms.

Neurostimulation
Of the studies identified, three used neurostimulation as a nonpharmacological treatment for adults with ADHD.One of these trials (NCT03663179) used transcranial magnetic stimulation (TSM), a noninvasive technique for electromagnetic stimulation of brain tissue.Specifically, the study investigated whether 20 sessions of active TMS targeting the left dorsal prefrontal cortex (DLPFC) could improve executive cognitive function in adults with ADHD compared to 20 sessions of sham TMS.To evaluate the efficacy of TSM as an alternative treatment for ADHD, only patients who were not receiving pharmacological treatment for ADHD were included.Of the 27 participants (9 males, mean [SD] age: 34.4 [13.0] years), 14 were assigned to active TSM and 13 to sham TSM.The study showed that active TSM did not significantly improve ADHD symptoms, as measured by the Conners Adult ADHD Rating Scale-Self-Report: Long Version (t-score, mean [SD]: active TMS − 4.4 [9.4] vs. sham TMS − 5.1 [7.6]).However, an isolated improvement in sustained attention was found using the Conners Continuous Performance Task (mean [SD]: active TMS − 16.2 [17.6] vs. sham .In this study, no serious adverse events were reported. Transcranial direct current stimulation (tDCS) was investigated in the other two studies.In the first study (NCT04003740), tDCS was used to improve symptoms of inattention in patients with ADHD.Adults with ADHD (n = 64, 34 males, all without ongoing pharmacological treatment for ADHD; mean [SD] age: 38.3 [9.6] years) participated in the study.Participants were randomised to receive tDCS stimulation with active or sham devices.After the first 4 weeks of daily stimulation, the active tDCS group significantly improved in terms of symptoms of inattention (p <0.001, effect size: not reported) as measured by the clinician administered ADHD Self-Report Scale-Part A, Inattention (CASRS-I), compared to the sham treatment.No serious adverse events were recorded during the study.
In another randomised, sham-controlled, double-blind study (NCT04175028) (Dubreuil-Vall et al., 2021), the cognitive and physiological effects of tDCS were investigated in 40 adults with ADHD (aged 18-67 years).Before and after each session (in which tDCS targeted the left DLPFC, the right DLPFC and was a sham treatment), participants completed tests to measure their response inhibition.For this purpose, the Eriksen-Flanker Task (EFT) or the Stop Signal Task (SST) were performed to assess interference cognitive control or action cancellation, respectively.Behavioral data (reaction time (RT), accuracy) and neurophysiological data (event-related potentials, ERPs) were also recorded.In the EFT, left-sided stimulation resulted in significantly faster RT compared to sham treatment (p <0.0001) and right-sided stimulation (p = 0.0183).In the EFT, left-sided stimulation also modulated physiological measures, resulting in a significant increase in P300 amplitude compared to sham (p = 0.022) and a significant decrease in N200 amplitude compared to right-sided stimulation (p = 0.027).Although a significant correlation was found between the RTs in the EFT and the ERPs (larger P200 amplitude (p = 0.046), and between larger P300 amplitudes (p = 0.046) and faster RT; smaller N200 amplitude and faster RT (p <0.0001)), no significant differences were found in these relationships before vs. after stimulation.This finding suggests that tDCS may not significantly modulate the relationship between RT and ERPs.As for Stop trials in SST, no significant cognitive or physiological changes were found after left-sided stimulation.The authors interpreted these results with the hypothesis that tDCS targeting the left DLPFC could lead to an improvement in cognitive control but not in action cancellation.

Physical activity
A RCT (NCT05049239) (Svedell et al., 2023) investigated the effects of a 12-week exercise program in 14 adults with ADHD (aged 27-54 years).The intervention consisted of a physiotherapist-led, small-group (4-6 participants) mixed exercise program with moderate to high intensity cardio, strength and flexibility exercises, targeting 60 %-90 % of maximum heart rate, taking place for 50 min, three times a week for twelve weeks.When analysing the differences between pre-and post-treatment in the intervention group and the control group (who received usual care), significant improvement was found only in the intervention group.Compared to baseline, the intervention group actually showed a reduction in ADHD symptoms (significant as measured by the ASRS [p=0.036];non-significant as measured by the CGI-S [p=0.11]), a general and significant improvement (determined by a composite score calculated from the scores of the Adult ADHD Self-Report Scale (ASRS), Clinical Global Impression-Severity (CGI-S), Patient Global Impression-Improvement (PGI-I), Montgomery-Åsberg Depression Rating Scale-Self-report (MADRS-S) and EQ visual analogue scaler (EQ-VAS) rating scales [p = 0.008]), and an improvement in cognitive functioning (significant, measured by the AX-CPT [p=0.032],non-significant for the Go/NoGo and emotion regulation tasks).Effect sizes were not reported.

Table 2
Completed RCTs of non-pharmacological treatments with positive results on at least one primary outcome and those with negative results on every primary outcome.with ADHD.Specifically, the Sustained Attention Control (SAC) mobile software, which tests sustained attention skills and self-awareness of attention control, was compared with the software game "Scrabble"," which is used to practice word processing and executive control functions.At the end of the 10-week treatment, significantly greater improvements were found in the SAC group than in the active control group on both primary outcome measures, namely the measure of sustained attention (measured using the Conners Continuous Performance Test Reaction Time Variability (p = 0.026)) and timed reading comprehension (using the Nelson-Denny Reading Test (p = 0.014)).
In addition, the authors analysed the ADHD symptoms between the two groups using the Adult Attention-Deficit Hyperactivity Disorder Self-Report Scale (ASRS).The participants in the Scrabble group showed a greater improvement on the inattentive subscale (p = 0.000001) and the hyperactive subscale (p = 0.00018).
A computer-based training program referred to as FOcused Concentration and Attention Learning (FOCAL+) was developed to improve the attention of drivers with ADHD by trying to reduce their long glances (≥2 seconds) away from the roadway.A group of 152 participants (38 % females) aged 16-19 years (note; this study was included, as the sample encompassed individuals aged 18 or older) were randomised to either this intervention group or the sham comparison group, which consisted of computerised training on traffic rules, laws, and regulations (NCT02848092) (Epstein et al., 2022)).Both the experimental and control training took place weekly for 5 weeks.During simulated driving after training, a significant reduction in the number of long glances away from the roadway was observed in the intervention group compared to the sham group after 1 month (P < 0.001) and after 6 months (P < 0.001).In addition, the rate of collisions and near-collisions during real driving was significantly lower in the intervention group one year after training (relative risk: 0.60).
Executive functions and emotional regulation were investigated in a group of 105 patients with ADHD (21.5 % females, aged 12-22 years) who received either cognitive training with a virtual reality video game (The Secret Trail of Moon, TSTM group) or cognitive training with therapeutic chess (TC) or no cognitive intervention (control group, CG) (NCT04355065 (Rodrigo-Yanguas et al., 2023)).Notably statistical threshold was set and reported in this study at p <0.10.Compared to the CG group, the TC group performed significantly better in terms of emotional control, emotional regulation, and inattention (p < 0.10).On the other hand, the TSTM group showed significantly better improvements compared to the CG group (p <0.10) on the measures of emotional regulation, inattention, and school context.

Dialectical behavioural therapy-based group treatment.
A study investigated the effects of 14 weeks of Dialectical Behavioural Therapybased Group Treatment (DBT-bGT) compared to treatment as usual (TAU) on executive functions and emotional regulation in adults with ADHD (n = 121, 56 % females) (NCT02685254) (Halmøy et al., 2022).Although emotional regulation (measured with the Difficulties in Emotion Regulation Scale, DERS) did not differ significantly between the groups, significant improvements in executive functions were found in the DBT-bGT group using the Behaviour Rating Inventory of Executive Function (BRIEF-A) (p = 0.005).Compared to participants receiving TAU, those assigned to DBT-bGT reported significant improvement in ADHD core symptoms (ASRS total score, p < 0.001), depressive symptoms (BDI total score, p < 0.001), and quality of life (AAQol total score, p = 0.004).However, DBT-bGT was not superior to TAU in reducing anxiety symptoms.The authors also found that these observed symptom reductions persisted in the DBT-bGT group at the 6-month follow-up.Effect sizes were not reported.
The efficacy of the Dialectical Behavior Therapy Skill Training Group (DBT-ST) was compared as an add-on treatment to ADHD medication vs to treatment as usual (TaU) in another study (NCT03326427) (Moritz et al., 2021)) involving 31 adults with ADHD (aged 18 and 60 years).After participating in 12 weeks of DBT-ST or TaU, ADHD symptoms were assessed using the ADHD Self-Rating Scale (ASRS).No significant difference was found between the groups in ASRS scores over time..3.4.3. Goal management training. Goal Management Training (GMT) was compared with Treatment as usual (TAU) in improving executive functions and reducing ADHD symptoms and comorbidity (NCT04638283) (Hanssen et al., 2023).In this study, the active intervention consisted of 16 hours of GMT and psychoeducation plus 4 individual sessions focusing on specific goals.Adults with ADHD (n = 81; aged 18-55 years; 58 % women; 23.5 % diagnosed with anxiety) were randomly assigned to either GMT or TAU.In both groups, executive functions, psychological well-being, and ADHD symptoms were assessed from baseline to 8-month follow-up.A significantly greater decrease in anxiety symptoms was found in the GMT compared to the TAU group (p = 0.014, measured with HSCL-25, anxiety; p = 0.048 with HSCL-25, total).Conversely, no statistically significant difference was found between the two groups in improvement in daily executive functioning (BRIEF-A) or reduction in ADHD symptom intensity (ASRS-v1.1).

Internet-based cognitive behavioural therapy.
In 2104 adults (18-65 years) with ADHD (69 % females), internet-based cognitive behavioural therapy (iCBT) was compared to internet-based applied relaxation training (iART) and treatment as usual (TAU) (NCT02041884) (Nasri et al., 2023).The change in scores on the Adult ADHD Self-Report Scale (ASRS), consisting of the two subscales of inattention and hyperactivity/impulsivity, was tested after 12 weeks of treatment (post-treatment) and 3 and 12 months after the end of treatment.ASRS scores improved significantly more with both iCBT (p < 0.01; Cohen's d = 0.42 at post-treatment and 0.67 at 3 months) and iART (p < 0.01; Cohen's d = 0.57 at post-treatment and 0.66 at 3 months) than with TAU.These improvements persisted over 12 months with both iCBT (p < 0.001) and iART (p < 0.001).However, no significant differences were found between the iCBT and iART groups.
3.3.4.5.Mindfulness-based cognitive therapy.Mindfulness-based cognitive therapy (MBCT), consisting of an 8-week group therapy with meditation exercises, psychoeducation, and group discussion, in addition to treatment as usual (TAU, i.e., pharmacotherapy and/or psychoeducation), was compared with TAU only in terms of core symptom reduction in one RCT (NCT02463396) involving 120 participants (Janssen et al., 2019).In the experimental arm (MBCT + TAU), a significant decrease in ADHD symptoms was observed after treatment (p = 0.004), and this significant difference remained stable during the 6-month follow-up period.In addition, more patients in the MBCT + TAU group showed a symptom reduction of ⩾30 % (p = 0.001) or symptomatic remission (p = 0.039) compared to the TAU group.Although patients in the MBCT + TAU group reported no improvement in executive functions immediately after treatment compared to the TAU group, the difference between the groups became significant over the 6-month follow-up period (effect size: d = 0.49).
3.3.4.6.Self-guided psychological internet-delivered intervention.The efficacy of a self-guided psychological internet-delivered intervention on ADHD symptom severity and quality of life in adults with ADHD was compared with a control intervention consisting of an online psychoeducation module (NCT04726813) (Kenter et al., 2023)).A sample with self-reported ADHD diagnoses (N = 120, 80 % females) was randomly assigned to one of these two groups.When comparing the two groups, a moderate to large improvement in ADHD symptoms (d = 0.70) and quality of life (d = 0.53) was found for the Self-guided psychological internet-delivered intervention, these effects also persisted at the 3-month follow-up (d = 0.76 and d = 0.52).

Non-pharmacological treatments in RCT with results of statistical analysis not reported
Non-pharmacological treatments in RCTs (other than those described above) with results of statistical analysis not reported for ADHD core symptoms or other outcomes included: psychological therapies: CBT ( 3

Discussion
To our knowledge, this is the first systematic review of ongoing or completed (in the last decade) RCTs of pharmacological or nonpharmacological treatments for ADHD in adults, providing an overview on recent developments in the field and treatments in the pipeline.When considering the overall body of RCTs of interventions for adult ADHD that have been registered over the past decade, it is striking that only around 30 % tested a pharmacological treatment, while the majority (nearly 70 %) explored the efficacy/safety of non-pharmacological options.This situation likely reflects two main aspects.First, the notion that currently available medications for the management of ADHD are quite effective for ADHD symptoms but have a symptomatic, rather than curative, action.Second, concerns around possible side effects of medications, in particular stimulants, including cardiovascular safety and abuse potential.However, it is interesting to note that amphetamines in adults have been found to have better acceptability than placebo in network meta-analytic evidence (Cortese et al., 2018).Furthermore, in relation to the potentially most concerning side effect of stimulant, i.e., cardiovascular safety, recent evidence from the large observational study with the longest follow-up indicated that longer cumulative use of methylphenidate for up to 14 years was correlated with a statistically significant but overall small increased risk of hypertension and arterial disease, but not of other serious cardiovascular conditions, such as heart failure (Zhang et al., 2024).
From the body of 90 RCT eligible for the present review (after discarding 25 RCTs of pharmacological compounds approved by the FDA and hence used in clinical practice) identified in clinical trial registries, about 27 % (n = 24) reported results with statistical analysis.From these RCTs, positive results in single trials for ADHD core symptoms were identified, in relation to pharmacological treatments, for centanafadine, mazindol, OPC-64005, solriamfetol, and, regarding non-pharmacological options, for rTMS, tDCS, physical activity, DBT, iCBT, mindfulness and self-guided support.However, when considering positive results replicated in at least one additional independent RCT, only centanafadine had this level of evidence, and the effect sizes were small (0.24, 0.28, 0.37, and 0.40) across the 4 active arms with positive results.
Focusing on pharmacological treatments, more specifically, the effect size found for non-stimulant compounds were generally small, with two isolated trials having large effect sizes of 1.1 (mazindol, solriamfetol isazol), but without replication (mazindol) or even with a trial without results reported (solriamfetol isazol), likely indicating non-significant or small effect.While it would be desirable to have compounds with effect size as high as those of stimulants (one of the highest effect sizes across psychiatry and more generally medicine, at least in the short term), being 0.79 for amphetamines and for 0.49 methylphenidate in adults (Cortese et al., 2018), and better tolerability profile, this has not been achieved yet.This state of affairs is not dissimilar from the situation in relation to medications in the pipeline for children.In the previous review focused on recent (last 10 years) registered phase II, III, or IV RCTs in children (Cortese et al., 2023b), only dasotraline had positive evidence, replicated in at least one additional RCT, of superiority versus placebo, with a small-moderate effect size (~0.4).In contrast, dasotraline was not superior in the trial in adults with ADHD when correcting for multiple comparisons, as summarized above.
An interesting development in the field, that may eventually lead to even more effective, well tolerated and possibly curative pharmacological treatments is represented by research on the so-called druggable genome, which refers to as a selection of genes that are potential targets for pharmacological interventions.Interestingly, through the analysis of data derived from genome-wide analyses (GWA) of ADHD, it has been discovered that none of the genes responsible for the primary targets of first-line pharmacotherapeutics for ADHD exhibited significant association with the disorder (Hegvik et al., 2021).This finding implies that FDA-approved ADHD medications might operate through mechanisms distinct from those underlying ADHD.Remarkably, three specific loci on chromosomes 1, 4, and 12 exhibited significant association with ADHD and harbored nine genes susceptible to pharmacological intervention, five of which encode well-established drug targets for conditions such as malignancies, autoimmune disorders, and neurodevelopmental disorders (Hegvik et al., 2021).
While we excluded from this review RCTs on compounds that are FDA approved, we highlight that an important area of research is represented by the additional development of formulations of already approved compounds that can have a longer duration of action and/or that can lead to a better adherence (such as liquid or chewable formulations), as well as formulations that are active in the early hours of the day, or patches.Indeed, adherence is a crucial issue in the pharmacological treatment of ADHD.During the 12-month follow-up periods examined in multiple studies within a systematic review of 91 original studies (Gajria et al., 2014), the mean duration of stimulant treatment was found to be 136 days for children and 230 days for adults.Notably, the highest rates of medication discontinuation were observed among individuals aged 15-21 years (Zetterqvist et al., 2013).Reasons cited for discontinuation encompassed side effects, perceived inefficacy, aversion to medication intake, determination of unnecessary treatment, social stigma, and challenges associated with transitioning from paediatric to adult healthcare services.Another issue to consider in future RCTs is around the length of the RCT.As the average length of currently available or planned RCTs is usually limited to a few weeks, the evidence they generate is not suitable to inform clinical decision making in the longer-term.While longer-term RCTs may be challenging due to logistic and ethical reasons (in terms of randomising participants to placebo over a sustained period of time when active medication is superior to placebo), discontinuation RCTs, where individuals treated with active medication for months or years are randomised for a short period to continuation of active treatment or switch to placebo should be encouraged.Another important aspect to bear in mind when planning future RCTs is sex/gender balance in terms of recruitment.We note that, compared to RCTs in children, those in adults have in general a more balanced recruitment in terms sex/gender, probably reflecting the more balanced sex/gender ratio in the diagnosis of ADHD in adults compared to children.In fact, while, due to a referral bias, boys, who tend to be more hyperactive than girls, are referred more frequently to clinical services for ADHD, in adulthood women who struggle mainly with inattentive presentation of ADHD are more prone to consult an ADHD specialist due to the impact of inattention and additional comorbidities that are highly frequent in adulthood (Cortese et al., 2016).
Finally, future RTs will need to address placebo effects, that have been shown to be present also in RCTs of medications for ADHD (Faraone et al., 2022).Evidence primarily derived from RCTs in schizophrenia indicates that certain factors enhance the likelihood of distinguishing between drug and placebo effects.These factors have led to the following recommendations: refrain from incorporating an open-label lead-in phase prior to randomization in general; minimize the number of study sites, active treatment arms, and participants; randomly allocate more participants to the placebo group, thereby reducing the expectancy bias associated with receiving an active intervention; consider employing an extended wash-out period after discontinuation of previous medication, if feasible and ethically sound given the condition; utilize validated diagnostic and symptom rating tools; conduct trials lasting longer than four weeks in acute settings; and include individuals severely affected by the condition as well as those experiencing a first episode or with shorter illness durations (Cortese et al., 2024;Correll et al., 2023).Additionally, regarding placebo, we suggest that researchers will need to consider possible ethical implications of testing active medications vs placebo when efficacious treatments are already available in the market.
Regarding non-pharmacological treatments, even though no individual treatment had evidence of superiority versus control for ADHD core symptoms in more than one RCT, the field looks forward to the results of an increasing body of ongoing RCTs on a variety of nonpharmacological interventions, spanning from psychological to dietary treatments and neurostimulation.Two possible developments in the field are of potential interest.First, the development of digital delivery, arguably fostered by the COVID-19 pandemic, of approaches traditionally delivered face-to-face, such as iCBT, which, however, needs additional evidence.Second, the development of more sophisticated or alternative versions of existing treatments, such as, just to cite two examples: 1) novel and unusual types of psychotherapy, such as brief motivational interviewing and behavioral activation, or acceptance and commitment-therapy; 2) functional near-infrared spectroscopy (fNIRS)based neurofeedback (NF).However, after decades of research on neurofeedback, there is no solid evidence that it can significantly change ADHD core symptoms when considering blinded outcomes (Coghill et al., 2023) (Sonuga-Barke et al., 2013), reflecting the findings in relation to other non-pharmacological approaches, such as cognitive training (Westwood et al., 2023) and behavioral interventions (Daley et al., 2014) in children.It is possible that novel neurofeedback approaches and protocol are more efficacious, but this possibility needs rigorous RCT and meta-analytic evidence.
Notably, for some non-pharmacological treatments it is challenging or virtually impossible to blind the trial.A series of meta-analyses by the European ADHD Guidelines Group (EAGG) (Sonuga- Barke et al., 2013;Westwood et al., 2023;Daley et al., 2014;Cortese et al., 2015;Cortese et al., 2016) focused on children with ADHD has established that, while, when considering probably blinded outcomes many non-pharmacological treatments are not more efficacious than control in terms of ADHD core symptoms, they may be efficacious for some outcomes, such as executive dysfunction for cognitive training (Westwood et al., 2023), or parenting for parent training behavior (Daley et al., 2014).Future RCTs of non-pharmacological treatments of adults with ADHD should take this possible discrepancy into account, by carefully assessing effects on core and non-core symptoms.While some unusual outcomes of interest have been recently examined (such as the number of long glances away from the roadway (Epstein et al., 2022)) with a computerized skills-training program, which significantly reduced the relevant endpoint of accidents, other increasingly relevant outcomes, such as quality of life, remain still underrepresented in ADHD RCTs (both of pharmacological and non-pharmacological treatments).
In addition to shorter-term RCTs, mainly aimed at obtaining regulatory approval, like those included in the present review, the field will need also pragmatic, longer-term RCTs, withdrawal RCTs and, crucially, comparative studies including pharmacological and nonpharmacological options, as well as RCTs examining the most effective sequencing or combination(s) of pharmacological and nonpharmacological treatments.
This study should be considered in light of some limitations.First, we systematically searched https://clinicaltrials.gov/and and https://www .clinicaltrialsregister.eu/ but not other national registries, which would have been unpractical.Second, we limited the search to 01/01/ 2010-10/18/2023, to cover a recent time span, but other search dates would have been also an option.Third, it was beyond the scope of the present work to systematically contact study authors or pharmaceutical companies to inquiry about the status of the trials and their results.Lastly, we did not systematically check any discrepancy between data reported in the publication and what was planned, which is the focus on another ongoing work from our group.
Despite these limitations, this review provided the currently most rigorous overview of RCTs of pharmacological and non-pharmacological treatments for adults with ADHD.Since to date no treatments more efficacious and safer the stimulants have been identified and given the frequency and relevance of ADHD in adults, it is important to continue developing and testing additional treatments for adults with ADHD seeking other effective and well tolerated treatments, and possibly curative intervention strategies.

Table 1
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Table 1
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Table 2
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Table 2
(continued ) Cognitive training.One RCT (NCT02489279) tested two cognitive training programs on personal mobile devices that were used to assess the attention of 85 adults (58.7 % females, 18-40 years old)