Original Investigation
Adjunctive Antipsychotics in Major Depressive Disorder. A Systematic Review and Network Meta-Analysis
Roger S. McIntyre, MD1,2,3; Stephen M. Stahl, MD, PhD4; Sung Ryul Shim, MPH, PhD5, et al. JAMA Psychiatry. Published Online: May 6, 2026. doi: 10.1001/jamapsychiatry.2026.0658
Key Points
Question How do US Food and Drug Administration (FDA)–approved atypical antipsychotics in major depressive disorder (MDD) compare with respect to overall efficacy and acceptability?
Findings In this systematic review and network meta-analysis, a hierarchy of efficacy and acceptability was observed, in which lumateperone had the highest effect size for efficacy, followed by aripiprazole, and in which aripiprazole had the highest overall acceptability, followed by cariprazine. Secondary and exploratory outcomes accorded with the coprimary outcomes across measures of efficacy, acceptability, and tolerability.
Meaning FDA-approved atypical antipsychotic agents for MDD exhibit differential efficacy, acceptability, and tolerability relevant to treatment selection and sequencing.
Abstract
Importance Most adults living with major depressive disorder (MDD) fail to achieve remission with conventional antidepressants. The US Food and Drug Administration (FDA) has approved 5 atypical antipsychotics in MDD on the basis of their substantial evidence of efficacy and safety.
Objective To compare the efficacy and acceptability of FDA-approved atypical antipsychotics for the adjunctive treatment of MDD in order to provide decision support to practitioners and persons with lived experience.
Data Sources A systematic search was conducted using PubMed/MEDLINE, PsycINFO, the Cochrane Library, and Embase from database inception through July 15, 2025.
Study Selection Six independent raters screened publications for eligibility. Inclusion criteria were atypical antipsychotics that are FDA approved in the adjunctive treatment of MDD.
Data Extraction and Synthesis Two independent raters obtained data and examined risk of bias in accordance with the Cochrane criteria. Effect sizes were synthesized using random-effects models. Data were analyzed from August to September 2025.
Main Outcomes and Measures The primary outcomes were efficacy (ie, ≥50% reduction from baseline in the total Montgomery-Åsberg Depression Rating Scale [MADRS] score) and acceptability (ie, all-cause discontinuation).
Results A total of 22 short-term studies comprising 10 962 participants (aripiprazole: n = 1297; brexpiprazole: n = 1973; cariprazine: n = 1894; lumateperone: n = 483; quetiapine extended release [XR]: n = 719; and placebo: n = 4596) were included for analysis. Lumateperone had the highest effect size for efficacy (risk ratio [RR], 1.72; 95% credible interval [CrI], 1.40-2.15), followed by aripiprazole (RR, 1.53; 95% CrI, 1.32-1.77), brexpiprazole (RR, 1.38; 95% CrI, 1.18-1.65), cariprazine (RR, 1.20; 95% CrI, 1.07-1.36), and quetiapine XR (RR, 1.15; 95% CrI, 0.96-1.35). A hierarchy of acceptability was observed, with aripiprazole exhibiting the highest acceptability (RR, 1.16; 95% CrI, 0.89-1.50), followed by cariprazine (RR, 1.44; 95% CrI, 1.15-1.82), brexpiprazole (RR, 1.47; 95% CrI, 1.18-1.85), quetiapine XR (RR, 1.56; 95% CrI, 1.14-2.12), and lumateperone (RR, 2.30; 95% CrI, 1.45-3.84). Secondary outcomes (eg, symptomatic remission) and exploratory outcomes (eg, clinically significant weight gain) accorded with the coprimary outcomes.
Conclusions and Relevance This systematic review and meta-analysis indicates that differences exist between adjunctive atypical antipsychotics in the treatment of MDD with respect to overall efficacy and acceptability, which should be simultaneously considered. The absence of adequate and well-controlled studies documenting maintenance efficacy of adjunctive atypical antipsychotics in MDD remains a knowledge gap.
Introduction
It has long been accepted that a substantial percentage of adults living with major depressive disorder (MDD) prescribed and self-administered antidepressants inadequately benefit, as evidenced by persisting depressive symptoms and deficits across patient-reported outcomes (eg, health-related quality of life, positive mental health, overall function).1–4 The hazards of nonremission are well documented and include, but are not limited to, higher rates of recurrence, chronicity of illness, incidence of medical and psychiatric comorbidity, suicidality, health care service utilization and health-related costs, as well as patient frustration and dissatisfaction with treatment.1,5
Although combining antidepressants is not uncommon practice, the adjunctive combination of select atypical antipsychotics in MDD has been US Food and Drug Administration (FDA) approved and/or is supported by a replicated evidence base of adequate and well-controlled short-term studies.6 For example, aripiprazole, brexpiprazole, cariprazine, lumateperone, and quetiapine extended release (XR) are all FDA-approved adjunctive therapies for the treatment of adults with MDD exhibiting inadequate response to antidepressants. In addition, the fixed-dose combination formulation olanzapine-fluoxetine is established as efficacious in adults with treatment-resistant depression (TRD).7
Whether differences exist between the FDA-approved atypical antipsychotics in MDD with respect to overall efficacy and acceptability is currently unknown and is highly relevant to shared decision-making. For example, it is well established that significant differences exist between atypical antipsychotics with respect to certain tolerability aspects that predispose treatment discontinuation (eg, psychotropic drug–related weight gain, drug-induced movement disorders).8,9
Herein, we conducted a systematic review and network meta-analysis of all currently FDA-approved adjunctive atypical antipsychotics in adults with MDD. Studies reporting on the efficacy of atypical antipsychotic monotherapy in MDD were not included, as this approach is not clinically recommended in most jurisdictions.10–12 Studies pertaining to antidepressant combinations or select atypicals that are not FDA-approved in MDD (eg, risperidone) were also not included, as they do not have substantial evidence of efficacy as defined by 2 adequate, positive, pivotal, well-controlled, double-blind, placebo-controlled randomized clinical trials (RCTs). Furthermore, olanzapine-fluoxetine was excluded from the analysis, as the emphasis was on atypical antipsychotics evaluated and FDA-approved in MDD in adults who were inadequate responders rather than those meeting criteria for TRD.1,13 It is the view of the FDA that the nomenclature pertaining to adequacy of response in MDD and TRD is imprecise and undoubtedly includes overlapping populations.1
Methods
Identification and Selection of Studies
Search Strategy
The study protocol was registered on PROSPERO (CRD420251114117). A systematic search was conducted using the databases PubMed/MEDLINE, PsycINFO, the Cochrane Library, and Embase using medical subject heading terms and text keywords. All relevant studies were also manually searched from the US National Institutes of Health–funded clinical trial registry, the European Union clinical trial registry, and Google Scholar. The searches were conducted from database inception through July 15, 2025, and no language restrictions were imposed. The 2 lumateperone studies that were identified and included were not published at the time of the analysis; access to these studies was provided by the first author, who is a coauthor on one of the studies (ie, study 501),14and the sponsor, Intra-Cellular Therapies, provided a copy of the second study (ie, study 502)15on request for the purpose of the network analysis. Both studies were subsequently published in 2025. Additional details are listed in the eMethods in Supplement 1 (eTables 1-3 in Supplement 1).
Eligibility Criteria
Inclusion criteria were established prior to article reviews and were as follow: (1) patients aged 18 years or older with a diagnosis of MDD using standardized diagnostic criteria (eg, DSM-IV, DSM-IV-TR, DSM-5, and DSM-5-TR) with inadequate responses to previous antidepressant trials; and (2) double-blind pivotal RCTs comparing FDA-approved adjunctive atypical antipsychotic therapies (ie, antidepressants combined with either aripiprazole, brexpiprazole, cariprazine, quetiapine XR, or lumateperone) to placebo.
Main Outcomes and Measures
The main outcomes were efficacy (ie, response defined as ≥50% improvement in overall depressive symptom severity using the Montgomery-Åsberg Depression Rating Scale [MADRS]) and acceptability (ie, all-cause discontinuation rate). The secondary outcome measures included remission (MADRS total score ≤8 or ≤10), change in overall severity of depressive symptoms, and discontinuation due to adverse events.
The outcome measures for efficacy, remission, and severity of depressive symptoms were based on the MADRS score, and the primary end point was at week 6, which accords with regulatory guidance in evaluating acute adjunctive efficacy in MDD.16Definitions of all outcome measures are listed in eTable 3 in Supplement 1. In addition to the aforementioned outcome measures, the following exploratory outcomes were also examined: Clinical Global Impressions–Severity (CGI-S), CGI-Improvement (CGI-I), 7% or greater weight gain, Sheehan Disability Scale (SDS), and extrapyramidal symptoms.17 ,18 Information on data extraction and quality assessment is listed in the eMethods in Supplement 1.
Statistical Analysis
First, we estimated a mean difference (MD) for a continuous outcome (standardized mean difference was not used as all studies used the MADRS as the primary efficacy parameter), severity of depressive symptoms, and risk ratios (RRs) for all other dichotomous outcomes and their corresponding 95% credible intervals ([CrIs] for bayesian approach) and 95% confidence intervals (for frequentist approach) using network meta-analyses. A single study identified that limited enrollment to the geriatric population (ie, age ≥60 years) was excluded from the main analysis due to potential heterogeneity.19 The geriatric study was, however, included in the sensitivity analysis.19
Group-level data and the normal likelihood function were used for continuous outcomes, and the binomial likelihood function was used for dichotomous outcomes. The study effect sizes were then synthesized using random-effects models. In particular, the gemtc package in R software version 4.3.1 (R Foundation for Statistical Computing) was used for bayesian network meta-analysis.20 ,21 Additional details (eg, bayesian and frequentist estimates) are provided in the eMethods in Supplement 1.
After conducting the main analyses, multiple subgroup and sensitivity analyses were also conducted using both bayesian and frequentist approaches. The analyses were repeated (1) with the inclusion of the study that had the older adult population only; (2) with studies published in or after 2010 only (to attenuate the placebo effects over time); and (3) stratified by individual dose (to understand dose-specific treatment effects better; see eTable 4 in Supplement 1 for rationale).19 Unless otherwise noted, a 2-sided P value less than .05 was considered statistically significant.
Results
Study Selection Process
The literature search yielded 1407 articles, of which 65 were eligible after screening titles and abstracts and removing duplicates. Of the eligible studies, 45 were further excluded after full-text screening. Six independent investigators (R.S.M., S.R.S., A.T.H.K., C.E.D., H.X., and T.G.R.) discovered 6 additional studies by manually searching reference lists, clinical registries, and Google Scholar, and 2 of these studies were included (eFigure 1 in Supplement 1).
Study Characteristics
A total of 22 studies comprising 10 962 participants (n = 1297 patients receiving aripiprazole; n = 1973 patients receiving brexpiprazole; n = 1894 patients receiving cariprazine; n = 483 patients receiving lumateperone; n = 719 patients receiving quetiapine XR; and n = 4596 patients receiving placebo) were included in the systematic review and network meta-analyses (eTable 3 in Supplement 1).19 ,22–42 All of the included RCTs were double blind and conducted in the outpatient setting, and 21 of 22 RCTs (95.5%) had sponsorship from industry (eTable 3 in Supplement 1). eTable 3 in Supplement 1 provides details of study characteristics, including mean age, proportion of female sex, and dosing information for all included studies. Meta-analytical networks were formulated (Figure 1).
Figure 1. Network Plot of Primary Outcomes, Efficacy and Acceptability
Across individual drugs (A) and stratified by individual drugs (B). The lines link treatments that were directly compared in randomized clinical trials (RCTs). The thickness of the lines corresponds to the number of RCTs evaluating the comparison. The size of the nodes corresponds to the number of participants assigned to the treatment. XR indicates extended release.
Primary Outcomes: Efficacy and Acceptability
Compared to placebo, lumateperone had the highest efficacy (RR, 1.72; 95% CrI, 1.40-2.15), followed by aripiprazole (RR, 1.53; 95% CrI, 1.32-1.77), brexpiprazole (RR, 1.38; 95% CrI, 1.18-1.65), cariprazine (RR, 1.20; 95% CrI, 1.07-1.36), and quetiapine XR (RR, 1.15; 95% CrI, 0.96-1.35) (Figure 2A).
Figure 2. Forest Plots Showing Efficacy (Response Rate [A]) and Acceptability (Dropout Rate [B]) at the End of Treatment (Week 6)
XR indicates extended release.
The highest acceptability was noted for aripiprazole (RR, 1.16; 95% CrI, 0.89-1.50), followed hierarchically by cariprazine (RR, 1.44; 95% CrI, 1.15-1.82), brexpiprazole (RR, 1.47; 95% CrI, 1.18-1.85), quetiapine XR (RR, 1.56; 95% CrI, 1.14-2.12), and lumateperone (RR, 2.30; 95% CrI, 1.45-3.84) compared to placebo (Figure 2B).
Surface under the cumulative ranking curve (SUCRA) values also aligned with the aforementioned hierarchy of efficacy and acceptability (eFigure 2 in Supplement 1). Pairwise comparisons of individual drugs are listed in the league table (eTable 5 in Supplement 1). These findings are consistent in the frequentist approach (eFigures 3 and 4 in Supplement 1) and in the following subgroup analyses: (1) network meta-analyses with the inclusion of the older adult population (eFigures 5-8 in Supplement 1) and (2) network meta-analyses with studies published in or after 2010 (eFigures 9-12 in Supplement 1).
Primary Outcomes: Efficacy and Acceptability, Stratified by Individual Dose
When compared to placebo, lumateperone, 42 mg, had the greatest effect size for efficacy (RR, 1.73; 95% CrI, 1.42-2.16), followed by aripiprazole, 11 mg (RR, 1.67; 95% CrI, 1.36-2.04), and aripiprazole, 3 mg (RR, 1.49; 95% CrI, 1.09-2.03) (Figure 3A). For acceptability, however, lumateperone, 42 mg, had overall lower estimate compared to placebo (RR, 2.35; 95% CrI, 1.49-3.81), followed by quetiapine XR, 300 mg (RR, 1.80; 95% CrI, 1.25-2.68), and brexpiprazole, 2 mg (RR, 1.63; 95% CrI, 1.24-2.16) (Figure 3B). SUCRA values showed similar patterns (eFigure 13 in Supplement 1). These findings were consistent in the frequentist approach (eFigures 14 and 15 in Supplement 1) and in the following subgroup analyses: (1) network meta-analyses with the inclusion of the older adult population (eFigures 16-19 in Supplement 1) and (2) network meta-analyses with studies published in or after 2010 (eFigures 20-23 in Supplement 1).
Figure 3. Forest Plots of Adjunctive Antipsychotics vs Placebo for Primary Outcomes, Stratified by Individual Dose, at the End of Treatment (Week 6)
Panels represent primary outcomes of efficacy (response [A]) and acceptability (dropout rate [B]). Network meta-analytic estimates of treatment effect of each drug vs placebo are reported as risk ratios (RRs) or mean differences and their corresponding 95% credible intervals (CrIs). For efficacy, an RR >1.0 favors the treatment compared to placebo. For acceptability, an RR <1.0 favors the treatment compared to placebo. XR indicates extended release.
Secondary Outcomes: Remission, Severity of Depressive Symptoms, and Discontinuation Due to Adverse Events
Lumateperone, when compared to placebo, had the greatest effect size for remission (RR, 1.87; 95% CrI, 1.31-2.69) and reduction in overall severity of depressive symptoms (MD, −4.83; 95% CrI, −6.42 to −3.21), followed by aripiprazole (RR, 1.58; 95% CrI, 1.28-1.95; MD, −2.34; 95% CrI, −3.33 to −1.37) (Figure 4).
Figure 4. Forest Plots Showing Secondary Outcomes at the End of Treatment (Week 6)
Panels represent secondary outcomes of remission (A), severity of depressive symptoms (B), and discontinuation due to adverse events (C). Network meta-analytic estimates of treatment effect of each drug versus placebo are reported as risk ratios (RRs) or mean differences and their corresponding 95% credible intervals (CrIs). For efficacy and remission, a risk ratio (RR) >1.0 favors the treatment compared to placebo. For severity of depressive symptoms, a mean difference <0 favors the treatment compared to placebo. For acceptability and discontinuation due to adverse events, an RR <1.0 favors the treatment compared to placebo. XR indicates extended release.
For discontinuation due to adverse events, lumateperone had a relatively higher rate (RR, 16.50; 95% CrI, 4.57-80.50), followed by quetiapine XR (RR, 6.70; 95% CrI, 2.90-17.90) (Figure 4). These results were consistent with SUCRA values. Findings were similar in the frequentist approach (eFigures 3 and 4 in Supplement 1) and in the following subgroup analyses: (1) network meta-analyses with the inclusion of the older adult population (eFigures 5-8 in Supplement 1) and (2) network meta-analyses with studies published in or after 2010 (eFigures 9-12 in Supplement 1). Pairwise comparisons of individual drugs are listed in the league table (eTable 5 in Supplement 1).
Secondary Outcomes: Remission, Severity of Depressive Symptoms, and Discontinuation Due to Adverse Avents, Stratified by Individual Dose
Lumateperone, 42 mg, compared to placebo had the greatest effect size for remission (RR, 1.86; 95% CrI, 1.33-2.62), followed by aripiprazole, 11 mg (RR, 1.77; 95% CrI, 1.35-2.36) (Figure 5A), and for reduction in severity of depressive symptoms (lumateperone, 42 mg: MD, −4.85; 95% CrI, −6.54 to −3.15; aripiprazole, 11 mg: MD, −3.27; 95% CrI, −5.07 to −1.45) (Figure 5B).
Figure 5. Forest Plots Showing Secondary Outcomes at the End of Treatment, Stratified by Individual Dose (at the End of Treatment [Week 6])
Panels represent secondary outcomes of remission (A), severity of depressive symptoms (B), and discontinuation due to adverse events (C). Network meta-analytic estimates of treatment effect of each drug vs placebo are reported as risk ratios (RRs) or mean differences and their corresponding 95% credible intervals (CrIs). For efficacy and remission, an RR >1.0 favors the treatment compared to placebo. For severity of depressive symptoms, a mean difference <0 favors the treatment compared to placebo. For acceptability and discontinuation due to adverse events, an RR <1.0 favors the treatment compared to placebo. XR indicates extended release.
For discontinuation due to adverse events, lumateperone, 42 mg, had the highest rate (RR, 15.60; 95% CrI, 4.62-78.10), followed by quetiapine XR, 300 mg (RR, 8.27; 95% CrI, 2.86-30.50) (Figure 5C). Findings of SUCRA estimates are consistent with these findings (eFigure 13 in Supplement 1). These main findings are consistent in the frequentist approach (eFigures 14 and 15 in Supplement 1) and in the following subgroup analyses: (1) network meta-analyses with the inclusion of the older adult population (eFigures 16-19 in Supplement 1) and (2) network meta-analyses with studies published in or after 2010 (eFigures 20-23 in Supplement 1). Pairwise comparisons of individual drugs stratified by individual dose are listed in the league table (eTable 6 in Supplement 1).
Exploratory Outcomes
For overall extrapyramidal symptoms, tremor and/or akathisia individual drugs were not significantly different from placebo (eFigure 24 in Supplement 1). Similar patterns were found when stratified by the individual dose (eFigure 25 in Supplement 1).
Model Assumptions and Publication Bias
We used the node-splitting method, which showed consistency between direct and indirect comparisons for all individual outcomes (all nonsignificant); no evidence of inconsistency was detected. In our primary analyses, we did not find any publication bias using the funnel plots, Egger tests, and Begg and Mazumdar tests (eFigure 26 in Supplement 1) and in subgroup analyses with the inclusion of older adult populations and analyses using publications in or after 2010 (eFigures 27 and 28 in Supplement 1). We also did not detect any potential publication bias in all network meta-analyses stratified by individual dose (eFigures 29-31 in Supplement 1).
Risk of Bias and Justification
Methodological quality of the included studies was rated low to high; justification is provided in eTable 7 in Supplement 1. Overall, 4 of 22 studies (18.2%) had some concerns for bias, and the other 18 of 22 studies (81.8%) had a low risk of bias.
Discussion
Taken together, these results indicate that the magnitude of improvement in depressive symptoms observed with adjunctive atypical antipsychotics is clinically meaningful (ie, ≥2 point improvement as measured by the MADRS compared to placebo).43–45 In addition, a hierarchy of efficacy (ie, response rate) was observed across the agents, with lumateperone followed by aripiprazole exhibiting higher relative efficacy. The relatively higher efficacy estimate for lumateperone was also supported by the secondary outcomes (eg, remission, overall depressive symptom improvement), as well as exploratory efficacy measures (eg, improvement in overall CGI-S and CGI-I scores and/or SDS).
A hierarchy of acceptability (ie, all-cause discontinuation rate) was also observed, with dopamine partial agonists (eg, aripiprazole, cariprazine, brexpiprazole) at the higher end of acceptability and quetiapine XR and lumateperone at the lower end. Results from the secondary outcome measures (ie, discontinuation due to adverse events) accorded with the coprimary outcomes. Also, results from the exploratory outcomes were largely supportive of the coprimary and secondary outcomes. Some of the exploratory outcomes, however, were discordant with the primary and secondary outcomes (eg, lumateperone was the only atypical antipsychotic not associated with a ≥7% weight increase compared to placebo, despite having lower overall acceptability) (eFigures 24 and 25 in Supplement 1).8,46
The acceptability of atypical antipsychotics is influenced by dosing initiation, titration, and target dosing. For example, aripiprazole, brexpiprazole, cariprazine, and quetiapine XR were studied using multiple fixed-dose and flexible-dose paradigms, while lumateperone was evaluated with a single fixed-dose design (ie, 42 mg). Whether initiating lumateperone at a lower dose (ie, 10.5 mg or 21 mg) and titrating to 42 mg as the target dose and/or implementing a flexible-dose design would have affected overall acceptability remains an open question.11 Dosing initiation, titration, and flexibility may inadvertently conflate tolerability with study design, which should be considered when interpreting our results.
Limitations
There are methodological aspects to our analysis that limit inferences and interpretations of our findings. First, most studies were industry sponsored with 1 exception (Lenze and colleagues,19 2015), and there are no head-to-head trials comparing atypical antipsychotics in the treatment of adults with MDD. In addition, eligibility was confined to those studies that enrolled adults aged 18 years or older, and results cannot be generalized to the pediatric population.47,48 This systematic review and network meta-analysis only included studies evaluating the short-term efficacy, tolerability, and safety of select adjunctive atypical antipsychotic agents in MDD that have been FDA-approved and supported by large, replicated pivotal trials.49
These results also need to be interpreted cautiously, as heterogeneity in the sample composition enrolled in each of the component studies could significantly affect the hierarchy of efficacy and/or tolerability observed. For example, differences in the baseline depression severity and duration of the index depressive episode, as well as the treatment history, could meaningfully affect not only the efficacy estimate of the atypical antipsychotic, but also response to placebo and drug-placebo difference. Hence, differences observed across atypical agents may not fully reflect intrinsic differences in pharmacology but instead may be by-products of the aforementioned sample heterogeneity.
Furthermore, we did not endeavor to identify baseline sociodemographic or illness characteristics that may moderate treatment outcomes for each of the atypical antipsychotics. For example, depressive episodes are highly heterogeneous, and clinicians often select an atypical antipsychotic to target specific phenomenological features.11,50–69 It should not be assumed that the efficacy hierarchy that we have observed, obtained in heterogeneous populations, would reflect the efficacy of each atypical antipsychotic in specifically targeting phenomenological features, such as mixed features, anxious distress, anhedonia, and rumination. Also, a cost-effectiveness analysis was not conducted, and concealment of allocation was not evaluated in the included studies.
The definition of inadequate response was not identical across the 5 atypical antipsychotic agents analyzed herein. For example, the studies that evaluated aripiprazole and brexpiprazole defined inadequate response as historical failure to 1 to 3 prior antidepressants, as well as a prospective antidepressant failure (ie, brexpiprazole). Studies evaluating cariprazine and lumateperone defined inadequate response as historical failure to 1 to 2 prior antidepressants without the requirement for a prospective antidepressant failure. With respect to quetiapine XR, the number of prior antidepressants and inadequate response was not consistently specified.
The magnitude of improvement in participants assigned to placebo influences the effect size estimates of the active treatment. As with all clinical trial programs, the placebo response in persons with MDD in the trials that we included were highly variable. For example, the overall improvement in the MADRS total score at week 6 in persons assigned to placebo were as follows: aripiprazole, −5.8 to −6.4; brexpiprazole, −5.15 to −6.33; cariprazine, −11.5 to −12.5; quetiapine XR, −11.7 to 12.21; and lumateperone, −9.8 to −10.2. Hence, a hierarchy of placebo response was also observed, with the highest placebo response in the cariprazine trials and lowest placebo response in the aripiprazole and brexpiprazole studies. Consequently, the positioning of each agent in the estimated efficacy hierarchy needs to be carefully interpreted within the broader context of meaningful differences across the studies in the placebo response.
Priority research vistas are the need for acute and/or long-term head-to-head comparative effectiveness studies in MDD comparing atypical antipsychotics to each other as well as alternative antidepressant switch options (eg, bupropion combination) or neuromodulation.70–75 Whether the 5 atypical antipsychotics herein are efficacious in adults with TRD and their relative efficacy to intranasal esketamine are additional priority research questions.70,76–80
Conclusions
Overall, this systematic review and network meta-analysis indicates that efficacy and acceptability differences exist between adjunctive atypical antipsychotics in the treatment of adults with MDD in inadequate response to antidepressants. Clinical decisions regarding atypical antipsychotics need to simultaneously weigh estimated relative efficacy as well as acceptability. These results address an important knowledge gap and provide decision support to practitioners and persons with lived experience, as well as providing data to inform treatment algorithms, policy, and reimbursement considerations.
Although this study focused on FDA-approved agents, not all agents are approved in other jurisdictions (ie, quetiapine XR is the only agent approved by the European Medicine Agencies in MDD). The absence of long-term maintenance efficacy for any adjunctive atypical antipsychotic remains a knowledge gap (although monotherapy maintenance therapy exists for quetiapine XR) and has precluded approvals of many atypicals in some jurisdiction in MDD (eg, European Medicine Agencies).81,82
Article Information
Accepted for Publication: February 10, 2026.
Published Online: May 6, 2026. doi:10.1001/jamapsychiatry.2026.0658
Corresponding Author: Roger S. McIntrye, MD, Brain and Cognition Discovery Foundation, 77 Bloor St W, Ste 617, Toronto, ON M5S 1M2, Canada (roger.mcintyre@bcdf.org)
Author Contributions: Dr McIntyre had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: McIntyre, Stahl, Shim, Goldberg, Correll, Kwan, Rhee.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: McIntyre, Shim, Kwan, Rhee.
Critical review of the manuscript for important intellectual content: All authors.
Statistical analysis: Shim, Goldberg, Rhee.
Administrative, technical, or material support: McIntyre, Stahl, Shim, Kwan, Dri, Rhee.
Supervision: McIntyre, Correll, Rhee.
Conflict of Interest Disclosures: Dr McIntyre reported grants from the Canadian Institutes of Health Research, the Global Alliance for Chronic Diseases, the Milken Institute, and the National Natural Science Foundation of China and speaker or consultation fees from AbbVie, Alkermes, atai Life Sciences, Axsome Therapeutics, Bausch Health, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Intra-Cellular Therapies, Janssen, Kris, Lundbeck, the Milken Institute, Mitsubishi Tanabe, Neumora Therapeutics, NeuraWell Therapeutics, Neurocrine Biosciences, NewBridge Pharmaceuticals, Novo Nordisk, Otsuka, Pfizer, Purdue, Sage, Sanofi, Sunovion, Takeda, and Viatris outside the submitted work. Dr Stahl reported personal fees from AbbVie, Acadia, AdhereTech, Alkermes, Autobahn, Axsome Therapeutics, Aytu BioPharma, Bristol Myers Squibb, Clexio Biosciences, Delix Therapeutics, Intra-Cellular Therapies, LivaNova, Lundbeck, Neurocrine Biosciences, Otsuka, Supernus Pharmaceuticals, Tonix Pharmaceuticals, and Vanda Pharmaceuticals during the conduct of the study and stock options in Delix Therapeutics, Genomind, Lipidio Pharmaceuticals, and NeuraWell Therapeutics. Dr Pompili reported receiving lecture and advisory board honoraria or engaged in clinical trial activities in the last 5 years with AbbVie, Angelini Pharma, Boehringer Ingelheim, EG Stada, Fidia, Johnson & Johnson, Lundbeck, Merck Sharp & Dohme, Newron Pharmaceuticals, Neopharmed Gentili, Otsuka, Pfizer, Recordati, Rovi, Teva, and Viatris outside the submitted work. Dr Goldberg reported personal fees from AbbVie, Alkermes, Alvogen, Axsome Therapeutics, Bristol Myers Squibb, Intra-Cellular Therapies, Johnson & Johnson, Otsuka, and Vanda Pharmaceuticals and royalties from American Psychiatric Publishing and from Cambridge University Press outside the submitted work. Dr Correll reported royalties fees from UpToDate; serving as a consultant and/or advisor to or receiving honoraria from AbbVie, Alkermes, Allergan, Angelini, Aristo, Boehringer Ingelheim, Bristol Myers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Eli Lilly, Gedeon Richter, Hikma, Holmusk, Intra-Cellular Therapies, Jamjoom Pharma, Janssen/Johnson & Johnson, Karuna, LB Pharma, Lundbeck, MapLight Therapeutics, MedinCell, MedLink, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neumora Therapeutics, Neurocrine Biosciences, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Saladax, Sanofi, Seqirus, Servier, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus Pharmaceuticals, Tabuk, Takeda, Terran, Teva, Tolmar, Vertex, Viatris, and Xenon Pharmaceuticals; providing expert testimony for Janssen, Lundbeck, and Otsuka; serving on a data safety monitoring board for Compass Pathways, Intra-Cellular Therapies, Relmada, Reviva, and Rovi; receiving grants from Boehringer Ingelheim, Janssen, and Takeda; and having stock options in Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Medlink, Mindpax, Quantic, and Terran outside the submitted work. Dr Vinberg reported speaker fees from Eli Lilly, Johnson & Johnson, and Lundbeck outside the submitted work. No other disclosures were reported.
Funding/Support: None reported.
Data Sharing Statement: See Supplement 2.
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