CAPLYTA – Network Meta-Analysis in Adjunctive Major Depressive Disorder

SUMMARY

• A Bayesian network meta-analysis (NMA) indirectly compared the treatment effect of CAPLYTA with other atypical antipsychotics (aripiprazole, brexpiprazole, cariprazine, and quetiapine extended release [XR]), when used as an adjunctive therapy in adults with major depressive disorder (MDD).¹
• An NMA compared the efficacy and acceptability of atypical antipsychotics (CAPLYTA, aripiprazole, brexpiprazole, cariprazine, and quetiapine XR) for the adjunctive treatment of MDD, across 22 clinical trials.²

NETWORK META ANALYSES

Cutler et al (2026)¹ conducted an NMA to indirectly compare the treatment effect of CAPLYTA with other atypical antipsychotics (aripiprazole, brexpiprazole, cariprazine, and quetiapine XR), when used as an adjunctive therapy in adults (18-65 years of age) with MDD.

Study Design/Methods

• The most recent Food and Drugs Administration (FDA) product labels were retrieved in August 2025 to identify relevant clinical trials of United States (US)-approved atypical antipsychotics used as adjunctive therapy to antidepressants for MDD in adults, including aripiprazole, brexpiprazole, cariprazine, CAPLYTA, and quetiapine XR.
• Data were extracted from primary and secondary publications, supplemented with ClinicalTrials.gov records and US prescribing information; CAPLYTA trial data were further supplemented with clinical study reports provided by Johnson & Johnson Innovative Medicine.
• Extraction covered study design, inclusion and exclusion criteria, patient characteristics, interventions and comparators, methods, assessment timing, summary statistics for baseline characteristics and efficacy and safety results and was conducted through dual independent review and adjudication.
• Study quality was evaluated using the Cochrane Collaboration's Risk of Bias 2.0 tool, assessing bias across the following 5 domains:
  • Randomization process
  • Intervention deviations
  • Missing outcome data
  • Outcome measurement
  • Selection of reported results
• The feasibility of conducting an NMA was assessed based on treatment network connectivity; presence of a common comparator; and cross-trial comparability of study design, patient baseline characteristics, outcome definitions and timing of assessments. NMAs were conducted for the following outcomes:
  • Efficacy: mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) score, mean change from baseline in Clinical Global Impression-Severity (CGI-S) score, MADRS clinical response (≥50% reduction in MADRS score from baseline), MADRS remission (MADRS score ≤10 or MADRS score ≤10 with ≥50% reduction from baseline, depending on the trial)
  • Safety outcomes: mean weight change from baseline, proportion of patients with ≥7% weight gain from baseline, akathisia, somnolence
• Separate Bayesian fixed-effect NMAs were conducted for each outcome using arm-level data, following guidance from the National Institute for Health and Care Excellence (NICE) and the Professional Society for Health Economics and Outcomes Research (ISPOR).
• Results were summarized versus placebo + antidepressant therapy (ADT) and as pairwise comparisons and as probabilities of treatment superiority.
• Outcomes were assessed at week 6 for all trials where available; for the 8-week cariprazine trial, week 8 data were used only when these were the only results reported.

Results

• A total of 10 randomized, double-blind, parallel-group, placebo-controlled, registrational trials identified from US prescribing information were included in the analysis, comprising 2 trials each for aripiprazole, brexpiprazole, cariprazine, CAPLYTA, and quetiapine XR.
  • Table: Characteristics of Included Registration Trials

• For results specific to change from baseline in MADRS score, change from baseline in CGI-S score, MADRS clinical response, and MADRS remission, respectively, see the following:
  • Figure: Forest Plot Comparing Change from Baseline in MADRS Score Versus Placebo + ADT
  • Figure: Forest Plot Comparing Change from Baseline in CGI-S Score Versus Placebo + ADT
  • Figure: Forest Plot Comparing Change from Baseline in MADRS Clinical Response Versus Placebo + ADT
  • Figure: Forest Plot Comparing Change from Baseline in MADRS Remission Versus Placebo + ADT

• For safety results specific to change from baseline in body weight, ≥7% weight increase, akathisia, somnolence, respectively, see the following:
  • Figure: Forest Plot Comparing Change from Baseline in Body Weight Versus Placebo + ADT
  • Figure: Forest Plot Comparing ≥7% Weight Increase Versus Placebo + ADT
  • Figure: Forest Plot Comparing Akathisia Versus Placebo + ADT
  • Figure: Forest Plot Comparing Somnolence Versus Placebo + ADT

Limitations

• Results were derived from indirect comparisons due to the absence of headtohead randomized trials and therefore depend on the validity of key NMA assumptions (eg, transitivity); although overall heterogeneity was limited, residual crosstrial differences (including differences in study phase, duration, dosing strategies, geographic distribution, and selected baseline characteristics) cannot be excluded.
• The impact of background antidepressant therapy on adverse event (AE) incidence could not be formally assessed in the NMA; however, post hoc analyses across included trials showed no meaningful differences in AE rates by background antidepressant use.
• The analysis was restricted to registrational trials considered informative by FDA; other trials may have been conducted that were not included in this NMA, therefore, interpretation of findings in the real-world population or trials outside the regulatory trial may be limited.
• Studied outcomes were limited to those consistently reported in registrational trials, and did not include key clinical domains (e.g., quality of life, social functioning, sexual dysfunction).
• CAPLYTA was evaluated at a fixed 42 mg/day dose, whereas comparators used flexible/multiple regimens; thus, its dose–response relationship in adjunctive MDD remains unassessed.

McIntyre et al (2026)² conducted an NMA to compare the efficacy and acceptability of FDA approved atypical antipsychotics (CAPLYTA, aripiprazole, brexpiprazole, cariprazine, and quetiapine XR), for their use as adjunctive therapy in adults with MDD.

Study Design/Methods

• A systematic literature search was conducted using PubMed/MEDLINE, PsycINFO, the Cochrane Library, and Embase from database inception through July 15, 2025.
• Studies were required to be doubleblind, pivotal, randomized clinical trials (RCTs) of FDA-approved atypical antipsychotics used as adjunctive therapy to antidepressants for MDD in adults (≥18 years of age), including aripiprazole, brexpiprazole, cariprazine, CAPLYTA, and quetiapine XR.
• Data extraction and risk of bias assessment were independently performed by 2 reviewers in accordance with Cochrane guidelines.
• Primary outcomes included efficacy, defined as response (≥50% reduction in depressive symptom severity based on the MADRS), and acceptability (all‑cause discontinuation rates).
• Secondary outcomes comprised of remission (MADRS total score ≤8 or ≤10), change in overall depressive symptom severity, 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.
• Exploratory outcomes included CGI‑S, ≥7% weight gain, and extrapyramidal symptoms (EPS).
• Continuous outcomes were analyzed using mean difference, while dichotomous outcomes were evaluated using risk ratios, with corresponding 95% CrI (Bayesian analyses).
• Unless otherwise specified, statistical significance was defined as a two-sided P<0.05.

Results

• A total of 22 double-blind, outpatient, RCTs were included in the analysis, comprising trials for aripiprazole, brexpiprazole, cariprazine, CAPLYTA, and quetiapine XR.
  • Table: Characteristics of Included RCTs

• For results specific to primary outcomes including efficacy (response rate) and acceptability (all-cause discontinuation rate) see the following:
  • Figure: Forest Plot of Adjunctive Antipsychotics vs Placebo for Response Rate at EOT
  • Figure: Forest Plot of Adjunctive Antipsychotics vs Placebo for Acceptability (All-cause Discontinuation Rate) at EOT

• For results specific to secondary outcomes including remission, severity of depressive symptoms and discontinuation due to AEs, see the following:²
  • Figure: Forest Plot of Adjunctive Antipsychotics vs Placebo for Remission at EOT
  • Figure: Forest Plot of Adjunctive Antipsychotics vs Placebo for Severity of Depressive Symptoms at EOT
  • Figure: Forest Plot of Adjunctive Antipsychotics vs Placebo for Discontinuation due to Adverse Events at EOT

• For results specific to outcomes including CGI-S, CGI-I response rate, ≥7% weight gain, SDS, EPS, and Akathisia, see the following:
  • Figure: Forest Plot of Adjunctive Antipsychotics vs Placebo for CGI-S by Bayesian analysis
  • Figure: Forest Plot of Adjunctive Antipsychotics vs Placebo for ≥7% weight gain by Bayesian analysis
  • Figure: Forest Plot of Adjunctive Antipsychotics vs Placebo for EPS by Bayesian analysis

Limitations

• Most included studies were industry-sponsored, with only 1 exception, and no direct head-to-head trials comparing atypical antipsychotics in adults with MDD were identified.
• The analysis was restricted to short-term outcomes related to efficacy, tolerability, and safety of selected FDA-approved adjunctive atypical antipsychotics supported by large pivotal trials. Interpretation of findings may be limited by variability in study populations across the included trials.
• Differences in baseline patient characteristics, including depression severity, duration of the current episode, and prior treatment exposure, may have influenced treatment effects, placebo response, and drug-placebo comparisons. The analysis did not evaluate the influence of baseline sociodemographic or clinical factors on treatment response.
• Variations observed between treatments may be attributable to differences in study populations rather than inherent pharmacologic properties.
• The reported comparative efficacy should not be interpreted as reflecting treatment effects for specific symptom profiles (e.g., mixed features, anxious distress, anhedonia, or rumination).
• Criteria used to define inadequate responses varied across studies.
• Variability in placebo response across studies, with relatively higher responses in cariprazine trials and lower responses in aripiprazole and brexpiprazole trials, should be considered when interpreting the relative positioning of treatments within the efficacy hierarchy.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 24 June 2026.