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(lumateperone)

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CAPLYTA® (lumateperone)
Medical Information

CAPLYTA - Network Meta-Analysis in Adjunctive Major Depressive Disorder

Last Updated: 05/04/2026

SUMMARY

  • The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
  • 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 adjunctive therapy in adults with major depressive disorder (MDD).1 

CLINICAL DATA

Network Meta-analysis

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

Study Design/Methods

  • Short-term, randomized, double-blind, placebo-controlled registrational trials were identified from Section 14 of United States (US) product labeling; and CAPLYTA, aripiprazole, brexpiprazole, cariprazine, and quetiapine XR were evaluated across 11 treatment doses.
  • To reflect treatment-level clinical decision-making, doses were pooled within each treatment, yielding a star-shaped network with placebo + antidepressant therapy (ADT) as the common comparator and 5 active treatment nodes as follows:
    • ADT + CAPLYTA (42 mg/day)
    • ADT + aripiprazole (2-20 mg/day)
    • ADT + brexpiprazole (1-3 mg/day)
    • ADT + cariprazine (1-4.5 mg/day)
    • ADT + quetiapine XR (150-300 mg/day)
  • Bayesian fixed-effect NMAs were conducted using 3 Markov Chain Monte Carlo simulations with 30,000 iterations each, including 20,000 burn-in iterations.
  • Outcomes included efficacy endpoints and adverse events that were consistently reported and available for ≥9 of 10 trials.
  • Outcomes were assessed at week 6 for all trials where available; for the 8-week cariprazine trial, week 8 data were used for Montgomery-Åsberg Depression Rating Scale (MADRS) remission, Clinical Global Impressions-Severity (CGI-S), and safety outcomes.
  • Results were summarized vs placebo + ADT and as pairwise treatment comparisons and pairwise probabilities of superiority.
  • A probability >85% or <15% indicated that a treatment was favored or unfavored relative to the comparator respectively, whereas a probability between these thresholds (15%-85%) indicated that the treatment was comparable to the comparator.

Results

  • A total of 10 registrational trials identified from US product labeling were included in the analysis, comprising 2 trials each for CAPLYTA, aripiprazole, brexpiprazole, cariprazine, and quetiapine XR. Characteristics of these trials are summarized in Table: Characteristics of the Included Registration Trials.

Characteristics of the Included Registration Trials1 
Atypical Antipsychotic
Clinical Trial Number
Phase
Duration of
Double-blind Phase
Dosage Type
Dosage
CAPLYTA
NCT04985942
3
6 weeks
Fixed dose
42 mg/day
CAPLYTA
NCT05061706
3
6 weeks
Fixed dose
42 mg/day
Aripiprazole
NCT00095823
3
6 weeks
Flexible dose
2-20 mg/day
Aripiprazole
NCT00095758
3
6 weeks
Flexible dose
2-20 mg/day
Brexpiprazole
NCT01360645
3
6 weeks
Fixed dose
2 mg/day
Brexpiprazole
NCT01360632
3
6 weeks
Fixed dose
1 mg/day
3 mg/day
Cariprazine
NCT03738215
3
6 weeks
Fixed dose
1.5 mg/day
3 mg/day
Cariprazine
NCT01469377
2
8 weeks
Flexible dose
1-2 mg/day
2-4.5 mg/day
Quetiapine XR
NCT00326105
3
6 weeks
Fixed dose
150 mg/day
300 mg/day
Quetiapine XR
NCT00351910
3
6 weeks
Fixed dose
150 mg/day
300 mg/day
Abbreviations: FDA, Food and Drug Administration; NCT, National Clinical Trial; XR, extended release.
Note: Three trials evaluated a dosage that differed slightly from the FDA label-recommended dose ranges for aripiprazole (2-15 mg/day) and cariprazine (1.5-3 mg/day).
  • All treatment nodes were favored vs placebo + ADT for MADRS change from baseline, MADRS response, and CGI-S change from baseline. Four out of 5 treatment nodes were favored versus placebo + ADT for MADRS remission, with the remainder comparable.

Forest Plot Comparing Change From Baseline in the MADRS Score vs Placebo + ADT1 

Abbreviations: ADT, antidepressant therapy; MADRS, Montgomery-Åsberg Depression Rating Scale; XR, extended release.

Note: Probabilities >99.5% are listed as 100% due to rounding.


Pairwise Treatment Comparisons and Pairwise Probabilities of Efficacy Outcomes vs CAPLYTA 42 mg1 
CAPLYTA 42 mg/day vs Comparator
Change from Baseline in MADRS Score, MD (95% CrI)
MADRS Response, OR (95% CrI)
MADRS Remission, OR (95% CrI)
Change from Baseline in CGI-S Score, MD (95% CrI)
Aripiprazole
2-20 mg/day
-1.77 (-3.2, -0.32)
Probability of superiority: 99%a
1.20 (0.78, 1.87)
Probability of superiority: 80%
1.15 (0.7, 1.9)
Probability of superiority: 72%
-0.16 (-0.36, 0.05)
Probability of superiority: 93%a
Brexpiprazole
1-3 mg/day
-2.54 (-4.02, -1.04)
Probability of superiority: 100%a
1.32 (0.84, 2.09)
Probability of superiority: 89%a
1.43 (0.83, 2.42)
Probability of superiority: 91%a
-0.37 (-0.55, -0.19)
Probability of superiority: 100%a
Cariprazine
1-4.5 mg/day
-2.87 (-4.44, -1.29)
Probability of superiority: 100%a
1.6 (1.13, 2.29)
Probability of superiority: 100%a
2.2 (1.45, 3.31)
Probability of superiority: 91%a
-0.4 (-0.62, -0.18)
Probability of superiority: 100%a
Quetiapine XR
150-300 mg/day
-2.01 (-3.66, -0.36)
Probability of superiority: 99%a
1.55 (1.05, 2.30)
Probability of superiority: 99%a
1.3 (0.84, 2.02)
Probability of superiority: 88%a
-0.25 (-0.45, -0.06)
Probability of superiority: 99%a
Abbreviations: CGI-S, Clinical Global Impressions-Severity; CrI, credible interval; MADRS, Montgomery-Åsberg Depression Rating Scale; MD, mean difference; OR, odds ratio; XR, extended release.
aCAPLYTA was favored vs the treatment comparator in the column (>85% probability of superiority).

Forest Plot Comparing ≥7% Weight Increase vs Placebo + ADT1 

Abbreviations: ADT, antidepressant therapy; XR, extended release.

Forest Plot Comparing Akathisia vs Placebo + ADT1 

Abbreviations: ADT, antidepressant therapy; XR, extended release.

Forest Plot Comparing Somnolence vs Placebo + ADT1 

Abbreviations: ADT, antidepressant therapy; XR, extended release.


Pairwise Treatment Comparisons and Pairwise Probabilities of Safety Outcomes vs CAPLYTA 42 mg1 
CAPLYTA 42 mg/day vs comparator
Weight Change from Baseline, MD (95% CrI)
≥7% Weight Increase from Baseline, OR (95% CrI)
Akathisia, OR (95% CrI)
Somnolence, OR (95% CrI)
Aripiprazole
2-20 mg/day
-1.42 (-1.82, -1.03)
Probability of superiority: 100%a
0.03 (0, 0.21)
Probability of superiority: 100%a
0.30 (0.05, 2.54)
Probability of superiority: 88%a
2.78 (0.84, 9.22)
Probability of superiority: 5%b
Brexpiprazole
1-3 mg/day
-1.34 (-1.7, -0.98)
Probability of superiority: 100%a
0.11 (0.01, 0.69)
Probability of superiority: 99%a
0.40 (0.06, 3.52)
Probability of superiority: 81%
0.45 (0.05, 2.04)
Probability of superiority: 83%
Cariprazine
1-4.5 mg/day
-0.86 (-1.17, -0.54)
Probability of superiority: 100%a
0.15 (0.02, 0.91)
Probability of superiority: 98%a
0.28 (0.04, 2.52)
Probability of superiority: 88%a
2.83 (1.21, 6.87)
Probability of superiority: 1%b
Quetiapine XR
150-300 mg/day
-1.01 (-1.4, -0.61)
Probability of superiority: 100%a
0.1 (0.01, 0.61)
Probability of superiority: 99%a
0.91 (0.09, 10.07)
Probability of superiority: 53%
0.61 (0.23, 1.58)
Probability of superiority: 85%
Abbreviations: CrI, credible interval; MD, mean difference; OR, odds ratio; XR, extended release.
aCAPLYTA was favored vs the treatment comparator in the column (>85% probability of superiority).
bCAPLYTA was unfavored vs the treatment comparator in the column (<15% probability of superiority).

Limitations

  • Results are based on indirect comparisons in the absence of head-to-head randomized trials and should therefore be interpreted in the context of the inherent limitations of indirect evidence and the assumptions underlying the NMA framework, including transitivity.
  • Pooling across doses assumes comparable effects across dose levels; if a dose-response relationship exists, the resulting estimates may be less interpretable and may not reflect the effects of individual doses. Nevertheless, findings from the pooled-dose NMA were consistent with those from the analysis conducted at the treatment-dose level.
  • Trials and patient populations were generally comparable, but some between-study heterogeneity may remain.
  • As the analysis was limited to registrational trials, results may not fully reflect outcomes observed in broader real-world clinical practice.

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, and DERWENT® (and/or other resources, including internal/external databases) was conducted on 23 April 2026.

References

Show
1 Cutler AJ, Lemyre A, Zhang Q, et al. Efficacy and safety of lumateperone versus atypical antipsychotics as adjunctive therapy in major depressive disorder: a pooled-dose network meta-analysis. Poster presented at: 2026 Neuroscience Education Institute (NEI) Spring Congress; May 1-3, 2026; Kissimmee, FL.