Early Week 2 Response Predicts Sustained Benefit with Adjunct Cariprazine in MDD

In a recent study, a response to adjunctive cariprazine by week 2 predicted sustained antidepressant benefit in major depressive disorder (MDD), with greater baseline depression linked to greater response.1

“This study highlights the importance of early symptom change, dose-response dynamics, and patient-level predictors in shaping response to adjunctive cariprazine,” wrote investigators Jeffrey R. Strawn, MD, and Jeffrey A. Mills, PhD, both from the department of pediatrics at the Cincinnati Children’s Hospital Medical Center.

In 2022, the US Food & Drug Administration (FDA) approved cariprazine (VRAYLAR) as an adjunctive treatment to antidepressants for MDD, supported by a phase 3 randomized, double-blind, placebo-controlled trial involving 751 participants across the US and Europe.2 Cariprazine is also approved to treat schizophrenia and depressive, acute manic, and mixed episodes associated with bipolar I disorder.

Three years after the FDA decision, methods for predicting which patients will respond to adjunctive cariprazine were still unknown.1 Strawn and Mills conducted a meta-analysis of 2 multicenter, double-blind, placebo-controlled phase 3 trials that compared adjunctive cariprazine 1.5 mg/day, 3 mg/day, and placebo in participants receiving stable antidepressant treatment. Across the 2 studies, there were 1501 participants.

The primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) scores, and secondary outcomes included Clinical Global Impressions–Improvement (CGI-I) and Hamilton Anxiety Rating Scale (HAM-A) scores. Investigators used Bayesian logarithmic trend models to characterize individual response trajectories and identify predictors of response.

Compared to placebo, adjunctive cariprazine at 1.5 mg/day (P <.001) and 3 mg/day (P =.002) significantly improved depressive symptoms. A response by week 2 predicted continued improvement across the 6-week trial.

Greater severity levels of depression at baseline predicted a larger response to adjunctive cariprazine (P <.001). Investigators observed a greater response in women and those using SSRIs (P <.001).

The analysis revealed that participants with comorbid anxiety had smaller reductions in MADRS scores (P <.001). Among patients with anxiety, a greater baseline HAM-A score predicted sustained improvement (P <.001). Greater baseline depression severity was linked to reduced anxiety improvement during adjunctive cariprazine treatment (P <.001). Only cariprazine 1.5 mg/day, not 3 mg/day, slightly improved HAM-A scores compared to placebo (P =.043).

“By leveraging a large, rich dataset of individual patient responses across multiple clinical trials and using a Bayesian framework, we move one step closer to understanding not just whether cariprazine works, but for whom, at what dose, and when,” investigators concluded.

Other Recent MDD Data

A recent phase 3 trial found that adjunctive lumateperone 42 mg led to statistically significant reductions in depressive symptoms and disease severity by day 43 in adults with MDD.3

The long-term data followed the FDA approval of Johnson & Johnson’s lumateperone as an adjunctive therapy for MDD in November 2025. Lumateperone, an oral, once-daily atypical antipsychotic, targets 3 neurotransmitters at the same time: serotonin, dopamine, and glutamate. The drug acts as a 5-HT2A antagonist and modulates dopamine by partially agonizing presynaptic D2 receptors and blocking postsynaptic ones.3

The trial met its primary endpoint (change from baseline to day 43 in MADRS total score; least squares mean difference [LSMD] versus placebo, −4.5; effect size, −0.56). The trial also met its secondary endpoint, change from baseline to day 43 in the Clinical Global Impressions Scale severity (CGI-S) score (LSMD, −0.5; effect size, −0.51). Participants on lumateperone had significantly improved patient-reported depression compared to those on placebo by day 43 (16-item Quick Inventory of Depressive Symptomatology-Self-Report, total score, SMD, −2.2; effect size, −0.45).3

“This is not new from the standpoint of other atypical antipsychotics have been approved by the FDA for this purpose,” said Ned Kalin, editor-in-chief of the American Journal of Psychiatry and psychiatry department chair at the University of Wisconsin, in a podcast.3 “So, we do have other agents in this class of drugs that are already shown and are approved by [the] FDA to help people with depression, but this is another medicine, and it's really helpful for us because it's not identical to the other medications.”

References

1. Strawn JR, Mills JA. Trajectories and predictors of depressive and anxiety symptom improvement with adjunctive cariprazine in antidepressant-treated adults with major depression: A Bayesian mega-analysis of two randomized trials. J Affect Disord. 2026;394(Pt B):120657. doi:10.1016/j.jad.2025.120657

2. Kunzmann K. FDA Approves Cariprazine as Adjunctive Major Depressive Disorder Therapy. HCPLive. Published December 17, 2022. Accessed January 2, 2026. https://www.hcplive.com/view/fda-approves-cariprazine-adjunctive-major-depressive-disorder-therapy.

3. Derman C. Adjunctive Lumateperone Significantly Improves MDD Symptoms by Day 43. HCPLive. Published on December 8, 2025. Accessed January 2, 2026. https://www.hcplive.com/view/adjunctive-lumateperone-significantly-improves-mdd-symptoms-day-43