Johnson & Johnson (J&J) has announced the expanded FDA approval of Caplyta (lumateperone) as an adjunctive therapy to antidepressants in adults with major depressive disorder (MDD).
The approval represents the fourth indication for Caplyta, which remains the first and only FDA-approved treatment for bipolar I and II depression in adults, available both as adjunctive therapy and monotherapy. It is also approved for the treatment of schizophrenia in adults.
MDD remains one of the leading causes of disability globally. According to the FDA-label release, about 22 million US adults are living with MDD and roughly two in three patients on a first-line antidepressant continue to experience residual symptoms, significantly impacting quality of life.
Residual symptoms, such as sleep disturbance, anhedonia, cognitive slowing and mood reactivity, are strongly correlated with relapse risk, longer time to recovery, functional impairment and increased economic burden.
The new approval addresses patients who continue to experience depressive symptoms despite treatment with an antidepressant, addressing the need for effective adjunctive options in MDD.
The FDA nod in MDD was supported by two pivotal Phase III trials, Study 501 and Study 502, in which Caplyta met all primary and key secondary endpoints.
In Study 501, patients on Caplyta had an average 4.9-point reduction on the Montgomery-Asberg Depression Rating Scale (MADRS) compared to placebo at Week 6.
In Study 502, patients with an inadequate response to ongoing antidepressant therapy showed a 4.5-point greater reduction in MADRS scores at Week 6 with Caplyta compared to placebo.
In Study 501, Caplyta began showing a significant separation from placebo after just one week, while in Study 502, separation emerged by the second week of treatment.
In the additional long-term open-label extension study (26 weeks), Study 503, about 80% of patients responded and 65% reached remission (MADRS total score ≤10) when lumateperone was added to an antidepressant at six months.
Significant reductions in the key secondary endpoint of mean change in total Clinical Global Impression Scale-Severity index (CGI-S) scores from baseline were also demonstrated at six weeks in Study 501 and Study 502.
Caplyta did not increase mean weight gain, metabolic changes or sexual side effects compared to placebo, which are concerns with some MDD medications.
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Although the precise mechanism is not fully established, lumateperone is described as having high serotonin 5-HT2A receptor occupancy and moderate dopamine D₂ receptor occupancy at therapeutic doses. It is also characterized by modulation of glutamate/neurotransmission in preclinical models.
With MDD being one of the most common psychiatric disorders (affecting ~4% of the global population), adding a new approved adjunctive therapy opens up commercial and clinical pathways for growth, especially in markets where treatment resistance and residual symptom burden remain high.
The expanded approval in MDD represents a significantly larger opportunity for Caplyta, which generated $680 million in sales in 2024 and has been a commercial and clinical success since its 2019 approval.
Analysts estimate the MDD market is at least three times the size of the bipolar segment, though it is already crowded with both established and emerging treatment options.
J&J received Caplyta at the beginning of this year through its $14.6 billion acquisition of Intra-Cellular Therapies.
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