Lumateperone (ITI-007)

Mechanism of action

Multi-target small molecule. High-affinity serotonin 5-HT2A receptor antagonist (human pKi 9.3, Ki ~0.50 nM) with comparatively lower affinity at dopamine D2 receptors (pKi 7.5, Ki ~32 nM) where it acts as a presynaptic partial agonist / postsynaptic antagonist (the developer's 'dopamine receptor phosphoprotein modulator' framing), and inhibition of the serotonin transporter (SERT; pKi 7.2, Ki ~63 nM). Also modulates dopamine D1-receptor-dependent glutamatergic signaling. The combined 5-HT2A antagonism plus low/region-selective D2 occupancy and SERT inhibition underlies its low metabolic/EPS burden and proposed antidepressant activity.

Formulations

Lumateperone (ITI-007) for Schizophrenia

ApprovedApprovedSchizophrenia indication →

Schizophrenia is lumateperone's original and lead indication. The FDA approved Caplyta (lumateperone) 42 mg once daily for the treatment of schizophrenia in adults on 20 December 2019 (Intra-Cellular Therapies announced it 23 December 2019). Efficacy was demonstrated in two positive 4-week, randomized, double-blind, placebo-controlled pivotal trials: Study 005 (NCT01499563; n=335; PANSS total LSMD for the 42 mg dose -13.2 vs -7.4 placebo, p=0.017, effect size ~0.4; Lieberman et al. 2016) and Study 301 (NCT02282761; n=450; drug-placebo PANSS difference -4.2, statistically significant at Week 4; Correll et al. 2020, JAMA Psychiatry). A third Phase 3 study, Study 302 (NCT02469155; n=696; 6-week), did NOT separate from placebo on PANSS (attributed to a high placebo response / assay sensitivity), and is tracked here for completeness. On 27 April 2026 the FDA approved a supplemental NDA (Study 304, NCT04959032, a randomized-withdrawal relapse-prevention trial) adding long-term relapse-prevention data to the label (hazard ratio 0.37, a 63% reduction in relapse risk vs placebo, p=0.0002; 84% relapse-free over six months). Originated by Intra-Cellular Therapies; following J&J's acquisition of ITCI (closed 2 Apr 2025), Caplyta is now marketed by Johnson & Johnson Innovative Medicine. is_lead_indication=true because schizophrenia was the first (lead) approved indication.

Lumateperone (ITI-007) for Major depressive disorder

ApprovedApprovedMajor depressive disorder indication →

FDA approved Caplyta (lumateperone) 42 mg once daily on 6 Nov 2025 as adjunctive therapy with antidepressants for major depressive disorder in adults. Approval (an sNDA, submitted 3 Dec 2024) was supported by two positive pivotal Phase 3 trials, Study 501 (NCT04985942) and Study 502 (NCT05061706), each showing a statistically significant MADRS separation from placebo at Week 6 (-4.9 / ES 0.61 and -4.5 / ES 0.56, both p<0.0001) plus a significant CGI-S key secondary, with a 6-month open-label extension (Study 503, NCT05061719) showing 80% response / 65% remission. This is MDD-specific; the compound was already approved for schizophrenia and for bipolar I/II depression. Originated by Intra-Cellular Therapies, which J&J acquired (closed 2 Apr 2025); Caplyta is now marketed by Johnson & Johnson Innovative Medicine. is_lead_indication=false because schizophrenia was the original (lead) approved indication.

Lumateperone (ITI-007) for Bipolar depression

ApprovedApprovedBipolar depression indication →

FDA approved Caplyta (lumateperone) 42 mg once daily on 20 Dec 2021 for the treatment of depressive episodes associated with bipolar I or bipolar II disorder in adults, both as MONOTHERAPY and as ADJUNCTIVE therapy with lithium or valproate. At the time it was the first and only FDA-approved treatment for both bipolar I and bipolar II depression as monotherapy and adjunctive therapy. Approval was supported by two positive Phase 3 placebo-controlled studies: the monotherapy Study 404 (NCT03249376), which met its MADRS Week-6 primary (LSMD vs placebo -4.6; ES -0.56; p<0.0001) and CGI-BP-S key secondary, and the adjunctive Study 402 (NCT02600507), in which lumateperone 42 mg added to lithium or valproate met its MADRS Week-6 primary (LSMD -2.4; p=0.02) and the CGI-BP-S depression key secondary (LSMD -0.3; p=0.01). An earlier US-only monotherapy trial (Study 401, NCT02600494) had missed its primary endpoint. is_lead_indication=false because schizophrenia was the original (lead) approved indication. Originated by Intra-Cellular Therapies; Caplyta is now marketed by Johnson & Johnson Innovative Medicine following the ITCI acquisition (closed 2 Apr 2025).

Lumateperone (ITI-007) for Bipolar disorder

Phase 3RecruitingBipolar disorder indication →

Active Phase 3 development program for lumateperone (Caplyta) 42 mg once daily in the ACUTE treatment of manic episodes or manic episodes with mixed features associated with bipolar I disorder (bipolar mania) — a label-expansion effort distinct from lumateperone's existing approvals. Intra-Cellular Therapies initiated two multicenter, randomized, double-blind, placebo-controlled Phase 3 acute-mania studies in Q2 2024: Study 451 (NCT06462586) and Study 452 (NCT06462612). Each randomizes ~350 patients (YMRS total >=20 at entry) 1:1 to lumateperone 42 mg or placebo over a 3-week double-blind period, with the PRIMARY endpoint the change from baseline in the Young Mania Rating Scale (YMRS) total score at Week 3 (key secondary CGI-BP-S). Both verified RECRUITING on ClinicalTrials.gov; estimated primary completion is March 2026 (Study 451) and May 2026 (Study 452); no topline results have been reported as of June 2026. Lumateperone is already FDA-approved for schizophrenia and for bipolar I/II DEPRESSION (mono + adjunctive; that depression indication is a separate program), so mania is an incremental indication. Originated by Intra-Cellular Therapies, which Johnson & Johnson acquired (closed 2 Apr 2025); the program is now sponsored by Johnson & Johnson Innovative Medicine. is_lead_indication=false because schizophrenia was the original (lead) approved indication.

Lumateperone (ITI-007) for Autism spectrum disorder

Phase 3RecruitingAutism spectrum disorder indication →

Active Phase 3 program evaluating lumateperone (Caplyta) for irritability associated with autism spectrum disorder in pediatric patients (ages 5-17). Intra-Cellular Therapies disclosed commencing patient enrollment in the fourth quarter of 2024 in two pivotal Phase 3 studies: Study 601 (NCT06690398) and Study 602 (NCT06706674). Each is a randomized, double-blind, placebo-controlled, multicenter study (n=174) randomizing patients 1:1:1 to lumateperone high dose (42 mg/day for ages 13-17), lumateperone low dose (21 mg/day for ages 13-17), or placebo over a 6-week double-blind period, with the Aberrant Behavior Checklist - Irritability (ABC-I) subscale at Week 6 as the primary endpoint. A separate 26-week open-label pediatric safety/tolerability study (NCT06229210) enrolls ASD-irritability patients alongside pediatric schizophrenia and bipolar disorder. Both pivotal trials are recruiting with estimated primary completion around March 2027; no efficacy readouts have occurred yet. is_lead_indication=false because schizophrenia is lumateperone's lead/original approved indication.

Clinical trials