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CAPLYTA® (lumateperone)

Medical Information

CAPLYTA - Adverse Event - Effects on Prolactin

Last Updated: 09/21/2026

SUMMARY

Kane et al (2021)¹ conducted a pooled analysis of 3 randomized, double-blind, trials in the treatment of schizophrenia. The mean (standard deviation [SD]) change in prolactin level from baseline to the last on-treatment value was -1.3 (8.86) ng/mL with CAPLYTA 42 mg vs -0.2 (8.46) ng/mL with placebo.¹
In a 2-part, open-label (OL), multicenter study in patients with schizophrenia (Study 303), the mean (SD) change in prolactin level from baseline to day 368 was
-2.67 (22.515) µg/L.²
Correll et al (2026)³ conducted a phase 3, 6-week, randomized, double-blind trial in patients with bipolar disorder (Study 401). In this study, the least squares (LS) mean (standard error [SE]) change in prolactin level from baseline to day 43 was 0.95 (0.48) µg/L in the CAPLYTA 42 mg group and 1.12 (0.46) µg/L in the lumateperone 28 mg group.
Tohen et al (2026)⁴ conducted a 6-month OL extension of a phase 3 study (Study 403). The mean (SE) change in prolactin level from baseline to day 175 in the CAPLYTA 42 mg group was 1.3 (0.58) µg/L.⁴
Calabrese et al (2021)⁵ conducted a phase 3, randomized, double-blind study in patients with bipolar I or bipolar II disorder who experienced a major depressive episode. The mean (SE) change in prolactin level from baseline to week 6 in the CAPLYTA 42 mg group was -0.8 (1.1) µg/L.⁵
Durgam et al (2025)⁶ conducted a post hoc analysis of pooled data from patients with bipolar II disorder experiencing an MDE. The mean (SD) change in prolactin level from baseline to end of treatment (EOT) in the CAPLYTA 42 mg group was 0.96 (2.52) µg/L.
Durgam et al (2025)⁷ conducted a phase 3, 6-week, randomized, double-blind study in patients with major depressive disorder (MDD) who had an inadequate response to antidepressant therapy (ADT; Study 501). In this study, the mean (SE) change in prolactin level from baseline to end of treatment in the CAPLYTA 42 mg+ADT group was 1.6 (0.76) ng/mL.
Durgam et al (2025)⁸conducted a phase 3, 6-week, randomized, double-blind study in patients with MDD who had an inadequate response to ADT (Study 502). The mean (SD) change in prolactin level from baseline to end of treatment in the CAPLYTA 42 mg+ADT group was 1.6 (0.76) ng/mL.
Durgam et al (2026)⁹ conducted a 26-week OL extension (Study 503) in adult patients with MDD who had completed Study 501 or Study 502. The mean (SD) change in prolactin level from baseline to end of treatment in the CAPLYTA 42 mg+ADT group was 1.1 (13.01) ng/mL.
Earley et al (2026)¹⁰ conducted a pooled analysis of Studies 501 and 502. The mean (SD) change in prolactin level from baseline to end of treatment (week 6) in the CAPLYTA 42 mg+ADT group was 1.1 (10.2) ng/mL.

CLINICAL DATA

Summary of Clinical Studies of CAPLYTA

Study Objective	Patients and Treatment Groups		Outcomes
Schizophrenia
Kane et al (2021)¹ conducted a pooled analysis of 3 randomized, double-blind, placebo-controlled trials (Studies 005, 301, and 302) to assess the safety and tolerability of CAPLYTA 42 mg in the treatment of schizophrenia.	The pooled population comprised of 1073 patients with an acute exacerbation of schizophrenia (CAPLYTA 42 mg, n=406; risperidone 4 mg, n=255; and placebo, n=412). Patients were treated with CAPLYTA for 4 weeks in studies 005 and 301 and for 6 weeks in study 302. Additionally, studies 005 and 302 included risperidone 4 mg as an active control for assay sensitivity.		A minor reduction was observed in the mean (SD) prolactin level from baseline to the last on-treatment value (CAPLYTA 42 mg, -1.3 [8.86] ng/mL; risperidone, 34.9 [39.38] ng/mL; placebo, -0.2 [8.46] ng/mL).
A 2-part (parts 1 and 2), OL, multicenter study (Study 303) evaluated the safety and effectiveness of CAPLYTA 42 mg in patients with schizophrenia (N=602). Results of part 2 have been reported.²	Part 1 involved 6 weeks of treatment with CAPLYTA 42 mg following a switch from standard-of-care antipsychotic therapy. Part 2 included 1 year of treatment and an extension of >1 year.		The mean (SD) change in prolactin level from baseline to day 368 in patients treated with CAPLYTA 42 mg (n=534) was -2.67 (22.515) µg/L.
Bipolar Depression
Correll et al (2026)³ conducted a phase 3, 6-week, randomized, double-blind, placebo-controlled, outpatient, multicenter study (study 401) to assess the efficacy and safety of CAPLYTA in patients with MDE associated with bipolar I or bipolar II disorder.	Patients were randomized (1:1:1) to receive CAPLYTA 28 mg (n=180), CAPLYTA 42 mg (n=184), or placebo (n=185) for 6 weeks; this was followed by a 2-week safety follow-up period.			CAPLYTA 42 mg (n=184)			Lumateperone 28 mg (n=180)			Placebo (n=185)
				Baseline Mean (SD)		LS Mean (SE) Change at EOT	Baseline Mean (SD)	LS Mean (SE) Change at EOT		Baseline Mean(SD)			LS Mean (SE) Change at EOT
			Prolactin, μg/L	9.5 (16.22)		0.95 (0.48)^a	8.5(9.62)	1.12 (0.46)^b		8 (7.18)			0.37 (0.45)
			^aDifference vs placebo, P=0.38. Analysis based on the last observation carried forward using an analysis of covariance. ^bDifference vs placebo, P=0.25. Analysis based on the last observation carried forward using an analysis of covariance.
Tohen et al (2026)⁴ conducted a 6-month OLE of the phase 3 study (Study 401) by Correll et al (2026)³ assessing the long-term safety of CAPLYTA in patients with MDEs associated with bipolar I or bipolar II disorder.	Eligible patients (N=127) received CAPLYTA 42 mg/day for 175 days; of these, in the 6-week randomized part of the study, 40 had received lumateperone 28 mg, 43 had received CAPLYTA 42 mg, and 44 had received placebo.		The mean (SE) change in prolactin level from baseline to day 175 in patients treated with CAPLYTA 42 mg (n=121) was 1.3 (0.58) µg/L. No clinically relevant changes were observed.
Calabrese et al (2021)⁵ conducted a phase 3, randomized, double-blind, placebo-controlled, multicenter study that evaluated the efficacy and safety of CAPLYTA 42 mg in patients with bipolar I or bipolar II disorder who experienced MDEs.	Patients received CAPLYTA 42 mg (n=188) or placebo (n=189) once daily for 6 weeks.		The mean (SE) change in prolactin level from baseline to week 6 was -0.8 (1.1) µg/L in the CAPLYTA 42 mg group and 1.7 (1.3) μg/L in the placebo group.
Durgam et al (2025)⁶ conducted a post hoc analysis pooled data from patients with bipolar II disorder experiencing an MDE in randomized, double-blind, placebo-controlled studies of CAPLYTA 42 mg monotherapy (Study 401, Study 404) and adjunctive therapy to lithium or valproate (Study 402).	The safety population included 964 patients (CAPLYTA 42 mg, n=89; placebo, n=89).					CAPLYTA 42 mg+ADT (n=241)		Placebo+ADT (n=243)
						Baseline Mean±SD	Mean (SE) Change at EOT	Baseline Mean±SD			Mean (SE) Change at EOT
			Prolactin, ng/mL			12.17 (10.44)	0.96 (2.52)	13.69 (16.22)			6.87 (2.48)
MDD
Durgam et al (2025)⁷ conducted a phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study (Study 501) to assess the efficacy and safety of CAPLYTA adjunctive to ADT in patients with MDD who had an inadequate response to ADT.	Patients were randomized (1:1) to receive either CAPLYTA 42 mg (n=242) or placebo (n=243) as adjunctive treatment to ADT for 6 weeks; this was followed by a 1-week safety follow-up period.					CAPLYTA 42 mg+ADT (n=241)		Placebo+ADT (n=243)
						Baseline Mean (SD)	Mean (SE) Change at EOT	Baseline Mean (SD)			Mean (SE) Change at EOT
			Prolactin, ng/mL			11 (14.57)	1.6 (0.76)	9.6 (8.83)			0.6 (0.48)
Durgam et al (2025)⁸conducted a phase 3, 6-week, randomized, double-blind, placebo-controlled, multicenter, international study (Study 502) to evaluate the efficacy and safety of CAPLYTA 42 mg adjunctive to ADT in patients with MDD who had an inadequate response to ADT.		Patients were randomized (1:1) to receive either CAPLYTA 42 mg (n=242) or placebo (n=238) as adjunctive treatment to ADT for 6 weeks; this was followed by a 1-week safety follow-up period.				CAPLYTA 42 mg+ADT (n=241)		Placebo+ADT (n=243)
						Baseline Mean (SD)	Mean (SD) Change at EOT	Baseline Mean (SD)			Mean (SD) Change at EOT
			Prolactin, ng/mL			9.5 (8.78)	0.6 (8.6)	9.5 (18.25)			1.3 (8.88)
Durgam et al (2026)⁹ conducted a 26-week OL extension study (Study 503) that evaluated the long-term safety and tolerability of CAPLYTA 42 mg as adjunctive therapy to ADT in adult patients with MDD who had completed studies 501 or 502.	Adult patients with MDD (N=809).						CAPLYTA 42 mg+ADT (N=778)
							Baseline Mean (SD)		Mean (SD) Change From Baseline to EOT
			Prolactin, ng/mL				10.07 (12.98)		1.1 (13.01)
Earley et al (2026)¹⁰ conducted a pooled analysis of the 6-week studies 501 and 502 that evaluated the safety and tolerability of CAPLYTA 42 mg adjunctive to ADT in patients with MDD with inadequate response to ADT.	The safety population included 964 patients (CAPLYTA 42 mg+ADT, n=483; placebo+ADT, n=481).				CAPLYTA 42 mg+ADT (n=438)			Placebo+ADT (n=466)
					Baseline Mean (SD)		Mean (SD) Change at EOT	Baseline Mean (SD)				Mean (SD) Change at EOT
			Prolactin, ng/mL		10 (9.37)		1.1 (10.2)	9.6 (14.48)				1 (8.17)
Abbreviations: ADT, antidepressant therapy; EOT, end of treatment; LS, least squares; MDD, major depressive disorder; MDE, major depressive episode; OL, open-label; OLE, open-label extension; SD, standard deviation; SE, standard error.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 29 July 2026.

References

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1	Kane JM, Durgam S, Satlin A, et al. Safety and tolerability of lumateperone for the treatment of schizophrenia: a pooled analysis of late-phase placebo- and active-controlled clinical trials. Int Clin Psychopharmacol. 2021;36(5):244-250.
2	Data on File. CAPLYTA. Clinical Study Report of Study 303. Intra-Cellular Therapies, Inc; 2025.
3	Correll CU, Durgam S, Kozauer SG, et al. Lumateperone monotherapy for major depressive episodes associated with bipolar disorder: efficacy and safety in a randomized placebo-controlled trial. Int Clin Psychopharmacol. 2026;41(1):120-129.
4	Tohen M, Durgam S, Kozauer SG, et al. Long-term safety and tolerability of lumateperone 42 mg in patients with bipolar disorder: results from a 6-month open-label extension study. Int Clin Psychopharmacol. 2026;41(2):130-137.
5	Calabrese JR, Durgam S, Satlin A, et al. Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. Am J Psychiatry. 2021;178(12):1098-1106.
6	Durgam S, Lakkis H, Kozauer S, et al. Efficacy of lumateperone in depression associated with bipolar II disorder: a pooled analysis of late-phase clinical trials. CNS Spectrums. 2025;30(1):1-7.
7	Durgam S, Earley WR, Kozauer SG, et al. Lumateperone as adjunctive therapy in patients with major depressive disorder: results from a randomized, double-blind, phase 3 trial. J Clin Psychiatry. 2025;86(4):25m15848.
8	Durgam S, Earley WR, Kozauer SG, et al. Adjunctive lumateperone in patients with major depressive disorder: results from a randomized, double-blind, phase 3 trial. Am J Psychiatry. 2025;182(12):1072-1082.
9	Durgam S, Earley WR, Kozauer SG, et al. Long-term adjunctive lumateperone 42 mg treatment in major depressive disorder: results from a 6-month open-label extension study. Eur Neuropsychopharmacol. 2026;108:112786.
10	Earley WR, Durgam S, Kozauer SG, et al. Safety and tolerability of adjunctive lumateperone for the treatment of major depressive disorder: a pooled analysis of two randomized placebocontrolled trials. CNS Drugs. 2026. doi:10.1007/s40263-026-01314-8.

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