Is Lumateperone Effective in Bipolar Depression? A Systematic Literature Review and Meta-Analysis on Placebo-Controlled Trials

Abstract

Bipolar depression is often difficult to treat and needs a specific therapeutic approach. This systematic review and meta-analysis aimed to evaluate the efficacy of lumateperone to be inclusive of more recently published studies with this agent in depressive episodes of bipolar disorder. Three meta-analyses were conducted to determine whether the mean Montgomery-Asberg Depression Rating Scale (MADRS) values in the placebo groups differ significantly from the mean MADRS scale values in the group receiving lumateperone 42 mg and whether the mean of Clinical Global Impression Bipolar Version - Severity Scale (CGI-BP-S) – (depression subscore and overall bipolar illness) values in the placebo groups differ significantly from the mean CGI-BP-S scale values in the group receiving lumateperone 42 mg. The meta-analysis showed a statistically significant difference between patients treated with lumateperone 42 mg and those treated with placebo for the MADRS and CGI subscores. The clinical profile of lumateperone indicates that it is a established and highly efficacious treatment option for major depressive episodes associated with bipolar disorder.

Keywords

bipolar disorder - lumateperone - meta-analysis - review

Publication History

Received: 23 January 2025

Accepted after revision: 12 March 2025

Article published online:
14 July 2025

• References

• 1 Goodwin FK, Jamison KR. Manic Depressive Illness. 2nd ed.. New York: Oxford University Press; 2007
• 2 Phillips ML, Kupfer DJ. Bipolar disorder diagnosis: Challenges and future directions. Lancet 2013; 381: 1663-1671
• 3 Ostergaard SD, Bertelsen A, Nielsen J. et al. The association between psychotic mania, psychotic depression and mixed affective episodes among 14,529 patients with bipolar disorder. J Affect Disord 2013; 147: 44-50
• 4 Tsitsipa E, Fountoulakis KN. The neurocognitive functioning in bipolar disorder: A systematic review of data. Ann Gen Psychiatry 2015; 14: 42
• 5 Kupka RW, Altshuler LL, Nolen WA. et al. Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disord 2007; 9: 531-535
• 6 De Dios C, Ezquiaga E, Garcia A. et al. Time spent with symptoms in a cohort of bipolar disorder outpatients in Spain: A prospective, 18-month follow-up study. J Affect Disord 2010; 125: 74-81
• 7 Miller S, Dell’Osso B, Ketter TA. The prevalence and burden of bipolar depression. J Affect Disord 2014; 169: S3-S11
• 8 McIntyre RS, Soczynska JK, Konarski JZ. et al. Should depressive syndromes be reclassified as “Metabolic Syndrome Type II” ?. Ann Clin Psychiatry 2007; 19: 257-264
• 9 Correll CU, Ng-Mak DS, Stafkey-Mailey D. et al. Cardiometabolic comorbidities, readmission, and costs in schizophrenia and bipolar disorder: A real-world analysis. Ann Gen Psychiatry 2017; 16: 9
• 10 Fornaro M, Novello S, Fusco A. et al. Clinical features associated with early drop-out among outpatients with unipolar and bipolar depression. J Psychiatr Res 2021; 136: 522-528
• 11 Baldessarini RJ, Tondo L, Pinna M. et al. Suicidal risk factors in major affective disorders. Br J Psychiatry. 2019: 1-6
• 12 Yildiz A, Siafis S, Mavridis D. et al. Comparative efficacy and tolerability of pharmacological interventions for acute bipolar depression in adults: A systematic review and network meta-analysis. Lancet Psychiatry 2023; 10: 693-705
• 13 Selle V, Schalkwijk S, Vázquez GH. et al. Treatments for acute bipolar depression: Meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics. Pharmacopsychiatry 2014; 47: 43-52
• 14 Baldessarini RJ, Faedda GL, Offidani E. et al. Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: A review. J Affect Disord 2013; 148: 129-135
• 15 Earley W, Burgess MV, Rekeda L. et al. Cariprazine treatment of bipolar depression: A randomized double-blind placebo-controlled phase 3 study. Am J Psychiatry 2019; 176: 439-448
• 16 Ragguett RM, McIntyre RS. Cariprazine for the treatment of bipolar depression: A review. Expert Rev Neurother 2019; 19: 317-323
• 17 Centorrino F, Masters GA, Talamo A. et al. Metabolic syndrome in psychiatrically hospitalized patients treated with antipsychotics and other psychotropics. Hum Psychopharmacol 2012; 27: 521-526
• 18 Pompili M, Berardelli I, Sarubbi S. et al. Lithium treatment versus hospitalization in bipolar disorder and major depression patients. J Affect Disord 2023; 340: 245-249
• 19 Bohlken J, Riedel-Heller S, Bauer M. et al. Bipolar disorder and outcomes of monotherapy with lithium, valproate, quetiapine, olanzapine, venlafaxine, and citalopram. Pharmacopsychiatry 2021; 54: 126-130
• 20 McIntyre RS, Calabrese JR. Bipolar depression: The clinical characteristics and unmet needs of a complex disorder. Curr Med Res Opin 2019; 35: 1993-2005
• 21 Snyder GL, Vanover KE, Davis RE. et al. A review of the pharmacology and clinical profile of lumateperone for the treatment of schizophrenia. Adv Pharmacol 2021; 90: 253-276
• 22 Intra-Cellular Therapies Announces U.S. FDA Approval of CAPLYTA^® (lumateperone) for the Treatment of Bipolar Depression in Adults; 2021
• 23 Corponi F, Fabbri C, Bitter I. et al. Novel antipsychotics specificity profile: A clinically oriented review of lurasidone, brexpiprazole, cariprazine and lumateperone. Eur Neuropsychopharmacol 2019; 29: 971-985
• 24 Tsapakis EM, Diakaki K, Miliaras A. et al. Novel compounds in the treatment of schizophrenia-a selective review. Brain Sci 2023; 13: 1193
• 25 Cooper D, Gupta V. Lumateperone. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025
• 26 Maini K, Hollier JW, Gould H. et al. Lumateperone tosylate, a selective and concurrent modulator of serotonin, dopamine, and glutamate, in the treatment of schizophrenia. Health Psychol Res 2021; 9: 24932
• 27 Kishi T, Sakuma K, Hamanaka S. et al. Discontinuation rate of lurasidone and quetiapine extended release in bipolar depression. Pharmacopsychiatry 2024; 57: 245-248
• 28 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: 244-250
• 29 Correll CU, Davis RE, Weingart M. et al. Efficacy and safety of lumateperone for treatment of schizophrenia: A randomized clinical trial. JAMA Psychiatry 2020; 77: 349-358
• 30 Page MJ, Moher D, Bossuyt PM. et al. PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews. BMJ 2021; 372: n160
• 31 Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382-389
• 32 Spearing MK, Post RM, Leverich GS. et al. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): The CGI-BP. Psychiatry Res 1997; 73: 159-171
• 33 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: 1098-1106
• 34 McIntyre RS, Durgam S, Kozauer SG. et al. The efficacy of lumateperone on symptoms of depression in bipolar I and bipolar II disorder: Secondary and post hoc analyses. Eur Neuropsychopharmacol 2023; 68: 78-88
• 35 McIntyre RS, Durgam S, Huo J. et al. The efficacy of lumateperone in patients with bipolar depression with mixed features. J Clin Psychiatry 2023; 84: 22m14739
• 36 Suppes T, Durgam S, Kozauer SG. et al. Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: Results from a randomized placebo-controlled clinical trial. Bipolar Disord 2023; 25: 478-488
• 37 Durgam S, Lakkis H, Kozauer SG. et al. Efficacy of lumateperone in pooled short-term late-phase clinical trials for the treatment of major depressive episodes associated with bipolar II disorder. Abstract presentation. 2023
• 38 Tohen M, Durgam S, Kozauer S. et al. Long-term lumateperone treatment in bipolar disorder: Six-month open-label extension study. CNS Spectrums 2023; 28: 233-233
• 39 Spearing MK, Post RM, Leverich GS. et al. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): The CGI-BP. Psychiatry Res 1997; 73: 159-171