Efficacy and Safety of Lumateperone for Treatment of Schizophrenia: A Randomized Clinical Trial | Psychiatry and Behavioral Health | JAMA Psychiatry | JAMA Network
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Kahn  RS, Sommer  IE, Murray  RM,  et al.  Schizophrenia.  Nat Rev Dis Primers. 2015;1:15067. doi:10.1038/nrdp.2015.67PubMedGoogle ScholarCrossref
Salomon  JA, Haagsma  JA, Davis  A,  et al.  Disability weights for the Global Burden of Disease 2013 study.  Lancet Glob Health. 2015;3(11):e712-e723. doi:10.1016/S2214-109X(15)00069-8PubMedGoogle ScholarCrossref
Solmi  M, Murru  A, Pacchiarotti  I,  et al.  Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review.  Ther Clin Risk Manag. 2017;13:757-777. doi:10.2147/TCRM.S117321PubMedGoogle ScholarCrossref
Leucht  S, Cipriani  A, Spineli  L,  et al.  Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.  Lancet. 2013;382(9896):951-962. doi:10.1016/S0140-6736(13)60733-3PubMedGoogle ScholarCrossref
Correll  CU, Detraux  J, De Lepeleire  J, De Hert  M.  Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder.  World Psychiatry. 2015;14(2):119-136. doi:10.1002/wps.20204PubMedGoogle ScholarCrossref
Olfson  M, Gerhard  T, Huang  C, Crystal  S, Stroup  TS.  Premature mortality among adults with schizophrenia in the United States.  JAMA Psychiatry. 2015;72(12):1172-1181. doi:10.1001/jamapsychiatry.2015.1737PubMedGoogle ScholarCrossref
Correll  CU, Solmi  M, Veronese  N,  et al.  Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls.  World Psychiatry. 2017;16(2):163-180. doi:10.1002/wps.20420PubMedGoogle ScholarCrossref
Hjorthøj  C, Stürup  AE, McGrath  JJ, Nordentoft  M.  Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis.  Lancet Psychiatry. 2017;4(4):295-301. doi:10.1016/S2215-0366(17)30078-0PubMedGoogle ScholarCrossref
Davis  RE, Correll  CU.  ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes.  Expert Rev Neurother. 2016;16(6):601-614. doi:10.1080/14737175.2016.1174577PubMedGoogle ScholarCrossref
Snyder  GL, Vanover  KE, Zhu  H,  et al.  Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.  Psychopharmacology (Berl). 2015;232(3):605-621. doi:10.1007/s00213-014-3704-1PubMedGoogle ScholarCrossref
Correll  CU.  From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics.  Eur Psychiatry. 2010;25(suppl 2):S12-S21. doi:10.1016/S0924-9338(10)71701-6PubMedGoogle ScholarCrossref
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
First  MB, Williams  JBW, Spitzer  RL, Gibbon  M.  Structured clinical interview for DSM-IV-TR Axis I disorders, clinical trials version (SCID-CT). New York: Biometrics Research, New York State Psychiatric Institute; 2007.
First  MB, Williams  JB, Karg  RS, Spitzer  RL.  Structured Clinical Interview for DSM-5 Disorders—Clinical Trials Version (SCID-5-CT, Modified for ITI-007-301). Arlington, VA: American Psychiatric Association; 2014.
Overall  JE, Gorham  DR.  The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment and scaling.  Psychopharmacol Bull. 1988;24:97-99.Google Scholar
US Department of Health Education, and Welfare.   ECDEU Assessment Manual for Psychopharmacology. MD: US Dept of Health Education, and Welfare; 1976.
Kay  SR, Fiszbein  A, Opler  LA.  The positive and negative syndrome scale (PANSS) for schizophrenia.  Schizophr Bull. 1987;13(2):261-276. doi:10.1093/schbul/13.2.261PubMedGoogle ScholarCrossref
Shen  J, Kobak  KA, Zhao  Y, Alexander  MM, Kane  JM.  Use of remote centralized raters via live 2-way video in a multicenter clinical trial for schizophrenia.  J Clin Psychopharmacol. 2008;28(6):691-693. doi:10.1097/JCP.0b013e31818c9ba3PubMedGoogle ScholarCrossref
Kobak  KA, Leuchter  A, DeBrota  D,  et al.  Site versus centralized raters in a clinical depression trial: impact on patient selection and placebo response.  J Clin Psychopharmacol. 2010;30(2):193-197. doi:10.1097/JCP.0b013e3181d20912PubMedGoogle ScholarCrossref
Patrick  DL, Burns  T, Morosini  P,  et al.  Reliability, validity and ability to detect change of the clinician-rated Personal and Social Performance scale in patients with acute symptoms of schizophrenia.  Curr Med Res Opin. 2009;25(2):325-338. doi:10.1185/03007990802611919PubMedGoogle ScholarCrossref
Purnine  DM, Carey  KB, Maisto  SA, Carey  MP.  Assessing positive and negative symptoms in outpatients with schizophrenia and mood disorders.  J Nerv Ment Dis. 2000;188(10):653-661. doi:10.1097/00005053-200010000-00003PubMedGoogle ScholarCrossref
Addington  D, Addington  J, Schissel  B.  A depression rating scale for schizophrenics.  Schizophr Res. 1990;3(4):247-251. doi:10.1016/0920-9964(90)90005-RPubMedGoogle ScholarCrossref
Simpson  GM, Angus  JW.  A rating scale for extrapyramidal side effects.  Acta Psychiatr Scand Suppl. 1970;212:11-19. doi:10.1111/j.1600-0447.1970.tb02066.xPubMedGoogle ScholarCrossref
Barnes  TR.  A rating scale for drug-induced akathisia.  Br J Psychiatry. 1989;154(5):672-676. doi:10.1192/bjp.154.5.672PubMedGoogle ScholarCrossref
Posner  K, Brown  GK, Stanley  B,  et al.  The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults.  Am J Psychiatry. 2011;168(12):1266-1277. doi:10.1176/appi.ajp.2011.10111704PubMedGoogle ScholarCrossref
Dmitrienko  A, Tamhane  AC, Wiens  BL.  General multistage gatekeeping procedures.  Biom J. 2008;50(5):667-677. doi:10.1002/bimj.200710464PubMedGoogle ScholarCrossref
Dmitrienko  A, Tamhane  AC.  Mixtures of multiple testing procedures for gatekeeping applications in clinical trials.  Stat Med. 2011;30(13):1473-1488. doi:10.1002/sim.4008PubMedGoogle ScholarCrossref
Dmitrienko  A, Kordzakhia  G, Brechenmacher  T.  Mixture-based gatekeeping procedures for multiplicity problems with multiple sequences of hypotheses.  J Biopharm Stat. 2016;26(4):758-780. doi:10.1080/10543406.2015.1074917PubMedGoogle ScholarCrossref
Lieberman  JA, Davis  RE, Correll  CU,  et al.  ITI-007 for the treatment of schizophrenia: a 4-week randomized, double-blind, controlled trial.  Biol Psychiatry. 2016;79(12):952-961. doi:10.1016/j.biopsych.2015.08.026PubMedGoogle ScholarCrossref
Leucht  S, Leucht  C, Huhn  M,  et al.  Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors.  Am J Psychiatry. 2017;174(10):927-942. doi:10.1176/appi.ajp.2017.16121358PubMedGoogle ScholarCrossref
Huhn  M, Nikolakopoulou  A, Schneider-Thoma  J,  et al.  Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis.  Lancet. 2019;394(10202):939-951. doi:10.1016/S0140-6736(19)31135-3PubMedGoogle ScholarCrossref
Fleischhacker  W, Galderisi  S, Laszlovszky  I,  et al.  The efficacy of cariprazine in negative symptoms of schizophrenia: post hoc analyses of PANSS individual items and PANSS-derived factors.  Eur Psychiatry. 2019;58:1-9. doi:10.1016/j.eurpsy.2019.01.015PubMedGoogle ScholarCrossref
Correll  CU, Stanford  AD, Claxton  A, Du  Y, Weiden  PJ.  Social and functional outcomes with two doses of aripiprazole lauroxil vs placebo in patients with schizophrenia: a post-hoc analysis of a 12-week phase 3 efficacy study.  Psychiatry Res. 2019;274:176-181. doi:10.1016/j.psychres.2019.02.021PubMedGoogle ScholarCrossref
Harvey  PD, Khan  A, Keefe  RSE.  Using the positive and negative syndrome scale (PANSS) to define different domains of negative symptoms: prediction of everyday functioning by impairments in emotional expression and emotional experience.  Innov Clin Neurosci. 2017;14(11-12):18-22.PubMedGoogle Scholar
Vanover  KE, Davis  RE, Zhou  Y,  et al.  Dopamine D2 receptor occupancy of lumateperone (ITI-007): a positron emission tomography study in patients with schizophrenia.  Neuropsychopharmacology. 2019;44(3):598-605. doi:10.1038/s41386-018-0251-1PubMedGoogle ScholarCrossref
Briggs  A, Wild  D, Lees  M,  et al.  Impact of schizophrenia and schizophrenia treatment-related adverse events on quality of life: direct utility elicitation.  Health Qual Life Outcomes. 2008;6(1):105. doi:10.1186/1477-7525-6-105PubMedGoogle ScholarCrossref
Correll  CU.  What are we looking for in new antipsychotics?  J Clin Psychiatry. 2011;72(suppl 1):9-13. doi:10.4088/JCP.10075su1.02PubMedGoogle ScholarCrossref
De Hert  M, Detraux  J, van Winkel  R, Yu  W, Correll  CU.  Metabolic and cardiovascular adverse effects associated with antipsychotic drugs.  Nat Rev Endocrinol. 2011;8(2):114-126. doi:10.1038/nrendo.2011.156PubMedGoogle ScholarCrossref
Vancampfort  D, Wampers  M, Mitchell  AJ,  et al.  A meta-analysis of cardio-metabolic abnormalities in drug naïve, first-episode and multi-episode patients with schizophrenia versus general population controls.  World Psychiatry. 2013;12(3):240-250. doi:10.1002/wps.20069PubMedGoogle ScholarCrossref
Vancampfort  D, Stubbs  B, Mitchell  AJ,  et al.  Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis.  World Psychiatry. 2015;14(3):339-347. doi:10.1002/wps.20252PubMedGoogle ScholarCrossref
Vancampfort  D, Correll  CU, Galling  B,  et al.  Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta-analysis.  World Psychiatry. 2016;15(2):166-174. doi:10.1002/wps.20309PubMedGoogle ScholarCrossref
Kane  JM, Kishimoto  T, Correll  CU.  Non-adherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies.  World Psychiatry. 2013;12(3):216-226. doi:10.1002/wps.20060PubMedGoogle ScholarCrossref
Druschky  K, Bleich  S, Grohmann  R,  et al.  Seizure rates under treatment with antipsychotic drugs: Data from the AMSP project.  World J Biol Psychiatry. 2018:1-10. doi:10.1080/15622975.2018.1500030PubMedGoogle Scholar
Wu  C-S, Wang  S-C, Yeh  I-J, Liu  S-K.  Comparative risk of seizure with use of first- and second-generation antipsychotics in patients with schizophrenia and mood disorders.  J Clin Psychiatry. 2016;77(5):e573-e579. doi:10.4088/JCP.15m09898PubMedGoogle ScholarCrossref
Vanover  K, Dmitrienko  A, Glass  S,  et al.  Lumateperone (ITI-007) for the treatment of schizophrenia: placebo-controlled clinical trials and an open-label safety switching study.  Schizophr Bull. 2018;44(suppl 1):S341-S341. doi:10.1093/schbul/sby018.831Google ScholarCrossref
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    Original Investigation
    January 8, 2020

    Efficacy and Safety of Lumateperone for Treatment of Schizophrenia: A Randomized Clinical Trial

    Author Affiliations
    • 1Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
    • 2Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, New York
    • 3Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany
    • 4Intra-Cellular Therapies Inc, New York, New York
    • 5Now with Axsome Therapeutics Inc, New York, New York
    • 6Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, New York
    • 7Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas
    JAMA Psychiatry. 2020;77(4):349-358. doi:10.1001/jamapsychiatry.2019.4379
    Key Points

    Question  Does 60 mg of lumateperone tosylate (42 mg of lumateperone) significantly reduce symptoms of schizophrenia compared with placebo without relevant motor, cardiometabolic, or endocrine adverse effects?

    Findings  In this randomized clinical trial of 450 patients with acute exacerbation of schizophrenia, 42 mg of lumateperone demonstrated statistically significant differences in reducing symptoms of schizophrenia without treatment-emergent motor, cardiometabolic, or endocrine adverse effects compared with placebo.

    Meaning  Lumateperone is a potential treatment for schizophrenia and has a favorable safety profile.


    Importance  Individuals living with schizophrenia are affected by cardiometabolic, endocrine, and motor adverse effects of current antipsychotic medications. Lumateperone is a serotonin, dopamine, and glutamate modulator with the potential to treat schizophrenia with few adverse effects.

    Objective  To examine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia.

    Design, Setting, and Participants  This randomized, double-blind, placebo-controlled, phase 3 clinical trial was conducted from November 13, 2014, to July 20, 2015, with data analyses performed from August 13 to September 15, 2015. Patients with schizophrenia who were aged 18 to 60 years and were experiencing an acute exacerbation of psychosis were enrolled from 12 clinical sites in the United States.

    Interventions  Patients were randomized 1:1:1 (150 patients in each arm) to receive lumateperone tosylate, 60 mg; lumateperone tosylate, 40 mg (equivalent to 42 or 28 mg, respectively, of the active moiety lumateperone); or placebo once daily for 4 weeks.

    Main Outcomes and Measures  The prespecified primary efficacy end point was mean change from baseline to day 28 in the Positive and Negative Syndrome Scale (PANSS) total score vs placebo. The key secondary efficacy measure was the Clinical Global Impression–Severity of Illness (CGI-S) score. The PANSS subscale scores, social function, safety, and tolerability were also assessed.

    Results  The study comprised 450 patients (mean [SD] age, 42.4 [10.2] years; 346 [77.1%] male; mean [SD] baseline PANSS score, 89.8 [10.3]; mean [SD] baseline CGI-S score, 4.8 [0.6]). In the prespecified modified intent-to-treat efficacy analysis (n = 435), 42 mg of lumateperone met the primary and key secondary efficacy objectives, demonstrating a statistically significant improvement vs placebo from baseline to day 28 on the PANSS total score (least-squares mean difference [LSMD], −4.2; 95% CI, −7.8 to −0.6; P = .02; effect size [ES], −0.3) and the CGI-S (LSMD, −0.3; 95% CI, −0.5 to −0.1; P = .003; ES, −0.4). For 28 mg of lumateperone, the LSMD from baseline to day 28 was −2.6 (95% CI, −6.2 to 1.1; P = .16; ES, −0.2) on the PANSS total score and −0.2 (95% CI, −0.5 to 0.0; P = .02; ES, −0.3) on the CGI-S. Both lumateperone doses were well tolerated without clinically significant treatment-emergent motor adverse effects or changes in cardiometabolic or endocrine factors vs placebo.

    Conclusions and Relevance  Lumateperone demonstrated efficacy for improving the symptoms of schizophrenia and had a favorable safety profile.

    Trial Registration  ClinicalTrials.gov identifier: NCT02282761