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A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia.

ABSTRACT: In a previous pilot study, MK-0777--a ?-aminobutyric acid (GABA)(A) ?2/?3 partial agonist--was reported to improve delayed memory and cognitive measures of prefrontal cortical function in people with schizophrenia. The current study was designed to further examine the efficacy and safety of MK-0777 for the treatment of cognitive impairments in schizophrenia.Sixty people with DSM-IV schizophrenia entered a 4-week, multi-center, double-blind, placebo-controlled, randomized clinical trial. Participants were randomized to: MK-0777 3 mg b.i.d. (n = 18); MK-0777 8 mg b.i.d. (n = 21); or placebo (n = 21). Participants were clinically stable. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, AX-Continuous Performance Test, and N-Back were used to assess cognition. The University of California San Diego (UCSD) Performance Based Skills Assessment-2 and the Schizophrenia Cognition Rating Scale assessed functional capacity and served as functional outcome coprimary measures.There were no significant group differences on the primary outcome measure, the MATRICS Consensus Cognitive Battery composite score. Secondary analyses suggested that participants randomized to placebo performed significantly better on visual memory and reasoning/problem-solving tests than participants assigned to either MK-0777 dose. There were no significant group differences on the AX-Continuous Performance Test or N-Back d prime scores or UCSD Performance-Based Skills Assessment-2 and Schizophrenia Cognition Rating Scale total scores. In general, MK-0777 was well-tolerated with minimal side effects.The study results suggest that MK-0777 has little benefit for cognitive impairments in people with schizophrenia. The GABA(A) receptor remains a promising target, but a more potent partial agonist with greater intrinsic activity at the GABA(A) ?2 site might be needed for cognitive enhancement in schizophrenia.

SUBMITTER: Buchanan RW

PROVIDER: S-EPMC3058394 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia.

Buchanan Robert W RW Keefe Richard S E RS Lieberman Jeffrey A JA Barch Deanna M DM Csernansky John G JG Goff Donald C DC Gold James M JM Green Michael F MF Jarskog L Fredrik LF Javitt Daniel C DC Kimhy David D Kraus Michael S MS McEvoy Joseph P JP Mesholam-Gately Raquelle I RI Seidman Larry J LJ Ball M Patricia MP McMahon Robert P RP Kern Robert S RS Robinson James J Marder Stephen R SR

Biological psychiatry 20101208 5

<h4>Background</h4>In a previous pilot study, MK-0777--a γ-aminobutyric acid (GABA)(A) α2/α3 partial agonist--was reported to improve delayed memory and cognitive measures of prefrontal cortical function in people with schizophrenia. The current study was designed to further examine the efficacy and safety of MK-0777 for the treatment of cognitive impairments in schizophrenia.<h4>Methods</h4>Sixty people with DSM-IV schizophrenia entered a 4-week, multi-center, double-blind, placebo-controlled, ...[more]

PMID: 21145041

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Project description:ImportanceIndividuals 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.ObjectiveTo examine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia.Design, setting, and participantsThis 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.InterventionsPatients 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 measuresThe 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.ResultsThe 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 relevanceLumateperone demonstrated efficacy for improving the symptoms of schizophrenia and had a favorable safety profile.Trial registrationClinicalTrials.gov identifier: NCT02282761.

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A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia.

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A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia.

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