Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study.
JAMA Psychiatry
; 71(6): 637-46, 2014 Jun.
Article
em En
| MEDLINE
| ID: mdl-24696094
ABSTRACT
IMPORTANCE In schizophrenia, the severity of negative symptoms is a key predictor of long-term disability. Deficient signaling through the N-methyl-D-aspartate receptor is hypothesized to underlie many signs and symptoms associated with schizophrenia in particular negative symptoms. Glycine acts as an N-methyl-D-aspartate receptor coagonist. Blockade of the glycine transporter type 1 to inhibit glycine reuptake and elevate synaptic glycine concentrations represents an effective strategy to enhance N-methyl-D-aspartate receptor transmission. OBJECTIVE:
To determine the efficacy and safety of bitopertin (RG1678), a glycine reuptake inhibitor, in patients with schizophrenia and predominant negative symptoms who were stable while taking an antipsychotic treatment. DESIGN, SETTING, ANDPARTICIPANTS:
This randomized, double-blind, placebo-controlled, phase 2 proof-of-concept trial involved 323 patients with schizophrenia and predominant negative symptoms across 66 sites worldwide.INTERVENTIONS:
Bitopertin (10, 30, or 60 mg/d) or placebo added to standard antipsychotic therapy for a treatment duration of 8 weeks. MAIN OUTCOMES ANDMEASURES:
Change from baseline in the Positive and Negative Syndrome Scale negative factor score.RESULTS:
In the per-protocol population, 8 weeks of treatment with bitopertin was associated with a significant reduction of negative symptoms in the 10-mg/d (mean [SE] reduction in negative symptoms score, -25% [2%]; P = .049) and 30-mg/d (mean [SE], -25% [2%]; P = .03) bitopertin groups, a significantly higher response rate and a trend toward improved functioning in the 10-mg/d group when compared with placebo (mean [SE], -19% [2%]). Results reached trend-level significance in the intent-to-treat population. Estimates of bitopertin binding to glycine transporter type 1 showed that low to medium levels of occupancy yielded optimal efficacy in patients, consistent with findings in preclinical assays. CONCLUSIONS AND RELEVANCE Bitopertin-mediated glycine reuptake inhibition may represent a novel treatment option for schizophrenia, with the potential to address negative symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier NCT00616798.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
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Esquizofrenia
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Psicologia do Esquizofrênico
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Sulfonas
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Antipsicóticos
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Proteínas da Membrana Plasmática de Transporte de Glicina
Tipo de estudo:
Clinical_trials
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Diagnostic_studies
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Guideline
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Prognostic_studies
Limite:
Adult
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article