Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study.

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, AND PARTICIPANTS:

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 AND MEASURES:

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.

• Authors: Daniel Umbricht, Daniela Alberati, Meret Martin-Facklam, Edilio Borroni, Eriene A Youssef, Michael Ostland, Tanya L Wallace, Frédéric Knoflach, Ernest Dorflinger, Joseph G Wettstein, Alexander Bausch, George Garibaldi, Luca Santarelli
• Journal: JAMA psychiatry (JAMA Psychiatry) Vol. 71 Issue 6 Pg. 637-46 (Jun 2014) ISSN: 2168-6238 [Electronic] United States
• PMID: 24696094 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• (4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone
• Antipsychotic Agents
• Glycine Plasma Membrane Transport Proteins
• Piperazines
• SLC6A9 protein, human
• Sulfones

Topics

• Adult
• Antipsychotic Agents (therapeutic use)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Glycine Plasma Membrane Transport Proteins (antagonists & inhibitors)
• Humans
• Male
• Piperazines (adverse effects, therapeutic use)
• Schizophrenia (diagnosis, drug therapy)
• Schizophrenic Psychology
• Sulfones (adverse effects, therapeutic use)
• Treatment Outcome