Format

Send to

Choose Destination
JAMA Psychiatry. 2014 Jun;71(6):637-46. doi: 10.1001/jamapsychiatry.2014.163.

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

Author information

1
F. Hoffmann-La Roche, Basel, Switzerland.
2
SRI International, Menlo Park, California.
3
F. Hoffmann-La Roche, Basel, Switzerland3now with Support Venture, Riehen, Switzerland.

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.

Comment in

PMID:
24696094
DOI:
10.1001/jamapsychiatry.2014.163
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center