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


METHODS
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.


METHODS
Bitopertin (10, 30, or 60 mg/d) or placebo added to standard antipsychotic therapy for a treatment duration of 8 weeks.


METHODS
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
Bitopertin-mediated glycine reuptake inhibition may represent a novel treatment option for schizophrenia, with the potential to address negative symptoms.


BACKGROUND
clinicaltrials.gov Identifier: NCT00616798.
F. Hoffmann-La Roche, Basel, Switzerland.
Daniel
D
Umbricht
F. Hoffmann-La Roche, Basel, Switzerland.
Daniela
D
Alberati
F. Hoffmann-La Roche, Basel, Switzerland.
Meret
M
Martin-Facklam
F. Hoffmann-La Roche, Basel, Switzerland.
Edilio
E
Borroni
F. Hoffmann-La Roche, Basel, Switzerland.
Eriene A
EA
Youssef
F. Hoffmann-La Roche, Basel, Switzerland.
Michael
M
Ostland
SRI International, Menlo Park, California.
Tanya L
TL
Wallace
F. Hoffmann-La Roche, Basel, Switzerland.
Frédéric
F
Knoflach
F. Hoffmann-La Roche, Basel, Switzerland.
Ernest
E
Dorflinger
F. Hoffmann-La Roche, Basel, Switzerland.
Joseph G
JG
Wettstein
F. Hoffmann-La Roche, Basel, Switzerland3now with Support Venture, Riehen, Switzerland.
Alexander
A
Bausch
F. Hoffmann-La Roche, Basel, Switzerland.
George
G
Garibaldi
F. Hoffmann-La Roche, Basel, Switzerland.
Luca
L
Santarelli
D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D013450:Sulfones / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
C550631:(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone; D014150:Antipsychotic Agents; D050487:Glycine Plasma Membrane Transport Proteins; D010879:Piperazines; C493268:SLC6A9 protein, human; D013450:Sulfones