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Original Investigation |

Effect of Bitopertin, a Glycine Reuptake Inhibitor, on Negative Symptoms of Schizophrenia:  A Randomized, Double-Blind, Proof-of-Concept Study

Daniel Umbricht, MD1; Daniela Alberati, PhD1; Meret Martin-Facklam, PhD1; Edilio Borroni, PhD1; Eriene A. Youssef, PharmD1; Michael Ostland, PhD1; Tanya L. Wallace, PhD2; Frédéric Knoflach, PhD1; Ernest Dorflinger, MD1; Joseph G. Wettstein, PhD1; Alexander Bausch, PhD1,3; George Garibaldi, MD1; Luca Santarelli, MD1
[+] Author Affiliations
1F. Hoffmann-La Roche, Basel, Switzerland
2SRI International, Menlo Park, California
3now with Support Venture, Riehen, Switzerland
JAMA Psychiatry. 2014;71(6):637-646. doi:10.1001/jamapsychiatry.2014.163.
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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

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Figure 1.
CONSORT Diagram

aPatients can be in more than 1 category for reason of exclusion. Reasons for exclusion from the specific analysis population and the number of patients in that category are given beneath the total of the specific analysis population.

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Figure 2.
Graphs of Score Changes and Response Rates

A, Change of Positive and Negative Syndrome Scale (PANSS) negative symptom factor score from baseline (mean [SE]). All patients were receiving primary antipsychotic treatment. B, Response rates at week 8. C, Clinical Global Impression–Global Improvement for negative symptoms at week 8. D, Personal and Social Performance Scale scores at baseline and week 8. All data shown are for the per-protocol population (placebo, n = 61; 10-mg–dose group, n = 60; 30-mg–dose group, n = 57; and 60-mg–dose group, n = 53).

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Figure 3.
Modeled Occupancies at Glycine Transporter Type 1 at Exposure Levels Observed in Patients in the 10-mg, 30-mg, and 60-mg/d Treatment Groups (10th to 90th Percentile of Average Plasma Concentration at Steady State)

The basis for modeling was occupancies observed in the thalamus, pons, and cerebellum in healthy volunteers after multiple doses of bitopertin.48

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