Effect of Bitopertin, a Glycine Reuptake Inhibitor, on Negative Symptoms of Schizophrenia

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.

Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans

“…Beside the dopaminergic system, dysfunctional glutamatergic neurotransmission has strongly been implicated in the etiology of schizophrenia, [1][2][3] particularly a hypofunction of the N-methyl-d-aspartate-receptor (NMDAR). 4 As NMDAR hypofunction is especially associated with negative symptoms, 5 the NMDAR is continuously discussed as being a promising target for the introduction of new medications.…”

Dimensional thinking in psychiatry in the era of the Research Domain Criteria (RDoC)

“…It is worth re-iterating that the majority of pharmacological advances in psychiatry have been spurred on by useful serendipity, but in the last 40 years and the current interest in ketamine (as a fast acting antidepressant) notwithstanding (Naughton et al 2014), very few therapeutics with novel mechanisms of action have progressed to phase III clinical trials or regulatory approval (Umbricht et al 2014). Major pharmaceutical companies have shifted drug discovery efforts away from psychiatric towards non-psychiatric disorders with identified biological targets (Miller, 2010).…”

L-Arginine Add-On Treatment for Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study

“…Ek olarak, glutamaterjik düzenleyicilerin yazında çelişen sonuçlar olmasına rağmen daha çok negatif belirtilerde etki gösterdiği bildirilmiştir (Sommer ve ark. 2012, Umbricht ve ark. 2014, Hashimoto ve ark.…”