Ernest Dorflinger

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

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.

Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity.

A retrospective pharmacogenetic study was conducted to identify possible genetic susceptibility factors in patients in whom the administration of the anti-Parkinson drug, tolcapone (TASMAR®), was associated with hepatic toxicity. We studied 135 cases of patients with elevated liver transaminase levels (ELT) of ≥1.5 times above the upper limit of normal, in comparison with matched controls that had also received the drug but had not experienced ELT. DNA samples were genotyped for 30 previously described or newly characterized bi-allelic single nucleotide polymorphisms (SNPs), representing 12 candidate genes selected based on the known metabolic pathways involved in the tolcapone elimination. SNPs located within the UDP-glucuronosyl transferase 1A gene complex, which codes for the enzymes involved in the main elimination pathway of the drug, were found to be significantly associated with the occurrence of tolcapone-associated ELTs.

Illness impact and adjustment to Parkinson's disease: before and after treatment with tolcapone.

Research on the impact of disease and treatment on health status and quality of life in patients with movement disorders is limited. We studied quality of life in 46 patients with Parkinsons disease (PD) to determine whether the impact of illness and psychosocial adjustment to illness were improved by 42 days of adjunctive therapy with tolcapone (50 mg, 200 mg, or 400 mg three times a day). This study was conducted in parallel with a double‐blind, placebo‐controlled, dose‐response study of the safety and efficacy of tolcapone in combination with levodopa/carbidopa therapy. Only a subset of individuals from the larger study participated. In the quality of life study, illness impact and adjustment to illness were measured subjectively by the Sickness Impact Profile (SIP) and the Psychosocial Adjustment to Illness Scale‐Self‐Report (PAIS‐SR). Patient ratings of total illness impact (p = 0.003), physical illness impact (p = 0.05), and psychosocial illness impact (p = 0.007) improved significantly in individuals receiving tolcapone compared with those receiving placebo. There was no statistically significant difference in adjustment to illness when the tolcapone and placebo groups were compared; however, 17 of 21 adjustment to illness indicators showed improvement.

Efficacy and safety of gantenerumab in prodromal Alzheimer’s disease: Results from scarlet road—a global, multicenter trial

Bruno Vellas, Isabelle Carrie, Sophie Guyonnet, Jacques Touchon, Thierry Dantoine, Jean-François Dartigues, Marie Noelle Cufi, Serge Bordes, Yves Gasnier, Philippe Robert, Lawrence Bories, Olivier Rouaud, Francoise Desclaux, Kristel Sudres, Marc Bonnefoy, Alain Pesce, Bertrand Fougere, Julien Delrieu, Catherine Faisant, Françoise Lala, Charlotte Dupuy, Christelle Cantet, Nicola Coley, Sylvie Belleville, Sherry L. Willis, Michael W. Weiner, Pierre Jean Ousset, Sandrine Andrieu, INSERM UMR 1027, Toulouse, France; University of Toulouse III, Toulouse, France; CHU Toulouse, Toulouse, France; CHU Toulouse, Toulouse, France; INSERM UMR 1027, Toulouse, France; CHU Montpellier, Montpellier, France; CHU Limoges, Limoges, France; INSERM U897, Bordeaux, France; Bordeaux University, Bordeaux, France; Memory consultation, CHU Bordeaux, Bordeaux, France; Bordeaux University Hospital, Bordeaux, France; CH Castres, Castres, France; CH Tarbes, Tarbes, France; CHU Nice, Nice, France; CH Foix, Foix, France; Hôpital General, Dijon, France; CH Lavaur, Lavaur, France; CH Montauban, Montauban, France; CHU Lyon SUD, Lyon, France; CH Princesse Grace, Monaco, Monaco; Institute of Aging, University Hospital Toulouse, Toulouse, France; Institut Universitaire de G eriatrie de Montr eal, Montr eal, QC, Canada; Universit e de Montr eal, Montr eal, QC, Canada; Indiana University, Indianapolis, IN, USA; University of California San Francisco, San Francisco, CA, USA; INSERM UMR 1027, Paul Sabatier University, Toulouse, France. Contact e-mail: vellas. b@chu-toulouse.fr

Biomarker data from scarlet road: A global phase 3 study of gantenerumab in patients with prodromal Alzheimer's disease

Bruno Vellas, Isabelle Carrie, Sophie Guyonnet, Jacques Touchon, Thierry Dantoine, Jean-François Dartigues, Marie Noelle Cufi, Serge Bordes, Yves Gasnier, Philippe Robert, Lawrence Bories, Olivier Rouaud, Francoise Desclaux, Kristel Sudres, Marc Bonnefoy, Alain Pesce, Bertrand Fougere, Julien Delrieu, Catherine Faisant, Françoise Lala, Charlotte Dupuy, Christelle Cantet, Nicola Coley, Sylvie Belleville, Sherry L. Willis, Michael W. Weiner, Pierre Jean Ousset, Sandrine Andrieu, INSERM UMR 1027, Toulouse, France; University of Toulouse III, Toulouse, France; CHU Toulouse, Toulouse, France; CHU Toulouse, Toulouse, France; INSERM UMR 1027, Toulouse, France; CHU Montpellier, Montpellier, France; CHU Limoges, Limoges, France; INSERM U897, Bordeaux, France; Bordeaux University, Bordeaux, France; Memory consultation, CHU Bordeaux, Bordeaux, France; Bordeaux University Hospital, Bordeaux, France; CH Castres, Castres, France; CH Tarbes, Tarbes, France; CHU Nice, Nice, France; CH Foix, Foix, France; Hôpital General, Dijon, France; CH Lavaur, Lavaur, France; CH Montauban, Montauban, France; CHU Lyon SUD, Lyon, France; CH Princesse Grace, Monaco, Monaco; Institute of Aging, University Hospital Toulouse, Toulouse, France; Institut Universitaire de G eriatrie de Montr eal, Montr eal, QC, Canada; Universit e de Montr eal, Montr eal, QC, Canada; Indiana University, Indianapolis, IN, USA; University of California San Francisco, San Francisco, CA, USA; INSERM UMR 1027, Paul Sabatier University, Toulouse, France. Contact e-mail: vellas. b@chu-toulouse.fr

Correction to: A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

Following publication of the original article [1], the author reported errors in the formatting of the table. The details of the errors are as follows: