Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: a proof-of-mechanism study

Neuropharmacology. 2013 Jan;64:197-204. doi: 10.1016/j.neuropharm.2012.06.040. Epub 2012 Jul 2.

Abstract

In this multicenter, double-blind, placebo-controlled, randomized, four way cross-over proof-of-mechanism study, we tested the effect of the positive allosteric α7 nicotinic acetylcholine receptor (nAChR) modulator JNJ-39393406 in a key translational assay (sensory P50 gating) in 39 regularly smoking male patients with schizophrenia. All patients were clinically stable and JNJ-39393406 was administered as an adjunct treatment to antipsychotics. No indication was found that JNJ-39393406 has the potential to reverse basic deficits of information processing in schizophrenia (sensory P50 gating) or has a significant effect on other tested electrophysiological markers (MMN, P300 and quantitative resting EEG). Sensitivity analyses including severity of disease, baseline P50 gating, medication and gene variants of the CHRNA7 gene did not reveal any subgroups with consistent significant effects. It is discussed that potential positive effects in subgroups not present or not large enough in the current study or upon chronic dosing are possible, but unlikely to be developed. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Trial registration: ClinicalTrials.gov NCT01137799.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Allosteric Regulation
  • Antipsychotic Agents / therapeutic use
  • Cognition Disorders / etiology
  • Cognition Disorders / prevention & control*
  • Cross-Over Studies
  • Diagnostic and Statistical Manual of Mental Disorders
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drugs, Investigational / administration & dosage
  • Drugs, Investigational / adverse effects
  • Drugs, Investigational / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Molecular Targeted Therapy*
  • Nicotinic Agonists / administration & dosage
  • Nicotinic Agonists / adverse effects
  • Nicotinic Agonists / therapeutic use*
  • Nootropic Agents / administration & dosage
  • Nootropic Agents / adverse effects
  • Nootropic Agents / therapeutic use*
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / metabolism*
  • Schizophrenia / drug therapy*
  • Schizophrenia / physiopathology
  • Sensory Gating / drug effects*
  • Smoking
  • Young Adult
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Antipsychotic Agents
  • Chrna7 protein, human
  • Drugs, Investigational
  • Nicotinic Agonists
  • Nootropic Agents
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor

Associated data

  • ClinicalTrials.gov/NCT01137799