Table of Contents
ISRN Psychiatry
Volume 2014, Article ID 652750, 8 pages
http://dx.doi.org/10.1155/2014/652750
Clinical Study

Metabotropic Glutamate Receptor 5 Negative Modulation in Phase I Clinical Trial: Potential Impact of Circadian Rhythm on the Neuropsychiatric Adverse Reactions—Do Hallucinations Matter?

1Rob Giel Research Centre, Department of Psychiatry, University Medical Centre Groningen (UMCG), Hanzeplein 1, 9713 GZ Groningen, The Netherlands
2Department of Epidemiology (Medical Statistics), University Medical Centre Groningen (UMCG), Hanzeplein 1, 9713 GZ Groningen, The Netherlands

Received 30 October 2013; Accepted 21 January 2014; Published 4 March 2014

Academic Editors: C. Bonetto and A. Squassina

Copyright © 2014 Khalid Abou Farha et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Metabotropic Glutamate Receptor 5 (mGluR5) negative allosteric modulators (NAMs) may play a role in some psychiatric disorders such as anxiety and depression. The pharmacokinetic profile and pharmacodynamics effects of mGluR5-NAMs have been previously reported. We performed a post hoc analysis of pharmacological and clinical data obtained from 18 young healthy female subjects who received a mGluR5-NAM in the context of a phase I drug-drug interaction study between a mGluR5 NAM and a monophasic oral contraceptive. mGluR5-NAM was administered in an escalating bidaily dose level design. There was no interaction between the OC and mGluR5-NAM. Higher morning mGluR5-NAM plasma concentrations were found compared to evening concentrations. Most of the observed clinically significant neuropsychiatric adverse reactions occurred nocturnally and included visual (pseudo) hallucinations, insomnia accompanied by secondary behavioural disorders, and cognitive dysfunction symptoms of sufficient severity to interfere with daily functioning. Circadian rhythm-related physiological variations in drug absorption and disposition may explain this pharmacokinetics-pharmacodynamics apparently disproportionate relationship. We suggest that clinical trials evaluating basic pharmacokinetic properties of psychiatric medications consider potential drug's chronopharmacokinetics. This may assist with dose optimization and minimize serious neuropsychiatric adverse reactions in the vulnerable psychiatric patient.