%0 Journal Article
%T Metabotropic Glutamate Receptor 5 Negative Modulation in Phase I Clinical Trial: Potential Impact of Circadian Rhythm on the Neuropsychiatric Adverse Reactions¡ªDo Hallucinations Matter?
%A Khalid Abou Farha
%A Richard Bruggeman
%A Corine Balj¨¦-Volkers
%J ISRN Psychiatry
%D 2014
%R 10.1155/2014/652750
%X 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. 1. Introduction Metabotropic glutamate receptors, members of the G protein-coupled receptor superfamily, are widely distributed throughout the central nervous system (CNS) on neuronal and glial cells. During the past two decades, a body of scientific evidence has accumulated indicating that metabotropic glutamate receptors play a substantial role in many CNS diseases and psychiatric disorders [1, 2]. Given their discrete localization within the human brain and thence the possibility of limiting off-target effect, metabotropic glutamate receptors subtype 5 (mGluR5) have been proposed as an attractive novel therapeutic target worth investigating [2]. In this context, negative allosteric modulation of mGluR5 has been suggested for the treatment of mental disorders, such as anxiety disorders and depression, and more recently for treatment of alcohol and drug addiction [1, 2]. A number of mGluR5 antagonists and selective NAMs have been identified in the last decade [1]. Selective mGluR5-NAMs have been reported to possess higher potency, selectivity, and brain penetrance and
%U http://www.hindawi.com/journals/isrn.psychiatry/2014/652750/