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

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.

β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X

“…If this conclusion is correct, then modulators that specifically target mGlu 5 coupling to β-arrestin2 might avoid side effects that arise from inhibition of G q and/or mTOR pathway signaling. First-generation mGlu 5 NAMs were all identified based on inhibition of G q signaling, and in humans one adverse side effect reported following treatment with these compounds is derealization and visual hallucinations (Abou Farha et al, 2014; Pecknold et al, 1982; Porter et al, 2005). Similarly in mice, mGlu 5 NAMs exacerbate hyperlocomotion in response to treatment with the potent pyschotomimetic MK801 (Homayoun et al, 2004; Pietraszek et al, 2005).…”

“…In humans, for example, it has been reported that inhibition of mGlu 5 produces dose-limiting psychotomimetic effects (Abou Farha et al, 2014; Pecknold et al, 1982; Porter et al, 2005). The first-generation mGlu 5 NAMs were identified based on their ability to inhibit G q signaling mediated by phosphoinositide hydrolysis and release of Ca 2+ from intracellular stores (Cosford et al, 2003; Gasparini et al, 1999; Lindemann et al, 2011).…”

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

“…Additional targets within the glutamatergic system include other ionotropic receptors (AMPA, kainate) (171,172), metabotropic receptors (173), and glutamate transporters.…”

VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy

“…CNS indications for mGlu 5 NAMs include fragile X syndrome, Ldopa induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety. Unfortunately, mGlu 5 NAMs have not been successful thus far as clinical therapeutics, in part because of the induction of side effects, including psychotomimetic activity (Pecknold et al, 1982;Porter et al, 2005;Rodriguez et al, 2005;Abou Farha et al, 2014) or the lack of efficacy in the treatment of L-DOPA-induced dyskinesia (Petrov et al, 2014) and fragile X syndrome [FRAXA mavoglurant posting (Novartis; http://www.fraxa.org/ novartis-discontinues-development-mavoglurant-afq056-fragile-x-syndrome/. in), FRAXA basimglurant posting (Roche; basimglurant, FRAXA, http://www.fraxa.org/rochereports-clinical-trial-negative-results/, in.)]…”

“…The mGlu 5 NAMs have reached or are now in active clinical studies to evaluate clinical efficacy for these disorders (Campbell et al, 2004;McGeehan et al, 2004;Pietraszek et al, 2004;Rodriguez et al, 2010;Zerbib et al, 2011). Despite these encouraging results, both clinical and preclinical studies suggest that mGlu 5 NAMs may induce ontarget adverse effects, including cognitive and memory impairments and psychotomimetic effects (Campbell et al, 2004;Porter et al, 2005;Rodriguez et al, 2010;Abou Farha et al, 2014), raising the question of whether complete blockade of mGlu 5 may contribute to these deleterious effects, thereby limiting the therapeutic utility of mGlu 5 NAMs.…”