Metabotropic Glutamate Receptor 5 Negative Modulation in Phase I Clinical Trial: Potential Impact of Circadian Rhythm on the Neuropsychiatric Adverse Reactions—Do Hallucinations Matter?
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
References
[1]
K. J. Gregory, E. N. Dong, J. Meiler, and P. J. Conn, “Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential,” Neuropharmacology, vol. 60, no. 1, pp. 66–81, 2011.
[2]
R. M. Brown, S. Mustafa, M. A. Ayoub, et al., “mGlu5 receptor functional interactions and addiction,” Front Pharmacology, vol. 7, no. 3, p. 84, 2012.
[3]
U. C. Campbell, K. Lalwani, L. Hernandez, G. G. Kinney, P. J. Conn, and L. J. Bristow, “The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats,” Psychopharmacology, vol. 175, no. 3, pp. 310–318, 2004.
[4]
D. Durand, L. Carniglia, C. Caruso, et al., “Metabotropic glutamate receptors in peripheral tissues: implications for toxicology,” in Anxiety Disorders, Mental and Behavioural Disorders and Diseases of the Nervous System, V. Kalinin, Ed., pp. 97–120, Slavka Krautzeka, Croatia, 2011.
[5]
American Psychiatric association, Diagnostic and Statistical Manual of Mental Disorders, APA, Washington, DC, USA, 4t edition, 1990.
[6]
M. Manford and F. Andermann, “Complex visual hallucinations. Clinical and neurobiological insights,” Brain, vol. 121, no. 10, pp. 1819–1840, 1998.
[7]
J. Barnes and A. S. David, “Visual hallucinations in Parkinson's disease: a review and phenomenological survey,” Journal of Neurology Neurosurgery and Psychiatry, vol. 70, no. 6, pp. 727–733, 2001.
[8]
T. Hakami, N. C. Jones, E. A. Tolmacheva et al., “NMDA receptor hypofunction leads to generalized and persistent aberrant γ oscillations independent of hyperlocomotion and the state of consciousness,” PLoS ONE, vol. 4, no. 8, Article ID e6755, 2009.
[9]
S. Sukumaran, R. R. Almon, D. C. DuBois, and W. J. Jusko, “Circadian rhythms in gene expression: relationship to physiology, disease, drug disposition and drug action,” Advanced Drug Delivery Reviews, vol. 62, no. 9-10, pp. 904–917, 2010.
[10]
P. Erkekoglu and T. Bayder, “Chronopharmacokinetics of drugs in toxicological aspects: a short review for pharmacy practitioners,” Joint Regional Planning Panel, vol. 1, no. 1, pp. 3–9, 2012.
[11]
S. L. Miksys and R. F. Tyndale, “Drug-metabolizing cytochrome P450s in the brain,” Journal of Psychiatry and Neuroscience, vol. 27, no. 6, pp. 406–415, 2002.
[12]
C. Ghosh, N. Marchi, N. K. Desai et al., “Cellular localization and functional significance of CYP3A4 in the human epileptic brain,” Epilepsia, vol. 52, no. 3, pp. 562–571, 2011.
[13]
C. S. Ferguson and R. F. Tyndale, “Cytochrome P450 enzymes in the brain: emerging evidence of biological significance,” Trends in Pharmacological Sciences, vol. 32, no. 12, pp. 708–714, 2011.
[14]
Y.-K. J. Zhang, R. L. Yeager, and C. D. Klaassen, “Circadian expression profiles of drug-processing genes and transcription factors in mouse liver,” Drug Metabolism and Disposition, vol. 37, no. 1, pp. 106–115, 2009.
[15]
B. Lemmer and G. Nold, “Circadian changes in estimated hepatic blood flow in healthy subjects,” British Journal of Clinical Pharmacology, vol. 32, no. 5, pp. 627–629, 1991.
[16]
Y. Touitou, C. Touitou, and A. Bogdan, “Differeneces between young and elderly subjects in seasonal and circadian variations of total plasma proteins and blood volume as reflected by hemoglobin, hematocrit, and erythrocyte counts,” Clinical Chemistry, vol. 32, no. 5, pp. 801–804, 1986.
[17]
H. Ito, K. Takahashi, J. Hatazawa, S.-G. Kim, and I. Kanno, “Changes in human regional cerebral blood flow and cerebral blood volume during visual stimulation measured by positron emission tomography,” Journal of Cerebral Blood Flow and Metabolism, vol. 21, no. 5, pp. 608–612, 2001.
[18]
D. A. Conroy, A. J. Spielman, and R. Q. Scott, “Daily rhythm of cerebral blood flow velocity,” Journal of Circadian Rhythms, vol. 3, no. 3, 2005.
[19]
I. Mody and J. Maguire, “The reciprocal regulation of stress hormones and GABAA receptors,” Frontiers in Cellular Neuroscience, vol. 6, 2012.
[20]
B. K. Hoffpauir and E. L. Gleason, “Modulation of synaptic function in retinal amacrine cells,” Integrative and Comparative Biology, vol. 45, no. 4, pp. 658–664, 2005.
[21]
M. J. Bradbury, D. R. Giracello, D. F. Chapman et al., “Metabotropic glutamate receptor 5 antagonist-induced stimulation of hypothalamic-pituitary-adrenal axis activity: Interaction with serotonergic systems,” Neuropharmacology, vol. 44, no. 5, pp. 562–572, 2003.
[22]
A. N. Vgontzas, E. O. Bixler, H.-M. Lin et al., “Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 8, pp. 3787–3794, 2001.
[23]
K. C. Marsden, J. B. Beattie, J. Friedenthal, and R. C. Carroll, “NMDA receptor activation potentiates inhibitory transmission through GABA receptor-associated protein-dependent exocytosis of GABAA receptors,” Journal of Neuroscience, vol. 27, no. 52, pp. 14326–14337, 2007.
[24]
R. M. Cleva and M. F. Olive, “Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders,” Molecules, vol. 16, no. 3, pp. 2097–2106, 2011.
[25]
H.-H. Chen, P.-F. Liao, and M.-H. Chan, “MGluR5 positive modulators both potentiate activation and restore inhibition in NMDA receptors by PKC dependent pathway,” Journal of Biomedical Science, vol. 18, no. 1, article 19, 2011.
[26]
J. Barnes and A. S. David, “Visual hallucinations in Parkinson's disease: a review and phenomenological survey,” Journal of Neurology Neurosurgery and Psychiatry, vol. 70, no. 6, pp. 727–733, 2001.
[27]
T. E. Kim, H. J. Kim, J. H. Park, et al., “Cognitive dysfunction with complex visual hallucinations due to focal nonconvulsive status epilepticus: a neuropsychological study and SISCOM,” Seizure, vol. 21, no. 8, pp. 658–660, 2012.
