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GABAB Receptors, Schizophrenia and Sleep Dysfunction

A Review of the Relationship and its Potential Clinical and Therapeutic Implications

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Abstract

Evidence for an intrinsic relationship between sleep, cognition and the symptomatic manifestations of schizophrenia is accumulating. This review presents evidence for the possible utility of GABAB receptor agonists for the treatment of subjective and objective sleep abnormalities related to schizophrenia.

At the phenotypic level, sleep disturbance occurs in 16–30% of patients with schizophrenia and is related to reduced quality of life and poor coping skills. On the neurophysiological level, studies suggest that sleep deficits reflect a core component of schizophrenia. Specifically, slow-wave sleep deficits, which are inversely correlated with cognition scores, are seen. Moreover, sleep plays an increasingly well documented role in memory consolidation in schizophrenia. Correlations of slow-wave sleep deficits with impaired reaction time and declarative memory have also been reported. Thus, both behavioural insomnia and sleep architecture are critical therapeutic targets in patients with schizophrenia. However, long-term treatment with anti-psychotics often results in residual sleep dysfunction and does not improve slow-wave sleep, and adjunctive GABAA receptor modulators, such as ben-zodiazepines and zolpidem, can impair sleep architecture and cognition in schizophrenia.

GABAB receptor agonists have therapeutic potential in schizophrenia. These agents have minimal effect on rapid eye movement sleep while increasing slow-wave sleep. Preclinical associations with increased expression of genes related to slow-wave sleep production and circadian rhythm function have also been reported. GABAB receptor deficits result in a sustained hyper-dopaminergic state and can be reversed by a GABAB receptor agonist. Genetic, postmortem and electrophysiological studies also associate GABAB receptors with schizophrenia.

While studies thus far have not shown significant effects, prior focus on the use of GABAB receptor agonists has been on the positive symptoms of schizophrenia, with minimal investigation of GABAB receptor agonists such as baclofen or γ-hydroxybutyric acid and their effects on sleep architecture, cognition and negative symptoms in patients with schizophrenia. Further study is needed.

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Acknowledgements

No sources of funding were used to assist in the preparation of this review.

Joshua Kantrowitz has conducted clinical research supported by Jazz Pharmaceuticals.

Leslie Citrome is a consultant for, has received honoraria from or has conducted clinical research supported by the following: Abbott Laboratories, AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals, Azur Pharma, Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Johnson & Johnson, Merck, Pfizer and Vanda Pharmaceuticals.

Daniel Javitt holds intellectual property rights for use of glycine, D-serine and glycine transport inhibitors in the treatment of schizophrenia, is a major shareholder in Glytech, Amino Acid Solutions and Medifoods, has received consultancy payments from Glytech, GlaxoSmithKline and Sepracor, and has conducted clinical research supported by Jazz Pharmaceuticals and Pfizer.

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Kantrowitz, J., Citrome, L. & Javitt, D. GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs 23, 681–691 (2009). https://doi.org/10.2165/00023210-200923080-00005

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