Binding of clozapine to the GABAB receptor: clinical and structural insights

doi:10.1038/s41380-020-0709-5

Review

. 2020 Sep;25(9):1910-1919.

doi: 10.1038/s41380-020-0709-5. Epub 2020 Mar 13.

Binding of clozapine to the GABA_B receptor: clinical and structural insights

Pramod C Nair^{1

2}, Ross A McKinnon³, John O Miners^{4

3}, Tarun Bastiampillai^{5

6}

Affiliations

¹ Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia. pramod.nair@flinders.edu.au.
² Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia. pramod.nair@flinders.edu.au.
³ Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
⁴ Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
⁵ Department of Psychiatry, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia. tarun.bastiampillai@flinders.edu.au.
⁶ South Australian Health and Medical Research Institute, Adelaide, SA, Australia. tarun.bastiampillai@flinders.edu.au.

PMID: 32203158
DOI: 10.1038/s41380-020-0709-5

Review

Binding of clozapine to the GABA_B receptor: clinical and structural insights

Pramod C Nair et al. Mol Psychiatry. 2020 Sep.

. 2020 Sep;25(9):1910-1919.

doi: 10.1038/s41380-020-0709-5. Epub 2020 Mar 13.

Authors

Pramod C Nair^{1

2}, Ross A McKinnon³, John O Miners^{4

3}, Tarun Bastiampillai^{5

6}

Affiliations

¹ Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia. pramod.nair@flinders.edu.au.
² Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia. pramod.nair@flinders.edu.au.
³ Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
⁴ Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
⁵ Department of Psychiatry, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia. tarun.bastiampillai@flinders.edu.au.
⁶ South Australian Health and Medical Research Institute, Adelaide, SA, Australia. tarun.bastiampillai@flinders.edu.au.

PMID: 32203158
DOI: 10.1038/s41380-020-0709-5

Abstract

Clozapine is the gold-standard agent for treatment resistant schizophrenia but its mechanism of action remains unclear. There is emerging evidence of the potential role of the GABA_B receptor in the pathogenesis of schizophrenia. It has been hypothesised that clozapine can mediate its actions via the GABA_B receptor. Baclofen is currently recognised as the prototype GABA_B receptor agonist. There are some potential clinical similarities between clozapine and baclofen. Indeed, baclofen has been previously proposed for use as an antipsychotic agent. Our analysis of the X-ray crystal structure of GABA_B receptor along with molecular docking calculations, suggests that clozapine could directly bind to the GABA_B receptor similar to that of baclofen. This finding could lead to a better understanding of the pharmacological uniqueness of clozapine, potential development of a biomarker for treatment resistant schizophrenia and the development of more targeted treatments leading to personalisation of treatment.

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Comment in

GABA_B receptor, clozapine, and catatonia-a complex triad.
Hirjak D, Northoff G, Taylor SF, Wolf RC. Hirjak D, et al. Mol Psychiatry. 2021 Jul;26(7):2683-2684. doi: 10.1038/s41380-020-00889-y. Epub 2020 Sep 25. Mol Psychiatry. 2021. PMID: 32978514 No abstract available.

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References

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1. Van Os J, Kapur S. Schizophrenia. Lancet. 2009;374:635–45. - PubMed - DOI
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[1] Insel TR. Rethinking schizophrenia. Nature. 2010;468:187–93. - PubMed - DOI

[2] Insel TR. Rethinking schizophrenia. Nature. 2010;468:187–93. - PubMed - DOI

[3] Van Os J, Kapur S. Schizophrenia. Lancet. 2009;374:635–45. - PubMed - DOI

[4] Van Os J, Kapur S. Schizophrenia. Lancet. 2009;374:635–45. - PubMed - DOI

[5] McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67–76. - PubMed - DOI

[6] McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67–76. - PubMed - DOI

[7] Marwaha S, Johnson S, Bebbington P, Stafford M, Angermeyer MC, Brugha T, et al. Rates and correlates of employment in people with schizophrenia in the UK, France and Germany. Br J Psychiatry. 2007;191:30–37. - PubMed - DOI

[8] Marwaha S, Johnson S, Bebbington P, Stafford M, Angermeyer MC, Brugha T, et al. Rates and correlates of employment in people with schizophrenia in the UK, France and Germany. Br J Psychiatry. 2007;191:30–37. - PubMed - DOI

[9] Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia data from a systematic review and meta-analysis. Can J Psychiatry. 2017;62:772–7. - PubMed - PMC - DOI

[10] Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia data from a systematic review and meta-analysis. Can J Psychiatry. 2017;62:772–7. - PubMed - PMC - DOI

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Binding of clozapine to the GABA_B receptor: clinical and structural insights

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