Genetic dissection of atypical antipsychotic-induced weight gain: Novel preliminary data on the pharmacogenetic puzzle

V. S. Basile, M. Masellis, R. S. McIntyre, H. Y. Meltzer, J. A. Lieberman, J. L. Kennedy*

*Corresponding author for this work

Research output: Contribution to journalReview article

201 Citations (Scopus)

Abstract

Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despite their benefits, use is limited by the occurrence of adverse reactions such as sedation and weight gain. This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain. There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-induced weight gain has been suggested. Therefore, genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome P450 1A2 gene (CYP1A2); the β3 and α1a-adrenergic receptor genes (ADRB3/ADRA1A); and tumor necrosis factor α (TNF-α). Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-α, and HTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects, such as antipsychotic-induced weight gain, and minimize the current "trial and error" approach to prescribing.

Original languageEnglish (US)
Pages (from-to)45-66
Number of pages22
JournalJournal of Clinical Psychiatry
Volume62
Issue numberSUPPL. 23
StatePublished - Oct 22 2001

Fingerprint

Pharmacogenetics
Clozapine
Antipsychotic Agents
Weight Gain
Dissection
Genes
Schizophrenia
Tumor Necrosis Factor-alpha
Obesity
Receptor, Serotonin, 5-HT2C
Advance Directives
Receptor, Serotonin, 5-HT2A
Histamine H1 Receptors
Cytochrome P-450 CYP1A2
Histamine H2 Receptors
Receptor, Serotonin, 5-HT1A
Aptitude
Genetic Polymorphisms
Genetic Predisposition to Disease
Adrenergic Receptors

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Basile, V. S., Masellis, M., McIntyre, R. S., Meltzer, H. Y., Lieberman, J. A., & Kennedy, J. L. (2001). Genetic dissection of atypical antipsychotic-induced weight gain: Novel preliminary data on the pharmacogenetic puzzle. Journal of Clinical Psychiatry, 62(SUPPL. 23), 45-66.
Basile, V. S. ; Masellis, M. ; McIntyre, R. S. ; Meltzer, H. Y. ; Lieberman, J. A. ; Kennedy, J. L. / Genetic dissection of atypical antipsychotic-induced weight gain : Novel preliminary data on the pharmacogenetic puzzle. In: Journal of Clinical Psychiatry. 2001 ; Vol. 62, No. SUPPL. 23. pp. 45-66.
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Basile, VS, Masellis, M, McIntyre, RS, Meltzer, HY, Lieberman, JA & Kennedy, JL 2001, 'Genetic dissection of atypical antipsychotic-induced weight gain: Novel preliminary data on the pharmacogenetic puzzle', Journal of Clinical Psychiatry, vol. 62, no. SUPPL. 23, pp. 45-66.

Genetic dissection of atypical antipsychotic-induced weight gain : Novel preliminary data on the pharmacogenetic puzzle. / Basile, V. S.; Masellis, M.; McIntyre, R. S.; Meltzer, H. Y.; Lieberman, J. A.; Kennedy, J. L.

In: Journal of Clinical Psychiatry, Vol. 62, No. SUPPL. 23, 22.10.2001, p. 45-66.

Research output: Contribution to journalReview article

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T1 - Genetic dissection of atypical antipsychotic-induced weight gain

T2 - Novel preliminary data on the pharmacogenetic puzzle

AU - Basile, V. S.

AU - Masellis, M.

AU - McIntyre, R. S.

AU - Meltzer, H. Y.

AU - Lieberman, J. A.

AU - Kennedy, J. L.

PY - 2001/10/22

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N2 - Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despite their benefits, use is limited by the occurrence of adverse reactions such as sedation and weight gain. This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain. There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-induced weight gain has been suggested. Therefore, genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome P450 1A2 gene (CYP1A2); the β3 and α1a-adrenergic receptor genes (ADRB3/ADRA1A); and tumor necrosis factor α (TNF-α). Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-α, and HTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects, such as antipsychotic-induced weight gain, and minimize the current "trial and error" approach to prescribing.

AB - Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despite their benefits, use is limited by the occurrence of adverse reactions such as sedation and weight gain. This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain. There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-induced weight gain has been suggested. Therefore, genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome P450 1A2 gene (CYP1A2); the β3 and α1a-adrenergic receptor genes (ADRB3/ADRA1A); and tumor necrosis factor α (TNF-α). Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-α, and HTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects, such as antipsychotic-induced weight gain, and minimize the current "trial and error" approach to prescribing.

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