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H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical... As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT2A and 5-HT2C serotonin receptors, H1-histamine receptors, α 1- and α 2-adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H1-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman ρ=−0.72; p<0.01), as were affinities for α 1A adrenergic (ρ=−0.54; p<0.05), 5-HT2C (ρ=−0.49; p<0.05) and 5-HT6 receptors (ρ=−0.54; p<0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H1, α 2A, α 2B, 5-HT2A, 5-HT2C, and 5-HT6 receptors were most highly correlated with the first principal component, and affinities for the D2, 5-HT1A, and 5-HT7 receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H1 and α 1A receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H1-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H1-histamine receptor antagonists are known to induce weight gain with chronic use, and because H1-histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H1-histamine receptors. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neuropsychopharmacology Springer Journals

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

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References (52)

Publisher
Springer Journals
Copyright
Copyright © 2003 by American College of Neuropsychopharmacology
Subject
Medicine & Public Health; Medicine/Public Health, general; Psychiatry; Neurosciences; Behavioral Sciences; Pharmacotherapy; Biological Psychology
ISSN
0893-133X
eISSN
1740-634X
DOI
10.1038/sj.npp.1300027
Publisher site
See Article on Publisher Site

Abstract

As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT2A and 5-HT2C serotonin receptors, H1-histamine receptors, α 1- and α 2-adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H1-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman ρ=−0.72; p<0.01), as were affinities for α 1A adrenergic (ρ=−0.54; p<0.05), 5-HT2C (ρ=−0.49; p<0.05) and 5-HT6 receptors (ρ=−0.54; p<0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H1, α 2A, α 2B, 5-HT2A, 5-HT2C, and 5-HT6 receptors were most highly correlated with the first principal component, and affinities for the D2, 5-HT1A, and 5-HT7 receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H1 and α 1A receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H1-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H1-histamine receptor antagonists are known to induce weight gain with chronic use, and because H1-histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H1-histamine receptors.

Journal

Neuropsychopharmacology – Springer Journals

Published: Mar 10, 2003

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