HL-Histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs

Wesley K. Kroeze*, Sandra J. Hufeisen, Beth A. Popadak, Sean M. Renock, Seanna Steinberg, Paul Ernsberger, Karu Jayathilake, Herbert Y. Meltzer, Bryan L. Roth

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

700 Scopus citations


As a result of superior efficacy and overalltolerability, atypicalantipsychotic 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 severalneurotransmitter receptors, including 5-HT2Aand 5-HT2C serotonin receptors, Hrhistamine receptors, α1 and α2-adrenergic receptors, and m3-muscarinic receptors. To determinethe receptor(s) likelyto be responsible for antipsychotic-drug-induced weight gain, we screened 17 typicalandatypicalantipsychotic drugs for binding to 12 neurotransmitter receptors. Hrhistamine receptor affinities for this group of typicalandatypicalantipsychotic drugs were significantly correlated with weight gain (Spearman ρ = —0.72; p<0.01), as were affinities for α1A adrenergic (ρ = —0.54; ρ <0.05), 5-HT2C (ρ = —0.49; ρ <0.05) and 5-HT6 receptors (ρ = —0.54; ρ <0.05), whereas eight other receptors affinities were not. A principal components analysis showed that affinities atthe H1, α2A, α2B, 5-HT2A, 5-HT2C, and 5-HT6 receptors were most highly correlated with the first principalcomponent, and affinities for the D2, 5-HT1A, and 5-HT7 receptors were most highly correlated with the second principalcomponent. A discriminant functions analysis showed that affinities for the H1 and α1A receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as wellas 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 typicalandatypicalantipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H1-histamine receptors.

Original languageEnglish (US)
Pages (from-to)519-526
Number of pages8
Issue number3
StatePublished - Mar 2003


  • Atypicalantipsychotic drugs
  • Clozapine
  • H-histamine receptors
  • Weight gain

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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