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

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-HT_2Aand 5-HT_2C 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 α_1A adrenergic (ρ = —0.54; ρ <0.05), 5-HT_2C (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, α_2A, α_2B, 5-HT_2A, 5-HT_2C, and 5-HT₆ receptors were most highly correlated with the first principalcomponent, and affinities for the D₂, 5-HT_1A, and 5-HT₇ receptors were most highly correlated with the second principalcomponent. 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 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.