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

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-HT 2A and 5-HT 2C serotonin receptors, H 1 -histamine receptors, a 1 -and a 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. H 1 -histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman r ¼ À0.72; po0.01), as were affinities for a 1A adrenergic (r ¼ À0.54; po0.05), 5-HT 2C (r ¼ À0.49; po0.05) and 5-HT 6 receptors (r ¼ À0.54; po0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H 1 , a 2A , a 2B , 5-HT 2A , 5-HT 2C , and 5-HT 6 receptors were most highly correlated with the first principal component, and affinities for the D 2 , 5-HT 1A , and 5-HT 7 receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H 1 and a 1A receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H 1 -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 H 1 -histamine receptor antagonists are known to induce weight gain with chronic use, and because H 1 -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 H 1 -histamine receptors.

H1-histamine Receptor Affinity Predicts Short-term Weight Gain for Typical and Atypical Antipsychotic Drugs

“…Allison et al (1999) stressed the importance of using a random effects model, and concluded that the 'most reasonable estimates' were the estimated weight changes after 10 weeks of treatment derived from a random effects model. However, rather surprisingly, none of the weight gain data cited by Kroeze et al (2003 , Table 1) were derived from this specific recommended index. Instead, some data were derived from index (i), for example data for loxapine and molindone; some from index (ii), for example data for risperidone and thioridazine; and some from index (iii), for example data for chlorpromazine and clozapine.…”

“…In their report, Kroeze et al (2003) conclude that antipsychotic-induced weight gain is mainly due to H 1 receptor antagonism. They suggest that 'The next generation of antipsychotic drugs be screened to avoid H 1 -histamine receptors'.…”

“…If valid, this important conclusion will drive drug discovery. However, a number of issues raised by Kroeze et al's (2003) paper merit consideration before these conclusions are accepted uncritically. The weight gain data used in the relevant analyses are all cited as taken from a meta-analysis conducted by Allison et al (1999).…”

“…Firstly, Kroeze et al (2003) cite weight gain data for the novel antipsychotic aripiprazole. However, Allison et al (1999) did not include aripiprazole in their meta-analysis at all, since this drug was not marketed until very recently.…”

Novel olanzapine analogues presenting a reduced H1 receptor affinity and retained 5HT2A/D2 binding affinity ratio

“…The inhibition of the H 1 receptors is directly involved in the activation of hypothalamic AMPK signaling, which stimulates food intake and positive energy balance and reverses the anorexigenic effect of leptin [36]. A strong link between the H 1 receptor affinity of antipsychotic agents and their weight gain propensity has been reported [39]. Clozapine and olanzapine which have higher affinity for the H 1 receptors ( K i  = 1.2 nM and K i  = 2.0 nM, respectively) showed a greater propensity to induce weight gain [40,41].…”