The role of histaminergic H1 and H3 receptors in food intake: A mechanism for atypical antipsychotic-induced weight gain?

Abstract

Atypical antipsychotics such as olanzapine and clozapine are effective at treating the multiple domains of schizophrenia, with a lowrisk of extra-pyramidal side-effects. However amajor downfall to their use is metabolicside-effects particularly weight gain/obesity,which occurs by unknownmechanisms. The present paper explores the potential candidature of histaminergic neurotransmission in the mechanisms of atypical antipsychoticinduced weight gain, with a focus on the histaminergic H1 and H3 receptors. Olanzapine and clozapine have a high affinity for the H1 receptor, andmeta-analyses showa strong correlation between risk ofweight gain andH1 receptor affinity. In addition, olanzapine treatment decreases H1 receptor binding and mRNA expression in the rat hypothalamus. Furthermore, a complex role is emerging for the histamine H3 receptor in the control of hunger. The H3 receptor is a pre-synaptic autoreceptor that inhibits the synthesis and release of histamine, and a heteroreceptor that inhibits other neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and acetylcholine (ACh),which are also implicated in the regulation of food intake. Thus, the H3 receptor is in a prime position to regulate food intake, boththrough its control of histamine and its influence onother feeding pathways. We proposed that a mechanism for atypical antipsychotic-induced weight gain may be partly through the H3 receptor, as a drug-induced decrease in H1 receptor activity may decrease histamine tone through the H3 autoreceptors, compounding theweight gain problem. In addition, atypical antipsychoticsmay affect food intake by influencing 5-HT, NA and ACh release via interactions with the H3 heteroreceptor. However a major downfall to their use is metabolic side-effects particularly weight gain/obesity, which occurs by unknown mechanisms. The present paper explores the potential candidature of histaminergic neurotransmission in the mechanisms of atypical antipsychotic-induced weight gain, with a focus on the histaminergic H1 and H3 receptors. Olanzapine and clozapine have a high affinity for the H1 receptor, and meta-analyses show a strong correlation between risk of weight gain and H1 receptor affinity. In addition, olanzapine treatment decreases H1 receptor binding and mRNA expression in the rat hypothalamus. Furthermore, a complex role is emerging for the histamine H3 receptor in the control of hunger. The H3 receptor is a pre-synaptic autoreceptor that inhibits the synthesis and release of histamine, and a heteroreceptor that inhibits other neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and acetylcholine (ACh), which are also implicated in the regulation of food intake. Thus, the H3 receptor is in a prime position to regulate food intake, both through its control of histamine and its influence on other feeding pathways. We proposed that a mechanism for atypical antipsychotic-induced weight gain may be partly through the H3 receptor, as a drug-induced decrease in H1 receptor activity may decrease histamin...

Obesity and psychiatric disorders: Commonalities in dysregulated biological pathways and their implications for treatment

“…This is supported by monozygotic twin and sibling studies (Wehmeier et al, 2005), and several genetic polymorphisms have also been identified as risk factors for weight gain (Muller et al, 2013). Serotonin and histamine receptors have received most attention as they seem to play important roles in eating behaviour and may contribute to weight gain via their influence on lipolytic activity (Deng et al, 2010). For example, at least 17 studies have reported an association between the 759 T/C SNP in the 5HT2C gene and antipsychotic medicationinduced weight gain.…”

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

“…In particular, histamine has been implicated in the regulation of energy homeostasis [12,43,44]. In other words, elevated hypothalamic histamine signalling contributed to decreased food intake and decreased body weight gain [45][46][47]35], while reduction in histamine levels was associated with increased body weight gain and food intake [37,42].…”

Altered reward anticipation: Potential explanation for weight gain in schizophrenia?

“…One candidate mechanism of increased weight gain is the antihistaminergic property of both olanzapine and clozapine (Deng et al, 2010). By blocking the histamine H1 and H3 receptors, these drugs may weaken a histamine-mediated satiety signal in the hypothalamus where histamine contributes to satiety and hunger signaling (Ishizuka et al, 2006).…”

“…They typically concentrate on i) dysregulation of neuroendocrinological circuits (e.g., hormonal regulation by the hypothalamus; Sharma et al, 2014); ii) dysregulation of peripheral hormones (e.g., leptin and ghrelin) implicated in weight homeostasis and in regulation of glucose (De Hert et al, 2009;Mitchell et al, 2013;Sentissi et al, 2008); and iii) the effect of antipsychotic medication on weight (Bak et al, 2014;Deng et al, 2010;Sharma et al, 2014). All of these factors are important.…”