Preventing Olanzapine-Induced Weight Gain Using Betahistine: A Study in a Rat Model with Chronic Olanzapine Treatment

Abstract

Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H1 receptors (H1R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H1R agonist and H3R antagonist) and olanzapine (O+B) reduced (−45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (−51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H1R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP1 and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H1R, pAMPKα, BAT UCP1 and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment.

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

“…Furthermore, co-treatment also reduced feeding efficiency, liver and fat mass [65]. In addition, olanzapine-treated rats significantly increased inguinal fat (p<0.001), and periovary, mesentery fat (p<0.05) compared to controls (Table 1).…”

“…In hypothalamic tissue slices, the level of pAMPK can be enhanced markedly by olanzapine, which indicates that the weight gain/obesity side-effects associated with olanzapine is mediated by activation of hypothalamic AMPK linked to blockade of the histaminergic H 1 R [63]. Further in vivo studies in a rat model showed that the pAMPK level was upregulated by olanzapine administration correlated with changes in weight gain [56,64,65]. Additionally, administration of olanzapine by acute ICV infusion increased hypothalamic pAMPK expression [98,99].…”

“…Several animal studies found that olanzapine could modulate histaminergic neurotransmission for the regulation of food intake and weight gain in rats [62,56,63]. Olanzapine treatment upregulated mRNA expression and protein levels of hypothalamic H 1 R, which was correlated with hyperphagia and weight gain induced by olanzapine [56,64,65]. Similarly, clinical studies demonstrated patients treated with antipsychotics showed a significant correlation between the genetic variants of H 1 R (rs346074 -rs346070), BMI (body mass index) and obesity [66,67].…”

“…In terms of the effect of SGAs on expression of POMC and CART, it was shown that olanzapine treatment resulted in attenuation of POMC but not CART expression in the hypothalamus of rats [98,65,160,128,129]. Ak and colleagues also reported that the plasma POMC level was elevated in first attack psychotic male patients treated with olanzapine, but no changes in plasma CART level were observed [100].…”

“…On the other hand, it is well known that antipsychotics cause a significant body weight gain not only in drug-naïve patients, but also in chronic patients who usually have already had previous antipsychotic exposure [6,65,170]. In order to investigate whether chronic co-treatment of O+B would have similar weight-attenuating effects, the effect of co-treatment with betahistine was trialled in a rat model with repeated and chronic exposure to olanzapine [65].…”