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

Abstract

Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapineinduced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.

Histological Study of the Effects of Olanzapine on the Liver of Adult Male Albino Rat with and without Vitamin C

“…Other hypothesis stated that lipidrelated effects have been attributed to drug-mediated blockade or antagonism of histamine H1 and serotonin 5-HT2 receptors as well as activation of hypothalamic adenosine mono phosphate activated protein kinase. This explanation pointed to a hypothalamic site of action for the metabolic deregulation of atypical antipsychotics [31][32][33] .…”

Histamine H1 Receptor Contributes to Vestibular Compensation

“…Vestibular compensation is responsible for spontaneous recovery of crude postural, locomotor, and oculomotor functions in patients with peripheral vestibular or posterior circulation abnormalities (Hoebeek et al, 2005;Chen et al, 2014;Kim and Zee, 2014;Brandt and Dieterich, 2017). Also, it is an attractive model for investigating lesion-induced plasticity in adult CNS (Straka et al, 2005;Gittis and du Lac, 2006;Lacour and Tighilet, 2010;Redon et al, 2011;Macdougall and Curthoys, 2012;Jamali et al, 2014;.…”

“…Vestibular disorders, characterized by postural imbalance, gaze instability, spatial disorientation, and vertigo, are common in the general population and strongly affect the quality of life (Angelaki and Cullen, 2008;Sajjadi and Paparella, 2008;Ward and Zee, 2016;Brandt and Dieterich, 2017). Both peripheral vestibular abnormalities, such as benign paroxysmal positional vertigo, vestibular neuritis, and Meniere's disease, and central vestibular le-sions caused by posterior circulation stroke usually lead to vestibular syndromes (Sajjadi and Paparella, 2008;Chen et al, 2014;Kim and Zee, 2014). Interestingly, some of the vestibular syndromes caused by unilateral vestibular lesions are gradually ameliorated over time in both humans and animals.…”

“…The effect of betahistine has traditionally been attributed to its antagonistic action on the presynaptic H3 receptor, which may serve as not only autoreceptor to inhibit histamine release but also heteroreceptor to modulate release of other neurotransmitters, particularly GABA (Tighilet et al, 2005;Bergquist et al, 2006). Notably, however, betahistine is also a weak agonist for postsynaptic histamine H1 receptor (Ali et al, 2010;Lian et al, 2016;Provensi et al, 2016). Yet little is known about the role of H1 receptor in the pathophysiology of vestibular disorders and the following vestibular compensation.…”

Management of the psychological comorbidities of dermatological conditions: practitioners' guidelines

“…In addition, it is important to recognize that almost all antipsychotic agents can cause weight gain and/or metabolic syndrome, with olanzapine and clozapine posing the greatest risk, and amisulpride and aripiprazole with little to none 110. As an interesting side note, studies have determined that this weight gain is mediated through an antagonistic effect on histaminergic H1 receptors (H1R), and the commonly prescribed H1R agonist and anti-vertigo drug, betahistine, is able to safely and effectively mitigate antipsychotic-associated weight gain 111–113…”