Reducing olanzapine-induced weight gain side effect by using betahistine: a study in the rat model

Abstract

Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug's antagonistic affinity to histamine H₁ receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H₁ receptor agonist and H₃ receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H₃ receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H₁ receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects.

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

“…These clinical findings correspond with the results of animal studies, in which it was demonstrated that the co-treatment with betahistine partially reduced olanzapine-induced weight gain sideeffects [169]. It is worthy to note that histaminergic modulation may counterbalance druginduced overfeeding and weight gain, however it may be ineffective when there is no drugdependent alteration as showed in clinical trials in obese (otherwise health) subjects [172,171].…”

“…However, cotreatment with betahistine cannot improve locomotor activities decreased by olanzapine. This finding may be one possible explanation of why betahistine can only partially improve olanzapine-induced weight gain [169] (Table 1).…”

“…Overall, in conjunction with previous preclinical and clinical trials in drug-naïve and repeated SGA administration subjects [169,65,174,173], it is necessary to conduct further clinical trials to investigate the effects of co-treatment with betahistine on reducing olanzapine- …”

“…Importantly, the O+B cotreatment group exhibited significantly reduced feeding efficiency and body weight (~50% net decrease) compared to the olanzapine only-treated group (p=0.015) in drug-naïve rats [169] (Figure 2A). Olanzapine treatment also increased white fat mass, but had no effect on water intake [169]. Furthermore, olanzapine reduced locomotor activity of rats, which was significantly correlated with weight gain.…”

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

“…Aripiprazole has a long plasma elimination half-life (60-70 hours) in humans (Grunder et al, 2008), while in rats aripiprazole reached the maximal plasma concentration (C max ) 2 hours after oral administration (10mg/kg) with an elimination half-life of 2.2 hours (Shimokawa et al, 2005). Therefore, all rats were treated three times per day, at 06:00, 14:00, and 22:00 h, orally by administering specially prepared sweet cookie dough pellets (0.3g) to ensure a consistently high concentration to better mirror the human scenario of oral administration once per day (Deng et al, 2012;Han et al, 2008;Weston-Green et al, 2011). The rats were sacrificed using carbon dioxide asphyxiation 48 hours after the last drug treatment.…”