Doctor of Philosophy
School of Medicine
Lian, Jiamei, The mechanisms for reducing olanzapineinduced weight gain/obesity by betahistine: clinical implications, Doctor of Philosophy thesis, School of Medicine, University of Wollongong, 2014. http://ro.uow.edu.au/theses/4315
Olanzapine, a second generation antipsychotic drug, is widely used to treat multiple domains of schizophrenia and other mental disorders. However, it is associated with substantial body weight gain/obesity side-effects. Since the antagonistic affinity to histaminergic H1 receptor (H1 R) has been identified as a major contributor for antipsychotic-induced weight gain, this thesis investigated the effects and mechanisms of co-treatment with betahistine (a histaminergic H1 R agonist and H3 receptor antagonist) for ameliorating olanzapine-induced weight gain/obesity in a series of four experiments using a female rat model.
The first experiment showed that short-term (2 weeks) combination treatment of betahistine and olanzapine (O+B) reduced (-45%) body weight gain and feeding efficiency caused by olanzapine in drug-naïve rats. Olanzapine significantly upregulated expressions of H1R, Neuropeptide Y (NPY), and AMP-activated protein kinase ɑ (AMPKɑ) phosphorylation, that were reversed by O+B co-treatment. Hypothalamic pro-opiomelanocortin (POMC) expression was decreased by olanzapine, but not affected by O+B co-treatment. These results suggest that O+B co-treatment may reduce olanzapine-induced weight gain via the H1 R-NPY and H1 R-pAMPKɑ pathways.
Since patients suffering with schizophrenia and other mental disorders often face chronic, even life-time, antipsychotic treatment, I further investigated effects of chronic O+B co-treatment on preventing olanzapine-induced weight gain. Chronic coadministration of O+B significantly reduced (-51.4%) weight gain, feeding efficiency, liver and fat mass induced by olanzapine. Consistently, the chronic olanzapine-only treatment increased expressions of hypothalamic H1 R, pAMPKɑ and NPY, while reducing uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1a) levels in brown adipose tissue. These olanzapineinduced changes could be reversed by chronic O+B co-treatment.
Following experiments investigated the effects of O+B co-treatment on the primary therapeutic receptor binding sites of olanzapine in various brain regions. Both shortterm olanzapine-only and O+B co-treatment significantly decreased 5-HT2A receptor (5- HT2AR) bindings in the prefrontal cortex (PFC), cingulate cortex (Cg), and nucleus accumbens (NAc), but had no effects on dopamine D2 receptors (D2R). Olanzapine also significantly decreased 5-HTT bindings in the ventral tegmental area (VTA) and substantia nigra (SN). The results confirmed the important role of 5-HT2AR in the efficacy of olanzapine, which was not influenced by short-term O+B co-treatment.
Both chronic olanzapine-only and O+B co-treatment significantly decreased the bindings of 5-HT2AR, 5-HT2CR, and 5-HTT in the PFC, Cg and NAc. The chronic olanzapine-only treatment significantly increased the D2R bindings in the Cg, NAc, and CPu (which might be attributed to “dopaminergic supersensitivity”), while the chronic betahistine-only treatment reduced D2R bindings. Chronic O+B co-treatment reversed the D2R bindings in the NAc and CPu that were increased by chronic olanzapine treatment. Therefore, chronic O+B co-treatment has similar effects on serotonin neurotransmission as olanzapine-only treatment, but reverses the D2R binding that is upregulated by chronic olanzapine treatment.
In brief, this thesis provided sound evidence that both short-term and chronic cotreatment with betahistine would be effective combination therapy to reduce olanzapineinduced weight gain without affecting its therapeutic effects. These results support further clinical trials to test the effectiveness of betahistine co-treatment for controlling weight gain/obesity side-effects in schizophrenia patients with antipsychotic treatment.