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.