Olanzapine is effective to treat for
schizophrenia and other
mood disorders, but limited by side effects such as
weight gain,
dyslipidemia, and liver injury.
Obesity in the US is at epidemic levels, and is a significant risk factor for
drug-induced liver injury.
Obesity incidence in the psychiatric population is even higher than in the US population as a whole. The purpose of this study was to test the hypothesis that
obesity worsens
olanzapine-induced hepatic injury, and to investigate the potential protective effects of
sulforaphane. 8-week old female C57BL/6 mice were fed either a high-fat or low-fat control diet (HFD and LFD). Mice also received either
olanzapine (8 mg/kg/d) or vehicle by osmotic minipump for 4 weeks. A subset of mice in the HFD + olanzapine group was administered
sulforaphane, a prototypical Nrf2 inducer (90 mg/kg/d).
Olanzapine alone increased
body weight, without a commensurate increase in food consumption.
Olanzapine also caused hepatic steatosis and injury. Combining
olanzapine and HFD caused further dysregulation of
glucose and lipid metabolism. Liver damage from concurrent HFD and
olanzapine was worse than liver damage from high-fat diet or
olanzapine alone.
Sulforaphane alleviated many metabolic side effects of
olanzapine and HFD. Taken together, these data show that
olanzapine dysregulates
glucose and lipid metabolism and exacerbates hepatic changes caused by eating a HFD. Activation of the intrinsic
antioxidant defense pathway with
sulforaphane can partially prevent these effects of
olanzapine and may represent a useful strategy to protect against liver injury.