Haloperidol and olanzapine mediate metabolic abnormalities through different molecular pathways

Area of Science:

• Pharmacology
• Metabolic Disorders
• Neuroscience

Background:

• Antipsychotic medications can cause glucose homeostasis disturbances.
• Increased visceral adiposity is a potential mechanism.
• Differential effects of antipsychotics on metabolic pathways are not fully understood.

Purpose of the Study:

• To compare the effects of olanzapine and haloperidol on visceral fat deposition.
• To investigate the impact of these antipsychotics on key insulin signaling proteins.
• To elucidate the molecular pathways underlying antipsychotic-induced metabolic changes.

Main Methods:

• Male Sprague-Dawley rats were treated with vehicle, haloperidol, or olanzapine for 8 weeks.
• Visceral fat deposition was measured using magnetic resonance imaging (MRI).
• Liver-protein levels of insulin receptor substrate 2 (IRS2) and glycogen synthase kinase (GSK3α/β) were analyzed.

Main Results:

• Haloperidol significantly increased visceral fat compared to olanzapine and vehicle groups.
• Olanzapine treatment reduced IRS2 levels and altered GSK3α/β phosphorylation.
• No significant changes in insulin signaling markers were observed in the haloperidol group.

Conclusions:

• Olanzapine and haloperidol induce glucose homeostasis disturbances via different molecular pathways.
• Olanzapine has a direct effect on the insulin signaling pathway.
• These findings may explain the greater clinical risk of metabolic adverse effects with olanzapine.