Weight gain in schizophrenia patients is becoming a major concern as second generation antipsychotics (SGAs) have been associated with considerable increase in weight. The mechanisms by which they produce this side effect are not known.
The orexins, are a family of hypothalamic neuropeptides that are selectively expressed in neurons of “feeding area” (lateral hypothalamus and perifornical area). They arise from the precursor peptide prepro-orexin by proteolytic processing and act through two closely related G-protein-coupled receptors, the orexin 1 (OX1R) and orexin 2 receptors (OX2R). Despite the small number of orexin cells, orexin axons are distributed throughout the brain. The orexins modulate feeding behavior, some metabolic processes and arousal.
Fos expression is induced in orexin neurons by SGAs that cause significant weight gain but not by those SGAs with low weight gain liability. Moreover, in the same paradigm, amphetamine also activated orexin neurons. Clozapine markedly increased fos expression in orexin neurons that innervate the PFC whereas amphetamine had a weak effect. These findings suggest that it is likely that changes in the activity of afferents or hormonal signals to these orexin neurons determine the differential response. One study has pointed that the same effect on fos-induction by olanzapine was reversed by Zonisamide, an anti-epilepsy drug.
It is suggested that the receptors targeted by SGAs may be present on orexin neurons or on their afferents and play a role in induction of weight gain.
Keywords: Orexin, obesity, schizophrenia, antipsychotics, metabolic syndrome, G-protein-coupled receptors, anti-epilepsy drug, hypertension, gallbladder disease, osteoarthritis, coronary heart disease