The role of hypothalamic endoplasmic reticulum stress in schizophrenia and antipsychotic-induced weight gain: A narrative review

Abstract

Schizophrenia (SCZ) is a serious mental illness that affects 1% of people worldwide. SCZ is associated with a higher risk of developing metabolic disorders such as obesity. Antipsychotics are the main treatment for SCZ, but their side effects include significant weight gain/obesity. Despite extensive research, the underlying mechanisms by which SCZ and antipsychotic treatment induce weight gain/obesity remain unclear. Hypothalamic endoplasmic reticulum (ER) stress is one of the most important pathways that modulates inflammation, neuronal function, and energy balance. This review aimed to investigate the role of hypothalamic ER stress in SCZ and antipsychotic-induced weight gain/obesity. Preliminary evidence indicates that SCZ is associated with reduced dopamine D2 receptor (DRD2) signaling, which significantly regulates the ER stress pathway, suggesting the importance of ER stress in SCZ and its related metabolic disorders. Antipsychotics such as olanzapine activate ER stress in hypothalamic neurons. These effects may induce decreased proopiomelanocortin (POMC) processing, increased neuropeptide Y (NPY) and agouti-related protein (AgRP) expression, autophagy, and leptin and insulin resistance, resulting in hyperphagia, decreased energy expenditure, and central inflammation, thereby causing weight gain. By activating ER stress, antipsychotics such as olanzapine activate hypothalamic astrocytes and Toll-like receptor 4 signaling, thereby causing inflammation and weight gain/obesity. Moreover, evidence suggests that antipsychotic-induced ER stress may be related to their antagonistic effects on neurotransmitter receptors such as DRD2 and the histamine H1 receptor. Taken together, ER stress inhibitors could be a potential effective intervention against SCZ and antipsychotic-induced weight gain and inflammation.