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.

A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response

“…Schizophrenia is a condition in which synaptic plasticity is implicated ( Mould et al, 2021 ). It is interesting to note that antipsychotic tranquiliser medications that are used to treat schizophrenia, such as olanzapine, are evidenced to induce cellular endoplasmic reticulum stress ( He et al, 2019 , 2021 ; Li W. et al, 2021 ; Zhou et al, 2022 ) that will induce ATF4 via the PERK-eIF2α pathway.…”

Comprehensive analysis of an endoplasmic reticulum stress-related gene prediction model and immune infiltration in idiopathic pulmonary fibrosis

“…Zhou et al. demonstrated that antipsychotic medications, such as olanzapine, induce ERS in hypothalamic neurons, leading to increased expression of neuropeptide Y and AGRP, autophagy, and resistance to leptin and insulin ( 48 ). This ultimately results in the inflammation of the central nervous system (CNS), leading to weight gain.…”

Association between DRD2/ANKK1 rs1800497 C > T polymorphism and post-traumatic stress disorder susceptibility: a multivariate meta-analysis

“…SNPs are the most common type of gene mutation in humans and contribute to individual susceptibility to several diseases through altered gene transcription, expression, and spatial structure. Some studies have suggested that the rs1800497 polymorphism is always accompanied by an abnormal expression of the DRD2 gene in the brain tissue and is associated with several psychiatric disorders, such as anxiety, depression, schizophrenia (Zhou et al, 2022 ), bipolar disorder (Zhang et al, 2021 ), and autism spectrum disorder (Liu, 2020 ). Rs1800497 was originally considered the DRD2 polymorphism locus in most published studies since it could regulate the synthesis of dopamine and reduce D2 receptor expression (Munaf et al, 2009 ).…”