Risperidone and Olanzapine induce ER stress
Hypothalamic neuronal endoplasmic reticulum stress and antipsychotic-induced weight gain
Studies have revealed that treatment with antipsychotic drugs including olanzapine, haloperidol, clozapine, and aripiprazole increases the expression of IRE1 and PERK in human and mouse hepatocytes (R; R; R).
Olanzapine or risperidone treatment causes significant ER stress in the pancreatic β-cell line of hamsters (R). This evidence suggests that antipsychotics activate ER stress. Our previous study showed that in human neuroblastoma SH-SY5Y cells, olanzapine treatment induces ER stress and activation of IKKβ-NF-κB signaling and secretion of the pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β (R).
Hence, olanzapine could directly act on neurons to induce ER stress and inflammation (R). The fact that the ER stress inhibitor 4-PBA suppresses olanzapine-induced ER stress and inflammation in SH-SY5Y cells suggests that olanzapine-induced inflammation is at least partly regulated by ER stress (R).
In rats, both acute (1 day) and short-term (8 days) olanzapine treatment induce ER stress via PERK-eIF2α signaling; activate inflammatory IKKβ-NF-κB signaling; and augment TNF-α, IL-6, and IL-1β expression in the hypothalamus (R).
These results suggest that olanzapine-induced ER stress and inflammation occur before rats are obese and could be a significant contributor rather than a consequence of obesity.
Moreover, co-treatment with 4-PBA reduces olanzapine-induced hyperphagia and weight gain and inhibits olanzapine-induced ER stress and inflammation (R).
These findings indicate that olanzapine treatment activates hypothalamic neuronal ER stress and its related inflammatory IKKβ-NF-κB signaling, and these effects could lead to weight gain partly by increasing food intake. Hypothalamic ER stress also plays an important role in modulating energy expenditure.
Numerous animal studies have revealed that obesogenic antipsychotics including olanzapine, clozapine, and risperidone reduce energy expenditure by inhibiting BAT thermogenesis, reducing tail artery vasoconstriction, and decreasing oxygen consumption and locomotor activity, all of which promote weight gain (R; R; R).
A study in humans reported that chronic olanzapine, risperidone, and quetiapine treatment (1, 3, 6, and 12 months) promotes weight gain with a hypometabolic state (R).
Therefore, a reduction in energy expenditure induced by antipsychotics might be related to activation of hypothalamic ER stress.
This eventuality should be evaluated in future studies. For example, investigating whether central inhibition of ER stress could reverse the antipsychotic-induced reduction in BAT thermogenesis and suppress the hypometabolic state in rodents would help to understand the role of ER stress in antipsychotic-induced decreased energy expenditure.