Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy

Abstract

Antipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.

MiRNA Differences Related to Treatment-Resistant Schizophrenia

“…Third, SIRT1 and its deacetylation substrate, DNMT1, are both present in the most connected subnetwork and have a direct involvement in the regulation of p53 transcription. Finally, bibliographic evidence supports the proposed pathway in four aspects: (i) the implication of p53/MDM2 in the multidrug resistance process [80][81][82][83], (ii) the involvement of p53 in autophagy, a process known to be related to antipsychotic response [92][93][94][95]; (iii) the observed dysregulations of this pathway in schizophrenia patients [96][97][98], and (iv) the relationship of this pathway to negative symptoms, such as memory, learning ability impairment [99], and major depression [100].…”

The regulatory effects of second-generation antipsychotics on lipid metabolism: Potential mechanisms mediated by the gut microbiota and therapeutic implications

“…mTORC1 activation interferes with lipid and energy metabolism, leading to the upregulation of lipid biosynthesis and the accumulation of TGs. Furthermore, activation of the mTOR pathway inhibits autophagy, thereby increasing intracellular lipid accumulation ( Zhuo et al, 2022 ). Enhanced mTOR activity disrupts hepatic lipid homeostasis by regulating the expression of the transcription factor SREBP-1c ( Takashima et al, 2009 ).…”

Modulation of Leucine Sensors to Mitigate Antipsychotics-Induced Metabolic Syndrome: A New Vista

“…mTORC1 is key in promoting anabolism and suppressing catabolism . Zhou et al have extensively reviewed the literature demonstrating that mTOR signaling is crucial in the pathogenesis of SGA-induced side effects, including metabolic abnormalities . Olanzapine, an SGA, has been reported to extensively affect hepatic mTORC, thereby disrupting autophagy, lipid homeostasis, and insulin sensitivity, all of which could lead to dysregulation of the metabolism.…”

“…Enhanced peripheral levels of glutamate have also been observed upon switching from conventional antipsychotics to olanzapine . Besides, mTORC1 is an enhancer of hepatic lipid biosynthesis by increasing the expression and phosphorylation of sterol regulatory binding-element protein 1 (SREBP-1c), a protein upregulated after treatment with olanzapine. ,, This evidence suggests that mTORC, especially mTORC1, could be a significant culprit to consider in SGA-induced metabolic syndrome.…”