Alteration in the mRNA expression profile of the autophagy-related mTOR pathway in schizophrenia patients treated with olanzapine

Abstract

Background The mammalian target of rapamycin protein (mTOR) signaling pathway is involved in the pathogenesis of schizophrenia and the mechanism of extrapyramidal adverse reactions to antipsychotic drugs, which might be mediated by an mTOR-dependent autophagy impairment. This study aimed to examine the expression of mTOR pathway genes in patients with schizophrenia treated with olanzapine, which is considered an mTOR inhibitor and autophagy inducer. Methods Thirty-two patients with acute schizophrenia who had been treated with olanzapine for four weeks (average dose 14.24 ± 4.35 mg/d) and 32 healthy volunteers were recruited. Before and after olanzapine treatment, the Positive and Negative Syndrome Scale (PANSS) was used to evaluate the symptoms of patients with schizophrenia, and the mRNA expression levels of mTOR pathway-related genes, including MTOR, RICTOR, RAPTOR, and DEPTOR, were detected in fasting venous blood samples from all subjects using real-time quantitative PCR. Results The MTOR and RICTOR mRNA expression levels in patients with acute schizophrenia were significantly decreased compared with those of healthy controls and further significantly decreased after four weeks of olanzapine treatment. The DEPTOR mRNA expression levels in patients with acute schizophrenia were not significantly different from those of healthy controls but were significantly increased after treatment. The expression levels of the RAPTOR mRNA were not significantly different among the three groups. The pairwise correlations of MTOR, DEPTOR, RAPTOR, and RICTOR mRNA expression levels in patients with acute schizophrenia and healthy controls were significant. After olanzapine treatment, the correlations between the expression levels of the DEPTOR and MTOR mRNAs and between the DEPTOR and RICTOR mRNAs disappeared. Conclusions Abnormalities in the mTOR pathway, especially DEPTOR and mTORC2, might play important roles in the autophagy mechanism underlying the pathophysiology of schizophrenia and effects of olanzapine treatment.

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].…”

Lipophilic vs. hydrophilic statins and psychiatric hospitalizations and emergency room visits in US Veterans with schizophrenia and bipolar disorder

“…Several molecular underexplored mechanisms could underlie the effects of statins. As autophagy-related pathway impairment has been reported in schizophrenia [ 162 ], it is possible that statin-mediated neuroprotection is based, at least in part, on restored autophagic mechanisms as robustly reported for rosuvastatin (the most prescribed hydrophilic statin) in Parkinson’s disease [ 163 ].…”

Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders

“…Some drugs used to treat schizophrenia also affect autophagy [62]. Olanzapine is considered an mTOR inhibitor and autophagy inducer [63]. Sertindole is a potent inducer of autophagy in neuroblastoma cells [64].…”