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

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.

Cytological Analysis of CSF in Patients with Acute Schizophrenia

Cerebrospinal fluid (CSF) analysis is one of the most important tests in the diagnosis of central nervous system (CNS) diseases. Although CSF analysis is most commonly used in neurological pathological conditions, it also has its place in psychiatry. Studies to date have described several valuable specific cytomorphological phenomena in the cerebrospinal fluid of patients with acute schizophrenia, which indicate inflammatory or immune-mediated etiopathogenesis of the disease. Additional and long-term research is needed to confirm and standardize the importance of cytological analysis of cerebrospinal fluid in the diagnosis and etiopathogenesis of acute schizophrenia.

Potential drug targets in the kynurenine pathway to treat acute schizophrenia

AimsSchizophrenia is a serious developmental psychiatric disorder with a neurodegenerative component that causes marked deterioration in social relationships and ability to work. Present treatments are not satisfactory. Meta-analysis of placebo-controlled studies in acute schizophrenia shows that only a minority of patients have a good response to current antipsychotic medications. Therefore, there is a need for more effective psychopharmacologic treatments for this disorder.MethodThe purpose of this paper is to provide new interpretations of existing data to provide a scaffolding for the development of novel drug targets for the treatment of schizophrenia. The causes of schizophrenia are most likely heterogeneous and involve both genetic and environmental factors. The authors examined a wide range of purported causes of schizophrenia to identify a common biochemical pathway that would contribute to this disorder. This review specifically did not consider pathways that supported the dopamine hypothesis of schizophrenia since historically drugs focused on dopaminergic mechanism, as noted in the aims, have not been successful for many patients with schizophrenia.ResultTwo prominent schizophrenia-associated factors that have been widely studied with significant supporting evidence are stress and inflammation. Stress and inflammation share a common biochemical pathway that converges on the kynurenine pathway of the metabolism of tryptophan, an essential amino acid. At one end of the pathway, recently hospitalized patients with schizophrenia have been found to have low plasma tryptophan levels, whereas chronic schizophrenics have not, suggesting stress- and/or inflammation-induced increased metabolism of tryptophan. At the other end of the pathway, there is increased level of cerebrospinal fluid kynurenic acid in patients with schizophrenia as compared with healthy controls. Salivary kynurenic acid is associated with stress intolerance in schizophrenia. Importantly, natural occurring compounds in this pathway have significant CNS effects that include neurotoxicity and altered neural transmitter behavior.ConclusionStress and inflammation, both associated as causes of schizophrenia, are linked by a common biochemical pathway involving kynurenine. Examination of specific elements of the kynurenine pathway may aid in the identification of drug targets for schizophrenia.

A network meta-analysis of the dose–response effects of lurasidone on acute schizophrenia

We compared the efficacy, safety, and acceptability of lurasidone at different doses to establish the dose–response relationships of lurasidone therapeutic and adverse effects in acute schizophrenia. Included trials were 4- to 16-week, fixed-dose, randomized controlled trials of lurasidone in adults with acute schizophrenia. Different doses of lurasidone, other antipsychotics, and placebo were considered as independent treatments. Apart from all-cause dropout rates, four therapeutic and four adverse outcomes were included in the frequentist network meta-analysis (NMA). Lurasidone 160, 120, 80, 40, and 20 mg/day were studied in ten trials of 3,366 adults with schizophrenia exacerbation. Lurasidone 160 mg/day reduced Positive and Negative Syndrome Scale (PANSS) total scores significantly more than lurasidone 120, 80, 40, and 20 mg/day (mean differences = − 7.63, − 7.04, − 8.83, and − 12.25, respectively). All-cause dropout rates were significantly lower in participants receiving lurasidone 160 mg/day and 80 mg/day compared with those taking placebo. The half-maximal effective doses of lurasidone for PANSS total, PANSS positive, and MADRS score reductions were higher than 80 mg/day. The confidence of all NMA estimates was low or very low. Lurasidone 160 mg/day is currently the most efficacious and acceptable dose for acute schizophrenia. Its maximal effective doses may be higher than 160 mg/day.

Alteration mRNA Expression Profile of Autophagy Related mTOR Pathway in Schizophrenic Patients with Olanzapine Treatment.

Background: mTOR signaling pathway involves in the pathogenesis of schizophrenia and the mechanism of extrapyramidal adverse reactions of antipsychotic drugs, which might mediate by mTOR-dependent autophagy impairment. This study aimed to examine the mRNA expression levels of Mammalian rapamycin target protein (mTOR) pathway genes in schizophrenia patients with olanzapine treatment, which is considered to be an mTOR inhibitor and autophagy inducer. Methods: Thirty-two acute schizophrenia patients had been treated with olanzapine for four weeks (average dose 14.24 ± 4.35 mg/d), along with 32 healthy volunteers. Before and after olanzapine treatment, the Positive and Negative Syndrome Scale (PANSS) was used to evaluate the symptoms of schizophrenia patients, and the mRNA expression levels of mTOR pathway-related genes, including MTOR, RICTOR, RPTOR, and DEPTOR, were detected by real-time quantitative PCR with the fasting venous blood of all the samples. Results: The MTOR and RICTOR mRNA expression levels of acute schizophrenia patients significantly decreased than them of healthy controls, and furtherly significantly decreased after four weeks of olanzapine treatment. While DEPTOR mRNA expression levels of acute schizophrenia patients had no significant difference with them of healthy controls, but significantly increased after treatment. And the mRNA expression levels of RPTOR had no significant difference in the three groups. The pairwise correlation of MTOR, DEPTOR, RPTOR, and RICTOR mRNA expression levels in acute schizophrenia patients and healthy controls showed significant correlationships. After olanzapine treatment, the correlationships of mRNA expression levels disappeared between DEPTOR and MTOR, and also between DEPTOR and RICTOR. Conclusions: The results inferred the abnormalities of mTOR pathway, especially DEPTOR, might play important roles in autophagy mechanism of the pathophysiology in schizophrenia and olanzapine treatment.