Neuroprotective effect of hesperidin and its combination with coenzyme Q10 on an animal model of ketamine-induced psychosis: behavioral changes, mitochondrial dysfunctions, and oxidative stress

Background Psychosis is a complex mental illness divided by positive symptoms, negative symptoms, and cognitive decline. Clinically available medicines are associated with some serious side effects which limit their use. Treatment with flavonoids has been associated with delayed onset and development, decreased risk, or increased improvement of various neuropsychiatric disorders including psychosis with negligible side effects. Therefore, the present study was aimed to investigate the protective effects of hesperidin (flavonoid) alone or its combination with coenzyme Q10 against ketamine-induced psychotic symptoms in mice. Results Ketamine (50 mg/kg, i.p.) was given for 21 days to induce psychosis in Laca mice of either sex. Locomotor activity and stereotypic behaviors, immobility duration (forced swim test), and increased transfer latency (elevated plus maze) were performed to test the effect of hesperidin (50 mg/kg, 100 mg/kg, 200 mg/kg, p.o.) and coenzyme Q10 (20 mg/kg, 40 mg/kg, p.o.) and combination of hesperidin + coenzyme Q10 followed by biochemical and mitochondrial complexes assays. For 21 days, ketamine (50 mg/kg, i.p.) administration significantly produced increased locomotor activity and stereotypic behaviors (positive symptoms), increased immobility duration (negative symptoms) and cognitive deficits (increases transfer latency) weakens oxidative defense and mitochondrial function. Further, 21 days’ administration of hesperidin and coenzyme Q10 significantly reversed the ketamine-induced psychotic behavioral changes and biochemical alterations and mitochondrial dysfunction in the discrete areas (prefrontal cortex and hippocampus) of mice brains. The potential effect of these drugs was comparable to olanzapine treatment. Moreover, the combination of hesperidin with coenzyme Q10 and or a combination of hesperidin + coenzyme Q10 + olanzapine treatment did not produce a significant effect compared to their per se effect in ketamine-treated animals. Conclusions The study revealed that hesperidin alone or in combination with coenzyme Q10 could reduce psychotic symptoms and improve mitochondrial functions and antioxidant systems in mice, suggesting neuroprotective effects against psychosis.

OLANZAPINE INDUCED HYPONATREMIA AND RHABDOMYOLYSIS

Rapid-onset hyponatremia as well as rhabdomyolysis are rare, but potential, complications of olanzapine treatment. We report a case of sudden-onset hyponatremia associated to a sever rhabdomyolysis resulting in a coma necessitating intensive care unit admission. His evolution was favorable after correction of all his metabolic disorders and Olanzapine suspension.

Olanzapine: Association Between a Typical Antipsychotic Drug and Aortic Calcification

Aims: This study concentrates on the relationship between antipsychotic drugs (APDs) and aortic calcification.Methods: All 56 patients with schizophrenia were divided into two groups according to aortic calcification index. APD equivalent dose was calculated via defined daily doses method.Results: In schizophrenia patients with higher aortic calcification index scores, APD equivalent doses were lower. APD equivalent dose was negatively related to aortic calcification index. Although equivalent APD dose in patients without olanzapine treatment was negatively related to aortic calcification index, it seems that equivalent APD dose did not associate with aortic calcification.Conclusion: Aortic calcification is negatively associated with APD dose in schizophrenia patients. Olanzapine seems to be vital to the relationship between aortic calcification and APD treatment.

Increased Homotopic Connectivity in the Prefrontal Cortex Modulated by Olanzapine Predicts Therapeutic Efficacy in Patients with Schizophrenia

Background. Previous studies have revealed the abnormalities in homotopic connectivity in schizophrenia. However, the relationship of these deficits to antipsychotic treatment in schizophrenia remains unclear. This study explored the effects of antipsychotic therapy on brain homotopic connectivity and whether the homotopic connectivity of these regions might predict individual treatment response in schizophrenic patients. Methods. A total of 21 schizophrenic patients and 20 healthy controls were scanned by the resting-state functional magnetic resonance imaging. The patients received olanzapine treatment and were scanned at two time points. Voxel-mirrored homotopic connectivity (VMHC) and pattern classification techniques were applied to analyze the imaging data. Results. Schizophrenic patients presented significantly decreased VMHC in the temporal and inferior frontal gyri, medial prefrontal cortex (MPFC), and motor and low-level sensory processing regions (including the fusiform gyrus and cerebellum lobule VI) relative to healthy controls. The VMHC in the superior/middle MPFC was significantly increased in the patients after eight weeks of treatment. Support vector regression (SVR) analyses revealed that VMHC in the superior/middle MPFC at baseline can predict the symptomatic improvement of the positive and negative syndrome scale after eight weeks of treatment. Conclusions. This study demonstrated that olanzapine treatment may normalize decreased homotopic connectivity in the superior/middle MPFC in schizophrenic patients. The VMHC in the superior/middle MPFC may predict individual response for antipsychotic therapy. The findings of this study conduce to the comprehension of the therapy effects of antipsychotic medications on homotopic connectivity in schizophrenia.

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.

Effect of probiotics on olanzapine-induced metabolic syndrome in Wistar albino rats

Purpose: Olanzapine is the most viable second-generation antipsychotic (SGA) used in the treatment of schizophrenia and at the same time, it is the most notorious SGA to cause metabolic syndrome (MS). The target of this study is to assess the adequacy of probiotics in fighting the unfriendly impacts of olanzapine treatment such as weight gain, hyperlipidemia, and hyperglycemia in the olanzapine-induced MS model in rodents. Methods: Thirty-six Wistar rodents were haphazardly separated into six groups (n=6). The groups were treated for a month as follows: Group-I: Normal saline 1 ml/kg/day orally, Group-II: olanzapine 2 mg/kg/day i.p., Group-III: probiotic-VSL#3: 0.6 g/kg/day orally, Group-IV: VSL#3: 1.2 g/kg/day orally, Group-V: olanzapine 2 mg/kg/day i.p. + VSL#3: 0.6 g/kg/day orally, and Group-VI: olanzapine 2 mg/kg/day i.p. + VSL#3: 1.2 g/kg/day orally. Bodyweight, fasting blood glucose (FBG), and lipid profile was assessed at baseline and consequently at the end of each week. Data were analyzed by applying repeated measures ANOVA, followed by post-hoc Bonferroni test. P-value <0.05 was considered statistically significant. Results: There was a noteworthy increment in the total cholesterol and triglycerides level after olanzapine treatment (P<0.01), and similarly a decline in the total cholesterol and triglycerides level in the probiotic treated groups (p < 0.05). There was a decrease in weight increase and FBG levels instigated by olanzapine in the probiotic-treated groups. Conclusion: Probiotics forestalled the advancement of hyperlipidemia and decreased the weight addition and increment in FBG levels initiated by olanzapine. A long-haul evaluation should be directed to additionally assess the impact of probiotics on MS and their plausible mechanism.

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.