Sex-specific association between antioxidant defense system and therapeutic response to risperidone in schizophrenia: a prospective longitudinal study

: There are various differences in the response to different antipsychotics and antioxidant defense system (ADS) by sex. Previous studies have shown that several ADS enzymes are closely related to the treatment response of patients with antipsychotics-naïve first-episode (ANFE) schizophrenia. Therefore, the main goal of this study was to assess the sex difference in the relationship between changes in ADS enzyme activities and risperidone response. The plasma activities of glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD) and total antioxidant status (TAS) were measured in 218 patients and 152 healthy controls. Patients were treated with risperidone for 3 months, and we measured PANSS for psychopathological symptoms and ADS biomarkers at baseline and at the end of 3 months of treatment. We compared sex-specific group differences between 50 non-responders and 168 responders at baseline and at the end of the three months of treatment. We found that female patients responded better to risperidone treatment than male patients. At baseline and 3-month follow-up, there were no significant sex differences in TAS levels and three ADS enzyme activities. Interestingly, only in female patients, after 12 weeks of risperidone treatment, the GPx activity of responders was higher than that of non-responders. These results indicate that after treatment with risperidone, changes in GPx activity were associated with treatment response, suggesting that changes in GPx may be a predictor of response to risperidone treatment in female patients with ANFE schizophrenia.

The association between BDNF levels and risperidone-induced weight gain is dependent on the BDNF Val66Met polymorphism in antipsychotic-naive first episode schizophrenia patients: a 12-week prospective study

A growing number of studies have shown that brain-derived neurotrophic factor (BDNF) is associated with weight gain during antipsychotic treatment in schizophrenia patients. However, there is still a lack of research results in the initial stage of antipsychotic treatment. This study aimed to evaluate the relationship between weight gain caused by risperidone monotherapy for 12 weeks and BDNF level in antipsychotic-naive and first-episode (ANFE) patients with schizophrenia, and we hypothesize that this may depend on BDNF Val66Met gene polymorphism. In a 12-week longitudinal trial, 225 ANFE patients were enrolled and treated with risperidone. Body weight was measured at baseline and during the 12-week follow-up. After treatment, the average weight of ANFE patients increased by 2.6 kg. Furthermore, we found that in patients with Val/Val genotype, the increase in serum BDNF levels was negatively correlated with risperidone-induced weight gain (r = −0.44, p = 0.008). Regression analysis showed that the baseline BDNF level was a predictor of weight gain after treatment (β = −0.45, t = −3.0, p = 0.005). Our results suggest that the BDNF signaling may be involved in weight gain caused by risperidone treatment. Furthermore, the negative association between weight gain and increased BDNF levels during risperidone treatment in ANFE schizophrenia depends on the BDNF Val66Met polymorphism.

The Role of Butyric Acid in Treatment Response in Drug-Naïve First Episode Schizophrenia

Background: Butyric acid, a major short-chain fatty acid (SCFA), has an important role in the microbiota–gut–brain axis and brain function. This study investigated the role of butyric acid in treatment response in drug-naïve first episode schizophrenia.Methods: The study recruited 56 Chinese Han schizophrenia inpatients with normal body weight and 35 healthy controls. Serum levels of butyric acid were measured using Gas Chromatography-Mass Spectrometer (GC-MS) analysis at baseline (for all participants) and 24 weeks after risperidone treatment (for patients). Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) for patients at both time points.Results: At baseline, there was no significant difference in serum levels of butyric acid between patients and healthy controls (p = 0.206). However, there was a significant increase in serum levels of butyric acid in schizophrenia patients after 24-week risperidone treatment (p = 0.030). The PANSS total and subscale scores were decreased significantly after 24-week risperidone treatment (p's < 0.001). There were positive associations between baseline serum levels of butyric acid and the reduction ratio of the PANSS total and subscale scores after controlling for age, sex, education, and duration of illness (p's < 0.05). Further, there was a positive association between the increase in serum levels of butyric acid and the reduction of the PANSS positive symptoms subscale scores (r = 0.38, p = 0.019) after controlling for potential confounding factors.Conclusions: Increased serum levels of butyric acid might be associated with a favorable treatment response in drug-naïve, first episode schizophrenia. The clinical implications of our findings were discussed.

Risperidone-Induced Neutropenia in a Schizophrenic Patient: A Case Report and Literature Review

Neutropenia is an adverse effect of various pharmacological therapies, including antipsychotics. Among the second-generation antipsychotic (SGA) medications, clozapine is most notable for neutropenic adverse effect. Risperidone, another SGA drug, is linked mainly with metabolic adverse effects, but rarely, blood dyscrasia adverse reactions have been reported. Hence, we report the case of a 56-year-old African American woman who developed severe neutropenia following two weeks of oral risperidone treatment. Her neutrophil levels returned to normal limits following discontinuation of risperidone and switching to haloperidol.

Association between hippocampal subfields and clinical symptoms of first-episode and drug naive schizophrenia patients during 12 weeks of risperidone treatment

Small hippocampal size, especially in CA1 may be implicated in the pathogenesis and psychopathology of schizophrenia (SCZ). However, does the volume of hippocampal subfields like CA1 in SCZ patients affect response to antipsychotic treatment? In this study, we used risperidone to treat first-episode and drug naïve (FEDN) SCZ patients for 12 weeks, and then explored the relationship between differences in baseline hippocampal subfield volumes, as well as any changes in the volumes of these hippocampal structures during treatment, and improvement in their psychopathological symptoms. By adopting a state-of the-art automated algorithm, the hippocampal subfields were segmented in 43 FEND SCZ inpatients at baseline and in 26 of them after 12 weeks of risperidone monotherapy, as well as in 30 matched healthy controls. We adopted the Positive and Negative Syndrome Scale (PANSS) to assess psychopathological symptoms in 43 SCZ patients at baseline and in 40 of them at post-treatment. Our results showed that before treatment, schizophrenia patients had no significant differences in total or subfield hippocampal volumes compared with healthy volunteers (all p>0.05). However, at baseline smaller volumes of the left CA1, right molecular layer of the dentate, left hippocampal tail and left pre-subiculum were significantly correlated with worse PANSS negative symptom scores, accounting for 41% of its variance. We also found a significant correlation between a larger left CA1 at baseline and a worse PANSS total score and general psychopathology sub-score at post-treatment (both p<0.05). Furthermore, the left CA1 at baseline was significantly smaller in responders, who had >50% improvement in PANSS total score, than in non-responders (p<0.05). Our results suggest that FEDN SCZ patients with smaller left CA1 had greater negative psychotic symptoms at baseline and more of them had a >50% improvement in PANSS total score after 12 weeks of risperidone treatment. Thus, smaller left CA1 volume may be a predicator for improvement in psychotic symptoms of FEDN SCZ patients, but hippocampal volumes overall did not differ in size from normal controls and did not change during treatment.

Gut microbial biomarkers for the treatment response in first-episode, drug-naïve schizophrenia: a 24-week follow-up study

Preclinical studies have shown that the gut microbiota can play a role in schizophrenia (SCH) pathogenesis via the gut-brain axis. However, its role in the antipsychotic treatment response is unclear. Here, we present a 24-week follow-up study to identify gut microbial biomarkers for SCH diagnosis and treatment response, using a sample of 107 first-episode, drug-naïve SCH patients, and 107 healthy controls (HCs). We collected biological samples at baseline (all participants) and follow-up time points after risperidone treatment (SCH patients). Treatment response was assessed using the Positive and Negative Symptoms Scale total (PANSS-T) score. False discovery rate was used to correct for multiple testing. We found that SCH patients showed lower α-diversity (the Shannon and Simpson’s indices) compared to HCs at baseline (p = 1.21 × 10−9, 1.23 × 10−8, respectively). We also found a significant difference in β-diversity between SCH patients and HCs (p = 0.001). At baseline, using microbes that showed different abundance between patients and controls as predictors, a prediction model can distinguish patients from HCs with an area under the curve (AUC) of 0.867. In SCH patients, after 24 weeks of risperidone treatment, we observed an increase of α-diversity toward the basal level of HCs. At the genus level, we observed decreased abundance of Lachnoclostridium (p = 0.019) and increased abundance Romboutsia (p = 0.067). Moreover, the treatment response in SCH patients was significantly associated with the basal levels of Lachnoclostridium and Romboutsia (p = 0.005 and 0.006, respectively). Our results suggest that SCH patients may present characteristic microbiota, and certain microbiota biomarkers may predict treatment response in this patient population.

The Difference in Negative Scale Score Measured with Positive and Negative Syndrome Scale in Schizophrenic Male Patient Treated with Risperidone in Addition to Vitamin E and Treated with Risperidone Alone at Prof. Dr. M. Ildrem Mental Hospital Medan

OBJECTIVES: The objectives of the study were to investigate the difference in negative scale score in schizophrenic male patients that received vitamin E-fortified risperidone and those receiving risperidone treatments alone. METHODS: This study was a pre- and post-test experimental design which compared two groups; a group of men with schizophrenia who were given risperidone treatment with added Vitamin E and another group of men with schizophrenia who were given only risperidone treatment. The study was conducted at the outpatient clinic of Prof.dr. M. Ildrem Mental Hospital Medan, North Sumatra within August to November 2019. The study has been approved by the Research Ethics Committee of the Faculty of Medicine, North Sumatera University. The instrument used to assess negative scale on the subjects is PANSS. RESULTS: We found that statistical analysis using corrected Mann–Whitney U-test obtained p < 0.001 (p < 0.05). CONCLUSIONS: There was a strongly significant difference in negative scale Positive and Negative Syndrome Scale (PANSS) scores on 4th and 8th weeks in the group which received risperidone treatment with additional Vitamin E compared to the other group that received risperidone alone.

Macrophage migration inhibitory factor as a potential novel biomarker for cognitive function in patients with first-episode schizophrenia

Objective: Cognitive impairment is prevalent in schizophrenia. Macrophage migration inhibitory factor which is released into the circulation under stress or inflammation, is associated with cognition and also plays an important role in immunity. However, no study has investigated the relationship between macrophage migration inhibitory factor and cognitive function in first-episode schizophrenia patients at baseline or after treatment. This study investigated the pre- and post-risperidone treatment correlations between serum macrophage migration inhibitory factor levels and cognitive function in first-episode schizophrenia patients. Methods: A total of 83 first-episode schizophrenia patients who received risperidone monotherapy and 57 healthy controls – matched for sex, age, smoking status, education (years), marital status and waist-to-hip ratio – were included. Macrophage migration inhibitory factor levels were measured before and 10 weeks after treatment in the patient group and at baseline in the controls. Pre- and post-treatment cognitive functions in patients were assessed using the MATRICS Consensus Cognitive Battery. Results: At baseline, macrophage migration inhibitory factor levels were significantly higher in first-episode schizophrenia patients than those in healthy controls ( p < 0.01) and decreased in patients after 10 weeks of risperidone treatment compared with baseline ( p < 0.05). The MATRICS Consensus Cognitive Battery total score and the sub-scores for the Trail Making Test, Symbol Coding, Letter Number Sequence, Maze and Brief Visuospatial Memory Test–Revised improved significantly after risperidone treatment. After controlling for age, sex, education, waist-to-hip ratio and smoking status, partial correlation analysis showed a positive correlation between baseline macrophage migration inhibitory factor levels and patients’ baseline MATRICS Consensus Cognitive Battery verbal memory scores ( r = 0.29, p = 0.01). Macrophage migration inhibitory factor changes correlated negatively with verbal memory changes ( r = −0.26, p = 0.04). Multiple linear regression analysis identified a definite correlation between the changes in word memory test score and macrophage migration inhibitory factor level (β = −0.09, p = 0.04). Conclusion: Macrophage migration inhibitory factor may be involved in the process of cognitive impairment in first-episode schizophrenia and repair mechanisms following risperidone treatment.

The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain

Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine—another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice.