Combination of Metformin and Lifestyle Intervention for Antipsychotic-Related Weight Gain: A Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Weight gain is a common antipsychotic (AP)-related adverse drug reaction (ADR) that can increase the risk of cardiovascular diseases and premature mortality. This meta-analysis examined the efficacy and tolerability of combining metformin and lifestyle intervention for AP-related weight gain in schizophrenia. METHODS: Randomized controlled trials (RCTs) with meta-analyzable data were searched and retrieved by 2 independent investigators. RevMan software (version 5.3) was used to synthesize data, and to calculate the standardized or weighted mean differences and risk ratio with their 95% confidence intervals. RESULTS: Six RCTs (n=732) were included and meta-analyzed. The metformin and lifestyle combination (MLC) group had significant reduction in weight and body mass index compared with the metformin group, lifestyle group, and placebo group. There was less frequent weight gain of≥7% in the MLC group over placebo. No other group differences in ADRs, total psychopathology, and all-cause discontinuation were found. In terms of study quality, 5 RCTs were open-labelled, 1 RCT had low risk allocation concealment, and 3 RCTs specifically described randomization methods. CONCLUSION: Combining metformin and lifestyle intervention shows significant effect in reducing AP-related weight gain. Higher quality and larger RCTs are needed to confirm these findings.Review registration: CRD42017059198.

Employment and financial burden of families with preschool children diagnosed with autism spectrum disorders in urban China: results from a descriptive study.

BACKGROUND: Autism spectrum disorder (ASD) affects many aspects of family life, such as social and economic burden. Little investigation of this phenomenon has been carried out in China. We designed this study to evaluate the employment and financial burdens of families with ASD-diagnosed preschoolers. METHODS: Four hundred and fifty-nine nuclear families of children with ASD, 418 with some other disability (OD) and 424 with typically developing (TD) children were recruited for this study. Employment and financial burdens of families were evaluated using a structured questionnaire; logistic regression was used to examine differences in job change measures by group, and ordinal logistic regression was used to investigate the association between household income and group. RESULTS: Fifty-eight percent of families with ASD children and 19% of families with OD children reported that childcare problems had greatly affected their employment decisions, compared with 9% of families with TD children (p < 0.001). Age of child, parental education and parental age notwithstanding, having a child with ASD and having a child with OD were both associated with increased odds of reporting that childcare greatly interfered with employment (ASD, OR: 15.936; OD, OR: 2.502; all p < 0.001) and decreased the odds of living in a higher-income household (ASD, estimate = -1.271; OD, estimate = -0.569; all p < 0.001). The average loss of annual income associated with having a child with ASD was Chinese RenMinBi (RMB) 44,077 ($7,226), compared with RMB 20,788 ($3,408) for families of OD children. CONCLUSIONS: ASD is associated with severe employment and financial burdens, much more than for OD, in families with preschool children.

[Pharmacokinetics for the solutable type injections of propofol glycoside in rats].

OBJECTIVE: To estimate the pharmacokinetics for two solution types of propofol glycoside injections in rats. METHODS: A high performance liquid chromatography-high resolution mass spectrometry (HPLC-MS) was established for measuring propofol in rat plasma. Two kinds of propofol glycoside injections were developed and intravenously administered to rats via tail vein, respectively, and a commercially available propofol emulsion injection was intravenously administered as a control. Propofol plasma concentration-time curves were determined, and the pharmacokinetic parameters were estimated. RESULTS: HPLC-MS measurement was performed by using a quadrupole-orbit trap high-resolution mass spectrometer on a C18 chromatographic column. The mobile phase consisted of water and methanol (20:80, V/V). The ion source was an atmospheric pressure chemical ion source, and the negative ion was used for detection with a scanning mode of selective ion monitoring in which m/z 177.127 4 was used for propofol and m/z 149.096 1 used for thymol as an internal standard. A linear correlation between concentration and peak area ratio was constructed in the range of 50 µg/L-10.0 mg/L propofol. The limit of quantification was 50 µg/L propofol. The average recoveries of propofol from plasma were in the range of 93.6%-101.1%, and intra-day or inter-day relative standard deviation for measurement was <14%. The pharmacokinetic results showed that the two kinds of propofol glycoside injections exhibited the same pharmacokinetic behavior. However, the clearance and area under curve values of propofol for the two propofol glycoside injections were evidently increased as compared with those for propofol emulsion injection, respectively. Furthermore, their apparent distribution volumes were increased as well. Nevertheless, the propofol elimination half-life (t1/2) value of the newly developed propofol glycoside injections was the same as that of commercial propofol emulsion injection (approximately 1.5 h). CONCLUSION: The established HPLC-MS method can be used for measuring propofol concentration accurately in rat plasma. The clearance and distribution volumes of propofol glycoside injection are bigger than those of the propofol emulsion injection.

Corrigendum: The association between cognitive deficits and clinical characteristic in first-episode drug naïve patients with schizophrenia.

[This corrects the article DOI: 10.3389/fpsyt.2021.638773.].

Corrigendum: The association between metabolic disturbance and cognitive impairments in early-stage schizophrenia.

[This corrects the article DOI: 10.3389/fnhum.2020.599720.].

[Preparation and in vitro and in vivo study on tinidazole in situ forming sustained-release injection].

This study is to prepare the in situ forming sustained-release injection which can perform sustained release behavior at the periodontal site for 7 days and to evaluate its in vitro and in vivo properties. After preparation of in situ forming sustained-release injection the in situ time was studied. And the surface of the solid injection was characterized by SEM. The rheological curve at 0 degrees C, 25 degrees C, 37 degrees C was determined and the impact of the temperature on the viscosity was examined. The in vitro release behavior was investigated. At last, rabbit periodontitis model was established to study its pharmacokinetics. The injection was stable, hard to stratify and decompose. The in situ forming time was about 6 seconds. It can easily adhere into periodontal pockets. There were lots of holes on the surface of the solid injection for the drug to diffuse. The drug releasing curves could be fit by Korsmeyer-Peppas equation. The drug smoothly released for 7 days at pH 7.4 PBS buffer with a very slight burst release and maintained a certain concentration. In vivo pharmacokinetics results indicated that after administration with the in situ forming injection, achievement of tinidazole (TNZ) concentration in gingival crevicular fluid (GCF) was more comparable and long-lasting than usual solution of TNZ management and relatively constant TNZ levels were attained until 168 h. All these results supported the prospect of tinidazole in situ forming sustained-release injection in clinical applications.

Developments in Biological Mechanisms and Treatments for Negative Symptoms and Cognitive Dysfunction of Schizophrenia.

The causal mechanisms and treatment for the negative symptoms and cognitive dysfunction in schizophrenia are the main issues attracting the attention of psychiatrists over the last decade. The first part of this review summarizes the pathogenesis of schizophrenia, especially the negative symptoms and cognitive dysfunction from the perspectives of genetics and epigenetics. The second part describes the novel medications and several advanced physical therapies (e.g., transcranial magnetic stimulation and transcranial direct current stimulation) for the negative symptoms and cognitive dysfunction that will optimize the therapeutic strategy for patients with schizophrenia in future.

The Association Between Cognitive Deficits and Clinical Characteristic in First-Episode Drug Naïve Patients With Schizophrenia.

Background: Schizophrenia is a severe mental disease which characterized by positive symptom, negative symptom, general pathology syndrome and cognitive deficits. In recent years, many studies have investigated the relationship between cognitive deficits and clinical characteristics in schizophrenia, but relatively few studies have been performed on first-episode drug-naïve patients. Methods: Eighty seven first-episode drug-naïve schizophrenia patients were assessed for positive symptom, negative symptom, general pathology symptom and cognitive deficits from the Positive and Negative Symptom Scale and MATRICS Consensus Cognitive Battery. Psychotics depression were assessed using the Calgary depressing scale for schizophrenia. The relationship between clinical characteristics and cognitive deficits were assessed using correlation analysis and linear regression analysis. Results: The prevalence of cognitive deficits among the patients in our study was 85.1% (74/87) which was much higher than that in the general population. According to correlation analysis, negative symptom was negatively correlated with speed of processing and social cognition, and general pathology showed a negative correlation with attention/vigilance. In addition, a positive correlation was found between age and speed of processing. No correlation was found between cognitive deficits and positive symptom. Conclusions: This study confirmed that negative symptom is negatively related with some domains of cognitive function in first-episode drug naïve schizophrenia patients. Trail Registration: NCT03451734. Registered March 2, 2018 (retrospectively registered).

Corrigendum: The Association Between Cognitive Deficits and Clinical Characteristic in First-Episode Drug Naïve Patients With Schizophrenia.

[This corrects the article DOI: 10.3389/fpsyt.2021.638773.].

Human torpor: translating insights from nature into manned deep space expedition.

During a long-duration manned spaceflight mission, such as flying to Mars and beyond, all crew members will spend a long period in an independent spacecraft with closed-loop bioregenerative life-support systems. Saving resources and reducing medical risks, particularly in mental heath, are key technology gaps hampering human expedition into deep space. In the 1960s, several scientists proposed that an induced state of suppressed metabolism in humans, which mimics 'hibernation', could be an ideal solution to cope with many issues during spaceflight. In recent years, with the introduction of specific methods, it is becoming more feasible to induce an artificial hibernation-like state (synthetic torpor) in non-hibernating species. Natural torpor is a fascinating, yet enigmatic, physiological process in which metabolic rate (MR), body core temperature (Tb ) and behavioural activity are reduced to save energy during harsh seasonal conditions. It employs a complex central neural network to orchestrate a homeostatic state of hypometabolism, hypothermia and hypoactivity in response to environmental challenges. The anatomical and functional connections within the central nervous system (CNS) lie at the heart of controlling synthetic torpor. Although progress has been made, the precise mechanisms underlying the active regulation of the torpor-arousal transition, and their profound influence on neural function and behaviour, which are critical concerns for safe and reversible human torpor, remain poorly understood. In this review, we place particular emphasis on elaborating the central nervous mechanism orchestrating the torpor-arousal transition in both non-flying hibernating mammals and non-hibernating species, and aim to provide translational insights into long-duration manned spaceflight. In addition, identifying difficulties and challenges ahead will underscore important concerns in engineering synthetic torpor in humans. We believe that synthetic torpor may not be the only option for manned long-duration spaceflight, but it is the most achievable solution in the foreseeable future. Translating the available knowledge from natural torpor research will not only benefit manned spaceflight, but also many clinical settings attempting to manipulate energy metabolism and neurobehavioural functions.

The Association Between Metabolic Disturbance and Cognitive Impairments in Early-Stage Schizophrenia.

Background: Cognitive impairment is one of the core symptoms of schizophrenia, which is considered to be significantly correlated to prognosis. In recent years, many studies have suggested that metabolic disorders could be related to a higher risk of cognitive defects in a general setting. However, there has been limited evidence on the association between metabolism and cognitive function in patients with early-stage schizophrenia. Methods: In this study, we recruited 172 patients with early-stage schizophrenia. Relevant metabolic parameters were examined and cognitive function was evaluated by using the MATRICS Consensus Cognitive Battery (MCCB) to investigate the relationship between metabolic disorder and cognitive impairment. Results: Generally, the prevalence of cognitive impairment among patients in our study was 84.7% (144/170), which was much higher than that in the general population. Compared with the general Chinese setting, the study population presented a higher proportion of metabolic disturbance. Patients who had metabolic disturbance showed no significant differences on cognitive function compared with the other patients. Correlation analysis showed that metabolic status was significantly correlated with cognitive function as assessed by the cognitive domain scores (p < 0.05), while such association was not found in further multiple regression analysis. Conclusions: Therefore, there may be no association between metabolic disorder and cognitive impairment in patients with early-stage schizophrenia. Trial Registration: Clinicaltrials.gov, NCT03451734. Registered March 2, 2018 (retrospectively registered).

Increased Appetite Plays a Key Role in Olanzapine-Induced Weight Gain in First-Episode Schizophrenia Patients

Weight gain and metabolic disturbances, potentially influenced by increased appetite, are common effects of olanzapine treatment in patients with schizophrenia. In this study, we explored the association between olanzapine-induced weight gain and metabolic effects with increased appetite. Drug-naïve, first-episode schizophrenia patients were treated with olanzapine for 12 weeks. Assessments included time to increased appetite, body weight, body mass index, biochemical indicators of blood glucose and lipids, proportion of patients who gained more than 7% or 10% of their baseline weight upon treatment conclusion, patients who developed dyslipidemia, and Positive and Negative Syndrome Scale scores. In total, 33 patients with schizophrenia receiving olanzapine were enrolled and 31 completed the study. During the 12-week olanzapine treatment, 77.4% (24/31) patients had increased appetite with 58.1% (18/31) patients having increased appetite within the first 4 weeks. The mean time for increased appetite was 20.3 days. More patients in the increased appetite group increased their initial body weight by more than 7% after 12 weeks when compared to patients with unchanged appetite (22/24 [91.7%] vs. 3/7 [42.9%], p = 0.004). Earlier increased appetite led to more weight gain during the following month. Overall, 50% of patients in the increased appetite group had dyslipidemia after 12 weeks. Our results demonstrated that olanzapine induced significantly appetite increase in first-episode patients with schizophrenia and appetite increase played a key role in olanzapine-induced weight gain and dyslipidemia. Clinical Trial Registration: NCT03451734. Registered March 2, 2018 (retrospectively registered).

Corrigendum: Increased Appetite Plays a Key Role in Olanzapine-Induced Weight Gain in First-Episode Schizophrenia Patients.

[This corrects the article DOI: 10.3389/fphar.2020.00739.].

ABCB1 Gene Is Associated With Clinical Response to SNRIs in a Local Chinese Han Population.

Background: The relation between the ATP-binding cassette subfamily B member 1 (ABCB1) gene and major depressive disorder (MDD) has been studied in a local Chinese Han population. MDD is associated with the rs2032582 (G2677T) and rs1128503 (C1236T) single-nucleotide polymorphisms (SNPs) of ABCB1 but not with rs1045642, rs2032583, rs2235040, and rs2235015. This study aims to explore the potential correlations of therapeutic responses with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in a local Chinese Han population. Methods: The study population included 292 patients with MDD. All patients were assessed at baseline and at first, second, fourth, and sixth weeks according to the 17-item Hamilton Rating Scale for Depression (HAM-D17) to determine their therapeutic responses to SSRIs and SNRIs. Results: In the SSRI therapy group, the genotype or allele distribution of six SNPs was not significantly different between responders and nonresponders. In the SNRI therapy group, only rs2032583 was associated with a therapeutic response to SNRIs. The C allele of the ABCB1 rs2032583 polymorphism was negatively correlated with therapeutic responses according to logistic regression analysis. Conclusion: The ABCB1 gene polymorphisms may not be associated with therapeutic responses to SSRIs but not with SNRIs. The TT genotype of rs2032583 could be a predictive factor of improved treatment responses to SNRIs in the Chinese population. These findings should be replicated in future studies with larger patient groups.

Effects of Aspirin in Rats With Ouabain Intracerebral Treatment-Possible Involvement of Inflammatory Modulation?

Bipolar disorder (BD) is a chronic and refractory disease with high probability of morbidity and mortality. Although epidemiological studies have established a strong association between BD and immune dysfunction, the precise etiology is still debatable, and the underpinning mechanism remains poorly investigated and understood. In the present study, manic-like symptoms of BD were induced in rats after intracerebroventricular administration of ouabain. Aspirin, a commonly used anti-inflammatory agent, was used to treat the induced manic-like symptoms and inflammation. Concentrations of a spectrum of inflammatory cytokines were examined by enzyme-linked immunosorbent assay in both plasma and brain tissues, and expression of Toll-like receptors 3 and 4 were determined in rat brains. Locomotor activity was monitored with open-field test to assess the effects of ouabain challenge and to evaluate the treatment efficacy of aspirin. Ouabain administration recapitulated many mania-like features such as increased stereotypic counts, traveling distance in open-field test, and decreased expression of brain-derived neurotrophic factor, interferon gamma, and Toll-like receptor 3, which were frequently found in patients with BD. These abnormalities could be partially reversed by aspirin. Our findings suggest that aspirin could be used as a promising adjunctive therapy for BD.

Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study.

OBJECTIVE: The purpose of this study was to assess the efficacy of metformin in preventing olanzapine-induced weight gain. METHOD: Forty patients with schizophrenia were randomly assigned to treatment for 12 weeks with olanzapine, 15 mg/day, plus metformin, 750 mg/day (N=20), or olanzapine, 15 mg/day, plus placebo (N=20). This investigation was conducted in a double-blind fashion. Planned assessments included body weight, body mass index, proportion of patients who gained more than 7% of their baseline weight at the end of the 12-week treatment, waist circumference, waist-to-hip ratio, fasting glucose and insulin, insulin resistance index, and scores on the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS). RESULTS: Of the 40 patients who were randomly assigned, 37 (92.5%) completed treatments. The weight, body mass index, waist circumference, and waist-to-hip ratio levels increased less in the olanzapine plus metformin group relative to the olanzapine plus placebo group during the 12-week follow-up period. The insulin and insulin resistance index values of the olanzapine plus placebo group increased significantly at weeks 8 and 12. In contrast, the insulin and insulin resistance index levels of the olanzapine plus metformin group remained unchanged. Significantly fewer patients in the olanzapine plus metformin group relative to patients in the olanzapine plus placebo group increased their baseline weight by more than 7%, which was the cutoff for clinically meaningful weight gain. There was a significant decrease in SAPS and SANS scores within each group from baseline to week 12, with no between-group differences. Metformin was tolerated well by all patients. CONCLUSIONS: Metformin was effective and safe in attenuating olanzapine-induced weight gain and insulin resistance in drug-naive first-episode schizophrenia patients. Patients displayed good adherence to this type of preventive intervention.

Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial.

CONTEXT: Weight gain, a common adverse effect of antipsychotic medications, is associated with medical comorbidities in psychiatric patients. OBJECTIVE: To test the efficacy of lifestyle intervention and metformin alone and in combination for antipsychotic-induced weight gain and abnormalities in insulin sensitivity. DESIGN, SETTING, AND PATIENTS: A randomized controlled trial (October 2004-December 2006) involving 128 adult patients with schizophrenia in the Mental Health Institute of the Second Xiangya Hospital, Central South University, China. Participants who gained more than 10% of their predrug weight were assigned to 1 of 4 treatment groups. INTERVENTIONS: Patients continued their antipsychotic medication and were randomly assigned to 12 weeks of placebo, 750 mg/d of metformin alone, 750 mg/d of metformin and lifestyle intervention, or lifestyle intervention only. MAIN OUTCOME MEASURES: Body mass index, waist circumference, insulin levels, and insulin resistance index. RESULTS: All 128 first-episode schizophrenia patients maintained relatively stable psychiatric improvement. The lifestyle-plus-metformin group had mean decreases in body mass index (BMI) of 1.8 (95% confidence interval [CI], 1.3-2.3), insulin resistance index of 3.6 (95% CI, 2.7-4.5), and waist circumference of 2.0 cm (95% CI, 1.5-2.4 cm). The metformin-alone group had mean decreases in BMI of 1.2 (95% CI, 0.9-1.5), insulin resistance index of 3.5 (95% CI, 2.7-4.4), and waist circumference of 1.3 cm (95% CI, 1.1-1.5 cm). The lifestyle-plus-placebo group had mean decreases in BMI of 0.5 (95% CI, 0.3-0.8) and insulin resistance index of 1.0 (95% CI, 0.5-1.5). However, the placebo group had mean increases in BMI of 1.2 (95% CI, 0.9-1.5), insulin resistance index of 0.4 (95% CI, 0.1-0.7), and waist circumference of 2.2 cm (95% CI, 1.7-2.8 cm). The lifestyle-plus-metformin treatment was significantly superior to metformin alone and to lifestyle plus placebo for weight, BMI, and waist circumference reduction. CONCLUSIONS: Lifestyle intervention and metformin alone and in combination demonstrated efficacy for antipsychotic-induced weight gain. Lifestyle intervention plus metformin showed the best effect on weight loss. Metformin alone was more effective in weight loss and improving insulin sensitivity than lifestyle intervention alone. Trial Registration clinicaltrials.gov Identifier: NCT00451399.

[Association of HTR2C-759C/T and -697G/C polymorphisms with antipsychotic agent-induced weight gain].

OBJECTIVE: To determine whether antipsychotic agent-induced weight gain was associated with 5-hydroxytryptamine 2C receptor (HTR2C) gene-759C/T and -697G/C polymorphisms. METHODS: A case-matching controlled study was done. Eighty-five patients who had gained more than 7% of their pre-drug body weight served as a study group, and 85 patients who had gained less than 7% of their pre-drug body weight served as a control group. The control group were matched with the study group in the kinds of antipsychotic agents and the course of antipsychotic treatment. The ligation diction reaction technique was used to analyse the frequencies of HTR2C gene-759C/T and -697G/C polymorphisms. RESULTS: The study group were more likely to be hemizygous for the -759C (for male) and the -759CC genotype (for female) than the control group. The study group were more likely to be hemizygous for the -697G (for male) and the -697CG/GG genotype (for female) (all P<0.05) than the control group. CONCLUSION: The -759C/T and -697G/C polymorphisms of the promoter region of HTR2C gene may be associated with antipsychotic agent-induced weight gain.

Altered functional connectivity strength and its correlations with cognitive function in subjects with ultra-high risk for psychosis at rest.

AIMS: Evidence of altered structural and functional connectivity in the frontal-occipital network is associated with cognitive deficits in patients with schizophrenia. However, the altered patterns of functional connectivity strength (FCS) in individuals with ultra-high risk (UHR) for psychosis remain unknown. In this study, whole-brain FCS was assessed to examine the altered patterns of FCS in UHR subjects. METHODS: A total of 34 UHR subjects and 37 age- and sex-matched healthy controls were enrolled to undergo resting-state functional magnetic resonance imaging. The imaging data were analyzed using the graph theory method. RESULTS: Compared with healthy controls, UHR subjects showed significantly decreased FCS in the left middle frontal gyrus and significantly increased FCS in the left calcarine cortex. The FCS values in the left middle frontal gyrus were positively correlated to the scores of the Brief Assessments of Cognitionin Schizophrenia Symbol Coding Test (r = 0.366, P = 0.033) in the UHR subjects. A negative correlation was found between the FCS values in the left calcarine cortex and the scores of the Stroop color-naming test (r = -0.475, P = 0.016) in the UHR subjects. A combination of the FCS values in the 2 brain areas showed an accuracy of 87.32%, a sensitivity of 73.53%, and a specificity of 100% for distinguishing UHR subjects from healthy controls. CONCLUSIONS: Significantly altered FCS in the frontal-occipital network is observed in the UHR subjects. Furthermore, decreased FCS in the left middle frontal gyrus and increased FCS in the left calcarine have significant correlations with the cognitive measures of the UHR subjects and thus improve our understanding of the underlying pathophysiological mechanisms of schizophrenia. Moreover, a combination of the FCS values in the 2 brain areas can serve as a potential image marker to distinguish UHR subjects from healthy controls.

Maternal dietary patterns, supplements intake and autism spectrum disorders: A preliminary case-control study.

The aim of this study was first to investigate associations between maternal dietary patterns and autism spectrum disorders (ASDs) and second to investigate association between maternal supplement intake and ASD.We used a case-control study design to enroll typically developing (TD) children and children with ASD, and data were derived from the Autism Clinical and Environmental Database (ACED).Three seventy four children with AUTISM and 354 age matched TD children were included. The multivariate logistic regression model revealed that maternal unbalanced dietary patterns before conception had a significant increased risk of ASD in offspring (mostly meat: adjusted OR, 4.010 [95% CI, 1.080, 14.887]; mostly vegetable: adjusted OR, 2.234 [95% CI, 1.009, 4.946]); maternal supplementation of calcium during pregnancy preparation was associated with decreased ASD risk (adjusted OR, 0.480 [95% CI, 0.276, 0.836]).This study provided preliminary evidence that maternal unbalanced dietary patterns may be a risk factor for ASD and supplementation of calcium during pregnancy preparation may be inversely associated with ASD in offspring.