Efficacy, Safety, and Tolerability of Ansofaxine (LY03005) Extended-Release Tablet for Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, Phase 2 Clinical Trial.

BACKGROUND: Ansofaxine (LY03005) extended-release tablet is a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. This study assessed the efficacy, safety, and appropriate dosage of ansofaxine for the treatment of major depressive disorder (MDD). METHODS: A multicenter, randomized, double-blind, placebo-controlled, dose-finding, Phase 2 clinical trial was conducted in China. Eligible patients with MDD (18-65 years) were randomly assigned to receive fixed-dose ansofaxine extended-release tablets (40, 80, 120, or 160 mg/d) or placebo for 6 weeks. The primary outcome measure was a change in the total score on the 17-item Hamilton Depression Rating Scale from baseline to week 6. RESULTS: A total of 260 patients were recruited from October 2015 to September 2017, and 255 patients received the study drug as follows: 40 mg (n = 52), 80 mg (n = 52), 120 mg (n = 51), and 160 mg (n = 51) ansofaxine and placebo (n = 49). Significant differences were found in mean changes in 17-item Hamilton Depression Rating Scale total scores at week 6 in the 4 ansofaxine groups vs placebo (-12.46; χ2 = -9.71, P = .0447). All doses of ansofaxine were generally well-tolerated. Treatment-related adverse events occurred in 141 patients (303 cases), yielding incidence rates of 51.92%, 65.38%, 56.86%, and 62.75% in the 40-, 80-, 120-, and 160-mg ansofaxine groups and 38.78% in the placebo group. CONCLUSION: Active doses (40, 80, 120, and 160 mg/d) of ansofaxine in a controlled setting were safe, tolerated, and effective in improving depression symptoms in MDD patients.

Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia.

AIM: The aim of the present study was to evaluate the efficacy and safety of lurasidone for the treatment of Chinese schizophrenic patients. METHODS: Hospitalized schizophrenia patients aged 18-65 were randomized to 6 weeks of double-blind, double-dummy, flexible-dose treatment with lurasidone (40 or 80 mg/day) or risperidone (2, 4 or 6 mg/day). Efficacy was evaluated using a non-inferiority comparison of lurasidone relative to risperidone based on week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score. Safety assessments included adverse events, clinical laboratory measures, and electrocardiograms. RESULTS: Four hundred and forty-four patients were screened to obtain an intent-to-treat sample of 384 patients, of whom 54 patients discontinued treatment prior to 6 weeks. Lurasidone met the criteria for non-inferiority versus risperidone on the PANSS total score. Adjusted mean (SE) change at week 6 on the PANSS total score was -31.2 (1.0) and -34.9 (1.0) in the lurasidone and risperidone group, respectively. The mean difference score was 3.7, and the upper boundary of the 95%-confidence interval (1.0-6.3) was less than the prespecified margin of 7.0. No clinically meaningful between-treatment group differences were evident on secondary efficacy measures, including PANSS positive, PANSS negative, Clinical Global Impression scale - Severity, and Calgary Depression Scale for Schizophrenia scales. The incidence of adverse events was lower for lurasidone vs risperidone for extrapyramidal symptoms (17.0% vs 38.2%), akathisia (7.2% vs 13.6%), prolactin increase (3.1% vs 14.1%), and weight increase (0.5% vs 5.2%). CONCLUSION: Lurasidone was found to be non-inferior to risperidone on the primary endpoint with minimal effects on weight, metabolic parameters, or prolactin levels.

Decreased white matter FA values in the left inferior frontal gyrus is a possible intermediate phenotype of schizophrenia: evidences from a novel group strategy.

Intermediate phenotype could be used to investigate genetic susceptibility. However, genetic and environmental heterogeneity may interfere with identification of intermediate phenotypes. In this study, we minimized these interferences by using a novel group strategy. A total of 22 drug-naive and first-episode schizophrenia (FES) patients, along with 22 of their kin healthy siblings (HS), 22 non-kin healthy siblings (nHS) of other schizophrenia patients and 22 healthy controls (HC), were recruited. Brain imaging was acquired from the participants. Voxel-based analysis was used to investigate differences in white matter integrity derived from diffusion tensor imaging among the four groups. Two cognitive tests related to our findings were selected to confirm the related phenotypic changes. All of the FES, HS, and nHS groups showed decreased fractional anisotropy (FA) values in the left inferior frontal gyrus (IFG) compared with the HC group (p < 0.05, FDR corrected). The scores of Hopkins Verbal learning Test-Revised and Animal Naming in FES patients were significantly lower than in participants belonging to the other three groups (p < 0.05). Significant correlation between Animal Naming scores and FA values in the left IFG was found in FES patients (r = 0.53, p = 0.01). Moreover, FES patients also showed decreased FA values in the left medial frontal gyrus, left inferior temporal gyrus, left parahippocampal gyrus, left posterior cingulate, and right middle temporal gyrus compared with HC (p < 0.05, FDR corrected). Decreased FA values in the left IFG is a possible intermediate phenotype of schizophrenia, and this finding supports the hypothesis that disrupted connectivity of white matter may be the key substrate of schizophrenia.

Olanzapine modulates the default-mode network homogeneity in recurrent drug-free schizophrenia at rest.

BACKGROUND: Previous studies on brain function alterations associated with antipsychotic treatment for schizophrenia have produced conflicting results because they used short treatment periods and different designs. METHODS: Resting-state functional magnetic resonance imaging scans were obtained from 17 drug-free patients with recurrent schizophrenia and 24 healthy controls. The patients were treated with olanzapine for 6 months and were scanned at three time points (baseline, 6 weeks of treatment and 6 months of treatment). Network homogeneity was used to analyze the imaging data to examine default-mode network homogeneity alterations associated with antipsychotic treatment. RESULTS: Compared with the controls, the patients at baseline showed increased network homogeneity in the bilateral precuneus and decreased network homogeneity in the bilateral middle temporal gyrus. Network homogeneity values in the bilateral precuneus decreased, and network homogeneity values in the left superior medial prefrontal cortex and the right middle temporal gyrus increased in patients administered olanzapine as antipsychotic treatment. By contrast, network homogeneity values in the left middle temporal gyrus remained unchanged in patients after treatment. CONCLUSION: This study provides evidence that antipsychotic treatment with olanzapine modulates the default-mode network homogeneity in schizophrenia. These findings contribute to the understanding of antipsychotic treatment effects on brain functions.

Efficacy and safety of prolonged-release trazodone in major depressive disorder: a multicenter, randomized, double-blind, flexible-dose trial.

OBJECTIVE: To investigate the efficacy, safety, and clinical benefit of prolonged-release trazodone (Trittico) in the treatment of major depressive disorder (MDD). METHODS: In this study, 363 Chinese patients with MDD were randomized 1:1 to receive either prolonged-release trazodone (150-450 mg) or placebo treatment for 6 weeks. The primary efficacy measurement was the change of the 17-item Hamilton Depression Rating Scale (HAMD-17) total score from baseline to the end of the study. The secondary efficacy measurements were the response and remission rates, the Clinical Global Impression - Improvement of Illness (CGI-I) score at the end of the study, and the change of the HAMD-14 total score and quality of sleep [evaluated by the Pittsburgh Sleep Quality Index (PSQI) scale] during the study period. RESULTS: The mean maximum daily dose was 273.11 mg for the trazodone group and 290.92 mg for the placebo group. At the end of the study, there was a significant difference between the two groups in the HAMD-17 change score (trazodone vs. placebo: -11.07 vs. -8.29, p < 0.001). Trazodone showed advantages at 1 week of treatment, and the effect lasted until the end of the study (week 6). The response and remission rates of the trazodone group were significantly higher than those in the placebo group (response rate: 59.6 vs. 37.2%, p < 0.001; remission rate: 35.5 vs. 22.2%, p = 0.005). The majority of the adverse reactions of trazodone were mild to moderate, and the most frequent adverse reactions (≥5%) were dizziness, dry mouth, somnolence, and nausea. CONCLUSIONS: Prolonged-release trazodone was more effective than placebo in MDD and was well tolerated.

A 6-week, phase IIb, randomized, double-blind, placebo-controlled trial of Anyu Peibo capsules for the treatment of major depressive disorder in adults.

Background: Almost one-third of patients with major depressive disorder (MDD) do not respond to conventional antidepressants, and new treatments for MDD are urgently needed. Objectives: This phase IIb clinical trial was designed to evaluate the efficacy and safety of Anyu Peibo capsules in the treatment of adults with MDD. Design: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study. Methods: A total of 172 patients with MDD from nine study centers were randomized (1:1) to receive placebo (n = 86) or oral Anyu Peibo capsules (0.8 g) twice per day (n = 86) for 6 weeks. The primary endpoint was the change in the Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to week 6, analyzed using an analysis of covariance (ANCOVA) approach with the baseline MADRS score, center effect and center by group interaction as the covariates. Other efficacy endpoints and variables included clinical response and remission rates according to the MADRS and the 17-item Hamilton Depression Rating Scale (HAMD-17) scores, the change in the HAMD-17, Clinical Global Impression - Severity scale and Clinical Global Impression - Improvement scale scores and the reduction in the Hamilton Anxiety Scale from baseline to week 6. Results: The mean baseline MADRS total scores were 29.20 and 29.72 in the Anyu Peibo (n = 82) and placebo groups (n = 81), respectively. The least squares mean change in the MADRS score from baseline to week 6 was 16.59 points in the Anyu Peibo group and 14.51 points in the placebo group. Although there were greater reductions in the MADRS score from baseline to week 6 in the Anyu Peibo capsule group compared to the placebo group, the difference did not reach statistical significance (least-squares mean difference, 2.07 points; 95% confidence interval, -0.27 to 4.41; p = 0.0819). The results of sensitivity analyses by ANCOVA with the last observation carried forward method for missing data indicated that the administration of Anyu Peibo capsules may lead to a significant reduction in depressive symptoms compared to the placebo (least-squares mean difference: 3.29 points; 95% confidence interval: 0.64-5.93; p = 0.0152). Furthermore, Anyu Peibo capsules showed significant benefits over placebo when the change in the HAMD-17 score from baseline to week 6 was evaluated as the secondary analysis (t = 2.01; 95% confidence interval, 0.03-4.23; p = 0.0464). Conclusion: Anyu Peibo capsules may have an effective and safe antidepressant effect, which warrants further research.

A multicenter, randomized, double-blind, duloxetine-controlled, non-inferiority trial of desvenlafaxine succinate extended-release in patients with major depressive disorder.

BACKGROUND: Desvenlafaxine and duloxetine are selective serotonin and norepinephrine reuptake inhibitors. Their efficacy has not been directly compared using statistical hypotheses. This study evaluated the non-inferiority of desvenlafaxine extended-release (XL) to duloxetine in patients with major depressive disorder (MDD). METHODS: In this study, 420 adult patients with moderate-to-severe MDD were enrolled and randomly assigned (1:1) to receive 50 mg (once daily [QD]) of desvenlafaxine XL (n = 212) or 60 mg QD of duloxetine (n = 208). The primary endpoint was evaluated using a non-inferiority comparison based on the change from baseline to 8 weeks in the 17-item Hamilton Depression Rating Scale (HAMD17) total score. Secondary endpoints and safety were evaluated. RESULTS: Least-squares mean change in HAM-D17 total score from baseline to 8 weeks was -15.3 (95% confidence interval [CI]: -17.73, -12.89) in the desvenlafaxine XL group and - 15.9 (95% CI, -18.44, -13.39) in the duloxetine group. The least-squares mean difference was 0.6 (95% CI: -0.48, 1.69), and the upper boundary of 95% CI was less than the non-inferiority margin (2.2). No significant between-treatment differences were found in most secondary efficacy endpoints. The incidence of the most common treatment-emergent adverse events (TEAEs) was lower for desvenlafaxine XL than for duloxetine for nausea (27.2% versus 48.8%) and dizziness (18.0% versus 28.8%). LIMITATIONS: A short-term non-inferiority study without a placebo arm. CONCLUSIONS: This study demonstrated that desvenlafaxine XL 50 mg QD was non-inferior to duloxetine 60 mg QD in efficacy in patients with MDD. Desvenlafaxine had a lower incidence of TEAEs than duloxetine did.

A phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to verify the efficacy and safety of ansofaxine (LY03005) for major depressive disorder.

Major depressive disorder (MDD) is the most prevalent form of depression and is becoming a great challenge for public health and medical practice. Although first-line antidepressants offer therapeutic benefits, about 35% of depressed patients are not adequately treated, creating a substantial unmet medical need. A multicenter, double-blind, randomized, placebo-controlled phase 3 clinical trial was conducted in patients with MDD in China to assess the efficacy and safety of ansofaxine (LY03005), a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. Eligible 588 MDD patients were included and randomly assigned (1:1:1) to 8-week treatment with ansofaxine 80 mg/day(n = 187), ansofaxine 160 mg/day(n = 186), or placebo(n = 185). The primary efficacy endpoint was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline to the end of the study. Safety indexes included adverse events, vital signs, physical examination, laboratory tests, 12-lead electrocardiogram (ECG), and evaluation of suicide tendency and sexual function. Significant differences were found in mean changes in MADRS total score at week 8 in the two ansofaxine groups (80 mg, -20.0; 160 mg, -19.9) vs. placebo (-14.6; p < 0.0001). All doses of ansofaxine were generally well-tolerated. Treatment-emergent adverse events (TEAEs) were reported by 137 (74.46%) patients in ansofaxine 80 mg group, 144 (78.26%) patients in ansofaxine 160 mg and 125 (67.93%) patients in the placebo group. The incidence of treatment-related adverse events (TRAEs) was 59.2% (109 patients), 65.22% (120 patients) in the 80, 160 mg ansofaxine groups, and 45.11% (83 patients) in the placebo group. The initial results of this trial indicate that ansofaxine at both the 80 mg/day and 160 mg/day was effective and safe in adult patients with MDD. ClinicalTrials.gov Identifier: NCT04853407.

Adiponectin gene +45T/G and +276G/T polymorphism and antipsychotic-induced weight gain.

OBJECTIVE: To investigate whether antipsychotic-induced weight gain was associated with adiponectin gene +45T/G and +276G/T polymorphism. METHODS: A case-matched study was done: 85 patients who gained more than 7% of their pre-drug body weight were designed to the study group and 85 patients who gained less than 7% of their pre-drug body weight served as the control group. Ligation diction reaction technique was used to analyze the frequencies of the +276G/T and +45T/G polymorphism of adiponectin gene. RESULTS: The presence of +276G allele was significantly higher in the study group as compared with the control group. CONCLUSION: Subjects with the +276G variant alleles may have a greater risk for weight gain after antipsychotic treatment.

[Effect of antipsychotic drugs on life quality of schizophrenic patients: one year follow-up study].

OBJECTIVE: To compare the effect of 7 antipsychotic drugs on the life quality of schizophrenia patients including chlorpromazine, sulpiride, clozapine, risperidone, olanzapine, quetiapine, and aripiprazole. METHODS: A total of 1,227 stable schizophrenic patients within 5 years onset who took 1 of the 7 study medications as maintenance treatment were followed up for 1 year at 10 China sites. Patients were evaluated by the short form-36 health survey (SF-36) at the baseline and at the end of 1 year. RESULTS: The life quality was improved obviously at the end of the follow-up. There was significant difference in body pain, vitality, and mental health (P<0.05) among these antipsychotic drugs. CONCLUSION: All 7 antipsychotic drugs can improve the life quality of schizophrenia patients. Atypical antipsychotic drugs, especially olazapine and quetiapine, are superior to typical antipsychotic drugs in improving life quality.

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.

Central and Peripheral Changes in FOS Expression in Schizophrenia Based on Genome-Wide Gene Expression.

Schizophrenia is a chronic, debilitating neuropsychiatric disorder. Multiple transcriptomic gene expression profiling analysis has been used to identify schizophrenia-associated genes, unravel disease-associated biomarkers, and predict clinical outcomes. We aimed to identify gene expression regulation, underlying pathways, and their roles in schizophrenia pathogenesis. We searched the Gene Expression Omnibus (GEO) database for microarray studies of fibroblasts, lymphoblasts, and post-mortem brains of schizophrenia patients. Our analysis demonstrated high FOS expression in non-neural peripheral samples and low FOS expression in brain tissues of schizophrenia patients compared with healthy controls. FOS exhibited predictive value for schizophrenia patients in these datasets. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that "amphetamine addiction" was among the top 10 significantly enriched KEGG pathways. FOS and FOSB, which are implicated in the amphetamine addiction pathway, were up-regulated in schizophrenia fibroblast samples. Protein-protein interaction (PPI) network analysis revealed that proteins closely interacting with FOS-encoded protein were also involved in the amphetamine addiction pathway. Pearson correlation test indicated that FOS showed positive correlation with genes in the amphetamine pathway. The results revealed that FOS was acceptable as a biomarker for schizophrenia and may be involved in schizophrenia pathogenesis.

Preliminary Clinical Investigation of Combinatorial Pharmacogenomic Testing for the Optimized Treatment of Depression: A Randomized Single-Blind Study.

This study aims to explore the potential benefits of antidepressant drugs related to metabolic enzyme and drug-targeted genes, identify the optimal treatment of major depression, and provide a reference for individualized medication selection. A prospective randomized single-blind investigation was conducted for 8 weeks. A pharmacogenomic-based interpretive report was provided to the treating physician in the guided group. Patients in this group were informed that their medication selection was directed by DNA testing. In the unguided group, treatment was provided based on the clinical experience of the physician without the guidance of pharmacogenomic testing. Pharmacogenomic-based interpretive report was not provided to these patients until treatment completion. The 17-item Hamilton depression scale (HAMD-17), Hamilton anxiety scale, and treatment emergent symptom scale were used to assess the clinical efficacy and side effects at baseline and after 2, 4, and 8 weeks of treatment. Among the 80 initially enrolled patients with depression, 71 participated in the full data analysis sets and were designated into guided (31) and unguided (40) groups, respectively. No significant difference (P > 0.05) in HAMD-17 total scores, response and remission rates was found between the guided and unguided groups at the end of the treatment. The incidence rate of adverse reaction was 55.56% in guided group and 57.89% in the unguided group. Our study suggested that pharmacogenomic testing might not considerably improve the clinical efficiency and safety for the guided group.

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.

Treatment effects of olanzapine on homotopic connectivity in drug-free schizophrenia at rest.

OBJECTIVES: Deficits in homotopic connectivity have been implicated in schizophrenia. However, alterations in homotopic connectivity associated with antipsychotic treatments in schizophrenia remain unclear due to lack of longitudinal studies. METHODS: Seventeen drug-free patients with recurrent schizophrenia and 24 healthy controls underwent resting-state functional magnetic resonance imaging scans. The patients were scanned at three time points (baseline, at 6 weeks of treatment, and at 6 months of treatment). Voxel-mirrored homotopic connectivity (VMHC) was applied to analyse the imaging data to examine alterations in VMHC associated with antipsychotic treatment. RESULTS: The results showed that patients with schizophrenia exhibited decreased VMHC in the default-mode network (such as the precuneus and inferior parietal lobule) and the motor and sensory processing regions (such as the lingual gyrus, fusiform gyrus and cerebellum lobule VI), which could be normalised or denormalised by olanzapine treatment. In addition, negative correlations were found between decreased VMHC and symptom severity in the patients at baseline. CONCLUSIONS: The present study shows that olanzapine treatment can normalise or denormalise decreased homotopic connectivity in schizophrenia. The findings also provide a new perspective to understand treatment effects of antipsychotic drugs on homotopic connectivity in schizophrenia that contribute to the disconnection hypothesis of this disease.

Reduced ventral anterior cingulate and amygdala volumes in medication-naïve females with major depressive disorder: A voxel-based morphometric magnetic resonance imaging study.

High resolution magnetic resonance imaging and voxel-based morphometry were used to compare regional gray matter volumes between 14 medication-naïve female participants with a first episode of major depressive disorder (MDD) and 13 female healthy comparison participants (HC). Volumes of bilateral ventral anterior cingulate cortex (vACC) and right amygdala were significantly smaller in the MDD group than in the HC group. These results suggest that volume reductions in vACC and amygdala in females with MDD are present at illness onset.

Family-based case-control study of homotopic connectivity in first-episode, drug-naive schizophrenia at rest.

Family-based case-control design is rarely used but powerful to reduce the confounding effects of environmental factors on schizophrenia. Twenty-eight first-episode, drug-naive patients with schizophrenia, 28 family-based controls (FBC), and 40 healthy controls (HC) underwent resting-state functional MRI. Voxel-mirrored homotopic connectivity (VMHC), receiver operating characteristic curve (ROC), and support vector machine (SVM) were used to process the data. Compared with the FBC, the patients showed lower VMHC in the precuneus, fusiform gyrus/cerebellum lobule VI, and lingual gyrus/cerebellum lobule VI. The patients exhibited lower VMHC in the precuneus relative to the HC. ROC analysis exhibited that the VMHC values in these brain regions might not be ideal biomarkers to distinguish the patients from the FBC/HC. However, SVM analysis indicated that a combination of VMHC values in the precuneus and lingual gyrus/cerebellum lobule VI might be used as a potential biomarker to distinguish the patients from the FBC with a sensitivity of 96.43%, a specificity of 89.29%, and an accuracy of 92.86%. Results suggested that patients with schizophrenia have decreased homotopic connectivity in the motor and low level sensory processing regions. Neuroimaging studies can adopt family-based case-control design as a viable option to reduce the confounding effects of environmental factors on schizophrenia.

Anatomical distance affects cortical-subcortical connectivity in first-episode, drug-naive somatization disorder.

BACKGROUND: Brain structural and functional alterations in the cortical-subcortical circuits have been observed in somatization disorder (SD). However, whether and how anatomical distance affects the cortical-subcortical connectivity in SD remain unclear. This study aims to examine whether anatomical distance affects the cortical-subcortical in first-episode, drug-naive SD. METHODS: Twenty-five first-episode, drug-naive patients with SD and twenty-eight healthy controls were recruited for a resting-state scan. Regional functional connectivity strength (FCS) was calculated for each voxel in the brain, which was further divided into short- and long-range FCSs. Correlation analyses were conducted between abnormal FCS and clinical/cognitive variables in the patients. RESULTS: Compared with the controls, the patients showed increased short-range positive FCS (spFCS) in the right superior frontal gyrus (SFG) and decreased spFCS in the left pallidum, and increased long-range positive FCS (lpFCS) in the left middle frontal gyrus and right inferior temporal gyrus (ITG). Positive correlations were observed between the spFCS values in the right SFG and Eysenck Personality Questionnaire psychoticism scores (r=0.441, p=0.027, uncorrected) and between the lpFCS values in the right ITG and scores of digit symbol-coding of Wechsler Adult Intelligence Scale (r=0.416, p=0.039, uncorrected) in the patients CONCLUSIONS: The patients exhibited increased spFCS/lpFCS in the cortical regions and decreased spFCS in the subcortical regions. The left pallidum is first reported here to show decreased spFCS in SD. The present results suggest that abnormal cortical-subcortical circuits may play an important role in SD neurobiology.