Minocycline and antipsychotics inhibit inflammatory responses in BV-2 microglia activated by LPS via regulating the MAPKs/ JAK-STAT signaling pathway.

BACKGROUND: Abnormal activation of microglia is involved in the pathogenesis of schizophrenia. Minocycline and antipsychotics have been reported to be effective in inhibiting the activation of microglia and thus alleviating the negative symptoms of patients with schizophrenia. However, the specific molecular mechanism by which minocycline and antipsychotics inhibit microglial activation is not clear. In this study, we aimed to explore the molecular mechanism of treatment effect of minocycline and antipsychotics on schizophrenia. METHODS: Microglia cells were activated by lipopolysaccharide (LPS) and further treated with minocycline, haloperidol, and risperidone. Then cell morphology, specific marker, cytokines, and nitric oxide production process, and the proteins in related molecular signaling pathways in LPS-activated microglia were compared among groups. RESULTS: The study found that minocycline, risperidone, and haloperidol significantly inhibited morphological changes and reduced the expression of OX-42 protein induced by LPS. Minocycline significantly decreased the production of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1ß). Risperidone also showed significant decrease in the production of IL-6 and TNF-α, while haloperidol only showed significant decrease in the production of IL-6. Minocycline, risperidone, and haloperidol were found to significantly inhibit nitric oxide (NO) expression, but had no effect on inducible nitric oxide synthase (iNOS) expression. Both minocycline and risperidone were effective in decreasing the activity of c­Jun N­terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in the mitogen-activated protein kinases (MAPKs) signal pathway. Additionally, minocycline and risperidone were found to increase the activity of phosphorylated-p38. In contrast, haloperidol only suppressed the activity of ERK. Minocycline also suppressed the activation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), while risperidone and haloperidol only suppressed the activation of STAT3. CONCLUSIONS: The results demonstrated that minocycline and risperidone exert stronger anti-inflammatory and neuroprotective effects stronger than haloperidol, through MAPKs and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways in BV2 cells stimulated with LPS, revealing the underlying mechanisms of minocycline and atypical antipsychotics in the treatment of negative schizophrenia symptoms.

Hippocampal Subfield Volumes Predict Disengagement from Maintenance Treatment in First Episode Schizophrenia.

OBJECTIVES: Disengagement from treatment is common in first episode schizophrenia (FES) and is associated with poor outcomes. Our aim was to determine whether hippocampal subfield volumes predict disengagement during maintenance treatment of FES. METHODS: FES patients were recruited from sites in Boston, New York, Shanghai, and Changsha. After stabilization on antipsychotic medication, participants were randomized to add-on citalopram or placebo and followed for 12 months. Demographic, clinical and cognitive factors at baseline were compared between completers and disengagers in addition to volumes of hippocampal subfields. RESULTS: Baseline data were available for 95 randomized participants. Disengagers (n = 38, 40%) differed from completers (n = 57, 60%) by race (more likely Black; less likely Asian) and in more alcohol use, parkinsonism, negative symptoms and more impairment in visual learning and working memory. Bilateral dentate gyrus (DG), CA1, CA2/3 and whole hippocampal volumes were significantly smaller in disengagers compared to completers. When all the eight volumes were entered into the model simultaneously, only left DG volume significantly predicted disengagement status and remained significant after adjusting for age, sex, race, intracranial volume, antipsychotic dose, duration of untreated psychosis, citalopram status, alcohol status, and smoking status (P < .01). Left DG volume predicted disengagement with 57% sensitivity and 83% specificity. CONCLUSIONS: Smaller left DG was significantly associated with disengagement status over 12 months of maintenance treatment in patients with FES participating in a randomized clinical trial. If replicated, these findings may provide a biomarker to identify patients at risk for disengagement and a potential target for interventions.

Relationship between RELN signaling pathway genes and language development of autism based on a cluster model. / RELNä¿¡å·é€šè·¯åŸºå› ä¸ŽåŸºäºŽèšç±»åˆ†æžæ¨¡åž‹çš„å­¤ç‹¬ç—‡è¯­è¨€å‘è‚²çš„å ³ç³».

OBJECTIVES: Autism is a neurodevelopment disorder with unclear etiology. High heterogeneity is one of the main issues in the etiological studies. This study explores the relationship between RELN signaling pathway related genes (RELN, VLDLR, LRP8, DAB1, CDK5, FYN) and language development of autism patients based on a cluster analysis model which is established to reduce the heterogeneity. METHODS: Autism children were recruited from 5 different medical/autism training institutes from Hunan, Shandong, and Henan provinces, and were divided into 2 parts according to the recruitment time: The first part was the training sample, which was recruited from October 2006 to May 2011, and the second part was the validation sample, which was recruited from July 2011 to May 2012. A two-step cluster analysis was performed to cluster 374 Chinese Han autism patients into different subgroups based on 2 parameters: Onset age of the first word and interval from the first word to the first phase. A Bayes discriminatory equation was established followed the cluster results. Then we used this equation to divide another 310 autism children into prior defined subgroups. After the genotyping data was screened, a single marker case-control association study was conducted. RESULTS: The cluster analysis clustered 374 samples into 3 subgroups. Onset ages of the first word in the Group A were (11.83±4.37) months and intervals from the first word to the first phase were (24.55±8.67) months; onset ages of the first word in the Group B were (12.17±3.46) months, intervals from the first word to the first phase were (7.07±3.79) months; onset ages of the first word of Group C were (30.94±7.60) months, intervals from the first word to the first phase were (4.73±4.80) months. The established equations based on the cluster analysis were YA=-14.442+0.525X1+0.810X2, YB=-4.964+0.477X1+0.264X2, YC=-19.843+1.175X1+0.241X2. Cross validated analysis showed that the false rate of the equation was 3.8%. A total of 341 single nucleotide polymorphism (SNP) in 6 genes passed the quality control. Before divided subgroups, none of these SNPs reached the significant P value (P>2.44×10-5, Bonferroni adjustment). However the result showed that rs1288502 of LRP8 in Group B was significantly different from the control group (P=6.45×10-6). CONCLUSIONS: Based on the cluster analysis of language development, we could establish a discriminatory equation to reduce heterogeneity of autism sample. The association test indicates that LRP8 genein RELN signaling pathway is related to a particular type of language development of autism patients.

Association of Aripiprazole With Reduced Hippocampal Atrophy During Maintenance Treatment of First-Episode Schizophrenia.

PURPOSE/BACKGROUND: Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation. METHODS/PROCEDURES: Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2). FINDINGS/RESULTS: Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES. IMPLICATIONS/CONCLUSIONS: These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established.

Clinical characteristics of familial schizophrenia.

INTRODUCTION: A family history of psychiatric disorders is one of the strongest risk factors for schizophrenia. The characteristics of patients with a family history of psychiatric disorders have not been systematically evaluated. METHODS: This multicenter study (26 centers, 2425 cases) was performed in a Chinese population to examine the sociodemographic and clinical characteristics of schizophrenia patients with a family history of psychotic disorders in comparison with those of patients with sporadic schizophrenia. RESULTS: Nineteen percent of patients had a family history of mental disease. Multiple logistic regression analysis revealed that ≥4 hospitalizations (OR = 1.78, P = .004), tobacco dependence (OR = 1.48, P = .006), alcohol dependence (OR = 1.74, P = .013), and physical illness (OR = 1.89, P = .001) were independently and significantly associated with a family history of mental disease. CONCLUSION: Patients with a family history of mental disorders present different demographics and clinical features than patients without a family history of psychiatric disorders.

Prognostic and diagnostic significance of Cavin 2 in lung adenocarcinoma.

INTRODUCTION: Cavin 2 down-regulation is reported in several malignant tumors and is associated with tumor progression. However, the role of Cavin 2 in lung adenocarcinoma is unknown. This study aimed to investigate the prognostic and diagnostic significance of Cavin 2 in lung adenocarcinoma. MATERIAL AND METHODS: Cavin 2 expression levels were examined in 150 cases of lung adenocarcinoma and matched adjacent normal lung tissues using RNA extraction and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting and immunohistochemistry (IHC) assays. Then, the relationship of Cavin 2 expression with clinicopathological characteristics and patients' survival was further evaluated in lung adenocarcinoma. RESULTS: QPCR and Western blotting analysis indicated that Cavin 2 expression levels were significantly lower in lung adenocarcinoma tissues compared with those in adjacent normal lung tissues (p < 0.0001). The IHC results showed that positive expression of Cavin 2 was mainly located in cytoplasm as brown, but was hard to detect in lung adenocarcinoma tissues. The low-expression rates of Cavin 2 in lung adenocarcinoma and adjacent normal lung tissues were 62.0% and 20.0%, respectively, and the difference was significant (p < 0.0001). Lower expression of Cavin 2 was significantly associated with tumor size, TNM stage and lymph node metastasis (p < 0.05). CONCLUSIONS: Cavin 2 has low expression in lung adenocarcinoma, which might be regarded as a potential prognostic and diagnostic biomarker.

Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.

The genotype-first approach has been successfully applied and has elucidated several subtypes of autism spectrum disorder (ASD). However, it requires very large cohorts because of the extensive genetic heterogeneity. We investigate the alternate possibility of whether phenotype-specific genes can be identified from a small group of patients with specific phenotype(s). To identify novel genes associated with ASD and abnormal head circumference using a phenotype-to-genotype approach, we performed whole-exome sequencing on 67 families with ASD and abnormal head circumference. Clinically relevant pathogenic or likely pathogenic variants account for 23.9% of patients with microcephaly or macrocephaly, and 81.25% of those variants or genes are head-size associated. Significantly, recurrent pathogenic mutations were identified in two macrocephaly genes (PTEN, CHD8) in this small cohort. De novo mutations in several candidate genes (UBN2, BIRC6, SYNE1, and KCNMA1) were detected, as well as one new candidate gene (TNPO3) implicated in ASD and related neurodevelopmental disorders. We identify genotype-phenotype correlations for head-size-associated ASD genes and novel candidate genes for further investigation. Our results also suggest a phenotype-to-genotype strategy would accelerate the elucidation of genotype-phenotype relationships for ASD by using phenotype-restricted cohorts.

The effect of minocycline on amelioration of cognitive deficits and pro-inflammatory cytokines levels in patients with schizophrenia.

BACKGROUND: Cognitive deficits of schizophrenia are predictors of poor function, but antipsychotic medication has limited efficacy for cognitive deficits. These deficits in learning and memory may result from activity of pro-inflammatory cytokines, which microglia produce. The microglia inhibitor minocycline might arrest this cytokine damage to the hippocampus and reverse the cognitive deficits of schizophrenia. METHODS: A double-blind, placebo-controlled study involved 75 patients with schizophrenia who randomly received low dose (100 mg/day) or high dose minocycline (200 mg/day) or placebo added to risperidone. MATRICS Consensus Cognitive Battery (MCCB) was used to assess the cognitive functioning, and serum levels of Interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) were assessed. RESULTS: Minocyclinehigh dose group was significantly superior to minocyclinelow dose or placebo group not only for the improvements in cognitive tests' scores as well (P < 0.05), but for IL-1ß and IL-6 serum levels reduction (P < 0.01). The amelioration of cognitive deficits with minocycline correlated not only with the remission of negative symptoms, but also with the reduction in serum levels of IL-1ß and IL-6. CONCLUSIONS: Minocycline adjunctive treatment was effective in improving cognitive deficits of patients with schizophrenia. The beneficial effect of minocycline may be related to reducing pro-inflammatory cytokines through microglia inhibition.

Altered Serum Tumor Necrosis Factor and Interleukin-1ß in First-Episode Drug-Naive and Chronic Schizophrenia.

Objective: Abnormality of the immune system might play a significant role in the pathogenesis of schizophrenia. We want to identity whether the serum TNF-α and IL-1ß levels were changed in FEDN patients and CP and to investigate the relationship between both cytokines and psychopathological symptoms. Methods: We recruited 69 FEDN patients, 87 CP and 61 healthy controls. Schizophrenia symptomatology was evaluated with the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS) and Clinical Global Impression Scale (CGI). Serum TNF-α and IL-1ß levels were examined using sandwich enzyme-linked immunosorbent assay (ELISA). Results: TNF-α and IL-1ß levels in CP were significantly higher compared to healthy controls, but TNF-α and IL-1ß levels in FEDN patients were significantly lower than in both CP and healthy controls. A moderate correlation between serum TNF-α or IL-1ß levels and PANSS negative subscore was found in CP. But there was no correlation between altered cytokines and clinical symptoms in FEDN patients. Conclusions: Increased TNF-α and IL-1ß levels in chronic patients may be associated with the progression, psychotropic drugs or other factors occur during chronic stage. Immune modulating treatments may become a new strategy of therapy for this subgroup of patients.

Minocycline adjunctive treatment to risperidone for negative symptoms in schizophrenia: Association with pro-inflammatory cytokine levels.

BACKGROUND: We attempted to replicate the efficacy of minocycline, a second-generation tetracycline, as adjunctive therapy for the negative symptoms of schizophrenia, and to investigate its association with pro-inflammatory cytokine levels. METHODS: Seventy-five schizophrenia patients with negative symptoms entered a 3-month, double blind, randomized, placebo-controlled clinical trial. Subjects were assigned low dose (100 mg per day) or high dose minocycline (200 mg per day) or placebo combined with risperidone. The outcomes used the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS)-negative subscale. We assessed three pro-inflammatory cytokines in serum: interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). RESULTS: Subjects receiving high dose minocycline not only had greater improvements on the SANS total scores and PANSS negative subscale scores (P < 0.01), but also had greater reductions in IL-1ß and IL-6 serum levels (P < 0.01) when compared with those receiving low dose minocycline or placebo. The improvement in negative symptoms with minocycline was significantly correlated with the reduction of IL-1ß and IL-6 serum levels (P < 0.05). CONCLUSIONS: Schizophrenia patients showed a significant improvement in negative symptoms with the addition of minocycline to risperidone. Reducing pro-inflammatory cytokines may play an important role in the potential mechanism for efficacy.

Changes in plasma levels of nitric oxide metabolites and negative symptoms after 16-week minocycline treatment in patients with schizophrenia.

OBJECTIVE: This study examined the effect of adjunctive minocycline on psychopathology and possibly relevant biomarkers in patients with schizophrenia. METHOD: In a 16-week randomized, double-blind, placebo-controlled study, subjects received either minocycline (200mg per day) or placebo. Psychopathology was assessed using the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS) at baseline and week 16. Plasma levels of tumor necrosis factor α (TNFα), interleukin-1 ß (IL-1ß) and nitric oxide metabolites were assessed at both time points. RESULTS: Fifty-five patients completed the study (27 in the minocycline group, 28 in the placebo group). The minocycline group had significant decreases in the SANS total sore, the PANSS total score and the PANSS negative symptoms score at week 16 compared to the placebo group. In addition, the minocycline group had a significant decrease in plasma levels of nitric oxide metabolites, but no significant difference in changes in plasma levels of IL-1ß or TNF-α, compared to the placebo group at week 16. Further, the more decrease in plasma levels of nitric oxide metabolites was associated with less improvement in negative symptoms. CONCLUSION: The beneficial effect of adjunctive minocycline treatment on negative symptoms might be through mechanisms other than the nitric oxide pathway. The implications for future studies were discussed.

Forkhead box C1 is targeted by microRNA-133b and promotes cell proliferation and migration in osteosarcoma.

Forkhead box C1 (FOXC1) has been demonstrated to act as an oncogene in a number of malignant tumors, though its underlying mechanism of action in osteosarcoma (OS) remains unknown. The present study evaluated the expression and regulatory role of FOXC1 in OS. Reverse transcription-quantitative polymerase chain reaction and western blot data indicated that FOXC1 was significantly upregulated in OS tissues and cell lines when compared with adjacent non-tumor tissues (P<0.001) and normal human osteoblast cells (P<0.01), respectively. Moreover, levels of FOXC1 expression were significantly higher in OS at advanced clinical stage (III-IV) when compared with that at low clinical stage (I-II; P<0.001). Knockdown of FOXC1 expression caused a significant decrease in the proliferation and migration of OS U2OS cells (P<0.01), while overexpression of FOXC1 significantly promoted U2OS cell proliferation and migration (P<0.01), relative to control U2OS cells. Furthermore, FOXC1 was identified as a direct target of microRNA (miR)-133b, a reported tumor-suppressive miR in OS. The protein expression of FOXC1 was negatively regulated by miR-133b in U2OS cells (P<0.01), and miR-133b expression was inversely correlated with FOXC1 expression in OS. In conclusion, the present study demonstrated that FOXC1, targeted by miR-133b, may promote cell proliferation and migration in OS. Thus, FOXC1 may be a potential therapeutic target in the treatment of OS.

Insertion of a knockout-first cassette in Ampd1 gene leads to neonatal death by disruption of neighboring genes expression.

AMPD1 is an adenosine monophosphate deaminase that catalyzes the deamination of AMP to IMP. To understand the physiological function of AMPD1, we obtained a strain of Ampd1 mutant mice from KOMP repository, which was generated by a knockout-first strategy. An elevated AMP level and almost complete lack of IMP was detected in the skeletal muscle of E18.5 Ampd1tm1a/tm1a mice. However, Ampd1tm1a/tm1a mice died in 2 days postnatally, which was contradicting to previous reports. After removal of the knockout-first cassette and critical exon, mice homozygous for the Ampd1tm1c/tm1c and Ampd1tm1d/tm1d alleles survived to adulthood. RNA-seq analysis indicated that the expression of two neighboring genes, Man1a2 and Nras, were disrupted in the Ampd1tm1a/tm1a mice, but normal in the Ampd1tm1c/tm1c and Ampd1tm1d/tm1d mice. The neonatal lethality phenotype in the Ampd1tm1a/tm1a mice was consistent with the Man1a2-deficient mice. Our results indicated the knockout-first cassette may cause off-target effect by influence the expression of neighboring genes. This study, together with other reports, strongly suggests that removal of targeting cassette by site-specific recombinases is very important for the accurate phenotypic interpretation on mice generated by target mutations.

[Progress in study on the role of exosome-derived microRNA in diagnosis and treatment of diseases].

Exosome is a kind of biological membrane structure at nanometer level. It is secreted by various cells in the body and widely distributed in most body fluids, such as saliva, blood, and milk. Biological active substances, including mRNAs, microRNAs, cytokines, and transcription factor, have been identified in the exosomes. MiRNAs are short and non-coding RNAs that modulate gene expression at the posttranscriptional level. MiRNAs extensively involves in henogenesis, cell proliferation and apoptosis. With various biological functions, exosome-derived miRNAs can not only be served as biomarkers to diagnose tumor, neurological diseases and mental disorders, but also possess potential as therapeutic targets.

Shuganjieyu capsule increases neurotrophic factor expression in a rat model of depression.

Shuganjieyu capsule has been approved for clinical treatment by the State Food and Drug Ad-ministration of China since 2008. In the clinic, Shuganjieyu capsule is often used to treat mild to moderate depression. In the rat model of depression established in this study, Shuganjieyu capsule was administered intragastrically daily before stress. Behavioral results confirmed that depressive symptoms lessened after treatment with high-dose (150 mg/kg) Shuganjieyu capsule. Immunohistochemistry results showed that high-dose Shuganjieyu capsule significantly increased phosphorylation levels of phosphorylation cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor expression in the medial prefrontal cortex and hippocampal CA3 area. Overall, our results suggest that in rats, Shuganjieyu capsule effec-tively reverses depressive-like behaviors by increasing expression levels of neurotrophic factors in the brain.

Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia.

OBJECTIVE: The present study aimed to examine the changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia. METHODS: Sixty-two drug naïve, first-episode schizophrenia (SZ group) and 60 healthy individuals (control group) were enrolled in the study. Serum interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) levels, and body weight were measured at baseline for both groups, and repeated for the SZ group at five different time points during 6-month risperidone treatment. RESULTS: At baseline, serum IL-1ß, IL-6, and TNF-α levels in the SZ group (53.28 ± 12.62, 33.98 ± 14.13, 50.08 ± 12.86 pg/mL, respectively) were significantly higher than those in the control group (23.49 ± 15.27, 15.53 ± 7.16, 32.12 ± 15.23 pg/mL, respectively) (p's < 0.001). Within the SZ group, serum IL-1ß levels decreased significantly at 2 weeks (48.02 ± 16.00 pg/mL, p < 0.01) and 1 month (44.70 ± 16.63 pg/mL, p < 0.001), but then gradually increased at 2 months (48.49 ± 18.87 pg/mL), 3 months (50.59 ± 18.48 pg/mL) and 6 months (53.64 ± 16.22 pg/mL) to the levels comparable to baseline; serum IL-6 levels changed significantly over the course of treatment (p = 0.001), but reached the levels comparable to baseline at 6 months (37.13 ± 13.23 pg/mL); serum levels of TNF-α increased significantly at 3 months (55.02 ± 16.69 pg/mL, p < 0.01) and 6 months (58.69 ± 13.57 pg/mL, p < 0.001); steady and significant weight gain was observed at each follow-up time point (p's < 0.001), from 56.71 ± 9.25 kg at baseline to 62.72 ± 9.53 kg at 6 months. CONCLUSIONS: Risperidone treatment is associated with changes in serum pro-inflammatory cytokines levels and weight. There is an initial anti-inflammatory effect that reduces with treatment, potentially due to its weight gain side effect.

Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study.

OBJECTIVE: Data on the treatment of antipsychotic-induced amenorrhea, particularly when occurring with weight gain, are limited. The authors investigated the efficacy and safety of metformin in the treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia. METHOD: Eighty-four women (ages 18-40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned, in a double-blind study design, to receive 1000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. The primary outcome measures were restoration of menstruation and change in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in insulin resistance index. Repeated mixed models with repeated-measures regression analyses and binary logistic regression were used in the analysis. RESULTS: A total of 76 patients completed the 6-month trial. Significantly more patients in the metformin group (N=28, 66.7%) than in placebo group (N=2, 4.8%) resumed their menstruation. Among patients treated with metformin, BMI decreased by a mean of 0.93 and the insulin resistance index by 2.04. In contrast, patients who received placebo had a mean increase in BMI of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the metformin group at months 2, 4, and 6, but these levels did not change in the placebo group. CONCLUSIONS: Metformin was effective in reversing antipsychotic-induced adverse events, including restoration of menstruation, promotion of weight loss, and improvement in insulin resistance in female patients with schizophrenia.

The nuclear factor-κB inhibitor pyrrolidine dithiocarbamate reduces polyinosinic-polycytidilic acid-induced immune response in pregnant rats and the behavioral defects of their adult offspring.

BACKGROUND: Epidemiological studies have indicated that maternal infection during pregnancy may lead to a higher incidence of schizophrenia in the offspring. It is assumed that the maternal infection increases the immune response, leading to neurodevelopmental disorders in the offspring. Maternal polyinosinic-polycytidilic acid (PolyI:C) treatment induces a wide range of characteristics in the offspring mimicking some schizophrenia symptoms in humans. These observations are consistent with the neurodevelopmental hypothesis of schizophrenia. METHODS: We examined whether suppression of the maternal immune response could prevent neurodevelopmental disorders in adult offspring. PolyI:C or saline was administered to early pregnant rats to mimic maternal infection, and the maternal immune response represented by tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) levels was determined by enzyme-linked immunosorbent assays (ELISA). The NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) was used to suppress the maternal immune response. Neurodevelopmental disorders in adult offspring were examined by prepulse inhibition (PPI), passive avoidance, and active avoidance tests. RESULTS: PolyI:C administration to early pregnant rats led to elevated serum cytokine levels as shown by massive increases in serum TNF-α and IL-10 levels. The adult offspring showed defects in prepulse inhibition, and passive avoidance and active avoidance tests. PDTC intervention in early pregnant rats suppressed cytokine increases and reduced the severity of neurodevelopmental defects in adult offspring. CONCLUSIONS: Our findings suggest that PDTC can suppress the maternal immune response induced by PolyI:C and partially prevent neurodevelopmental disorders of adult offspring.

Sex differences in patients with schizophrenia: A prospective, multi-center study.

This study aimed to determine sex differences in socio-demographic and clinical characteristics of Chinese schizophrenia patients. In a multi-center, randomized, controlled, longitudinal study, 404 clinically stable patients with schizophrenia were randomly assigned to a maintenance group (optimal therapeutic doses continued throughout the study), a 26-week group (optimal therapeutic doses continued for 26 weeks, followed by a 50% dose reduction maintained until the end of the study), or a 4-week group (optimal therapeutic doses continued for 4 weeks, followed by a 50% dose reduction maintained until the end of the study). Participants were interviewed regularly using standardized assessment instruments, and followed up for 12-26 months. In the univariate analyses, the following factors were significantly associated with the male sex: not married, smoking, younger age, earlier age at onset, higher body mass index (BMI) at baseline, and more severe negative and hostility-excitement symptoms at baseline. The following factors were independently associated with the male sex in the multivariate analyses: not being married, smoking, a higher BMI at baseline, less deterioration in disorganized thoughts (4-week group) and positive symptoms (26-week group) and less increase in BMI in all three treatment groups over the study period. The majority of the sex differences in schizophrenia patients in this study are in accordance with results of previous studies worldwide suggesting that sex differences seen in schizophrenia are not dependent on cultural differences between geographically separate patients.