Elevated peripheral blood glutamate levels in major depressive disorder Masatoshi Inoshita,1 Hidehiro Umehara,1 Shin-ya Watanabe,1 Masahito Nakataki,1 Makoto Kinoshita,1 Yukiko Tomioka,1 Atsushi Tajima,2 Shusuke Numata,1 Tetsuro Ohmori1 1Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan; 2Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Ishikawa, Japan Purpose: There is growing evidence that glutamatergic signaling may be involved in major depressive disorder (MDD). In regard to peripheral blood glutamate changes in MDD, inconsistent findings have been reported. The purpose of the present study was to evaluate whether blood glutamate levels differed between MDD patients and control participants. Materials and methods: We conducted a systematic review and meta-analysis of 12 association studies between blood glutamate levels and MDD in a total of 529 MDD patients and 590 controls. Subsequently, we conducted subgroup analyses and a meta-regression analysis to examine the sources of potential heterogeneity. Results: A random effects model showed that blood glutamate levels were significantly higher in MDD patients than in controls (standardized mean difference=0.54, 95% CI=0.27–0.82, p=8.5×10-5) with high heterogeneity (I2=75.0%, p<0.05). Subgroup analyses showed elevated glutamate levels in MDD patients compared with controls in plasma, but not serum studies, and in studies using high-performance liquid chromatography but not with mass spectrometry for glutamate assay. A meta-regression analysis showed no effects of age, gender, medication use, sample size, and published year on blood glutamate levels. Conclusion: Our findings suggest that altered glutamate levels may be implicated in MDD, which provides further evidence of glutamatergic dysfunction in MDD. Keywords: glutamate, major depressive disorder, blood, association study, meta-analysis

Purpose: The purpose of the present study was to examine clinical factors related to social function in people with schizophrenia. Patients and methods: The participants were 55 stabilized outpatients with schizophrenia. Their mean age was 39.36 (SD =10.65) years. Social function was assessed using the Quality of Life Scale (QLS). Cognitive function was evaluated with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia, and the Drug-Induced Extrapyramidal Symptoms Scale. Results: Neither the MCCB cognitive domain score nor composite score was correlated with the QLS scores. However, of the 10 MCCB subtests, the Trail Making Test Part A and the Brief Assessment of Cognition in Schizophrenia-Symbol Coding (BACS-SC) scores were positively correlated with the QLS scores. Among clinical variables, especially the PANSS negative syndrome scale score had a strong negative correlation with the QLS scores. Stepwise regression analyses showed that the PANSS negative syndrome scale score was an independent predictor of the QLS scores, and although the BACS-SC score predicted the QLS common objects and activities subscale score, the association was not so strong compared to the PANSS negative syndrome scale score. Conclusion: These results indicate that speed of processing evaluated by BACS-SC could predict some aspect of social function but negative symptoms have a much stronger impact on global social function in people with schizophrenia.

Purpose: Recently, cognitive variables such as negative and positive self-belief and thoughts have attracted much attention because they are associated with functional outcomes and quality of life (QOL). However, it is unclear how cognitive variables affect subjective and objective QOL. This study aimed to investigate the relationship of negative and positive self-belief and thoughts with subjective and objective QOL. Participants and methods: Thirty-six people with schizophrenia participated in this study. Subjective and objective QOL were assessed with the Schizophrenia Quality of Life Scale (SQLS) and Quality of Life Scale (QLS), respectively. Neurocognitive function was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Clinical symptoms were assessed with the Positive and Negative Syndrome Scale and Calgary Depression Scale for Schizophrenia. Side effects were assessed with the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS). Negative and positive self-belief and thoughts were assessed with the Defeatist Performance Belief Scale and Automatic Thoughts Questionnaire-Revised. A generalized linear model was tested, with subjective and objective QOL as the response variable and symptoms, neurocognitive function, and cognitive variables that were significantly correlated with subjective and objective QOL as explanatory variables. Results: In the schizophrenia group, the common objects score on the QLS was predicted by the composite BACS score, and the total QLS score was predicted by the DIEPSS score. Motivation and Energy, Psychosocial, and Symptoms and Side effects scores on the SQLS were predicted by depression and by negative automatic thought (NAT) and positive automatic thought (PAT). Conclusion: Our results indicated that key targets for improving objective and subjective QOL in people with schizophrenia are side effects, neurocognitive function, depression, and NAT and PAT.

It has been reported that drugs which promote the N-Methyl-D-aspartate-type glutamate receptor function by stimulating the glycine modulatory site in the receptor improve negative symptoms and cognitive dysfunction in schizophrenia patients being treated with antipsychotic drugs. We performed a placebo-controlled double-blind crossover study involving 41 schizophrenia patients in which D-cycloserine 50 mg/day was added-on, and the influence of the onset age and association with white matter integrity on MR diffusion tensor imaging were investigated for the first time. The patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Brief Assessment of Cognition in Schizophrenia (BACS), and other scales. D-cycloserine did not improve positive or negative symptoms or cognitive dysfunction in schizophrenia. The investigation in consideration of the onset age suggests that D-cycloserine may aggravate negative symptoms of early-onset schizophrenia. The better treatment effect of D-cycloserine on BACS was observed when the white matter integrity of the sagittal stratum/ cingulum/fornix stria terminalis/genu of corpus callosum/external capsule was higher, and the better treatment effect on PANSS general psychopathology (PANSS-G) was observed when the white matter integrity of the splenium of corpus callosum was higher. In contrast, the better treatment effect of D-cycloserine on PANSS-G and SANS-IV were observed when the white matter integrity of the posterior thalamic radiation (left) was lower. It was suggested that response to D-cycloserine is influenced by the onset age and white matter integrity. UMIN Clinical Trials Registry (number UMIN000000468 ). Registered 18 August 2006

Aims: The purpose of the present study was to investigate the correlation between cognitive function and clinical variables in people with schizophrenia.Methods: The subjects were 61 stabilized outpatients with schizophrenia (DSM‐IV). Their mean age was 40.1 (SD = 12.2) years. All subjects gave written informed consent to participate in the research. Cognitive function was evaluated using the Brief Assessment of Cognition in Schizophrenia. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, and the Drug‐Induced Extrapyramidal Symptoms Scale.Results: The Positive and Negative Syndrome Scale Negative syndrome score was significantly correlated with verbal memory score (r = −0.37, P < 0.01), working memory score (r = 0.38, P < 0.01), attention and speed of information processing score (r = −0.51, P < 0.01), verbal fluency score (r = −0.39, P < 0.01), and composite score (r = −0.54, P < 0.01). In addition, the Drug‐Induced Extrapyramidal Symptoms Scale score was significantly correlated with attention and speed of information processing (r = −0.45, P < 0.01), and composite score (r = −0.41, P < 0. 01). Dose of antipsychotics and anti‐Parkinson drugs was not significantly correlated with the Brief Assessment of Cognition in Schizophrenia scores.Conclusions: These results indicate that cognitive dysfunction of people with schizophrenia might be associated with negative and drug‐induced extrapyramidal symptoms, suggesting that their minimization would be important for improving cognitive dysfunction.