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Background Lysophosphatidic acid (LPA) is involved in numerous biological processes, including neurodevelopment, chronic inflammation, and immunologic response in the central nervous system. Autotaxin (ATX) is a secreted enzyme that produces LPA from lysophosphatidylcholine (LPC). Previous studies have demonstrated decreased protein levels of ATX in cerebrospinal fluid (CSF) of patients with major depressive disorder (MDD). Based on those studies, the current study investigated the levels of lysophospholipids species including LPA and related metabolic enzymes, in CSF of patients with MDD and schizophrenia (SCZ). Methods The levels of lysophospholipids species and related metabolic enzymes were measured with either liquid chromatography-tandem mass spectrometry or enzyme-linked immunosorbent assay. Japanese patients were diagnosed with DSM-IV-TR. CSF was obtained from age- and sex-matched healthy controls (n = 27) and patients with MDD (n = 26) and SCZ (n = 27). Results Of all lysophospholipids species, the levels of LPA 22:6 (LPA - docosahexaenoic acid) were significantly lower in patients with MDD and SCZ than in healthy controls. These levels were negatively correlated with several clinical symptomatic scores of MDD, but not those of SCZ. In addition, the levels of LPA 22:6 were significantly correlated with the levels of LPC 22:6 among all 3 groups. On the other hand, the levels of LPA 22:6 were not correlated with ATX activity in patients with MDD and SCZ. Conclusion The lower levels of LPA 22:6 in patients with MDD and SCZ suggest an abnormality of LPA 22:6 metabolism. In addition, several depressive symptoms in patients with MDD were significantly associated with the lower levels of LPA 22:6, suggesting an involvement of LPA 22:6 in the pathophysiology of MDD.

Aim The ε4 allele of apolipoprotein E gene (APOE) is a well‐known risk factor of late‐onset Alzheimer's disease. However, little is known why this variant confers a risk for Alzheimer's disease. The aim of this study was to examine the influence of the APOE genotype on cerebrospinal fluid (CSF) protein levels. Methods The present study performed a secondary analysis on our previously generated database to compare the CSF levels of 1128 proteins between APOE‐ε4 carriers (28 subjects) and noncarriers (104 subjects). All subjects were physically healthy Japanese individuals without dementia. Results CSF levels of apoE2, apoE3, and apoE4 were significantly higher (all nominal P, The CSF levels of apoE2, apoE3, and apoE4 were higher in APOE‐ε4 carriers. The CSF levels of TNF‐α were significantly lower in APOE‐ε4 carriers. Our findings indicate the possible roles of apoE and TNF‐α in the pathogenesis of APOE‐ε4‐associated Alzheimer's disease.

Bipolar disorder (BD) is a mental disorder characterized by extreme changes in mood polarity. It is also characterized by cognitive and metabolic dysfunctions. Fibroblast growth factor 21 (FGF21) is an endocrine protein that has a multifaceted function such as glucose and lipid regulation in the periphery, and neuroprotection and induction of synaptic plasticity in the central nervous system. Previous studies reported inconsistent results concerning peripheral FGF21 levels in patients with BD. In this study, we compared plasma FGF21 levels between 26 patients with BD and 51 healthy controls using a human FGF21 ELISA Kit. There was no significant difference in plasma FGF21 levels between the patients and controls. We found significant positive correlations between plasma FGF21 levels and some cognitive parameters (word association and motor speed). If our results are replicated that higher peripheral FGF21 may be associated with better cognitive performance in patients with BD., We compared plasma FGF21 levels between 26 bipolar disorder patients and 51 healthy controls. Although FGF21 concentrations were not different between the patients and controls, we found significant positive correlations between the levels and some cognitive parameters.

We aimed to examine the possible association of obesity (body mass index [BMI] ≥ 30) with symptoms, psychotropic medication, and whole-brain structure in patients with schizophrenia.Participants were 65 patients diagnosed with schizophrenia (mean age: 37.2 ± 11.3 years, 32 females). All participants were Japanese and right-handed. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and Pittsburgh Sleep Quality Index (PSQI). Voxel based morphometry (VBM) and diffusion tensor imaging (DTI) were performed to analyze the association of obesity with gray and white matter structures, respectively.There was no significant difference in PANSS scores between obese and non-obese patients, while the PSQI score was significantly higher in the former than in the latter (p 0.05). The daily dose of typical antipsychotics was significantly higher in obese patients than in non-obese patients (p 0.001). In VBM, there was no significant difference in gray matter volume between obese and non-obese patients. In DTI, fractional anisotropy values in the corpus callosum, corona radiata, corticospinal tract, superior longitudinal fasciculus, and posterior thalamic radiations were significantly lower in obese patients than in non-obese patients (corrected p 0.05). Axial diffusivity was significantly lower while radial and mean diffusivities values were significantly higher in obese patients than in non-obese patients (corrected p 0.05) in similar but more restricted brain regions.Our results suggest that obesity is related to sleep disturbances, daily dose of typical antipsychotics, and regional white matter microstructure impairments in patients with schizophrenia.

Inflammation and altered polyunsaturated fatty acid (PUFA) levels have been implicated in bipolar disorder (BD). A recent genome-wide association study identified a locus in the fatty acid desaturase (FADS) gene cluster conferring susceptibility to BD. In this study, we examined PUFA levels in patients with BD in relation to proinflammatory cytokines, FADS genotype, and dietary habits. We enrolled 83 patients with BD and 217 healthy controls who underwent plasma PUFA measurement. A subsample of 65 patients and 90 controls underwent plasma interleukin (IL)-6 and tumor necrosis factor alpha (TNFα) measurement, and three FADS single nucleotide polymorphisms (SNPs) were genotyped. Information on fish consumption was obtained by a self-reported diet history questionnaire. In comparing PUFA levels between patients and controls, significant differences were found for all 7 PUFAs tested. Specifically, n-3 eicosapentaenoic acid (EPA) level was decreased, and n-6 arachidonic acid level was increased in the patients (p FADS genotype, which was associated with increased n-6 PUFA levels, was also associated with marked elevation in TNFα levels. Less frequent fish intake was associated with low EPA and high IL-6 level. Taken together, our results provide strong evidence for altered plasma PUFA and proinflammatory cytokine levels in patients with BD. Furthermore, FADS genotype and fish consumption may contribute not only to altered PUFA levels but also to inflammation in BD.

Major depressive disorder (MDD) is one of the most common psychiatric diseases. However, early detection and diagnosis of MDD is difficult, largely because there is no known biomarker or objective diagnostic examination, and its diagnosis is instead based on a clinical interview. The aim of this study was to develop a novel diagnostic tool using DNA methylation as a blood biomarker. We sought to determine whether unmedicated patients with MDD showed significant differences in DNA methylation in the promoter region of the SHATI/N-acetyltransferase 8 like (SHATI/NAT8L) gene compared to healthy controls. Sixty participants with MDD were recruited from all over Japan. They were diagnosed and assessed by at least two trained psychiatrists according to DSM-5 criteria. DNA was extracted from peripheral blood. We then assessed DNA methylation of the SHATI/NAT8L promoter regions in patients with MDD by pyrosequencing. Methylation levels of the SHATI/NAT8L promoter region at CpG sites in peripheral blood from unmedicated patients were significantly higher than in healthy controls. In contrast, medicated patients with MDD showed significantly lower methylation levels in the same region compared to healthy controls. Since previous studies of DNA methylation in MDD only assessed medicated patients, the methylation status of the SHATI/NAT8L promoter region in unmedicated patients presented herein may prove useful for the diagnosis of MDD. To our knowledge, this is the first attempt to measure methylation of the SHATI/NAT8L gene in drug-naïve patients with psychiatric diseases. Based on our findings, methylation of SHATI/NAT8L DNA might be a diagnostic biomarker of MDD.

Background The autotaxin/lysophosphatidic acid axis is involved in diverse biological processes including neurodevelopment, inflammation, and immunological functioning. The lysophosphatidic acid 1 receptor has been implicated in the pathophysiology of major depressive disorder and in the mechanism of action of antidepressants. However, it is unclear whether central or peripheral autotaxin levels are altered in patients with major depressive disorder. Methods Serum autotaxin levels were measured by an enzyme-linked immunosorbent assay in 37 patients with major depressive disorder diagnosed using DSM-IV-TR who underwent electroconvulsive therapy and were compared with those of 47 nondepressed controls matched for age and sex between January 2011 and December 2015. Patient serum levels of autotaxin before and after electroconvulsive therapy were also compared. In a separate sample set, cerebrospinal fluid autotaxin levels were compared between 26 patients with major depressive disorder and 27 nondepressed controls between December 2010 and December 2015. A potential association was examined between autotaxin levels and clinical symptoms assessed with the Hamilton Depression Rating Scale. Results Before electroconvulsive therapy, both serum and cerebrospinal fluidautotaxin levels were significantly lower in major depressive disorder patients than in controls (serum: P = .001, cerebrospinal fluid: P = .038). A significantly negative correlation between serum, but not cerebrospinal fluid, autotaxin levels and depressive symptoms was observed (P = .032). After electroconvulsive therapy, a parallel increase in serum autotaxin levels and depressive symptoms improvement was observed (P = .005). Conclusion The current results suggest that serum autotaxin levels are reduced in a state-dependent manner. The reduction of cerebrospinal fluid autotaxin levels suggests a dysfunction in the autotaxin/lysophosphatidic acid axis in the brains of patients with major depressive disorder.

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (P(best) = 4.1 × 10(−10)), SLC38A3 (P(best) = 5.7 × 10(−10)), and CABP1-ACADS (P(best) = 9.8 × 10(−9)). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (P(best) = 4.0 × 10(−11)) and between SCZ and BD in the JPN population (P ~ 10(−40)); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, r(g) = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ “risk” effect is shared with other psychiatric disorders even across populations.

Etiology of depression and its vulnerability remains elusive. Using a latent profile analysis on dimensional personality traits, we previously identified 3 different phenotypes in the general population, namely stress-resilient, -vulnerable, and -resistant groups. Here we performed microarray-based blood gene expression profiling of these 3 groups (n = 20 for each group) in order to identify genes involved in stress vulnerability as it relates to the risk of depression. Identified differentially expressed genes among the groups were most markedly enriched in ribosome-related pathways. These ribosomal genes, which included ribosomal protein L17 (RPL17) and ribosomal protein L34 (RPL34), were upregulated in relation to the stress vulnerability. Protein-protein interaction and correlational co-expression analyses of the differentially expressed genes/non-coding RNAs consistently showed that functional networks involving ribosomes were affected. The significant upregulation of RPL17 and RPL34 was also observed in depressed patients compared to healthy controls, as confirmed in 2 independent case-control datasets by using pooled microarray data and qPCR experiments (total number of subjects was 122 and 166, respectively). Moreover, the upregulation of RPL17 and RPL34 was most marked in DSM-IV major depressive disorder, followed by in bipolar disorder, and then in schizophrenia, suggesting some diagnostic specificity of these markers as well as their general roles in stress vulnerability. These results suggest that ribosomal genes, particularly RPL17 and RPL34, can play integral roles in stress vulnerability and depression across nonclinical and clinical conditions. This study presents an opportunity to understand how multiple psychological traits and underlying molecular mechanisms interact to render individuals vulnerable to depression.

Background Although inflammatory cytokines are established biomarkers of mood disorders, their molecular mechanism is not known. We hypothesized that circulating mitochondrial DNA (mtDNA) contributes to inflammation and could be used as biomarkers. We investigated if circulating mtDNA level is associated with inflammatory cytokines and can be used as a biomarker of mood disorders. Methods Plasma mtDNA concentration was measured with real-time quantitative PCR targeting two regions of the mtDNA and plasma levels of four cytokines (GM-CSF, IL-2, IL-4, and IL-6) were measured with a multiplex immunoassay method in 109 patients with major depressive disorder (MDD). The most significantly correlated cytokine was verified with an enzyme-linked immunosorbent assay (ELISA). The data from 28 patients with bipolar disorder (BD), 17 patients with schizophrenia (SZ), and 29 healthy controls were compared. Results MtDNA levels showed a nominal positive correlation with GM-CSF, IL-2 and IL-4 in patients with MDD. The most significant correlation with IL-4 ( ρ = 0.38, P ρ = 0.19, P = 0.049). Unexpectedly, patients with MDD and BD showed significantly lower plasma mtDNA levels than controls. MtDNA levels were lower in the depressive state than in the euthymic state in patients with MDD. Patients with depression, bipolar disorder, and schizophrenia did not show significantly higher levels of these four cytokines than controls. Limitations There is a possibility that the patients in this study are different from previous studies in which increased cytokine levels were reported. MtDNA levels should be measured in patients showing elevated plasma cytokine levels. A larger sample is required to generalize the results. Conclusions The present findings coincide with our hypothesis that circulating mtDNA contributes to the inflammation in MDD. Further studies are needed to conclude whether plasma mtDNA would be a biomarker of mood disorders.

Obesity has been implicated in the pathophysiology of major depressive disorder (MDD), which prompted us to examine the possible association of obesity with cognitive function and brain structure in patients with MDD.Three hundred and seven patients with MDD and 294 healthy participants, matched for age, sex, ethnicity (Japanese), and handedness (right) were recruited for the study. Cognitive function was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS). Gray and white matter structures were analyzed using voxel-based morphometry and diffusion tensor imaging in a subsample of patients (n = 114) whose magnetic resonance imaging (MRI) data were obtained using a 1.5 T MRI system.Verbal memory, working memory, motor speed, attention, executive function, and BACS composite scores were lower for the MDD patients than for the healthy participants (p0.05). Among the patient group, working memory, motor speed, executive function, and BACS composite scores were lower in obese patients (body mass index ≥ 30, n = 17) than in non-obese patients (n = 290, p0.05, corrected). MRI determined frontal, temporal, thalamic, and hippocampal volumes, and white matter fractional anisotropy values in the internal capsule and left optic radiation were reduced in obese patients (n = 7) compared with non-obese patients (n = 107, p0.05, corrected).Sample size for obese population was not very large.Obesity is associated with decreased cognitive function, reduced gray matter volume, and impaired white matter integrity in cognition-related brain areas in patients with MDD.

Idiopathic normal pressure hydrocephalus (iNPH) is caused by the accumulation of cerebrospinal fluid (CSF) and is characterized by gait disturbance, urinary incontinence, and dementia. iNPH dementia is treatable by shunt operation; however, since the cognitive symptoms of iNPH are often similar to those of other dementias, including Alzheimer's disease (AD), accurate diagnosis of iNPH is difficult. To overcome this problem, the identification of novel diagnostic markers to distinguish iNPH and AD is warranted. Using comparative proteomic analysis of CSF from patients with iNPH and AD, protein tyrosine phosphatase receptor type Q (PTPRQ) was identified as a candidate biomarker protein for discriminating iNPH from AD. ELISA analysis indicated that the PTPRQ concentration in the CSF was significantly higher in patients with iNPH compared with those with AD. In addition, the PTPRQ concentration in the CSF of non-responders to shunt operation (SNRs) tended to be relatively lower compared with that in the responders. PTPRQ may be a useful biomarker for discriminating between patients with iNPH and AD, and may be a potential companion biomarker to identify SNRs among patients with iNPH. Additional large-scale analysis may aid in understanding the novel aspects of iNPH.

Neural cell adhesion molecule (NCAM) plays an important role in neural plasticity, and its altered function has been implicated in psychiatric disorders. However, previous studies have yielded inconsistent results on cerebrospinal fluid (CSF) NCAM levels in psychiatric disorders. The aim of our study was to examine CSF NCAM levels in patients with schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD), and their possible relationship with clinical variables.The participants comprised 85 patients with schizophrenia, 57 patients with BD, 83 patients with MDD and 111 healthy controls, all matched for age, sex, and Japanese ethnicity. The CSF samples were drawn using a lumbar puncture and NCAM levels were quantified by an enzyme-linked immunosorbent assay.Analysis of covariance controlling for age and sex revealed that CSF NCAM levels were lower in all patients (p=0.033), and in those with BD (p=0.039), than in the controls. NCAM levels positively correlated with age in patients with BD (p0.01), MDD (p0.01), and the controls (p0.01). NCAM levels negatively correlated with depressive symptom scores in patients with BD (p=0.040). In patients with schizophrenia, NCAM levels correlated negatively with negative symptom scores (p=0.029), and correlated positively with scores for cognitive functions such as category fluency (p=0.011) and letter fluency (p=0.023) scores.We showed that CSF NCAM levels were lower in psychiatric patients, particularly bipolar patients than in the controls. Furthermore, we found correlations of NCAM levels with clinical symptoms in patients with BD and in those with schizophrenia, suggesting the involvement of central NCAM in the symptom formation of severe psychiatric disorders.

Aim Ethanolamine-containing phospholipids are synthesized in endoplasmic reticulum (ER) and mitochondria. ER stress and mitochondrial dysfunction have been implicated in bipolar disorder (BP). In this study, we aimed to examine the relationship of ethanolamine plasmalogen (PLE) and phosphatidylethanolamine (PTE) levels in blood plasma with BP. Methods Plasma PLE and PTE levels were compared between 34 patients with BP (DSM-IV) and 38 healthy control participants matched for age, sex, and ethnicity (Japanese). Furthermore, the relationships of plasma PLE and PTE levels with clinical variables were explored. Results Plasma PLE levels were significantly lower in patients with BP than in healthy controls (P = 0.0033). In subgroup analyses, plasma PLE levels were significantly lower in patients with BP type I (BP I) than in healthy controls (P = 0.0047); furthermore, plasma PTE levels were significantly lower in patients with BP I than in controls (P = 0.016) and patients with BP type II (BP II) (P = 0.010). Receiver-operating characteristic curve analysis revealed that the discriminatory power of plasma PTE levels for distinguishing between BP I and II was fair (area under the curve = 0.78; P = 0.0095). There were no significant correlations of plasma PLE or PTE levels with depression or manic symptoms in patients. Conclusions Plasma PLE and PTE levels were associated with BP I, but not with BP II. Moreover, plasma PTE levels differed between patients with BP I and II. Our findings highlight the importance of ethanolamine phospholipids in the pathophysiology of BP, especially BP I.

Glucose is the principal energy substrate for the brain, although ketone bodies are an effective alternative. Evidence suggests that elevation of plasma ketone body levels through oral intake of medium chain triglycerides (MCTs) may improve cognitive function.We tried to examine the possible effects of a ketogenic meal serving on cognition in elderly non-demented subjects.Subjects were 19 non-demented elderly adults over 60 years old (13 females; mean age: 66.1 ± 2.9 years) who underwent neurocognitive tests 90 and 180 min after oral intake of a ketogenic meal (Ketonformula®) containing 20 g of MCTs and an isocaloric placebo meal without MCTs on separate days.Elevation of plasma ketone concentration after intake of a single ketogenic meal containing 20 g of MCTs was confirmed (all p 0.001). As for cognition, improvements were observed in the digit span test, Trail-Making Test B, and the global score (Z = -2.4, p = 0.017) following the ketogenic meal and the change in the executive functioning score was positively correlated with that of the plasma β-hydroxybutyrate level. The cognition-enhancing effect was observed predominantly for individuals who had a relatively low global score at baseline (Z = -2.8, p = 0.005), compared to individuals with a high global score (Z = -0.7, p = 0.51).Plasma levels of ketone bodies were successfully increased after intake of the ketogenic meal. The ketogenic meal was suggested to have positive effects on working memory, visual attention, and task switching in non-demented elderly.

The Wechsler Memory Scale (WMS) is a standardised battery for assessing memory functions. We aimed to investigate the relationship between all WMS scores, including subtests, and whole-brain structure in a relatively large sample.Participants were 93 patients with schizophrenia and 117 healthy individuals, all right-handed and of Japanese ethnicity, and matched for age and sex. Their memory functions were assessed using the WMS-Revised (WMS-R). Their grey and white matter structure was analyzed using voxel-based morphometry and diffusion tensor imaging.Verbal memory score correlated positively with volumes of the left parahippocampal gyrus and hippocampus, while general memory score correlated positively with volumes of the left parahippocampal and fusiform gyri and hippocampus (p 0.05, corrected), while there was no correlation with white matter fractional anisotropy values in healthy individuals. No correlation was observed between any WMS-R score and grey or white matter structure in patients.Using whole-brain structural magnetic resonance imaging, we found several significant correlations between WMS-R scores and grey matter volume in the brains of healthy individuals, while no correlation was found in those of patients with schizophrenia.

The role of brain-derived neurotrophic factor (BDNF) and its related molecules has been extensively studied in the context of psychiatric disorders. In the present study, we focused on the newly identified BDNF pro-peptide, which is generated together with mature BDNF by proteolytic processing of their precursor, proBDNF. Here, we report, for the first time, that BDNF pro-peptide is present in human cerebrospinal fluid (CSF) and quantifiable by western blotting. We measured CSF BDNF pro-peptide levels in 27 patients with schizophrenia, 18 patients with major depressive disorder (MDD), and 27 healthy controls matched for age, sex, and ethnicity (Japanese). The ratio of the BDNF pro-peptide level to the total protein level in MDD patients was significantly lower than that in controls (Kruskal-Wallis with Dunn's multiple comparisons test; p = 0.046). When men and women were examined separately, males with MDD had a significantly lower BDNF pro-peptide/protein ratio than male controls (p = 0.047); this difference was not found in female subjects. The ratio tended to be lower in male schizophrenia patients (p = 0.10). Although we tried to measure the levels of mature BDNF in CSF, they were below the limit of detection of the ELISA and multiple analyte profiling technology. Taken together, the results suggest that reduced CSF BDNF pro-peptide levels are associated with MDD, particularly in males. Further studies involving a larger sample size are warranted.

It is suggested that lysophosphatidic acid (LPA) plays a key role in the pathophysiology of schizophrenia. In this study, we measured LPA levels by enzyme-linked immunosorbent assay in cerebrospinal fluid (CSF) and plasma samples. The participants were 49 patients with schizophrenia and 49 normal healthy controls for CSF study, and 42 patients and 44 controls for plasma study. We found that LPA levels in the patients were not significantly different from those of controls in CSF (controls: 0.189 ± 0.077 µM, patients: 0.175 ± 0.067 µM; P = 0.318) and plasma samples (controls: 0.131 ± 0.067 µM, patients: 0.120 ± 0.075 µM; P = 0.465). On the other hand, CSF levels in medicated patients (0.162 ± 0.061 µM) were significantly lower than those observed in unmedicated patients (0.224 ± 0.067 µM, P = 0.038), suggesting that our findings could be masked by the influence of medication with antipsychotics. Interestingly, we detected significant negative correlation between PANSS scores and plasma LPA levels, especially in males and in unmedicated patients. Our result suggests that LPA levels in CSF and plasma samples would not serve as a diagnostic biomarker, but plasma levels could be used for symptomatic assessment of schizophrenia.

Background Although the clinical efficacy of electroconvulsive therapy (ECT) is well established, the underlying mechanisms of action remain elusive. The aim of this study was to elucidate structural changes of the brain following ECT in patients with major depressive disorder (MDD).Method: Fifteen patients with MDD underwent magnetic resonance imaging scanning before and after ECT. Their gray matter volumes were compared between pre- and post-ECT. Results There were significant volume increases after ECT in the bilateral medial temporal cortices, inferior temporal cortices, and right anterior cingulate. Further, the increase ratio was correlated with the clinical improvement measured by the Hamilton Depression Rating scale. Limitation All subjects were treated with antidepressants that could have a neurotoxic or neuroprotective effect on the brain. Conclusions We found that there were significant increases of gray matter volume in medial temporal lobes following ECT, suggesting that a neurotrophic effect of ECT could play a role in its therapeutic effect.

Inflammation has been implicated in a variety of psychiatric disorders. We aimed to determine whether levels of complement C5 protein in the cerebrospinal fluid (CSF), which may reflect activation of the complement system in the brain, are altered in patients with major psychiatric disorders. Additionally, we examined possible associations of CSF C5 levels with clinical variables. Subjects comprised 89 patients with major depressive disorder (MDD), 66 patients with bipolar disorder (BPD), 96 patients with schizophrenia, and 117 healthy controls, matched for age, sex, and ethnicity (Japanese). Diagnosis was made according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria. CSF C5 levels were measured by enzyme-linked immunosorbent assay. CSF C5 levels were significantly increased in the patients with MDD (p 0.001) and in the patients with schizophrenia (p = 0.001), compared with the healthy controls. The rate of individuals with an "abnormally high C5 level" (i.e., above the 95th percentile value of the control subjects) was significantly increased in all psychiatric groups, relative to the control group (all p 0.01). Older age, male sex, and greater body mass index tended to associate with higher C5 levels. There was a significantly positive correlation between C5 levels and chlorpromazine-equivalent dose in the patients with schizophrenia. Thus, we found, for the first time, elevated C5 levels in the CSF of patients with major psychiatric disorders. Our results suggest that the activated complement system may contribute to neurological pathogenesis in a portion of patients with major psychiatric disorders.

The Purdue Pegboard Test (PPT) is a motor coordination task used to assess manual dexterity. Although several brain regions are thought to be involved in PPT performance, the relationship of the task with decreased insular volume has not been investigated. The PPT was administered to 83 subjects diagnosed with schizophrenia (mean ± standard deviation age: 38.6 ± 11.2 years; 47 males, 36 females) and 130 healthy controls (42.1 ± 15.2 years; 67 males, 63 females). All subjects were Japanese and right-handed. Gray matter volume was analyzed using voxel-based morphometry in statistical parametric mapping, while white matter measures were analyzed using diffusion tensor imaging in tract-based spatial statistics. For the patients with schizophrenia, the left-hand scores positively correlated with the right insular and bilateral operculum volumes, while the summation score (sum of left-, right-, and both-hands scores) positively correlated with the right insular volume, and the summation and assembly (number of assemblies completed) scores correlated with the diffuse white matter fractional anisotropy, axial diffusivity, and radial diffusivity values. In contrast, no significant correlations were found for the controls. These results suggested that decreased insular volume and white matter measures contributed to the impairments in manual dexterity observed in subjects with schizophrenia.

Cocaine- and amphetamine-regulated transcript (CART) peptide is a candidate neuropeptide as a biomarker for major depressive disorder (MDD) because of its effects on emotion and distribution covering brain areas involved in the pathophysiology of MDD symptoms. However, it is unknown whether CART peptide levels are altered in the cerebrospinal fluid (CSF) of patients with MDD patients and are correlated with MDD symptoms.Subjects were 24 patients with MDD and 25 healthy controls matched for age, gender and ethnicity (Japanese). We measured CSF CART levels by a commercially available immunoassay kit and analyzed the relationships of the levels with antidepressant dose and symptoms assessed with the 21 item Hamilton Depression Rating Scale (HAMD-21).CSF CART levels were significantly decreased in the patients than in the controls (p0.05). In MDD patient group, the CART levels had a negative correlation with antidepressant dose (imipramine-equivalent dose) (ρ = -0.55, p0.01) and significantly decreased in antidepressant-treated group (AD-treated group) compared to controls (p0.05). CSF CART levels showed significant negative correlations with psychomotor retardation, somatic anxiety, and general somatic symptoms (all p0.05) and a positive correlation with obsessive and compulsive symptoms (p0.05).In our analysis, all classes of antidepressants were combined together and the effects of medication use in a longitudinal manner did not confirm.We report for the first time that CSF CART peptide levels are reduced in patients with MDD compared with healthy controls. The CART levels showed negative correlations with antidepressant dose and some symptoms, supporting the possibility that CART peptide is involved in the development of depressive symptoms.

Background Diagnostic biomarkers of major depressive disorder, bipolar disorder, and schizophrenia are urgently needed, because none are currently available. Methods We performed a comprehensive metabolome analysis of plasma samples from drug-free patients with major depressive disorder (n=9), bipolar disorder (n=6), schizophrenia (n=17), and matched healthy controls (n=19) (cohort 1) using liquid chromatography time-of-flight mass spectrometry. A significant effect of diagnosis was found for 2 metabolites: nervonic acid and cortisone, with nervonic acid being the most significantly altered. The reproducibility of the results and effects of psychotropic medication on nervonic acid were verified in cohort 2, an independent sample set of medicated patients [major depressive disorder (n=45), bipolar disorder (n=71), schizophrenia (n=115)], and controls (n=90) using gas chromatography time-of-flight mass spectrometry. Results The increased levels of nervonic acid in patients with major depressive disorder compared with controls and patients with bipolar disorder in cohort 1 were replicated in the independent sample set (cohort 2). In cohort 2, plasma nervonic acid levels were also increased in the patients with major depressive disorder compared with the patients with schizophrenia. In cohort 2, nervonic acid levels were increased in the depressive state in patients with major depressive disorder compared with the levels in the remission state in patients with major depressive disorder and the depressive state in patients with bipolar disorder. Conclusion These results suggested that plasma nervonic acid is a good candidate biomarker for the depressive state of major depressive disorder.

Some amino acids act as neurotransmitters themselves, or are precursors of neurotransmitters. Previous studies reported inconsistent results regarding their changes in blood in major depressive disorder (MDD), which prompted us to examine plasma levels of amino acids and related molecules in two independent case-control sample sets. In total, 511 subjects were recruited. Sample set A consisted of 164 patients with MDD (147 currently depressed [dMDD]; 17 in remission, DSM-IV) and 217 healthy controls. Sample set B consisted of 65 patients (51 dMDD; 14 in remission) and 65 controls. Plasma amino acid levels were measured using high-performance liquid chromatography for set A and liquid chromatography/mass spectrometry for set B. We further analyzed the relationships between plasma amino acid levels and clinical variables. In sample set A, plasma asparagine, histidine+1-methylhistidine, methionine, phenylalanine, tryptophan, and tyrosine levels were decreased, while plasma glutamate and phosphoethanolamine were elevated in dMDD compared to controls (all P

Background D -serine is an endogenous co-agonist of N-methyl-D-aspartate receptor (NMDAR) and plays an important role in glutamate neurotransmission. Several studies suggested the possible involvement of D -serine related in the pathophysiology of psychiatric disorders including major depression disorders (MDD). We tried to examine whether cerebrospinal fluid (CSF) or plasma D -serine concentrations are altered in MDD and whether D -serine concentrations correlated with disease severity. Methods 26 MDD patients and 27 healthy controls matched for age, sex and ethnicity were enrolled. We measured amino acids in these samples using by high-performance liquid chromatography with fluorometric detection. Results D -serine and L -serine, precursor of D -serine, levels in CSF or plasma were not significantly different in patients of MDD compared to controls. Furthermore, a significant correlation between D -serine levels in CSF and Hamilton Depression Rating Scale (HAMD)-17 score was observed (r = −0.65, p = 0.006). Furthermore, we found a positive correlation between CSF D -serine and HVA concentrations in MDD patients (r = 0.54, p = 0.007). CSF D -serine concentrations were correlated with those of plasma in MDD (r = 0.61, p = 0.01) but not in controls. In CSF, we also confirmed a significant correlation between D -serine and L -serine levels in MDD (r = 0.72, p Conclusions The study has some limitations; sample size was relatively small and most patients were medicated. We revealed that CSF D -serine concentrations were correlated with depression severity and HVA concentrations and further investigation were required to reveal the effect of medication and disease heterogeneity.

ObjectiveRecent studies have detected similarities between autism spectrum disorder and schizophrenia. We investigated structural abnormalities associated with autistic-like traits in patients with schizophrenia by voxel-based morphometry.MethodsPatients with schizophrenia and healthy subjects were evaluated by the adult version of the social responsiveness scale (SRS-A), which is sensitive to autistic traits and symptoms even under subthreshold conditions, and magnetic resonance imaging.ResultsThere were significant decreases in the anterior cingulate cortex, bilateral hippocampi, cerebellums, and right insula of patients with schizophrenia, compared with healthy subjects. We found significant negative correlations of the social communication and interaction (SCI) score, a subscale of SRS-A, with grey matter volume in the left posterior superior temporal region of schizophrenia patients. When subscales of SCI were examined separately in schizophrenic patients, negative correlations were observed between the social cognition score and the volumes of the left posterior superior temporal region, and between social motivation and the posterior cingulate cortex.ConclusionWe found significant negative correlation between the SCI score and the grey matter volume in the left posterior superior temporal region of schizophrenia patients. This area was the region affected in previous studies of autistic spectrum disorders. Further, this area was associated with the theory of mind. Schizophrenia patients not necessarily show the impairment of SCI, nor this correlated region was not always the point with schizophrenia-specific change. However, we reveal the relationship between the left posterior superior temporal gyrus and the severity of the SCI in schizophrenia by using with SRS-A.

Synthetic glucocorticoids such as dexamethasone are widely used to treat a variety of inflammatory and autoimmune conditions, but they may induce adverse events including hyperglycemia. To shed light on the effect and action mechanism of dexamethasone, we examined the alterations of gene expression levels caused by dexamethasone.Microarray analysis was performed on whole blood collected from 24 physically healthy subjects at baseline and after dexamethasone administration. The expression levels of resistin mRNA were found to be significantly increased after the dexamethasone administration. In a separate sample of 12 subjects, we examined plasma resistin protein levels and found that they were increased after dexamethasone administration. Furthermore, the plasma mRNA and protein levels of resistin were significantly higher in individuals who carried the A allele of RETN single nucleotide polymorphism rs3219175 than in those who did not carry the allele. There was no significant interaction between the genotype and dexamethasone administration. No significant correlation was found between plasma levels of cortisol and resistin. Consistent with previous studies, the genotype of RETN rs3219175 was a strong determinant of resistin levels. The present study showed that oral administration of dexamethasone increases the protein and mRNA levels of resistin irrespective of the rs3219175 genotype.

A recent genome-wide analysis indicated that a polymorphism (rs2535629) of ITIH3 showed the strongest association signal with susceptibility to psychiatric disorders in Caucasian populations. The aim of the study was to replicate the association of rs2535629 with schizophrenia and major depressive disorder (MDD) in Japanese subjects. A total of 611 patients with schizophrenia, 868 with MDD, and 1193 healthy controls were successfully genotyped for rs2535629. A significant difference in allele distribution was found between patients with schizophrenia and controls (odds ratio [OR] = 1.21, 95% confidence interval [CI]: 1.05-1.39, P = 0.0077). A similar trend was found for patients with MDD (OR = 1.11, 95% CI: 0.98-1.26, P = 0.092). The allele distribution in the combined patient group (schizophrenia and MDD) was significantly different from that of the control group (OR = 1.15, 95% CI: 1.03-1.28, P = 0.011). Gene expression microarray analysis of whole blood samples in 39 MDD patients and 40 healthy controls showed that rs2535629 has a strong influence on the expression levels of ITIH4 and GLT8D1. The expression levels of GLT8D1 were significantly higher in patients with MDD than in controls (P = 0.021). To our knowledge, the present study showed for the first time the association of rs2535629 with psychiatric disorders in an Asian population. Our findings suggest that rs2535629 influences the susceptibility to psychiatric disorders by affecting the expression level of GLT8D1.

Background Depression is associated with dysfunctional coping styles and dysregulated hypothalamic–pituitary–adrenal (HPA) axis function. Studies have shown that maladaptive coping strategies relate to abnormal HPA axis function; however, such a relationship has been under-studied in patients with depression. We aimed to examine whether dysfunctional coping styles in depression would be associated with abnormal cortisol reactivity. Methods Seventy-four outpatients with major depressive disorder and 133 age- and sex-matched healthy individuals were recruited. Coping was assessed by the Ways of Coping Checklist. Psychological distress was assessed by the Hopkins Symptom Checklist. Cortisol reactivity was measured by the combined dexamethasone/corticotropin-releasing hormone test. Results Compared to healthy individuals, depressed patients demonstrated significantly less use of problem-solving, positive reappraisal and social support coping styles and more use of self-blame and wishful thinking styles. Such a pattern of coping styles was significantly associated with patients' greater distress. Partial correlation analysis in patients, controlling for age and sex, revealed a significant correlation between more use of escape–avoidance coping and lower levels of reactive cortisol measures. A stepwise multiple regression analysis predicting cortisol reactivity from age, sex, distress, symptom severity and coping styles revealed that escape–avoidance coping was a significant predictor. Limitations The neuroendocrine challenge test was administered only once, based on a simple test protocol. Conclusions More use of escape–avoidance coping in depressed patients was associated with less cortisol reactivity. Our findings shed light on the heterogeneity of depression in terms of low and high levels of avoidance associated with exaggerated and blunted HPA axis reactivity, respectively.

Background Although schizophrenia and major depressive disorder (MDD) differ on a variety of neuroanatomical measures, a diagnostic tool to discriminate these disorders has not yet been established. We tried to identify structural changes of the brain that best discriminate between schizophrenia and MDD on the basis of gray matter volume, ventricle volume, and diffusion tensor imaging (DTI). Method The first exploration sample consisted of 25 female patients with schizophrenia and 25 females with MDD. Regional brain volumes and fractional anisotropy (FA) values were entered into a discriminant analysis. The second validation sample consisted of 18 female schizophrenia and 16 female MDD patients. Results The stepwise discriminant analysis resulted in correct classification rates of 0.80 in the schizophrenic group and 0.76 in MDD. In the second validation sample, the obtained model yielded correct classification rates of 0.72 in the schizophrenia group and 0.88 in the MDD group. Conclusion Our results suggest that schizophrenia and MDD have differential structural changes in the examined brain regions and that the obtained discriminant score may be useful to discriminate the two disorders.

PurposeSmoking rates in schizotypic individuals are shown to be elevated, as in patients with schizophrenia, although findings on the association of smoking with different symptomatology of schizotypy have been mixed. Moreover, possible moderating effects of schizotypy on the relationship between smoking and cognition have not been well documented.Subjects and methodsThe Schizotypal Personality Questionnaire (SPQ) and the full version of the Wechsler Memory Scale-Revised (WMS-R) were administered to 501 healthy adults. Subjects were divided into smokers (n = 85) and non-smokers (n = 416) based on the presence/absence of current smoking.ResultsThe analysis of covariance (ANCOVA) on the three factor scores as well as the total score of the SPQ, controlling for age and gender, revealed that cognitive-perceptual factor was significantly associated with an increased rate of smoking (P = 0.048). The ANCOVA on the WMS-R indices, with smoking group as a fixed factor and age, gender and total SPQ score as covariates, revealed that the schizotypy-by-smoking interaction was significant for attention/working memory (P = 0.029).Discussion and conclusionPositive schizotypy may be associated with more smoking. Schizotypy and smoking could interact with each other to negatively affect attention/working memory.

信州大学博士（医学）・学位論文・平成25年3月31日授与（甲第944号）・篠山 大明, Elevated peripheral levels of interleukin-6 (IL-6) are common findings in schizophrenia and depression. However, previous studies that measured cerebrospinal fluid (CSF) IL-6 levels in these disorders reported controversial results. The present study examined whether CSF IL-6 levels are altered in patients with schizophrenia and those with depression. Lumbar punctures were performed in 32 patients with schizophrenia, 30 with major depressive disorder (MDD), and 35 healthy controls. Serum samples were simultaneously collected from all subjects in the patient groups and from 32 of the control group. CSF and serum IL-6 levels were determined by enzyme-linked immunosorbent assay. Both the patients with schizophrenia and MDD had significantly higher CSF IL-6 levels compared to the controls (schizophrenia: P = 0.0027; MDD: P = 0.012). IL-6 levels were significantly higher in the CSF than in the serum. No significant correlation was observed between CSF and serum IL-6 levels. The present findings suggest that IL-6 of central origin is associated with the pathophysiology of schizophrenia and MDD, although confounding effect of smoking status can not be entirely excluded. (C) 2012 Elsevier Ltd. All rights reserved., Article, JOURNAL OF PSYCHIATRIC RESEARCH. 47(3):401-406 (2013)

Aim The brief assessment of cognition in schizophrenia (BACS) is a concise tool designed to evaluate cognitive deficits in schizophrenia. We examined the possible association between BACS scores and whole-brain structure, as observed using magnetic resonance imaging (MRI) with a relatively large sample. Methods The study sample comprised 116 patients with schizophrenia (mean age, 39.3 ± 11.1 years; 66 men) and 118 healthy controls (40.0 ± 13.6; 58 men) who completed the Japanese version of the BACS (BACS-J). All participants were of Japanese ethnicity. The MRI volume and diffusion tensor imaging data were processed with voxel-based morphometry and tract-based spatial statistics, respectively. Results There were significant reductions in the regional gray matter volumes and white matter fractional anisotropy (FA) values in patients with schizophrenia compared to healthy controls. For the gray matter areas, the working memory score had a significant positive correlation with the anterior cingulate and medial frontal cortices volumes positively in the patients. For the white matter areas, the motor speed score had a significant positive correlation with FA values in the corpus callosum, internal capsule, superior corona radiata, and superior longitudinal fasciculus positively in the patients. However, there was no significant correlation among either the gray or white matter areas in the controls. Conclusion Our results suggest that among the BACS-J measures, the working memory and motor speed scores are associated with several structural alternations in the brain of patients with schizophrenia.

ObjectiveObesity is a risk factor for psychiatric diseases. Recently, a number of single nucleotide polymorphisms (SNPs) have been shown to be related to body mass index (BMI). In this study, we investigated the association of BMI-related SNPs with psychiatric diseases and one of their endophenotypes, memory performance, in a Japanese population.MethodsThe subjects were 1624 patients with one of three psychiatric diseases (799 patients with major depressive disorder, 594 with schizophrenia, and 231 with bipolar disorder) and 1189 healthy controls. Memory performance was assessed using the Wechsler Memory Scale – Revised (WMS-R). Genomic DNA was prepared from venous blood and used to genotype 23 BMI-related SNPs using the TaqMan 5′-exonuclease allelic discrimination assay. We then analysed the relationships between the SNPs and psychiatric disease and various subscales of the WMS-R.ResultsThree SNPs (rs11142387, rs12597579, and rs6548238) showed significant differences in the genotype or allele frequency between patients with any psychiatric diseases and controls. Furthermore, six SNPs (rs11142387, rs12597579, rs2815752, rs2074356, rs4776970, and rs2287019) showed significant differences in at least one subscale of the WMS-R depending on the genotypes of the healthy controls. Interestingly, rs11142387 near the Kruppel-like factor 9 (KLF9) was significantly associated with psychiatric disease and poor memory function.ConclusionsWe identified three and six BMI-related SNPs associated with psychiatric disease and memory performance, respectively. In particular, carrying the A allele of rs11142387 nearKLF9was found to be associated with psychiatric disease and poor memory performance, which warrants further investigations.

Background While major depressive disorder (MDD) is considered to be a heterogeneous disorder, the nature of the heterogeneity remains unclear. Studies have attempted to classify patients with MDD using latent variable techniques, yet the empirical approaches to symptom-based subtyping of MDD have not provided conclusive evidence. Here we aimed to identify homogeneous classes of MDD based on personality traits, using a latent profile analysis. Methods We studied 238 outpatients with DSM-IV MDD recruited from our specialized depression outpatient clinic and assessed their dimensional personality traits with the Temperament and Character Inventory. Latent profile analysis was conducted with 7 dimensions of the Temperament and Character Inventory as indicators. Relationships of the identified classes with symptomatology, prescription pattern, and social function were then examined. Results The latent profile analysis indicated that a 3-class solution best fit the data. Of the sample, 46.2% was classified into a “neurotic” group characterized by high harm avoidance and low self-directedness; 30.3% into an “adaptive” group characterized by high self-directedness and cooperativeness; and 23.5% into a “socially-detached” group characterized by low reward dependence and cooperativeness and high self-transcendence. The 2 maladaptive groups, namely neurotic and socially-detached groups, demonstrated unique patterns of symptom expression, different classes of psychotropic medication use, and lower social functioning. Limitations Generalizability of the findings was limited since our patients were recruited from the specialized depression outpatient clinic. Conclusions Our personality-based latent profile analysis identified clinically meaningful 3 MDD groups that were markedly different in their personality profiles associated with distinct symptomatology and functioning.

Many studies have investigated cerebrospinal fluid (CSF) monoamine metabolite levels in depressive disorders. However, their clinical significance is still unclear. We tried to determine whether CSF monoamine metabolite levels could be a state-dependent marker for major depressive disorder (MDD) based on analyses stratified by clinical variables in a relatively large sample.Subjects were 75 patients with MDD according to DSM-IV criteria and 87 healthy controls, matched for age, sex, and ethnicity (Japanese). They were recruited between May 2010 and November 2013. We measured homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in CSF samples by high-performance liquid chromatography. We analyzed the relationships of the metabolite levels with age, sex, diagnosis, psychotropic medication use, and depression severity.There was a weak positive correlation between age and 5-HIAA levels in controls (ρ = 0.26, P.016) and a similar trend in patients, while sex was unrelated to any metabolite. All monoamine metabolites in moderately to severely depressed patients (17-item Hamilton Depression Rating Scale score12) were significantly lower than those in controls (P.0005 for all 3 metabolites). We found that antidepressants decreased the levels of 5-HIAA (ρ = -0.39, P.001) and MHPG (ρ = -0.49, P.0001) and that antipsychotics increased levels of HVA (ρ = 0.24, P.05). There was a strong correlation between HVA and 5-HIAA levels (controls: ρ = 0.79, P = .000001; MDD: ρ = 0.66, P = .000001). HVA levels (ρ = -0.43, P.001) and 5-HIAA levels (ρ = -0.23, P.05), but not MHPG levels (ρ = -0.18, P.1), were related to depression severity.CSF 5-HIAA and HVA levels could be state-dependent markers in MDD patients. Since 5-HIAA levels greatly decrease with the use of antidepressants, HVA levels might be more useful in the clinical setting.

Many MRI studies have reported a volume reduction of the hippocampus in psychiatric diseases. However, disease-related volume differences in hippocampus subfields remain unclear. Here we compared the volumes of hippocampus subfields in patients with schizophrenia, patients with major depressive disorder (MDD), and healthy subjects as controls. T2-weighted images were acquired in 20 patients with schizophrenia, 36 with MDD, and 35 healthy volunteers by 3-Tesla MRI. Hippocampal subfields were segmented using an automatic algorithm, Automatic Segmentation of Hippocampal Subfields (ASHS). Schizophrenia patients exhibited significant volume reductions in the cornu ammonis (CA)1 compared to the controls, and in the dentate gyrus compared to the controls and MDD patients without medication, whereas there was no significant difference between the MDD patients and controls. There was a nominal negative correlation between the perirhinal cortex volume and depression severity in the MDD patients without medication, whereas there were negative correlations between CA2 volume and both negative symptoms and the duration of illness in the schizophrenia patients. We identified differing volume reductions in hippocampal subfields and varying correlations between disease severity and subfield volumes depending on diagnosis, suggesting that volume differences in hippocampus subfields may provide important information regarding the pathophysiology of schizophrenia and MDD.

There is an urgent need for diagnostic biomarkers of bipolar disorder (BD) and schizophrenia (SZ); however, confounding effects of medication hamper biomarker discovery. In this study, we conducted metabolome analyses to identify novel plasma biomarkers in drug-free patients with BD and SZ.We comprehensively analyzed plasma metabolites using capillary electrophoresis time-of-flight mass spectrometry in patients with SZ (n = 17), BD (n = 6), and major depressive disorder (n = 9) who had not received psychotropics for at least 2 weeks, and in matched healthy controls (n = 19). The results were compared with previous reports, or verified in an independent sample set using an alternative analytical approach.Lower creatine level and higher 2-hydroxybutyric acid level were observed in SZ than in controls (uncorrected P = 0.016 and 0.043, respectively), whereas they were unaltered in a previously reported dataset. Citrulline was nominally significantly decreased in BD compared to controls (uncorrected P = 0.043); however, this finding was not replicated in an independent sample set of medicated patients with BD. N-methyl-norsalsolinol, a metabolite of dopamine, was suggested as a candidate biomarker of BD; however, it was not detected by the other analytical method. Levels of betaine, a previously reported candidate biomarker of schizophrenia, were unchanged in the current dataset.Our preliminary findings suggest that the effect of confounding factors, such as duration of illness and medication, should be carefully controlled when searching for plasma biomarkers. Further studies are required to establish robust biomarkers for these disorders.

Objective We aimed to find the alterations in the profiles of low-molecular-weight metabolites in the brains of schizophrenia patients that may reflect the pathophysiology of the disorder. Method Human postmortem brain tissues from the frontal cortex (15 schizophrenia patients and 15 controls) and the hippocampus (14 schizophrenia patients and 15 controls) were obtained from the Stanley Foundation Neuropathology Consortium. We analyzed ~ 300 metabolites, using capillary electrophoresis with time-of-flight mass spectrometry. Results In the frontal cortex, the mean levels of 29 metabolites were significantly different between the schizophrenia and control groups. In the hippocampus, only a dipeptide, glycylglycine was significantly ( p ≤ 0.001, nominal p -value) increased in schizophrenia. Glycylglycine was also significantly ( p = 0.007) increased in the frontal cortex of schizophrenia. The pathway analyses revealed that several metabolic pathways including KEGG “Central carbon metabolism in cancer” and “Protein digestion and absorption” were commonly affected in the frontal cortex and the hippocampus of schizophrenia patients. Conclusion These findings point out alterations in glucose metabolism and proteolysis in the brains of schizophrenia.

Background Growing evidence suggests that schizotypy and genetic loading for schizophrenia both represent risk for the development of schizophrenia. Although these conditions are known to be associated with neurocognitive impairments, such an association has not been studied in patients with bipolar II disorder (BPII) or unipolar major depressive disorder (UP). Methods Forty-one depressed patients with BPII, 131 patients with UP and demographically matched 225 healthy controls were recruited. Schizotypy was assessed by the Schizotypal Personality Questionnaire. Neuropsychological functioning was measured by the Wechsler Memory Scale-Revised, the Wechsler Adult Intelligence Scale-Revised and the Wisconsin Card Sorting Test. Results Mood disorder patients performed significantly worse than controls in verbal and visual memory, working memory and processing speed. BPII patients performed significantly more poorly than UP patients in verbal memory and executive functioning. Both BPII and UP patients demonstrated significantly greater schizotypal traits than controls. Schizotypy was significantly negatively correlated with verbal comprehension both in BPII and UP patients and with working memory and processing speed in healthy controls. Patients who had one or more first-degree relatives with schizophrenia performed significantly more poorly than the remaining patients in all cognitive domains. Limitations Most of our patients were on psychotropic medication, and the sample of BPII patients was not very large. Conclusions Liability for schizophrenia could play a pivotal role in neurocognitive functioning in mood disorders, suggesting that such liability might lie on a continuum ranging from normality through mood disorders to full-blown schizophrenia.

Human P-glycoprotein (P-gp), which is encoded by ABCB1 (ATP-binding cassette, sub-family B member 1), is expressed in the blood brain barrier and protects the brain from many kinds of drugs and toxins including glucocorticoids by acting as an efflux pump. We examined whether functional polymorphisms of ABCB1 give susceptibility to major depressive disorder (MDD). The five functional single nucleotide polymorphisms (SNPs), A-41G (rs2188524), T-129C (rs3213619), C1236T (Gly412Gly: rs1128503), G2677A/T (Ala893Ser/Thr: rs2032582), and C3435T (Ile1145Ile: rs1045642) were genotyped in 631 MDD patients and 1100 controls in the Japanese population. A tri-allelic SNP, G2677A/T, was genotyped by pyrosequencing and the remaining SNPs were genotyped by the TaqMan 5'-exonuclease allelic discrimination assay. The minor T3435 allele was significantly increased in MDD patients than in the controls (χ(2) = 4.5, df = 1, p = 0.034, odds ratio [OR] 1.16, 95% confidential interval [CI] 1.01-1.34). Homozygotes for the T3435 allele was significantly more common in patients than in the controls (χ(2) = 7.5, df = 1, p = 0.0062, OR 1.43, 95%CI 1.11-1.85). With respect to the other 4 SNPs, there was no significant difference in genotype or allele distribution. In the haplotype-based analysis, the proportion of individuals with the TT1236-TT3435 haploid genotype was significantly increased in patients than in controls (χ(2) = 8.5, df = 1, p = 0.0037, OR 1.50, 95%CI 1.14-1.98). Our results suggest that the T3435 allele or carrying two copies of this allele confers susceptibility to MDD in the Japanese population.

Background: Mood disorders are associated with various neurocognitive deficits. However, few studies have reported the impairment of motor dexterity in unipolar depression and bipolar disorder. In the present study, manual dexterity was compared between unipolar major depression, bipolar disorder, and healthy controls. Methods: Manual dexterity was assessed by the Purdue pegboard test in 98 patients with unipolar major depression, 48 euthymic or depressed patients with bipolar disorder, and 158 healthy controls, matched for age and gender. Results: Compared to healthy controls, sum of the scores of right, left, and both hands subtests (R + L+ B) was significantly lower in both patients with unipolar depression and bipolar disorder (P= 0.0034 and P, Article, JOURNAL OF AFFECTIVE DISORDERS. 136(3):1047-1052 (2012)

Ca2+-dependent activator protein for secretion 2 (CADPS2), a secretory granule associate protein, mediates monoamine transmission and neurotrophin release. Both monoamines and neurotrophins play a crucial role in cognition, learning and memory. An aberrant splice variant of CADPS2, CADPS2ΔExon3, was reported to be associated with autism. Therefore, we examined the possible association between the expression of CADPS2/CADPS2ΔExon3 in peripheral blood and brain functions such as intelligence and memory. Quantitative polymerase chain reaction analysis was performed in 271 healthy adults (age range 20–74 years, mean ± SD 43.3 ± 15.3). Data on intelligence quotient (IQ) and memory were obtained by using full versions of the Wechsler Adult Intelligence Scale-Revised (WAIS-R), and the Wechsler Memory Scale-Revised (WMS-R), respectively. CADPS2 expression levels were not significantly associated with any scores/sub-scores of these scales. However, CADPS2ΔExon3 expression was significantly associated with lower IQ (p = 0.022; effect size: ηp2 = 0.031), particularly verbal IQ of WAIS-R (p = 0.019; ηp2 = 0.032), lower verbal memory (p = 0.026; ηp2 = 0.026) and delayed recall (p = 0.042; ηp2 = 0.021) of WMS-R. Our results suggest that CADPS2ΔExon3 affects intelligence and memory in the non-clinical population.

Recent studies indicate a role of excessive interleukin-6 (IL-6) signaling in the pathogenesis of schizophrenia. A previous study reported a significant association of schizophrenia with the IL-6 receptor (IL-6R) gene Asp358Ala polymorphism, which is known to regulate circulating IL-6 and soluble IL-6R (sIL-6R) levels in healthy subjects. To further examine the influence of the polymorphism in schizophrenic patients, we compared the plasma levels of IL-6 and sIL-6R between schizophrenic patients and healthy controls for each genotype of the Asp358Ala polymorphism. Asp358Ala genotyping and plasma IL-6 level measurements were performed in 104 patients with schizophrenia and 112 healthy controls. Of these participants, 53 schizophrenic patients and 49 controls were selected for the measurement of plasma sIL-6R levels. A two-way factorial analysis of covariance was performed with the transformed plasma levels as the dependent variable, diagnosis and genotype as independent variables, and sex and age as covariates. No significant diagnosis × genotype interaction was observed for IL-6 and sIL-6R levels. The Ala allele of Asp358Ala was significantly associated with higher levels of both IL-6 and sIL-6R. IL-6 levels were significantly elevated in schizophrenic patients compared to those in controls, whereas no significant difference in sIL-6R levels was observed between schizophrenic patients and controls. Our findings suggest that the presence of schizophrenia is associated with elevated IL-6 levels, whereas sIL-6R levels are mainly predetermined by the Asp358Ala genotype and are not associated with the disease status. Increased IL-6 levels without alterations in sIL-6R levels may result in excessive IL-6 signaling in schizophrenia.

Background: Although some core personality variables are known to be characteristic of unipolar or bipolar depression, few studies have compared the personality profile between these two disorders. Methods: Temperament and Character Inventory (TCI) was employed to assess the personality of 36 depressed patients with bipolar II disorder (BPII), 90 patients with unipolar major depressive disorder (UP), and 306 healthy controls. The TCI was administered during the depressive episode in BPII and UP patients so that the results can be applied in a clinical setting. Results: Significantly higher scores in harm avoidance (p, Article, JOURNAL OF AFFECTIVE DISORDERS. 132(3):319-324 (2011)

Background/Aims: Schizotypy is viewed as a dimensional trait ranging from healthy people to schizophrenic spectrum patients. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, and accumulated evidence suggests that schizophrenia is associated with altered HPA axis function; however, HPA axis function in relation to schizotypal personality has not been well documented. Methods: We examined the relationship between schizotypal traits as assessed with the Schizotypal Personality Questionnaire (SPQ) and cortisol responses to the combined dexamethasone/corticotropin- releasing hormone test in 141 healthy volunteers. Subjects were divided into three groups based on their cortisol responses to the dexamethasone/corticotropin-releasing hormone test: incomplete suppressors, moderate suppressors, and enhanced suppressors. SPQ scores were compared between these three groups using the analysis of covariance, controlling for age and sex. Results: The analysis of covariance showed significant main effects of the suppressor status on the ideas of reference and suspiciousness/paranoid ideation subscales and cognitive-perceptual factor. Post-hoc analyses with Bonferroni correction revealed that the enhanced suppressors scored significantly higher than the moderate suppressors on these SPQ indices. Conclusion: These results indicate that nonclinical schizotypal traits in healthy adults are associated with blunted cortisol reactivity, potentially suggesting a shared neuroendocrinological mechanism across schizophrenia spectrum pathology.

Fyn, a Src-family kinase, is highly expressed in brain tissue and blood cells. In the mouse brain, Fyn participates in brain development, synaptic transmission through the phosphorylation of N-methyl-d-aspartate (NMDA) receptor subunits, and the regulation of emotional behavior. Recently, we found that Fyn is required for the signal transduction in striatal neurons that is initiated by haloperidol, an antipsychotic drug. To determine whether Fyn abnormalities are present in patients with schizophrenia, we analyzed Fyn expression in platelet samples from 110 patients with schizophrenia, 75 of the patients' first-degree relatives, and 130 control subjects. A Western blot analysis revealed significantly lower levels of Fyn protein among the patients with schizophrenia and their relatives, compared with the level in the control group. At the mRNA level, the splicing patterns of fyn were altered in the patients and their relatives; specifically, the ratio of fynDelta7, in which exon 7 is absent, was elevated. An expression study in HEK293T cells revealed that FynDelta7 had a dominant-negative effect on the phosphorylation of Fyn's substrate. These results suggest novel deficits in Fyn function, manifested as the downregulation of Fyn protein or the altered transcription of the fyn gene, in patients with schizophrenia.

Background Bifidobacterium and Lactobacillus in the gut have been suggested to have a beneficial effect on stress response and depressive disorder. We examined whether these bacterial counts are reduced in patients with major depressive disorder (MDD) than in healthy controls. Method Bifidobacterium and Lactobacillus counts in fecal samples were estimated in 43 patients and 57 controls using bacterial rRNA-targeted reverse transcription-quantitative polymerase chain reaction Results The patients had significantly lower Bifidobacterium counts (P=0.012) and tended to have lower Lactobacillus counts (P=0.067) than the controls. Individuals whose bacterial counts below the optimal cut-off point (9.53 and 6.49 log10 cells/g for Bifidobacterium and Lactobacillus, respectively) were significantly more common in the patients than in the controls for both bacteria (Bifidobacterium: odds ratio 3.23, 95% confidence interval [CI] 1.38–7.54, P=0.010; Lactobacillus: 2.57, 95% CI 1.14–5.78, P=0.027). Using the same cut-off points, we observed an association between the bacterial counts and Irritable bowel syndrome. Frequency of fermented milk consumption was associated with higher Bifidobacterium counts in the patients. Limitations The findings should be interpreted with caution since effects of gender and diet were not fully taken into account in the analysis. Conclusion Our results provide direct evidence, for the first time, that individuals with lower Bifidobacterium and/or Lactobacillus counts are more common in patients with MDD compared to controls. Our findings provide new insight into the pathophysiology of MDD and will enhance future research on the use of pro- and prebiotics in the treatment of MDD.

Evaluating the severity of depression (SOD), especially suicidal ideation (SI), is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD)-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ)-9. However, these evaluation systems have relied on a person's subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS), and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB), betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA)) are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In addition, modification of these metabolites by diet and/or medications may be a novel therapeutic target for depression. To clarify these aspects, clinical trials measuring metabolites before/after interventions should be conducted. Larger cohort studies including non-clinical subjects are also warranted to clarify our pilot findings.