[Show abstract][Hide abstract] ABSTRACT: Several microarray-based studies have investigated gene expression profiles in major depressive disorder (MDD), yet with highly variable findings. We examined blood-based genome-wide expression signatures of MDD, focusing on molecular pathways and networks underlying differentially expressed genes (DEGs) and behaviours of hypothesis-driven, evidence-based candidate genes for depression. Agilent human whole-genome arrays were used to measure gene expression in 14 medication-free outpatients with MDD who were at least moderately ill and 14 healthy controls matched pairwise for age and sex. After filtering, we compared expression of entire probes between patients and controls and identified DEGs. The DEGs were evaluated by pathway and network analyses. For the candidate gene analysis, we utilized 169 previously prioritized genes and examined their case-control separation efficiency and correlational co-expression network in patients relative to controls. The 317 screened DEGs mapped to a significantly over-represented pathway, the "synaptic transmission" pathway. The protein-protein interaction network was also significantly enriched, in which a number of key molecules for depression were included. The co-expression network of candidate genes was markedly disrupted in patients. This study provided evidence for an altered molecular network along with several key molecules in MDD and confirmed that the candidate genes are worthwhile targets for depression research.
[Show abstract][Hide abstract] ABSTRACT: Altered tryptophan-kynurenine (KYN) metabolism has been implicated in major depressive disorder (MDD). The l-[1- 13 C]tryptophan breath test (13 C-TBT) is a noninvasive, stable-isotope tracer method in which exhaled 13 CO 2 is attributable to tryptophan catabolism via the KYN pathway. We included 18 patients with MDD (DSM-IV) and 24 age- and sex-matched controls. 13 C-tryptophan (150 mg) was orally administered and the 13 CO 2 / 12 CO 2 ratio in the breath was monitored for 180 min. The cumulative recovery rate during the 180-min test (CRR 0-180; %), area under the δ 13 CO 2 -time curve (AUC; %∗min), and the maximal δ 13 CO 2 (C max; %) were significantly higher in patients with MDD than in the controls (p = 0.004, p = 0.008, and p = 0.002, respectively). Plasma tryptophan concentrations correlated negatively with C max in both the patients and controls (p = 0.020 and p = 0.034, respectively). Our results suggest that the 13 C-TBT could be a novel biomarker for detecting a subgroup of MDD with increased tryptophan-KYN metabolism.
Full-text · Article · Nov 2015 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: Major depressive disorder (MDD) presumably includes heterogeneous subgroups with differing pathologies. To obtain a marker reflecting such a subgroup, we analyzed the cerebrospinal fluid (CSF) levels of fibrinogen, which has been reported to be elevated in the plasma of patients with MDD. Three fibrinogen-related proteins were measured using aptamer-based analyses and CSF samples of 30 patients with MDD and 30 controls. The numbers of patients with an excessively high level (>99 percentile of the controls) was significantly increased (17 to 23%). Measurement reproducibility of these results was confirmed by an ELISA for fibrinogen (Pearson's r = 0.77). In an independent sample set from 36 patients and 30 controls, using the ELISA, results were similar (22%). When these two sample sets were combined, the number of patients with a high fibrinogen level was significantly increased (15/66; odds ratio 8.53; 95% confidence interval 1.9-39.1, p = 0.0011). By using diffusion tensor imaging, we found white matter tracts abnormalities in patients with a high fibrinogen level but not those patients with a normal fibrinogen level, compared with controls. Plasma fibrinogen levels were similar among the diagnostic groups. Our results point to a subgroup of MDD represented by increased CSF fibrinogen and white matter tract abnormalities.
[Show abstract][Hide abstract] ABSTRACT: Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. Previous studies suggested that l-theanine affects the glutamatergic neurotransmission and ameliorates symptoms in patients with schizophrenia. The aims of the present study were twofold: to examine the possible effects of l-theanine on symptoms in chronic schizophrenia patients and to evaluate the changes in chemical mediators, including glutamate + glutamine (Glx), in the brain by using 1H magnetic resonance spectroscopy (MRS).
The subjects were 17 patients with schizophrenia and 22 age- and sex-matched healthy subjects. l-Theanine (250 mg/day) was added to the patients' ongoing antipsychotic treatment for 8 weeks. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), Pittsburgh Sleep Quality Index scores and MRS results.
There were significant improvements in the PANSS positive scale and sleep quality after the l-theanine treatment. As for MRS, we found no significant differences in Glx levels before and after the 8 week l-theanine treatment. However, significant correlations were observed between baseline density of Glx and change in Glx density by l-theanine.
Our results suggest that l-theanine is effective in ameliorating positive symptoms and sleep quality in schizophrenia. The MRS findings suggest that l-theanine stabilises the glutamatergic concentration in the brain, which is a possible mechanism underlying the therapeutic effect.
No preview · Article · Apr 2015 · Acta Neuropsychiatrica
[Show abstract][Hide abstract] ABSTRACT: Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipo-lar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of evaluating autistic like traits/symptoms underlying adult-onset psychiatric disorders for the best-suited treatment. Further studies with a prospective design and larger samples are needed.
[Show abstract][Hide abstract] ABSTRACT: Amino acids play key roles in the function of the central nervous system, and their alterations are implicated in psychiatric disorders. In the search for a biomarker for major depressive disorder (MDD), we used high-performance liquid chromatography to measure amino acids and related molecules in the cerebrospinal fluid (CSF) of 52 patients with MDD (42 depressed and 10 remitted; DSM-IV) and 54 matched controls. Significant differences were found in four amino acid concentrations between the depressed patients and controls. After Bonferroni correction, only ethanolamine (EA) levels remained significantly reduced in depressed patients (nominal P = 0.0000011). A substantial proportion of the depressed patients (40.5%) showed abnormally low CSF EA levels (<12.1 μM) (P = 0.000033; OR = 11.6, 95% CI: 3.1-43.2). When patients with low EA and those with high EA levels were compared, the former had higher scores for overall depression severity (P = 0.0033) and 'Somatic Anxiety' symptoms (P = 0.00026). In unmedicated subjects, CSF EA levels showed a significant positive correlation with levels of homovanillic acid (P = 0.0030) and 5-hydroxyindoleacetic acid (P = 0.019). To our knowledge, this is the first study showing that patients with MDD have significantly lower CSF EA concentrations compared with control subjects. CSF EA could be a state-dependent biomarker for a subtype of MDD.
Full-text · Article · Jan 2015 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: FK506 binding protein 5 (FKBP5) is induced by stress and regulates glucocorticoid receptor sensitivity. The T allele of the single nucleotide polymorphism (SNP) FKBP5 rs1360780 (C/T) is associated with an increased risk of post-traumatic stress disorder (PTSD) and reduced hippocampal volume in traumatized or depressed subjects. To examine whether this SNP affects brain structures that regulate stress response, we obtained magnetic resonance imaging data of the brain in 162 healthy subjects using a 1.5 Tesla system. Gray matter volumes and diffusion tensor imaging data were compared between individuals with and without the T allele, using optimized voxel-based morphometry. We found that the dorsal anterior cingulate cortex (dACC) volume was smaller in T carriers than in non-T carriers (P < 0.001). T carriers also showed significantly higher mean diffusivity values in the dACC and posterior cingulate cortex (PCC) compared with non-T carriers (P < 0.001). Our results suggest that carrying the T allele of FKBP5 rs1360780 is associated with smaller gray matter volumes in the dACC and altered white matter integrity in the dACC and PCC in the non-clinical population, which might constitute the structural basis of stress-related psychiatric disorders including PTSD.
No preview · Article · Nov 2014 · Journal of Psychiatric Research
[Show abstract][Hide abstract] ABSTRACT: AimThe Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) recognizes some subtypes of major depressive disorder (MDD). It is known that the effectiveness of antidepressants differs among the MDD subtypes, and thus the differentiation of the subtypes is important. However, little is known as to structural brain changes in MDD with atypical features (aMDD) in comparison with MDD with melancholic features (mMDD), which prompted us to examine possible differences in white matter integrity assessed with diffusion tensor imaging (DTI) between these two subtypes.Methods
Subjects were 21 patients with mMDD, 24 with aMDD, and 37 age- and sex-matched healthy volunteers whose DTI data were obtained by 1.5 tesla magnetic resonance imaging. We compared fractional anisotropy (FA) and mean diffusivity (MD) value derived from DTI data on a voxel-by-voxel basis among the 2 diagnostic groups and healthy subjects.ResultsThere were significant decreases of FA and increases of MD in patients with MDDs compared with healthy subjects in the corpus callosum, inferior fronto-occipital fasciculus, and left superior longitudinal fasciculus. However, we detected no significant difference in any brain region between mMDD and aMDD.Conclusion
Our results suggest that patients with MDD had reduced white matter integrity in some regions; however, there was no major difference between aMDD and mMDD.
No preview · Article · Nov 2014 · Psychiatry and Clinical Neurosciences
[Show abstract][Hide abstract] ABSTRACT: The common single nucleotide polymorphism (SNP) rs1360780 (C/T) of the FK506 Binding Protein 5 (FKBP5) gene has been reported to be associated with an altered response of the hypothalamic-pituitary-adrenal (HPA) axis and the development of stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD). In the present study, we examined whether this SNP is associated with cognitive function in a non-clinical population. The full versions of the Wechsler Memory Scale-Revised and Wechsler Adult Intelligence Scale-Revised were administered to 742 and 627 Japanese individuals, respectively, followed by genotyping of rs1360780 by the TaqMan 5'-exonuclease allelic discrimination assay. For both cognitive tests, we found significantly poorer attention/concentration (working memory) in aged (>50 years old) individuals carrying the T allele compared with their counterparts. This finding accords with an altered HPA axis and vulnerability to stress-related psychiatric disorders.
Full-text · Article · Oct 2014 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: Patients with schizophrenia are at increased risk for suicide. Various risk factors for suicide have been reported in schizophrenia; however, few studies have examined the association between personality traits and suicidal behavior. We administered the Schizotypal Personality Questionnaire (SPQ) to 87 Japanese patients with schizophrenia (49 males; mean age 38.1±10.6 years) with and without a history of suicide attempts (SA and nSA groups, respectively), and 322 controls (158 males; mean age 40.8±13.9 years). As expected, an analysis of covariance (ANCOVA) controlling for age and sex showed that all SPQ indices (total SPQ score and all three factors, i.e., cognitive-perceptual, interpersonal, and disorganized) were significantly higher in patients with schizophrenia (SA+nSA groups), than controls (p<0.001 for all comparisons). Furthermore, there were significant differences in the total score and the interpersonal and disorganized factors between the SA and nSA groups (nSA<SA, p<0.01 for all comparisons). Receiver operating characteristic analysis showed that a total SPQ score of 33.5 was the optimal cut-off value to discriminate the SA group from the nSA group (χ2 = 10.6, p = 0.002, odds ratio: 4.7, 95% confidence interval: 1.8-12.1, sensitivity: 0.70, specificity: 0.67). These results suggest that high schizotypy is associated with lifetime suicide attempts, and that the total SPQ score might be useful to assess the risk of suicide attempt in patients with schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: Previous studies have suggested that schizophrenia patients have dysfunctional thermoregulation. The aim of this study was to examine whether brain temperature (BT) in schizophrenia patients differs from that in patients with bipolar disorder and healthy subjects by using magnetic resonance imaging. We also evaluated the possible relationship between BT and cerebral blood flow (CBF). We analyzed the temperature of lateral ventricles as the mean BT using diffusion-weighted imaging (DWI) thermometry, and evaluated the relationships between the BT and the CBF using pseudo-continuous arterial spin labeling (pCASL) among 3 diagnostic groups, 22 male patients with schizophrenia, 19 male patients with bipolar disorder, and 23 healthy male subjects. There were significant positive correlations between BT in the lateral ventricles and CBF in both the patients with bipolar disorder and healthy subjects. By contrast, there were significant negative correlations in patients with schizophrenia. We could not detect the significant difference in the surrogates of BT among three diagnostic groups. We showed that patients with schizophrenia, but not those with bipolar disorder, have dysfunctional thermoregulation in the brain. Brain temperature is highly dependent on cerebral metabolism and CBF, and thus uncoupling of cerebral metabolism and CBF may occur in schizophrenics.Journal of Cerebral Blood Flow & Metabolism advance online publication, 3 September 2014; doi:10.1038/jcbfm.2014.151.
[Show abstract][Hide abstract] ABSTRACT: Tryptophan, an essential amino acid, is the precursor to serotonin and is metabolized mainly by the kynurenine pathway. Both serotonin and kynurenine have been implicated in the pathophysiology of major depressive disorder (MDD). However, plasma tryptophan concentration in patients with MDD has not unequivocally been reported to be decreased, which prompted us to perform a meta-analysis on previous studies and our own data.
No preview · Article · Sep 2014 · The Journal of Clinical Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Background
Most previous studies that examined regional cerebral blood flow (rCBF) abnormalities in major depressive disorder (MDD) required the injection of radioisotopes into subjects. Here by using magnetic resonance imaging (MRI) with the pseudo-continuous arterial spin labeling (pCASL) method which does not require radioisotopes, we examined rCBF in patients with MDD in comparison with that in patients with schizophrenia and healthy subjects, taking the regional cerebral gray matter volume into account.
Subjects were 27 patients with MDD, 42 with schizophrenia and 43 healthy volunteers who underwent 3-T MRI with pCASL. Obtained pCASL imaging data were subject to the voxel-by-voxel statistical analysis.
There were significant reductions of rCBF in the right inferior prefrontal cortex and anterior cingulate cortices (ACCs) in the MDD patients compared with the healthy controls. When compared with the schizophrenic patients, the MDD patients showed lower rCBF in the subgenual ACC and higher rCBF in left occipital region.
The abnormalities of rCBF in MDD were known to reverse during symptom remission. Further study with follow-up period would bring the perception about the treatment response.
The rCBF reduction in the subgenual region may be a specific functional abnormality to MDD patients, which may provide a biological marker for MDD. The MRI with pCASL method is a promising tool to detect rCBF abnormalities controlling for gray matter volume in psychiatric disorders.
No preview · Article · Aug 2014 · Journal of Affective Disorders
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Jul 2014 · Hormone and Metabolic Research
[Show abstract][Hide abstract] ABSTRACT: AimPrevious studies consistently reported increased harm avoidance (HA) assessed with the Temperament and Character Inventory (TCI) in patients with major depressive disorder (MDD). However, such findings may have been related with depression severity and number of depressive episodes. The aims of the present study were two-fold: to examine TCI personality profile in remitted MDD (DSM-IV) patients and to compare TCI personality between MDD patients with single episode (SGL-MDD) and those with recurrent episodes (REC-MDD) in order to elucidate personality profile associated with recurrence.MethodsTCI was administered to 86 outpatients with remitted SGL-MDD (12 male and 17 female patients; mean age 43.2 ± 12.1 years) and REC-MDD (26 male and 31 female patients; 40.3 ± 11.6 years), and 529 healthy controls (225 males and 304 females; 43.4 ± 15.5 years), matched for age, sex and education years. Logistic regression analyses were performed, in which single/recurrent episodes of depression was the dependent variable and age, sex, age of onset, family history of psychiatric disease and TCI scores were entered as possible predictors.ResultsThe remitted MDD patients had significantly higher scores on HA (p<0.001) and lower scores on self-directedness (p<0.001), compared with the controls. HA (p=0.03) and its subscore, fatigability (p=0.03) as well as family history of psychiatric disease were found to be positive predictors for recurrence.Conclusion
There are differences in personality profile between remitted MDD patients and controls, and between remitted REC-MDD and SGL-MDD patients, suggesting that they are trait markers. HA and fatigability might be useful to assess risk for recurrence of depression.
No preview · Article · Jul 2014 · Psychiatry and Clinical Neurosciences
[Show abstract][Hide abstract] ABSTRACT: While research on remission in schizophrenia has gained attention, personality characteristics associated with remission in schizophrenia have been under-studied. A functional valine-to-methionine (Val158Met) polymorphism in the catechol-O-methyltransferase (COMT) gene is shown to modify clinical presentation of schizophrenia despite weak or no association with the disorder itself. Studies also report that this polymorphism can affect personality traits. We aimed to examine personality traits of remitted patients with schizophrenia as compared to symptomatic patients and healthy controls and to investigate whether the COMT Val158Met polymorphism influences their personality. Scores on the Temperament and Character Inventory were compared between 34 remitted outpatients with schizophrenia, age- and sex-matched 72 symptomatic outpatients with schizophrenia, and matched 247 healthy individuals. The effect of COMT Val158Met polymorphism on personality was examined in each group. The analysis of covariance, controlling for confounding variables, revealed that compared to healthy controls, symptomatic patients exhibited a pervasively altered personality profile whereas remitted patients showed alterations in more limited personality dimensions and demonstrated normal levels of novelty-seeking, reward dependence and cooperativeness. The two-way analysis of covariance, with genotype and sex as between-subject factors and confounders as covariates, revealed that Met carriers demonstrated significantly lower reward dependence and cooperativeness than Val homozygotes in symptomatic patients; while no significant genotype effect was found in remitted patients or in healthy individuals. These findings indicate that remitted patients with schizophrenia have a relatively adaptive personality profile compared to symptomatic patients. The COMT Val158Met polymorphism might have a modulating effect on the relationship between personality and remission.
No preview · Article · May 2014 · Journal of Psychiatric Research
[Show abstract][Hide abstract] ABSTRACT: Regulation of hypothalamic-pituitary-adrenal (HPA) axis reactivity plays an important role in the development of stress-related psychiatric disorders. FK506 binding protein 5 (FKBP5) modulates HPA axis reactivity via glucocorticoid receptor (GR; NR3C1) sensitivity and signaling. The T allele of the single nucleotide polymorphism, FKBP5 rs1360780 (C/T), is associated with higher FKBP5 induction by glucocorticoids. In the present study, we performed the dexamethasone/corticotropin releasing hormone (DEX/CRH) test and quantitative real-time PCR analysis of peripheral blood mononuclear cell (PBMC) cDNA samples in 174 and 278 non-clinical individuals, respectively. We found increased suppression of the stress hormone (cortisol) response to the DEX/CRH test (P = 0.0016) in aged (> 50 years) individuals carrying the T allele compared with aged non-T allele carriers. T carriers showed significant age-related changes in GR and FKBP5 mRNA expression levels in PBMCs (P = 0.0013 and P = 0.00048, respectively). Our results indicate that FKBP5 rs1360780 regulates HPA axis reactivity and expression levels of GR and FKBP5 in PBMCs in an age-dependent manner. Because these phenotypes of aged T carriers are similar to endophenotypes of people with post-traumatic stress disorder, our findings may be useful for determining the molecular mechanisms, treatment, and preventive strategies for this disease.
No preview · Article · Apr 2014 · Psychoneuroendocrinology