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Aim Understanding premorbid personality is important, especially when considering treatment selection. Historically, the premorbid personality of patients with major depression in Japan was described as Shuchaku-kishitsu [similar to Typus melancholicus], as proposed by Shimoda in the 1930s. Since around 2000, there have been increased reports in Japan of young adults with depression who have had premorbid personality differing from the traditional type. In 2005, Tarumi termed this novel condition 'dysthymic-type depression,' and more recently the condition has been called Shin-gata/Gendai-gata Utsu-byo [modern-type depression (MTD)]. We recently developed a semi-structured diagnostic interview to evaluate MTD. Development of a tool that enables understanding of premorbid personality in a short time, especially at the early stage of treatment, is desirable. The object of this study was to develop a self-report scale to evaluate the traits of MTD, and to assess the scale's psychometric properties, diagnostic accuracy, and biological validity. Methods A sample of 340 participants from clinical and community settings completed measures. Psychometric properties were assessed with factor analysis. Diagnostic accuracy of the MTD traits was compared against a semi-structured interview. Results The questionnaire contained 22 items across three subscales, thus we termed it the 22-item Tarumi's Modern-Type Depression Trait Scale: Avoidance of Social Roles, Complaint, and Low Self-Esteem (TACS-22). Internal consistency, test-retest reliability, and convergent validity were all satisfactory. Among patients with major depression, the area under the curve was 0.757 (sensitivity of 63.1% and specificity of 82.9%) and the score was positively correlated with plasma tryptophan. Conclusion The TACS-22 possessed adequate psychometric properties and diagnostic accuracy in an initial sample of Japanese adults. Additional research on its ability to support clinical assessment of MTD is warranted.

Aim Hikikomori, a form of severe social withdrawal, is an emerging issue in mental health, for which validated measurement tools are lacking. The object was to develop a self-report scale of hikikomori, and assess its psychometric properties and diagnostic accuracy. Methods A sample of 399 participants from clinical and community settings completed measures. Psychometric properties were assessed with factor analysis; diagnostic accuracy was compared against a semi-structured diagnostic interview. Results The Hikikomori Questionnaire contained 25 items across three subscales representing socialization, isolation, and emotional support. Internal consistency, test-retest reliability, and convergent validity were all satisfactory. The area under the curve was 0.86 (95% confidence interval, 0.80-0.92). A cut-off score of 42 (out of 100) was associated with a sensitivity of 94%, specificity of 61%, and positive predictive value of 17%. Conclusion The 25-item Hikikomori Questionnaire (HQ-25) possesses robust psychometric properties and diagnostic accuracy in an initial sample of Japanese adults. Additional research on its psychometric properties and ability to support clinical assessment of hikikomori is warranted.

BackgroundHigher daytime cortisol levels because of a hyperactive hypothalamic–pituitary–adrenal axis have been reported in patients with major depressive disorder (MDD). The elevated glucocorticoids inhibit the proliferation of the oligodendrocytes that are responsible for myelinating the axons of white matter fibre tracts.AimsTo evaluate the relationship between white matter integrity and serum cortisol levels during a first depressive episode in drug-naive patients with MDD (MDD group) using a tract-based spatial statistics (TBSS) method.MethodThe MDD group (n= 29) and a healthy control group (n= 47) underwent diffusion tensor imaging (DTI) scans and an analysis was conducted using TBSS. Morning blood samples were obtained from both groups for cortisol measurement.ResultsCompared with the controls, the MDD group had significantly reduced fractional anisotropy values (PPConclusionsOur findings indicate that the elevated cortisol levels in the MDD group may injure the white matter integrity in the frontal–subcortical and frontal–limbic circuits.

Catechol-O-methyltransferase (COMT) is a methylation enzyme engaged in the degradation of dopamine and noradrenaline by catalyzing the transfer of a methyl group from S-adenosylmethionine. An association was found between the Valine (Val) 108/158Methionine (Met) COMT polymorphism (rs4680) and major depressive disorder (MDD). The authors prospectively investigated the relationship between the Val108/158Met COMT genotype and voxel-based morphometry (VBM) findings for patients with first-episode and treatment-naïve MDD and healthy subjects (HS). Participants comprised 30 MDD patients and 48 age- and sex-matched HS who were divided according to the COMT genotype. Effects of diagnosis, COMT genotype, and the genotype-diagnosis interaction in relation to brain morphology in the Val/Met and Val/Val individuals were evaluated using a VBM analysis of high-resolution magnetic resonance imaging findings. Among the Val/Met individuals, the volume of the bilateral caudate was significantly smaller for MDD patients than for HS. In the Val/Val individuals, the caudate volume was comparable between MDD patients and HS. Significant genotype-diagnosis interaction effects on brain morphology were noted in the right caudate.

Background: Selective serotonin reuptake inhibitors (SSRIs) are considered first-line treatments for major depressive disorders (MDD). It has been reported, however, that 30–40% of patients with MDD who received SSRIs failed to respond to treatment. Use of lithium (Li) to augment SSRIs seems to be the most common strategy in such cases. It was recently demonstrated that atypical antipsychotics are effective augmentation agents in MDD. Here, we present a randomized controlled study that compared augmentation with Li, olanzapine (OLA) or aripiprazole (ARI) in paroxetine-refractory patients with MDD. Methods: Participants were 30 patients who met Diagnostic and Statistical Manual of Mental Disorders IV criteria for MDD and refractory to paroxetine treatment. Treatment with Li, OLA or ARI was added to paroxetine in a randomized protocol for 4 weeks. We defined the patients whose scores on the Hamilton Rating Scale for Depression decreased 50% or more as responders. Results: Two patients dropped out because of adverse effects. Response rates to Li, OLA or ARI augmentation were 4/10 (40%), 3/10 (30%) and 4/10 (40%), respectively. In addition, Li, OLA and ARI did not influence plasma paroxetine concentrations. Conclusions: We concluded that OLA or ARI could be used as alternatives to Li as options for patients who do not respond to paroxetine treatment.

Objective We investigated the plasma levels of interleukin (IL)-6 and 5-HTT polymorphisms in patients with major depressive disorder (MDD). This is the first report, to our knowledge, of an investigation into the association between 5-HTT gene polymorphism, plasma IL-6 levels, and responses to selective serotonin reuptake inhibitors (SSRIs) in Japanese patients with MDD. Method One-hundred and eighteen patients (51 male, 67 female) who met the DSM-IV criteria for MDD were enrolled. Their ages ranged from 24 to 78 (mean ± SD = 44 ± 12) years. The patients were treated with SSRIs (paroxetine in 66 cases, sertraline in 42 cases) for 8 weeks. Results The plasma levels of IL-6 were significantly higher in the SSRI responders than in the nonresponders (p = 0.0328), and the changes in plasma IL-6 levels correlated significantly with the changes in severity of depressive state (p = .0.007). No difference was found in baseline and the changes in plasma IL-6 levels between the patients with a 5-HTT gene (5-HTTLPR) L-carrier and those with S/S. Conclusion These results suggest that the plasma levels of IL-6 reflect the severity of MDD and that plasma IL-6 levels might be another biological-state marker for the depressive state. In addition, the 5-HTTLPR polymorphism might be independent of plasma IL-6 levels. Copyright © 2013 John Wiley & Sons, Ltd.

Objective Electroconvulsive therapy (ECT) has proven to be effective in treatment-resistant depression (TRD). In recent reports, 70% to 90% of patients with TRD responded to ECT. However, post-ECT relapse is a significant problem. There are no studies investigating risk factors associated with reintroducing ECT in depressive patients after remission previously achieved with former ECT. The aim of the present study is to examine such risk factors using a sample of TRD patients. Methods We conducted a chart review to examine patient outcomes and adverse events over short- and long-term periods. Forty-two patients met the criteria for major depressive disorder. Results The response rate was 85.7% (36/42). There were no significant differences in the baseline characteristics of patients exhibiting remission, response or non-response. The rate of adverse events was 21.4% (9/42). Among 34 patients who were available for follow-up, 18 patients relapsed (relapse rate, 52.9%), and 6 patients were reintroduced to ECT. The patients' age and age of onset were significantly higher in the re-ECT group than non re-ECT group. Conclusion Our results suggest that older age and older age of onset might be considered for requirement of re-ECT after remission previously achieved with former ECT.

Objectives Neuropsychiatric systemic lupus erythematosus (NPSLE) is accompanied by neurological or psychiatric symptoms that can be severe. We hypothesized plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) levels were the biological marker that reflected the severity of the NPSLE psychiatric symptoms, and we examined MHPG and HVA levels in systemic lupus erythematosus (SLE) patients. Methods The participants were 42 healthy volunteers and 41 SLE patients. SLE patients were divided into the three groups: NPSLE with psychiatric symptoms (NP group), NPSLE without psychiatric symptoms (NN group), and SLE without neuropsychiatric symptoms (S group). All blood samples were drawn before (T0) and after 4 weeks of treatment (T4) in all SLE patients, and once in the healthy volunteers. Plasma levels of MHPG and HVA were analyzed using high-performance liquid chromatography. Results Plasma MHPG levels at T0 were significantly increased in the SLE compared to those in healthy volunteers. The NN group had the greatest increase compared with other SLE patient groups. There were no significant differences in plasma HVA levels at T0 between the four groups, and there was also no difference in MHPG and HVA plasma levels between T0 and T4. Conclusion Hyperactivity of noradrenergic neurons and/or sympathetic nerves might be involved in SLE pathophysiology. Copyright © 2013 John Wiley & Sons, Ltd.

AIM: Burnout is a psychological condition that may occur in all workers after being exposed to excessive work-related stresses. We investigated suicidal ideation and burnout among Japanese psychiatric trainees as a part of the Burnout Syndrome Study (BoSS) International. METHODS: In the Japanese branch, 91 trainees fully completed suicide ideation and behaviour questionnaire (SIBQ) and Maslach Burnout Inventory-General Survey (MBI-GS). RESULTS: Passive suicidal ideation was reported by 38.5% of Japanese trainees and 22.0% of them had experienced active suicidal ideation. The burnout rate among Japanese subjects was 40.0%. These results were worse compared to the all 1980 trainees who fully completed the main outcome measure in BoSS International, 25.9%, 20.4% and 36.7%, respectively. CONCLUSIONS: Our results suggest a higher risk of suicide among Japanese residents. Japan has a higher suicide rate than other countries. Early detection of, and appropriate intervention for, suicidal ideation is important in preventing suicide in psychiatry residents.

ObjectWe investigated an association between the polymorphism of brain-derived neurotrophic factor (BDNF) gene Val66Met and the response to mirtazapine in Japanese patients with major depressive disorder (MDD). We also examined mirtazapine's effects on the serum BDNF and plasma levels of catecholamine metabolites in these patients.MethodsEighty-four patients who met the DSM-IV-TR criteria for MDD were treated with only mirtazapine for 4 weeks. The BDNF Val66Met polymorphism was detected by direct sequencing in the region, and serum BDNF levels and plasma levels of catecholamine metabolites were measured by ELISA and HPLC-ECD, respectively.ResultsMirtazapine treatment for 4 weeks significantly increased serum BDNF levels in the responders, whereas nonresponders showed significant decreases. No association was found between either of the two genotypes (Val/Val vs. Met-carriers) and the response to mirtazapine at T4 or the serum BDNF levels at T0. Mirtazapine did not alter the plasma levels of homovanillic acid (HVA) or 3-methoxy-4-hydroxyphenylglycol (MHPG).DiscussionThe dynamics of serum BDNF levels, but not plasma levels of HVA and MHPG, reflect the response to mirtazapine treatment; the BDNF Val66Met polymorphism in patients with depression is, however, associated with neither a particular response to mirtazapine treatment nor baseline serum BDNF levels.ConclusionSerum BDNF levels, but not plasma levels of HVA or MHPG, and BDNF Val66Met polymorphism are related to the mirtazapine response in MDD.

The serotonin 1A receptor gene (HTR1A) has been associated with mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Therefore, we conducted a systematic review and meta-analysis between rs6295 (C-1019G) as well as rs878567 in HTR1A and MDs. Searching PubMed through May 2012, 15 studies, including our own, previously unpublished association study (135 MDD patients and 107 healthy controls), met inclusion criteria for the meta-analysis of rs6295 (4,297 MDs patients and 5,435 controls). Five association studies met criteria for the meta-analysis of rs878567 (2041MDs patients and 2,734 controls). rs6295 was associated with combined MDs (P allele model = 0.007 and P recessive model = 0.01). When divided by diagnostic subgroup (MDD = 3,119 patients and 4,380 controls or BP = 1,170 patients and 2,252 controls), rs6295 was associated with each MDs separately (MDD: P allele model = 0.006, P recessive model = 0.01; BP: P dominant model = 0.003). Likewise, rs878567 was associated with combined MDs (2,041 patients and 2,734 controls (P allele model = 0.0002, P dominant model = 0.0008, and P recessive model = 0.01). When divided by diagnostic subgroup (MDD = 1,013 patients and 1,728 controls or BP = 1,051 patients and 2,099 controls), rs878567 was associated with MDD (P allele model = 0.0007 and P dominant model = 0.01), while only one BP study had such data, precluding a meta-analysis. All of these significances survived correction for multiple comparisons. Results from this expanded meta-analysis, which included our own new study, suggest that rs6295 (C-1019G) and rs878567 in HTR1A are related to the pathophysiology of MDs, with overlap between MDD and BP. Findings provide additional clues to the underlying biology and treatment targets in MDs.

We investigated the effects of the atypical antipsychotics risperidone, olanzapine, and aripiprazole on the cognitive functions of Japanese patients with schizophrenia with respect to dosage amounts and dosing schedules. We performed a cross-sectional survey using the Brief Assessment of Cognition in Schizophrenia - Japanese Language Version (BACS-J) to evaluate the neurocognitive functions of 101 schizophrenic patients who took the same dose of one of the three aforementioned antipsychotics for at least 3 months. The BACS-J composite score correlated negatively with the prescribed dosages of risperidone and olanzapine. In contrast, we did not find a correlation between the BACS-J composite score and the prescribed dosage of aripiprazole. Moreover, the primary scores for verbal learning, motor function, and attention and processing speed were significantly lower among the patients who were taking the prescribed dosage of risperidone. The scores for verbal learning and motor function were also significantly lower when correlated with the prescribed dosage of olanzapine. We did not find a correlation between any of the primary scores on the BACS-J and the prescribed dosage of aripiprazole. In fact, the results suggest there is no linear relationship between the dose of aripiprazole and cognitive impairment, which may be due to its unique pharmacological profile.

Objective: The present study sought to determine changes in plasma levels of catecholamine metabolites and serum levels of brain-derived neurotorophic factor (BDNF) among smokers with schizophrenia who were treated with varenicline. Methods: We compared plasma homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and serum BDNF levels across 4 groups, divided as follows: smokers with schizophrenia (S-Sc), nonsmokers with schizophrenia (NS-Sc), smokers who were otherwise healthy (S-HC) and nonsmokers who were otherwise healthy (NS-HC). In addition, we also examined plasma HVA and MHPG levels and serum BDNF levels prior to study initiation (T0) and 8 weeks after varenicline treatment (T8) in the S-Sc and S-HC groups. Results: Plasma HVA levels in the S-Sc group at T0 were significantly higher than in the NS-Sc, S-HC and NS-HC groups at the same time point (S-Sc at T0; 7.6 ± 1.6 ng/mL, NS-Sc; 4.8 ± 1.0 ng/mL, S-HC; 4.3 ± 0.9 ng/mL, NS-HC; 3.4 ± 1.4 ng/mL, p < 0.0001). Plasma MHPG levels in the S-Sc group at T0 were significantly higher than in the NS-Sc and S-HC groups; in addition, plasma MHPG levels in the NS-HC group were significantly higher than in the S-HC group (S-Sc at T0; 5.2 ± 0.7 ng/mL, NS-Sc; 2.8 ± 1.2 ng/mL, S-HC; 1.9 ± 0.8 ng/mL, NS-HC; 3.6 ± 1.3 ng/mL, p < 0.0002). Serum BDNF levels did not differ between the S-Sc and NS-Sc groups. In contrast, no difference in plasma HVA levels, plasma MHPG levels or serum BDNF levels was observed between T0 and T8. Conclusions: In conclusion, plasma levels of HVA and MHPG in the S-Sc group were significantly higher than in the NS-Sc group. Serum BDNF levels did not differ between the S-Sc and NS-Sc groups. Plasma HVA and MHPG levels and serum BDNF levels did not change after treatment with varenicline.

Objective We investigated the effects of aripiprazole on plasma levels of brain-derived neurotrophic factor (BDNF) and catecholamine metabolites in first-episode untreated schizophrenia patients. Methods The subjects were 50 Japanese first-episode untreated schizophrenia patients who met the Diagnostic and Statistical Manual of Mental Disorders Text Revision criteria and were treated with aripiprazole monotherapy. Twenty-nine were males, and 21 were females. The age ranged from 21 to 42 years (mean ± SD; 30.8 ± 5.3 years). Plasma BDNF and catecholamine metabolites were measured by ELISA and HPLC, respectively. Psychiatric symptoms were evaluated using by Positive and Negative Syndrome Scale. Results Treatment with aripiprazole for 8 weeks significantly increased plasma BDNF levels. It also changed plasma levels of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. A negative correlation was also observed between duration of psychosis and plasma BDNF levels. No correlation was observed however between plasma BDNF levels and the dose of aripiprazole. Conclusions To the best of our knowledge, this is the first report showing that aripiprazole increases plasma BDNF levels in first-episode untreated schizophrenia patients. Furthermore, the BDNF Val66Met polymorphism was independent of the response to aripiprazole. Copyright © 2011 John Wiley & Sons, Ltd.

Background Depression is a risk factor for coronary heart disease. Nitric oxide (NO) plays an important role in both coronary heart disease and depression. Methods Fifty-one inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition criteria for major depressive disorder (MDD) in the university hospital of the University of Occupational and Environmental Health and 58 age-matched and sex-matched healthy controls enrolled in this study. We investigated the association between the three polymorphisms of the endothelial nitric oxide synthase (eNOS) gene (single-nucleotide polymorphism (SNP); rs2070744, rs1799983, variable number tandem repeat (VNTR) in intron 4) and scores on the Hamilton Rating Scale for Depression, plasma metabolites of NO (NOx) or ankle brachial index in patients with MDD and healthy controls. Results We did not find significant differences in the genotype distributions between patients with MDD and healthy volunteers. No associations were observed between any of the polymorphisms of the eNOS gene and the Hamilton Rating Scale for Depression or ankle brachial index in patients with MDD. However, plasma NOx level was significantly associated with a polymorphism of the eNOS gene (rs207044 and variable number tandem repeat in intron 4). Conclusion These results suggest that the direct association was not observed between the polymorphisms of the eNOS gene and the pathogenesis of depression. Copyright © 2011 John Wiley & Sons, Ltd.

To explore whether the 'hikikomori' syndrome (social withdrawal) described in Japan exists in other countries, and if so, how patients with the syndrome are diagnosed and treated.Two hikikomori case vignettes were sent to psychiatrists in Australia, Bangladesh, India, Iran, Japan, Korea, Taiwan, Thailand and the USA. Participants rated the syndrome's prevalence in their country, etiology, diagnosis, suicide risk, and treatment.Out of 247 responses to the questionnaire (123 from Japan and 124 from other countries), 239 were enrolled in the analysis. Respondents' felt the hikikomori syndrome is seen in all countries examined and especially in urban areas. Biopsychosocial, cultural, and environmental factors were all listed as probable causes of hikikomori, and differences among countries were not significant. Japanese psychiatrists suggested treatment in outpatient wards and some did not think that psychiatric treatment is necessary. Psychiatrists in other countries opted for more active treatment such as hospitalization.Patients with the hikikomori syndrome are perceived as occurring across a variety of cultures by psychiatrists in multiple countries. Our results provide a rational basis for study of the existence and epidemiology of hikikomori in clinical or community populations in international settings.

Background We investigated the relationship between a brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) and the clinical response of patients with major depressive disorder to selective serotonin reuptake inhibitors (SSRIs; here, paroxetine and sertraline). In addition, serum BDNF levels in these patients were considered together with the clinical response. Methods A total of 132 patients who met the DSM-IV criteria for major depressive disorder were enrolled in the study. 54 of these patients were male and 78 were female (age range, 20–74 years; mean ± S.D., 51 ± 15). The patients' clinical improvement was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17) before (T0) and at 8 weeks after the administration of SSRI treatment (T8). Patients with at least a 50% decrease in the HAMD-17 score were classified as responders. Results No correlation was observed between the BDNF Val66Met polymorphism and response to SSRIs or between the BDNF Val66Met polymorphism and serum BDNF levels at T0. An inverse correlation was found between serum BDNF levels and HAMD-17 scores at T0. Conclusions These results suggest that the BDNF Val66Met polymorphism is independent of both the response to SSRI treatment and serum BDNF levels. The findings in the present study reconfirm that the serum BDNF level is a state biomarker for depression.

Background Brain-derived neurotrophic factor (BDNF) plays an important role in the regulation of synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems. Recent studies have suggested that BDNF plays a role in the pathogenesis of psychiatric symptoms in patients with systemic lupus erythematosus (SLE). Objectives We hypothesized that the polymorphism of BDNF Val66Met is associated with the emergence of psychiatric symptoms (PS) and serum BDNF levels in SLE patients. To examine the hypothesis, we compared the BDNF Val66Met polymorphism and serum BDNF levels in patients with SLE with or without PS. Methods Psychiatric symptoms were assessed in 54 patients with SLE. PS were evaluated using the Brief Psychiatric Rating Scale. Genotyping was carried out using a 54-nuclease assay. Serum BDNF levels were measured by using enzyme-linked immunosorbent assay. Results The presence of the Met allele was not significantly associated with the presence of PS or with serum BDNF levels in patients with SLE. Conclusion Our data do not support the common variant Val66Met of the BDNF gene as an etiologic factor in the various forms of PS and serum BDNF levels in SLE. Copyright © 2011 John Wiley & Sons, Ltd.

In the present study, we investigated the serum BDNF levels and plasma IL-6 levels in patients with dysthymic disorder, major depressive disorder and control subjects. Eighteen patients who met the DSM-IV criteria (American Psychiatric Association, 1994) for dysthymic disorder (male/female: 5/13; age: 36 ± 9 year) and 20 patients (male/female: 7/13; age: 38 ± 10 year) who met the criteria for major depressive disorder were enrolled. The serum BDNF levels in patients with dysthymic and major depressive disorder were significantly lower than those in the control subjects. However, no difference was found between the dysthymic group and major depression group. The plasma IL-6 levels in the dysthymic group and major depression group were significantly higher than those in the control group. No difference was observed in the plasma IL-6 levels between the dysthymic group and major depression group. These results suggest that the pathophysiology of dysthymic disorder and major depression might be similar in terms of the blood levels of BDNF and IL-6. Copyright © 2011 John Wiley & Sons, Ltd.

Background Many studies including our previous ones as to PROKR2 and CLOCK have suggested that circadian genes may be involved in the mechanisms of mood disorders and their treatment responses. Also several recent investigations have reported that SIRT1 plays an important role in the circadian system as conventional circadian clock genes, and also have some relation to dopaminergic metabolism. So we considered the SIRT1 gene to be a good candidate gene for the pathophysiology for MDD and SSRI responses in MDD, and conducted a case–control study using four tagging SNPs (450 MDD patients, including 261 patients treated by SSRIs and 766 controls). Method The MDD patients in this study had scores of 12 or higher on the 17 items of the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a clinical response as a decrease of more than 50% in baseline SIGH-D within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks. Marker-trait association analysis was used to evaluate allele and genotype association with the chi-square test, and haplotype association analysis was evaluated with a likelihood ratio test. Result We found an association between rs10997875 in SIRT1 gene and MDD in the allele/genotype analysis. In addition, this significance of these associations survived Bonferroni correction. However, we did not find any association between SIRT1 gene and SSRI therapeutic response in MDD in the allele/genotype analysis or haplotype analysis. Limitations A replication study using larger samples may be required for conclusive results, since our sample size was small. Conclusions Our results suggest that rs10997875 in SIRT1 gene may play a role in the pathophysiology of MDD in the Japanese population.

Psychiatry has been strongly influenced by culture, society, history and the prevailing public needs of the particular country.1–3 Accordingly, psychiatric training systems differ from country to country, which might be a mirror of the particular country's current situation and its future prospects toward mental health.4 A well-balanced view toward psychiatry, which is often described as a ‘biopsychosocial model of psychiatry’, has been proclaimed as ideal. However, recent increasing demand for biological factors of psychiatry presents a potential gap between expected and actually acquired skills in terms of psychosocial factors, leading younger psychiatrists to fall between mind–brain (or mind–body) dichotomy.5–8 How do young psychiatrists (in this article, ‘young psychiatrists’ are defined as psychiatric residents, trainees, and certified psychiatrists with clinical experience of 10 years or fewer) see themselves from biopsychosocial perspectives? Do they define themselves as doctors of the ‘brain’, doctors of the ‘mind’, or doctors who address sociocultural issues? The answer may be influenced by multiple factors, including their original motivation to become psychiatrists, their domains of interests, and the level of acquired skills and education/training undertaken. Facing recent sociocultural changes, such as aging society and high suicide rate, Japan implemented a new system of postgraduate medical education (PGME) in 2004. Until that time, psychiatric residents would start their psychiatric training immediately after graduating from medical school, join a specific clinical department of psychiatry in medical universities, known as ikyoku,9 and rotate through psychiatric hospitals.9–11 Therefore, under the pre-2004 PGME system, psychiatrists used to devote most of their time to psychiatry11 and have very little experience with medical approaches epitomized by evidence-based medicine and the systematic problem–solution approach. Since 2004, a two-year general residency has been required of medical graduates,12–14 in order to improve basic clinical skills of all medical doctors in primary care settings.15 In this new PGME system, first-year residents rotate in internal medicine, surgery, emergency medicine and anesthesiology, and second-year residents rotate in pediatrics, community medicine, obstetrics/gynecology and psychiatry for at least one month each. Thereafter, residents start their specialty training, including psychiatry, for up to 4 years.9 The balance among biological, psychological and sociocultural orientations may have been influenced by the implementation of the new PGME system. We hypothesized that psychiatrists trained in the new PGME system might lay more emphasis on biological factors because of their two-year rotation in medicine. Thus, the present study aimed to explore the balance among biological, psychological and sociocultural factors in young psychiatrists' attitudes – namely, to explore whether young psychiatrists consider themselves doctors of ‘brain’, doctors of ‘mind’, or doctors who address sociocultural issues. Changes in their attitudes before and after implementation of the new PGME system, as well as possible contributing factors, were also explored. The same questionnaire was distributed to both psychiatrists in and out of Japan, in order to highlight their differences.

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat both anxiety disorders and depressive disorders. However, nonadherence to SSRIs is a major issue in recurrence. In the present study, we investigated paroxetine adherence in depressed patients by monitoring the plasma paroxetine concentrations between patients with rapid and those with a late response to paroxetine treatment. Twenty inpatients in our university hospital, who met the DSM-IV-TR diagnosis of major depressive disorder in a single episode, were enrolled in the study. Twelve patients (M/F: 7/13, age: 37.4 +/- 10.4 years) were treated with paroxetine (40 mg/day), and all achieved remission (HAMD < or = 7) within at least 12 weeks. We divided the patients into two groups, an early-remission group (HAMD < or = 7 within 4 weeks) and a late-remission group (HAMD < or = 7 within 8-12 weeks). Their dosages of paroxetine were constant because of no emerging adverse effects. Blood samples were obtained on the day the subjects were discharged (B) and 12 weeks after discharge. The paroxetine concentrations in the early-remission group were significantly decreased 12 weeks after discharge, and no difference was found between the early- and late-remission groups. These results suggest that adherence to paroxetine was independent of the duration of the depressive state suffered by the patients. Clinicians always take their cautions for the adherence to paroxetine regardless of the clinical time courses the patients recovering from their depressive symptoms.

Several evidence suggests that alterations in serotonin 6 (5-HT6) receptors might be associated with the pathophysiology of mood disorders. Therefore, to evaluate the association between HTR6 and BP and MDD, we conducted a case-control study of Japanese population samples (1007 BP patients, 447 MDD patients and 1753 controls) with five tagging SNPs, including rs1805054 (C267T), in HTR6. In addition, we conducted a meta-analysis of rs1805054, which has been examined in other studies. We selected five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997). Moreover, three association studies for BP and four association studies for MDD, including this study, met our criteria for the meta-analysis of rs1805054. We did not detect an association between tagging SNPs in HTR6 and BP and MDD in the allele/genotype, haplotype analysis or meta-analysis. In conclusion, we found no association involving polymorphism and mood disorder in the Japanese population. However, because changes in expression level or signal transduction of this receptor may be involved in the pathology of these diseases, it will be necessary to conduct the further study about the relationship between this receptor and mood disorders in the future.

Several investigations have reported that abnormalities in circadian rhythms might be related with the pathophysiology of psychiatric disorders, since many psychiatric patients have insomnia and sleep-awake disturbance. A recent animal study reported that Magel2, which encodes a member of the MAGE/necdin family of proteins, might be associated in the pathophysiology of psychiatric disorders. Magel2 gene knockout mice showed altered concentrations of both dopamine and serotonin in several parts of the brain compared with controls. In addition, the authors of that study detected a bilateral reduction in cortical volume in distinct regions of the Magel2 gene knockout mice brain, including focused regions in the parieto-temporal lobe of the cerebral cortex, the amygdala, the hippocampus, and the nucleus accumbens. These mice were also found to have hypoactivity and abnormalities in circadian rhythms. From this evidence, we considered Magel2 gene (MAGEL2) to be a good candidate gene for the pathophysiology of schizophrenia and mood disorder, and we conducted a case-control study among Japanese (731 schizophrenia patients, 465 MDD patients, 156 BP patients and 758 controls) using three tagging SNPs in MAGEL2 (rs850815, rs8920 and rs4480754), selected using the HapMap database. We did not find any association between MAGEL2 and schizophrenia, BP or MDD in allele/genotype-wise analysis or haplotype-wise analysis. Our results suggest that MAGEL2 may not play a role in the pathophysiology of schizophrenia and mood disorders in the Japanese population. A replication study using larger samples may be required for conclusive results, since our sample size was small and our study analyzed only three SNPs in MAGEL2.

Only two-thirds of depressive patients respond to antidepressant treatment. Recently, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we examined the effects of various atypical antipsychotic drugs as adjuvant to antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants and mood stabilizers, on plasma BDNF levels in refractory depressed patients. Forty-five patients who met the DSM-IV criteria for major depressive disorder (n=31) or bipolar disorder (10 with bipolar I, 4 with bipolar II) were enrolled in the study. Twenty-one were male and 24 were female, and their ages ranged from 28 to 71 (mean+/-SD=49+/-12) years. Plasma BDNF levels were measured using a sandwich ELISA. The plasma BDNF levels in responders (those showing a decline in HAM-D scores of 50% or more) were significantly increased 4weeks after the administration of each atypical antipsychotic drug, while the levels in non-responders were not changed. Furthermore, there was a significant correlation between the changes in HAM-D scores and the changes in plasma BDNF levels. These results suggest that adding an atypical antipsychotic drug to ongoing treatment with an antidepressant or mood stabilizer is useful and well-tolerated for refractory depressed patients, and the efficacy of atypical antipsychotics as an adjuvant might involve an increase of plasma BDNF levels.

Schizophrenic patients demonstrate a variety of cognitive deficits, including attention, executive functions, and working memory, even in the early stage of disease. In the present study, we examined the association between blood levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), or brain-derived neurotrophic factor (BDNF) and scores on the Wisconsin Card Sorting Test (WCST) in patients with early-stage schizophrenia. We also investigated the association between frontal GABA levels using 1H-magnetic resonance spectroscopy (MRS) at 3T and scores on the WCST in the same patients. Blood levels of BDNF and catecholamine metabolites and brain GABA levels using 1H-MRS were measured in 18 schizophrenic patients (nine males, nine females; age range 13-52 year). A significantly positive correlation was observed between plasma MHPG levels and %PEM (rho = -0.686, p = 0.0047). A trend toward negative correlation was found between frontal lobe GABA levels and the per cent of preservation error (%PEM) in the early stage of schizophrenia (rho = -0.420, p = 0.0836). These results suggest that noradrenergic neurons might be involved in neuropsychological functions in early-stage of schizophrenia.

In the present study, we investigated the effects of sertraline on plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and serum brain-derived neurotrophic factor (BDNF) levels in 59 depressed patients treated with sertraline. We also examined the relationship between the dynamics of the catecholamine metabolites, BDNF, serotonin transporter-linked polymorphic region (5-HTTLPR) gene polymorphism (long and short alleles), and the clinical response to sertraline. The extent of clinical improvement was evaluated using the 17-item Hamilton Rating Scale for Depression (Ham-D) before and 8 weeks after treatment with sertraline. Responders were defined as showing at least a 50% decrease in the Ham-D score. Baseline plasma HVA levels of responders to sertraline treatment were significantly lower than those of non-responders (p = 0.02). In addition, a positive correlation was identified between changes in plasma HVA levels and the rate of response to sertraline treatment (p = 0.001). A trend toward higher baseline serum BDNF levels was found in responders compared with non-responders (p = 0.095). In addition, serum BDNF levels were slightly increased (not significant) in responders (p = 0.058), but not in non-responders. Responders had a higher short-allele genotype frequency in the 5-HTTLPR for the promoter region than did non-responders (p = 0.037). These results suggest that pre-treatment plasma HVA levels and the 5-HTTLPR genotype for the promoter might be associated with a response to sertraline.

Alcohol dependence is often comorbid with depression. The purpose of the present study was to compare serum brain-derived neurotrophic factor (BDNF) levels between depressive patients with and without alcohol dependence. Our subjects were 16 inpatients (M/F: 13/3, age: 48 +/- 8 years) at our university hospital who met the DSM-IV-TR criteria for both major depressive disorder and alcohol dependence and whose Hamilton Rating Scale for Depression (HAM-D) scores were at least 15. Twenty sex- and age-matched depressive patients and 20 healthy subjects were also examined. Serum BDNF levels in the depressive patients with (9.0 +/- 4.3 ng/ml) and without (9.8 +/- 5.2 ng/ml) alcohol dependence were significantly lower than those in the healthy subjects (21.1 +/- 7.0 ng/ml); however, no significant difference was found in the serum BDNF levels of depressive patients with and without alcohol dependence. Eight of the 16 (50%) depressive patients suffering from both depression and alcohol dependence responded to 8 weeks of treatment with antidepressant drugs which significantly increased their serum BDNF levels. These results suggest that the serum BDNF level is a useful biological marker for depression in patients with alcohol dependence.

In the present study, we compared plasma levels of interleukin-6 (IL-6), tumor necrosis factor-alpha(TNFalpha), and brain-derived neurotrophic factor (BDNF) among selective serotonin reuptake inhibitor (SSRI)- or serotonin noradrenaline reuptake inhibitor (SNRI)-responsive depressed patients (n=31), SSRI- or SNRI-refractory depressed patients (n=20), and healthy controls (n=30). The plasma levels of IL-6 and TNF-alpha were significantly higher in depressed patients than in healthy controls. Treatment with antidepressants significantly reduced plasma levels of IL-6 and TNF-alpha. In addition, the plasma IL-6 level, but not the plasma TNF-alpha level, was higher in SSRI-refractory than SSRI-responsive depressed patients, and higher in SNRI-refractory than SNRI-responsive depressed patients. On the other hand, the plasma BDNF level was significantly lower in depressed patients than in healthy controls, whereas no difference was found in plasma BDNF levels between SSRI-responsive and -refractory depressed patients or between SNRI-responsive and -refractory depressed patients. These results suggest that higher plasma IL-6 activity is associated with the refractoriness of depression, and plasma IL-6 levels might be a predictor for response to SSRIs or SNRI.

In the present study, we compared the plasma levels of the active moiety (i.e. risperidone plus 9-hydroxyrisperidone) in a steady state in 54 Japanese schizophrenic patients with or without emerging extrapyramidal symptoms (EPS and non-EPS groups, respectively) who were treated with 4 mg/day risperidone. No differences were observed in the plasma levels of the active moiety at 4 and 8 weeks after risperiodne administration in both groups. However, the EPS group patients showed a greater number of fluctuations/larger fluctuations in the plasma active moiety levels than those in the non-EPS group. These results suggest that a stable plasma active moiety level maybe important for preventing EPSs during treatment with risperidone.

In the present study, we examined the efficacy of risperidone addition on sertraline-resistant depressed patients and the effects of risperidone on the metabolism of sertraline. Ten patients (M/F: 4/6, age: 54 +/- 10 years) met the DSM-IV criteria for major depressive disorder enrolled the study. Hamilton Dating Scale for Depression (HAM-D) scores (mean +/- SD) in all 10 patients significantly decreased from 19 +/- 4 (before risperidone addition) to 11 +/- 3 (4 weeks after risperidone addition). Plasma levels of sertraline and desmethylsertraline did not change after risperidone addition. Serum BDNF levels in responders to risperidone addition were changed from 8.1 +/- 2.7 ng/ml (before risperidone addition) to 11.5 +/- 0.9 ng/ml (4 weeks after risperidone addition); in contrast, those in nonresponders changed from 7.8 +/- 2.2 ng/ml (before risperidone addition) to 7.9 +/- 2.4 ng/ml (4 weeks after risperidone addition). These results suggest that the addition of risperidone to sertraline is effective and well tolerated for sertraline-resistant depressive patients, which is accompanied with the increase in serum BDNF levels in responders to the risperidone addition, and the addition of risperidone to sertraline does not seem to influence sertraline metabolism.

Excessive cigarette smoking and caffeine intake are often seen in schizophrenic patients being treated with antipsychotic drugs, particularly typical antipsychotic drugs. Using nicotine and caffeine sometimes influences psychotic symptoms in these patients. Clozapine is the only antipsychotic drug reported to reduce the amount of cigarette smoking, however, still remains controversial of its efficacy. In the present study, we examined the effect of acute risperidone treatment on the amount of cigarette smoking and plasma levels of cotinine and caffeine in schizophrenic patients. Treatment with risperidone for 4 weeks did not increase daily cigarette consumption or plasma levels of cotinine and caffeine. The results suggest that acute risperidone treatment does not promote the intake of nicotine and caffeine at least by 4 weeks in schizophrenic patients.

No support for replication of the genetic variants identified by a recent mega-analysis of the treatment response to antidepressants

The effect of the catechol-O-methyltransferase (COMT) Val158Met polymorphism on brain morphology has been investigated but remains controversial. We hypothesized that a comparison between Val/Val and Val/Met individuals, which may represent the most different combinations concerning the effects of the COMT genotype, may reveal new findings. We investigated the brain morphology using 3-Tesla magnetic resonance imaging in 27 Val/Val and 22 Val/Met individuals. Voxel-based morphometry revealed that the volumes of the bilateral caudate and posterior cingulate cortex were significantly smaller in Val/Val individuals than in Val/Met individuals [right caudate: false discovery rate (FDR)-corrected p = 0.048; left caudate: FDR-corrected p = 0.048; and bilateral posterior cingulate cortex: FDR-corrected p = 0.048]. This study demonstrates that interacting functional variants of COMT affect gray matter regional volumes in healthy subjects.

Kenji Hayashi,1 Reiji Yoshimura,1 Shingo Kakeda,2 Taro Kishi,3 Osamu Abe,4 Wakako Umene-Nakano,1 Asuka Katsuki,1 Hikaru Hori,1 Atsuko Ikenouchi-Sugita,1 Keita Watanabe,2 Satoru Ide,2 Issei Ueda,2 Junji Moriya,2 Nakao Iwata,3 Yukunori Korogi,2 Marek Kubicki,5 Jun Nakamura1 1Department of Psychiatry, 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan; 3Department of Psychiatry, Fujita Health University, Toyoake, Japan; 4Department of Radiology, Nihon University School of Medicine, Tokyo, Japan; 5Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Abstract: We investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age ± standard deviation [SD] =44±12 years) and 30 sex- and age-matched healthy controls (17 males and 13 females, aged 44±13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P

Objective. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic family found in both the central and the peripheral nervous system. Blood BDNF levels are considered as a state marker for depression. Methods. We investigated serum and plasma levels of BDNF levels in 103 healthy volunteers (M/F: 39/64, age: 37±12 years) using ELISA methods. Results and Conclusions. Serum BDNF levels were 14-fold higher than plasma BDNF levels, and a close relationship was found between serum and plasma BDNF levels.

The brain-derived neurotrophic factor (BDNF) relates to basic neuronal functions, such as cell survival, axonal outgrowth, and dendritic growth. The Val66Met polymorphism of the BDNF gene may affect genetic susceptibility to major depressive disorder (MDD). We prospectively investigated the relationship between the Val66Met BDNF genotype and voxel-based morphometry (VBM) findings for first episode and drug-naive MDD patients and healthy subjects (HS). Participants comprised 38 MDD patients and 42 age- and sex-matched HS were divided into groups based on their BDNF genotype. The effects of diagnosis and genotype, as well as the genotype–diagnosis interaction, in relation to brain morphology were evaluated using a voxel-by-voxel statistical analysis of high-resolution magnetic resonance imaging (MRI) findings. Among the Met-carriers, the volume of the left middle frontal gyrus (composition of the prefrontal cortex [PFC]) was significantly smaller for MDD patients than for the HS, i.e., there was a significant genotype–diagnosis interaction effect on brain morphology noted in the left PFC. The BDNF polymorphism was associated with atrophy of the PFC in MDD patients, which suggests that the BDNF Val66Met polymorphism may play an important role in the pathogenesis of early stages of MDD.

In the present study, we aimed to investigate the difference in white matter between smokers and nonsmokers. In addition, we examined relationships between white matter integrity and nicotine dependence parameters in smoking subjects. Nineteen male smokers were enrolled in this study. Eighteen age-matched non-smokers with no current or past psychiatric history were included as controls. Diffusion tensor imaging scans were performed, and the analysis was conducted using a tract-based special statistics approach. Compared with nonsmokers, smokers exhibited a significant decrease in fractional anisotropy (FA) throughout the whole corpus callosum. There were no significant differences in radial diffusivity or axial diffusivity between the two groups. There was a significant negative correlation between FA in the whole corpus callosum and the amount of tobacco use (cigarettes/day; R = − 0.580, p = 0.023). These results suggest that the corpus callosum may be one of the key areas influenced by chronic smoking.

We investigated the plasma levels of 3-methoxy-4-hydroxyglycol (MHPG) in patients who failed to paroxetine treatment and switched to milnacipran. The aim of the present study is to predict responders to serotonin noradrenaline reuptake inhibitor (SNR) who were resistant to selective serotonin reuptake inhibitor (SSRI) based on the plasma MHPG levels. The HAMD17 scores decreased from 17.0 ± 2.2 to 9.5 ± 2.5 after 4 weeks of milnacipran treatment. Eight of 20 (40%) patients were responded 4 weeks after milnacipran treatment. Five of 20 (25%) became remission. Plasma MHPG was changed neither in responders (from 4.9 ± 0.7 ng/ml to 5.6 ± 0.8 ng/ml) (t=-1.604, p=0.132) nor in nonresponders (from 5.1 ± 1.3 ng/ml to 5.3 ± 1.2 ng/ml) (t=-0.363, p=0.719). No difference was found in the change of plasma MHPG before and 4 weeks after milnacipran administration in two groups (t=1.894, p=0.073). These results suggest that the change of plasma MHPG level was not related to the improvement when switching from paroxetine to milnacipran.

Depression is a risk factor for coronary heart disease (CHD). It has been demonstrated that there is a potential role of nitric oxide (NO) in the relationship between depression and CHD risk as well as an effect of antidepressants on NO production. This study included 40 in- or outpatients in our university hospital who met the DSM-IV-TR criteria for major depressive disorder (M/F: 15/25, age: 47+/-19 years) and 30 age- and sex-matched healthy controls (M/F: 10/20, age: 45+/-15 years), and also examined the effects of the antidepressants on the plasma NOx levels in depressed patients. The baseline plasma NOx levels were significantly lower in the whole depressed group than in the control group (p

Further evidence of an association between a genetic variant in BMP7 and treatment response to SSRIs in major depressive disorder

Objective We investigated the effects of duloxetine on the plasma levels of catecholamine metabolites and serum brain-derived neurotrophic factor (BDNF) in 64 patients with major depressive disorder (MDD). Methods Major depressive episode was diagnosed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-fourth edition (DSM-IV) according to the DSM-IV text revision (DSM-IV-TR) criteria. The severity of depression was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17). Blood sampling and clinical evaluation were performed on days 0, 28, and 56. Results Duloxetine treatment for 8 weeks significantly increased the plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels but not the homovanillic acid (HVA) levels in responders with MDD. Conclusion These results imply that noradrenaline plays an important role in alleviating depressive symptoms.

Objective It is important to predict a response to an antidepressant in early time after starting the antidepressant. We previously reported that serum brain-derived neurotrophic factor (BDNF) levels in responders to treatment with antidepressants were increased, whereas, those in nonresponders were not. Therefore, we hypothesized that the changes in serum levels of BDNF from baseline (T0) to 4 weeks (T4) after treatment with selective serotonin reuptake inhibitors (SSRIs) predict the response to the treatment at 8 weeks (T8) in depressed patients. To confirm the hypothesis, we measured serum BDNF at T0, T4, and T8 during the treatment with SSRIs (paroxetine, sertraline, and fluvoxamine). Methods One hundred fifty patients (M/F; 51/99, age; 50.4±15.1 years) met major depressive disorder (MDD) using by DSM-IV-TR enrolled in the present study. We measured serum BDNF concentrations at T0, T4, and T8 in patients with MDD treated with SSRIs. Results The changes in serum BDNF, age, sex, dose of SSRIs, and HAMD-17 score did not predict the response to SSRIs at T8. Conclusion These results suggest that the changes in serum BDNF levels from T0 to T4 could not predict the subsequent responses to SSRIs at T8.

The association between smoking and psychiatric disorders (PD) has been known for many years. Support for smoking cessation among patients with PD is provided in advanced nations, but there is a little support for smoking cessation among patients with PD in Japan, where few studies have investigated the smoking rate. The aim of the present study is to determine the smoking rate and smoking habits of Japanese patients with PD. The subjects included outpatients who visited the outpatient psychiatric clinic at a University hospital between January and March of 2011. They answered a questionnaire consisting of questions about their sociodemographic background and smoking habits. In an analysis of 733 subjects, the overall smoking rate was 25.1%. The smoking rates among the patients with schizophrenia and depression were 17.3% and 23.9%, respectively, and these rates were lower than the results of previous studies. Among the current smokers, 43.4% had experienced smoking cessation, and only 26.1% were not interested in smoking cessation. Of the current smokers, 37.5% spent between US$128.88 and US$257 per month on cigarettes.