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Aims: To determine the prevalence and impact of emotional blunting (EB) in patients with major depressive disorder (MDD) in Japan, and identify treatment needs for EB using patients' perceptions and attitudes. Methods: Eligible patients in Japan (aged 18–59 years) who reported a diagnosis of MDD and antidepressant medication use for >3 months were eligible to complete an online survey. The primary outcome was the prevalence of EB, self‐reported using a validated screening question. Secondary outcomes included the correlation between EB symptoms (measured by the Oxford Depression Questionnaire [ODQ]) and scores on the Patient Health Questionnaire 9‐item (PHQ‐9), Generalized Anxiety Disorder 7‐item (GAD‐7), Work and Social Adjustment Scale (WSAS), and the EuroQol 5‐Dimension 5‐Levels questionnaire (EQ‐5D‐5L). Descriptive questions were used to explore patients' perceptions and attitudes toward EB. Results: In total, 3376 patients were included in the analysis (56% male; 48% aged 50–59 years). Overall, 67.1% of patients self‐reported symptoms of EB, with 10% rating these as severe. The mean (SD) ODQ total score was 78.2 (21.5), which increased with worsening EB symptoms. There were correlations between ODQ total scores and the PHQ‐9, GAD‐7, WSAS, and EQ‐5D‐5L scores (correlation coefficients: 0.67, 0.55, 0.56, −0.51, respectively; all p < 0.0001). Descriptive analyses showed that one‐third of patients reporting EB symptoms did not tell their physician, with two‐thirds finding these symptoms distressing and likely to affect recovery. Conclusion: EB is an important clinical issue in Japan that needs to be considered alongside functional recovery when managing treatment of patients with MDD. [ABSTRACT FROM AUTHOR]

Background: Little information is available on the association between gender nonconformity during adolescence and subsequent mental health. While the distress related to gender nonconformity may be socially produced rather than attributed to individual-level factors, further research is needed to better understand the role of psychosocial factors in this context. Method: We analyzed data from the Tokyo Teen Cohort, obtained through random sampling of adolescents born between 2002 and 2004. We used inverse probability weighting to examine the association of gender nonconformity at ages 12 and 14 as a time-varying variable with subsequent mental health at age 16, while accounting for time-fixed and time-varying confounders. Furthermore, we used a weighting approach to investigate the mediating role of modifiable psychosocial factors in this association, addressing exposure-mediator and mediator–mediator interactions. Results: A total of 3171 participants were analyzed. Persistent gender nonconforming behavior at ages 12 and 14 was associated with subsequent depression (β = 2.02, 95% confidence interval [CI] 0.85 to 3.19) and psychotic experiences (β = 0.33, 95% CI 0.14 to 0.52) at age 16. The results remained robust in sensitivity analyses. Approximately 30% of the association between gender nonconformity and depression was consistently mediated by a set of psychosocial factors, namely loneliness, bullying victimization, and relationships with mother, father, and friends. Conclusions: Persistent gender nonconformity during adolescence is associated with subsequent mental health. Psychosocial factors play a vital mediating role in this association, highlighting the essential need for social intervention and change to reduce stigmatization and ameliorate mental health challenges. [ABSTRACT FROM AUTHOR]

Aim: Interview quality is an important factor in the success of clinical trials for major depressive disorder (MDD). There is a substantial need to establish a reliable, remote clinical assessment interview system that can replace traditional in‐person interviews. Methods: We conducted a multicenter, randomized, unblinded, prospective, cross‐sectional study to assess the reliability of remote interviews in patients with MDD (UMIN000041839). Eligible patients with MDD underwent remote and in‐person sessions of the Montgomery‐Åsberg Depression Rating Scale (MADRS) assessment performed by different raters within 28 days of providing consent. Patients were randomized to a group first assessed using in‐person interviews and secondarily using remote interviews (in‐person‐first group) or a group first assessed by remote interviews and secondarily using in‐person interviews (remote‐first group). Nineteen trained people (15 clinical psychologists, 3 nurses, and 1 clinical laboratory technologist) performed interviews. Results: Of 59 patients (in‐person‐first group, n = 32; remote‐first group, n = 27) who completed both remote and in‐person interviews, 51% (n = 30) were women; the mean age was 41.6 years (range, 21–64 years). There was a strong association between remote and in‐person MADRS scores (r = 0.891, kappa = 0.901). An overall intraclass correlation coefficient (ICC) of 0.886 (95% confidence interval, 0.877–0.952) indicated good consistency between MADRS scores in remote and in‐person interviews. The ICC decreased as the severity of depression increased. Conclusion: Our results suggest remote interviews are a feasible alternative option to in‐person interviews in assessing symptom severity in MDD patients and could promote clinical trials in Japan. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of escitalopram (ESC) in a 48-week relapse prevention study in Japanese adolescents with major depressive disorder (MDD). Methods: This was a 48-week multicenter randomized double-blind placebo-controlled parallel-group study of patients aged 12–17 years with MDD. Patients received ESC for 12 weeks as an open-label treatment period (open-label period). Patients who achieved criteria for remission or response in the open-label period received either ESC or placebo for 36 weeks as a double-blind treatment period (double-blind period). The primary endpoint was the time to relapse during the double-blind period. Safety was evaluated in terms of type, incidence, and severity of adverse events. Results: Of the 128 patients who entered the open-label period, 80 patients entered the double-blind period, all of whom were in the primary analysis population. The primary endpoint, time to relapse, was marginally less than statistically significant between the ESC and placebo groups (p = 0.051, log-rank test). In the Cox proportional hazards model, the estimated hazard ratio [two-sided 95% confidence interval] for relapse in the placebo group versus the ESC group was 2.96 [0.94, 9.30]. There were statistically significant differences between the ESC and placebo groups in several secondary endpoints (change in Children's Depression Rating Scale-Revised, change in Clinical Global Impressions-Severity Scale, etc.). No notable safety/tolerability issues were observed in this study compared with the results of studies in Japanese adults with MDD. Conclusions: Superiority of ESC over placebo for relapse prevention in Japanese adolescents aged 12–17 years with MDD could not be verified with time to relapse evaluated by log-rank test. However, secondary endpoint results and a post hoc analysis of time to relapse suggest that ESC may be effective in preventing MDD relapse. No notable safety/tolerability issues were observed compared with the results of studies in Japanese adults with MDD. Study Registry Number: jRCT2080224520 [ABSTRACT FROM AUTHOR]

Aim: This study aims to examine the real‐world effectiveness of education regarding clinical guidelines for psychiatric disorders using 'the Effectiveness of guidelines for dissemination and education in psychiatric treatment (EGUIDE)' project. Methods: The EGUIDE project is a nationwide prospective implementation study of two clinical practice guidelines, i.e., the Guideline for Pharmacological Therapy of Schizophrenia and the Treatment Guidelines for Major Depressive Disorders, in Japan. Between 2016 and 2019, 782 psychiatrists belonging to 176 hospitals with psychiatric wards participated in the project and attended lectures on clinical practice guidelines. The proportions of guideline‐recommended treatments in 7405 patients with schizophrenia and 3794 patients with major depressive disorder at participating hospitals were compared between patients under the care of psychiatrists participating in the project and those not participating in the project. Clinical and prescribing data on the patients discharged from April to September each year from participating hospitals of the project were also analyzed. Results: The proportions of three quality indicators (antipsychotic monotherapy regardless of whether other psychotropics medication, antipsychotic monotherapy without other psychotropics and no prescription of anxiolytics or hypnotics) for schizophrenia were higher among participating psychiatrists than among nonparticipating psychiatrists. As similar results were obtained in major depressive disorder, the effectiveness of the project for the dissemination of guideline‐recommended treatment has been replicated. Conclusion: This strategy of providing education regarding the clinical guidelines for psychiatric disorders was effective in improving the treatment‐related behavior of psychiatrists. The use of this education‐based strategy might contribute to resolving the mental health treatment gap. [ABSTRACT FROM AUTHOR]

Objective confirmation of MDD diagnosis through review of medical records. Conclusion: This study demonstrated a significant association between MDD status and exhibiting ADHD traits. Adult MDD patients screened ASRS-J-positive experienced significantly higher humanistic burden than patients screened ASRS-J-negative. Our results emphasize the importance of ensuring appropriate screening of ADHD and looking out for potentially hidden ADHD symptoms when diagnosing and treating MDD in adulthood. [ABSTRACT FROM AUTHOR]

Background: Acupuncture is a non-pharmacological therapy used clinically for mood disorders. Relief of physical symptoms with acupuncture treatment may lead to relief of depressive symptoms and improvement of quality of life (QoL). Few studies have examined the effect of acupuncture on the physical symptoms and QoL of patients with mood disorders. Objectives: To examine the effect of acupuncture on physical symptoms and QoL of patients with treatment-resistant major depressive disorder (MDD) and bipolar disorder (BD). Methods: This prospective, single-arm, longitudinal study included patients with MDD and BD from an outpatient psychiatric clinic. Acupuncture was performed weekly for 12 weeks in combination with regular treatment, with fixed acupoints and individualized treatment for each patient. Psychiatric symptoms were evaluated using the Himorogi Self-Rating Depression Scale (HSDS) and Himorogi Self-Rating Anxiety Scale (HSAS). Physical symptoms such as physical pain, gastrointestinal symptoms, and sleep disorders were evaluated using the Japanese version of the Somatic Symptom Scale-8 (SSS-8) and Visual Analog Scale (VAS). QoL was evaluated using the 8-item Short-Form (SF-8) Health Survey. Results: A total of 36 patients (15 MDD and 21 BD patients) were analyzed. After 12 weeks of acupuncture, HSDS and HSAS scores significantly decreased (p < 0.05). Physical symptoms evaluated using SSS-8 and VAS scores also significantly improved (p < 0.05). In particular, neck pain and insomnia improved at an early stage. Among the SF-8 subscales, scores of bodily pain, general health perception, role limitations due to emotional problems, and mental health significantly increased (p < 0.05). Conclusion: Acupuncture may improve not only psychiatric symptoms but also physical symptoms and QoL in patients with treatment-resistant mood disorders. Further studies are required for confirmation of the preliminary data collected thus far. [ABSTRACT FROM AUTHOR]

Cognitive symptoms in major depressive disorder (MDD) contribute to impaired functional abilities and work productivity, particularly presenteeism. We investigated the association between baseline cognitive symptoms and subsequent presenteeism, and global functional impairment in Japanese patients with MDD from PERFORM-J (Prospective Epidemiological Research on Functioning Outcomes Related to Major Depressive Disorder in Japan) – a 6-month, multicenter, epidemiological study data. A total of 518 patients initiating antidepressant monotherapy (first-line or switched from another drug) were enrolled. Assessments include Perceived Deficits Questionnaire – Depression (PDQ-D) for cognitive complaints, Sheehan Disability Scale (SDS) for global function (analysed n = 318), and Work Productivity and Activity Impairment Questionnaire for presenteeism (analysed n = 122). A strong association between changes in presenteeism and changes in SDS scores (r: total = 0.636; work/school = 0.686) was observed. After adjusting for sociodemographic and MDD-related factors, patients without cognitive complaints at baseline showed lower odds of impaired presenteeism at 6 months versus patients with cognitive complaints (0.243, 95% CI: 0.079 to 0.747, p = 0.014) and also in patients with first episode of MDD against with recurrent MDD (0.327 (95% CI: 0.136 to 0.787). Similarly, patients without cognitive complaints had healthier global functioning (lower mean SDS total score) than patients with cognitive complaints (8.3 vs 11.2; 95% CI, −5.189 to −0.578; p = 0.014). First depressive episode (lower risk of presenteeism), being male, and low baseline SDS total score (better global functioning) were also associated with improved outcomes. These results highlight the potential value of baseline PDQ-D scores in predicting subsequent workplace and global functioning in patients undergoing treatment for MDD. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study was to identify the clinical significance of anxiety in those with depression, the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) defined criteria for an anxious distress specifier for major depressive disorder (MDD). The Clinically Useful Depression Outcome Scale (CUDOS) supplemented with questions for the DSM-5 anxious distress specifier (CUDOS-A) is a self-report instrument to assess the clinical significance of anxiety in addition to assess symptoms and the severity of depression. This study aimed to evaluate the psychometric properties of the Japanese version of the CUDOS-A., Methods: An observational, prospective study was conducted with 131 MDD outpatients and 200 healthy controls. The Japanese version of the CUDOS-A, along with other measures, was administered to assess depressive symptoms, anxiety, social function, and biological rhythm. Reliability and validity analyses were performed, including internal consistency, test-retest reliability, convergent validity, and contrasted-groups validity., Results: The Japanese version of the CUDOS-A demonstrated excellent internal consistency (Cronbach's alpha = 0.96) and test-retest reliability (ICC = 0.78). Significant positive correlations were found between the CUDOS-A and measures of depression, anxiety, social function, and biological rhythm (all, p < 0.001), supporting its convergent validity. The CUDOS-A effectively differentiated between patients with MDD and healthy controls (p < 0.001), indicating good contrasted-groups validity., Conclusions: The Japanese version of the CUDOS-A is a useful measure for research and for clinical practice, enabling the efficient assessment of anxious distress in individuals with depression., (© 2024 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Objective: The goal of this study was to evaluate the efficacy and safety of duloxetine in children and adolescents (9-17 years of age) with major depressive disorder (MDD) in Japan. Methods: This study consists of two clinical trials. First, a 6-week, randomized double-blind placebo-controlled clinical trial (RCT) was conducted. The primary endpoint of RCT was the change in Children's Depression Rating Scale-Revised (CDRS-R) total scores from baseline. Following RCT, an open-label long-term extension trial (OLE) was conducted to investigate the longer-term safety of duloxetine for ∼1 year. Results: In RCT, CDRS-R total score changes from baseline to 6 weeks after the start of administration (primary endpoint) were -21.03 in the duloxetine group (n = 74) and -22.42 in the placebo group (n = 74). No significant difference was observed in the primary endpoint between the groups (p = 0.5587). In addition, no significant difference was observed in secondary endpoints such as CDRS-R response rates. The proportion of patients with ≥1 treatment-emergent adverse event (TEAE) in RCT was significantly higher in the duloxetine group (78.7%) than in the placebo group (62.2%), and most were mild or moderate in severity. Changes in CDRS-R total scores during OLE, in consecutive patients from the duloxetine group in RCT (n = 63), or placebo group (n = 59) in RCT, and newly enrolled patients (n = 28), were -12.1, -11.3, and -17.8, respectively. The proportion of patients with ≥1 TEAE in OLE was 90.5%, 88.1%, and 89.3% in the respective groups, and most of them were mild or moderate in severity. Conclusions: Duloxetine did not show superiority to placebo in efficacy in children and adolescents with MDD in Japan. Overall reported TEAEs were consistent with the currently available duloxetine safety profile and no new safety finding was observed in the two clinical trials. [ABSTRACT FROM AUTHOR]

Aim: Anhedonia in major depressive disorder may be resistant to first-line antidepressants. We examined the effect of vortioxetine, a multimodal antidepressant, on anhedonia-like symptoms in Japanese patients with major depressive disorder. Methods: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20– 75 years with recurrent major depressive disorder and a Montgomery–Åsberg Depression Rating Scale (MADRS) total score of at least 26. The primary outcome was the mean change from baseline to week 8 in anhedonia-like symptoms as measured by MADRS anhedonia factor score, composed of: Q1, apparent sadness; Q2, reported sadness; Q6, concentration; Q7, lassitude; and Q8, inability to feel. Mean change in MADRS total score and anhedonia factor score were compared among treatment groups, with data categorized by median baseline anhedonia factor score (0– 17 or ≥ 18). Results: Data were available for 489 patients. The least-squares mean difference in MADRS anhedonia factor score change from baseline to week 8 versus placebo was − 1.34 for vortioxetine 10 mg (P = 0.0300) and − 1.77 for vortioxetine 20 mg (P = 0.0044). The least-squares mean difference between vortioxetine and placebo in MADRS total score change from baseline to week 8 was − 3.11 (10 mg dose) and − 3.37 (20 mg dose) for patients with a higher baseline anhedonia factor score (≥ 18), and − 2.08 (10 mg) and − 2.61 (20 mg) for patients with a lower baseline score (0– 17). Conclusion: This post hoc analysis suggests that vortioxetine may have therapeutic potential in patients with anhedonia-like symptoms of major depressive disorder. ClinicalTrials.gov identifier for primary study: NCT02389816. [ABSTRACT FROM AUTHOR]

Aim: Antidepressants, including selective serotonin reuptake inhibitors, often elicit a poor response in patients with major depressive disorder (MDD) with significant anxiety symptoms. This study investigated the effects of the multimodal antidepressant vortioxetine in patients with MDD and associated anxiety. Methods: This was a post hoc analysis of data from an 8-week, randomized, double-blind, placebo-controlled, Phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20– 75 years with recurrent MDD and a Montgomery–Åsberg Depression Rating Scale (MADRS) score of at least 26. Changes from baseline to week 8 in MADRS total score and Hamilton Depression Rating Scale (HAM-D) anxiety/somatization factor score were assessed in patients with anxious depression (HAM-D anxiety/somatization factor score ≥ 7) and without anxious depression. Results: Data were available for 489 patients. In patients with anxious depression, the least-squares (LS) mean difference (95% confidence interval [CI]) versus placebo in change in MADRS total score was − 3.44 (− 6.10, − 0.77) for vortioxetine 10 mg and − 4.51 (− 7.15, − 1.87) for vortioxetine 20 mg. In patients with non-anxious depression, the LS mean difference (95% CI) versus placebo was − 1.81 (− 4.71, 1.09) and − 1.05 (− 4.00, 1.90) for vortioxetine 10 mg and 20 mg, respectively. Changes from baseline in HAM-D anxiety/somatization factor score were greater in patients treated with vortioxetine 10 mg or 20 mg than in those treated with placebo. Conclusion: Vortioxetine may be effective for patients with anxiety symptoms in MDD. Further research is warranted to investigate these effects in a real-world clinical setting. Clinical Trials Registration: ClinicalTrials.gov identifier for primary study: NCT02389816. [ABSTRACT FROM AUTHOR]

Aim: Several weeks of treatment with an antidepressive agent may be required before efficacy is demonstrated in patients with major depressive disorder. This study investigated the predictive value of early partial improvement with vortioxetine for treatment response and remission. Methods: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, Phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20– 75 years with recurrent major depressive disorder and a Montgomery–Åsberg Depression Rating Scale (MADRS) score of at least 26. The key outcomes were the predictive value of early partial improvement (reduction in MADRS total score of ≥ 20% from baseline to week 2) with vortioxetine for MADRS response (≥ 50% decrease in score from baseline) and remission (decrease in score to ≤ 10) at week 8. Results: Relevant data were available for 478 patients; 62/158 patients receiving placebo, 71/162 receiving vortioxetine 10 mg, and 66/158 receiving vortioxetine 20 mg were early improvers. Early improvers receiving vortioxetine (10 mg or 20 mg) were more likely than non-early improvers to achieve a week 8 response (71.2– 73.2% vs 29.7– 38.0%) or remission (50.7– 51.5% vs 17.4– 18.7%). Positive predictive values for response and remission with vortioxetine were ∼ 70% and ∼ 50%, respectively; negative predictive values were ∼ 70% and ∼ 80%, respectively. Conclusion: Improvement with vortioxetine may be predicted by early partial improvement in MADRS score. Some patients may benefit from longer-term treatment even without early improvement, another finding that may aid clinical decision-making. ClinicalTrials.gov registration for primary study: NCT02389816. [ABSTRACT FROM AUTHOR]

Background: Residual insomnia is associated with a risk of depression recurrence.Methods: In this retrospective, longitudinal cohort study, the recurrence pattern of depression in patients with or without residual insomnia was assessed using a health insurance claims database. Patients who were diagnosed with major depressive disorder and prescribed antidepressants, between January 2006 and June 2017 in Japan, were enrolled in the study. Residual insomnia was defined by a prescription of hypnotics, and recurrence of depression by prescription of antidepressants. Main outcomes included time to recurrence and the 1-year recurrence rate. Factors associated with recurrence of depression were assessed by multivariate analyses. The effect of residual insomnia on the frequency of recurrence was assessed by Chi-square test.Results: Of the 30,381 patients analyzed, there were 4,166 and 26,215 patients with or without residual insomnia, respectively. Time to recurrence in patients with residual insomnia was significantly shorter compared with those without residual insomnia (p <0.001), with a 1-year recurrence rate (95% CI) of 43.4% (41.9-45.0) and 7.4% (7.1-7.7), respectively. The frequency of recurrence was significantly higher in patients with residual insomnia than in those without (p <0.0001). A higher risk of depression recurrence (odds ratio 9.98, 95% CI 9.22-10.81) was found for residual insomnia compared with other significant factors.Limitations: The diagnosis stated in the receipt data may not accurately reflect the patient's condition, and medication adherence was unknown but assumed.Conclusions: Residual insomnia is a significant risk factor for depression recurrence in Japanese patients. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is highly prevalent in Japan and frequently accompanied by insomnia that may persist even with MDD remission. Hypnotics are used for the pharmacological treatment of insomnia, but their influence on MDD recurrence or residual insomnia following MDD remission is unclear. This retrospective, longitudinal, cohort study utilized a large Japanese health insurance claims database to investigate patterns of hypnotic prescriptions among patients with MDD, and the influence of hypnotic prescription pattern on MDD recurrence. Methods: Eligible patients (20–56 years) were those registered in the Japan Medical Data Center database between 1 January 2005 and 31 December 2018, and prescribed antidepressant and hypnotic therapy after being diagnosed with MDD. Patients who had ceased antidepressant therapy for > 180 days were followed for 1 year to evaluate depression recurrence, as assessed using Kaplan-Meier estimates. Logistic regression modelling was used to analyze the effect of hypnotic prescription pattern on MDD recurrence. Results: Of the 179,174 patients diagnosed with MDD who initiated antidepressant treatment between 1 January 2006 and 30 June 2017, complete prescription information was available for 2946 eligible patients who had been prescribed hypnotics. More patients were prescribed hypnotic monotherapy (70.8%) than combination therapy (29.2%). The most prescribed therapies were benzodiazepine monotherapy (26.2%), non-benzodiazepine monotherapy (28.9%), and combination therapy with two drugs (21.1%). Among patients prescribed multiple hypnotics, concomitant prescriptions for anxiolytics, antipsychotics, mood stabilizers and sedative antidepressants were more common. The 1-year recurrence rate for MDD was approximately 20%, irrespective of hypnotic mono- versus combination therapy or class of hypnotic therapy. Being a spouse (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.03–2.02) or other family member (OR, 1.46, 95% CI, 0.99–2.16) of the insured individual, or being prescribed a sedative antidepressant (OR, 1.50, 95% CI, 1.24–1.82) conferred higher odds of MDD recurrence within 1 year of completing antidepressant therapy. Conclusions: Benzodiazepines are the most prescribed hypnotic among Japanese patients with MDD, though combination hypnotic therapy is routinely prescribed. Hypnotic prescription pattern does not appear to influence real-world MDD recurrence, though hypnotics should be appropriately prescribed given class differences in efficacy and safety. [ABSTRACT FROM AUTHOR]

Background: Social withdrawal is a feature of a number of psychiatric disorders including major depressive disorder (MDD), yet research examining social withdrawal as a feature of MDD is rare.Methods: This was a retrospective case-control study. Participants (N = 67) were recruited through an outpatient clinic at an academic medical center in Japan. Major depressive disorder (MDD) and social withdrawal were established with the Structured Clinical Interview for DSM-IV Axis I Disorders and a semi-structured psychiatric interview, respectively. Participants also completed self-report measures.Results: We classified 24 participants as cases (MDD with social withdrawal) and 43 participants as controls (MDD without social withdrawal). Cases, on average, were more likely to have lower education level, prior episodes of depression, and higher suicidal ideation at baseline than controls. In unadjusted regression models, cases had significantly less social connection, less reward dependence, less self-directedness, and higher scores on scales of modern-type depression and hikikomori. In adjusted regression models, associations between social withdrawal and hikikomori (p<0.01) and reward dependence (p = 0.03) remained significant.Limitations: The sample was limited in size and drawn from a single site.Conclusions: In patients with MDD, social withdrawal may have subtle associations with clinical symptoms, social connection, and personality traits. Developing a better understanding of social withdrawal's phenotype in depression requires more in-depth examination. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the present study was to elucidate the foreseeable risk factors for suicidal ideation among Japanese perinatal women. Methods: This cohort study was conducted in Nagoya, Japan, from July 2012 to March 2018. The Edinburgh Postnatal Depression Scale (EPDS) questionnaire was conducted at four time points: early pregnancy, late pregnancy, 5 days postpartum, and 1 month postpartum. A total of 430 women completed the questionnaires. A logistic regression analysis was performed using the presence of suicidal ideation on the EPDS as an objective variable. The explanatory variables were age, presence of physical or mental disease, smoking and drinking habits, education, hospital types, EPDS total score in early pregnancy, bonding, and quality and amount of social support, as well as the history of major depressive disorder (MDD). Results: The rate of participants who were suspected of having suicidal ideation at any of the four time points was 11.6% (n=52), with the highest (n=25, 5.8%) at late pregnancy. For suicidal ideation, education level (OR: 1.19; 95% CI: 1.00–1.41; p=0.047), EPDS total points in the pregnancy period (OR: 1.25; 95% CI: 1.16–1.34; p < 0.000), a history of MDD (OR: 2.16; 95% CI: 1.00–4.79; p=0.049), and presence of mental disease (OR: 2.39; 95% CI: 1.00–5.70; p=0.049) were found to be risk factors for suicidal ideation. Age [odds ratio (OR): 0.88; 95% confidence interval (CI): 0.80–0.95; p=.002] and quality of social support (OR: 0.77; 95% CI: 0.60–0.99; p=.041) were found to be protective factors. Conclusion: Based on these results, effective preventive interventions, such as increasing the quality of social support and confirming the history of depression, should be carried out in pregnant depressive women at the early stage of the perinatal period. [ABSTRACT FROM AUTHOR]

Background: Ketamine and its enantiomers have recently been highlighted as one of the most effective therapeutic options in refractory depression. However, racemic ketamine and esketamine have not been directly compared. The aim of this study is to assess the efficacy and safety of esketamine compared to ketamine in patients with treatment-resistant depression (TRD).Methods: This is a randomized, double-blind, active-controlled, bicentre, non-inferiority clinical trial, with two parallel groups. Participants were randomly assigned to a 40-min single intravenous infusion of ketamine 0.5 mg/kg or esketamine 0.25 mg/kg. The primary outcome was the difference in remission rates for depression 24 h following intervention using the Montgomery-Åsberg Depression Rating Scale (MADRS), with a non-inferiority margin of 20%.Results: 63 subjects were included and randomly assigned (29 to receive ketamine and 34 to receive esketamine). At 24 h, 24.1% of participants in the ketamine group and 29.4% of participants in the esketamine group showed remission, with a difference of 5.3% (95% CILB -13.6%), confirming non-inferiority. MADRS scores improved from 33 (SD 9.3) to 16.2 (SD 10.7) in the ketamine group and from 33 (SD 5.3) to 17.5 (SD 12.2) in the esketamine one, with a difference of -5.27% (95% CILB, -13.6). Both groups presented similar mild side effects.Conclusions: Esketamine was non-inferior to ketamine for TRD 24 h following infusion. Both treatments were effective, safe, and well tolerated.Trial Registration: Registered in Japan Primary Registries Network: UMIN000032355. [ABSTRACT FROM AUTHOR]

Aim: The burden of major depressive disorder (MDD) in Japan is high. This study aimed to evaluate the efficacy and safety of the multimodal antidepressant vortioxetine in Japanese patients with MDD. Methods: Japanese patients aged 20–75 years with recurrent MDD and a Montgomery–Åsberg Depression Rating Scale (MADRS) score ≥ 26 were randomized to vortioxetine 10 or 20 mg or placebo in a phase‐3, double‐blind, 8‐week study. The primary end‐point was change in MADRS total score from baseline. Secondary end‐points included MADRS response and remission rates, change in Hamilton Rating Scale for Depression‐17 item (HAM‐D17) score, and other measures of depressive symptoms, including Clinical Global Impression of Severity (CGI‐S), Clinical Global Impression of Improvement (CGI‐I), and Sheehan Disability Scale (SDS). Cognitive function was assessed using Digit Symbol Substitution Test (DSST) score and Perceived Deficits Questionnaire‐5 item (PDQ‐5) score. Results: Vortioxetine 10 mg (n = 165) and 20 mg (n = 163) reduced MADRS total score by 2.66 and 3.07 points versus placebo (n = 161) after 8 weeks (P < 0.01 for each dose), respectively. MADRS response and remission rates were also significantly greater with vortioxetine than with placebo (P < 0.05 for both doses). Vortioxetine 10 and 20 mg significantly improved HAM‐D17 score, CGI‐I score, and SDS total score after 8 weeks. PDQ‐5 score was significantly improved in subjects administered vortioxetine, while DSST scores showed no significant difference. Vortioxetine was generally well tolerated. Conclusion: Vortioxetine at both the 10‐ and 20‐mg/day doses demonstrated robust antidepressant efficacy in Japanese patients with MDD, and was well tolerated over the 8‐week treatment period. [ABSTRACT FROM AUTHOR]

Aims: Inadequate antidepressant response interrupts effective treatment of major depressive disorder (MDD). The BLESS study evaluates the dosage, efficacy, and safety of brexpiprazole adjunctive therapy in Japanese patients with inadequate antidepressant therapy (ADT) response., Methods: This placebo-controlled, randomized, multicenter, parallel-group phase 2/3 study randomized Japanese MDD patients (Hamilton Rating Scale for Depression 17-item total score ≥ 14; historical inadequate response to 1-3 ADTs) with inadequate response to 8-week single-blind, prospective SSRI/SNRI treatment to 6-week adjunctive treatment with brexpiprazole 1 mg, 2 mg, or placebo. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline. Secondary endpoints included MADRS response, remission rate, and Clinical Global Impression-Improvement score. Safety was comprehensively evaluated, especially regarding antipsychotic adverse events (AEs)., Results: Of 1194 screened patients, 740 were randomized and 736 (1 mg, n = 248; 2 mg, n = 245; placebo, n = 243) had ≥1 baseline/post-baseline MADRS total score. The LSM (SE) change from baseline in MADRS total score at Week 6 by MMRM analysis was -8.5 (0.47) with brexpiprazole 1 mg, -8.2 (0.47) with brexpiprazole 2 mg, and -6.7 (0.47) with placebo (placebo-adjusted LSM difference [95% CI]: 1 mg, -1.7 [-3.0, -0.4]; P = 0.0089; 2 mg, -1.4 [-2.7, -0.1]; P = 0.0312). Secondary efficacy results supported the primary endpoint. Brexpiprazole was generally well tolerated., Conclusion: Brexpiprazole 1 mg daily was an appropriate starting dose and both 1 mg and 2 mg daily were effective and well tolerated as adjunctive therapy for Japanese MDD patients not adequately responsive to ADT., (© 2023 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Introduction: The clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) in Japan has not been adequately investigated. Furthermore, the relationship between stimulation-site pain and the antidepressant effects of rTMS has not been thoroughly examined. Therefore, this study aimed to clarify (1) the real-world efficacy and safety of rTMS for TRD in Japan and (2) the relationship between stimulation-site pain and clinical improvement of depressive symptoms., Methods: We conducted a retrospective observational study involving 50 right-handed patients with TRD. All patients received high-frequency rTMS for up to 6 weeks. Depressive symptoms were assessed using the Montgomery-Åsberg depression rating scale (MADRS). Pain at the stimulation site was reported by the patients using a visual analog scale (VAS) after each session. Remission and response rates at 3 and 6 weeks were calculated based on the MADRS scores. The correlation between changes in the MADRS and VAS scores was examined., Results: Remission and response rates were 36% and 46%, respectively, at the end of 3 weeks, and 60% and 70%, respectively, at 6 weeks. At the end of the treatment, there was significant correlation between the reduction of MADRS and VAS scores (r = 0.42, p = 0.003)., Conclusion: This study demonstrates the clinical efficacy of rTMS in Japan and the correlation between its antidepressant effects and stimulation-site pain., (© 2024 S. Karger AG, Basel.)

aimei Sasayama,1 Hiroaki Hori,1 Takamasa Noda,2 Sumiko Yoshida,2 Fuyuko Yoshida,1 Hiroshi Kunugi11Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan; 2Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan Purpose: Orexins are hypothalamic neuropeptides involved in the regulation of sleep, appetite and arousal. An altered orexin system has been implicated in the pathophysiology of psychiatric disorders. This study aimed to examine whether plasma orexin-A levels differ in patients with schizophrenia, major depressive disorder (MDD), or bipolar disorder (BD) compared to in healthy controls. We also examined the possible correlations between plasma orexin-A levels and clinical variables. Patients and methods: All participants were Japanese. The sample consisted of 80 patients with schizophrenia (42 women, 52.5%; mean age 36.8 years), 80 patients with MDD (43 women, 53.8%; 43.7 years), and 40 patients with BD (24 women, 60%; 41.1 years), as well as 80 healthy controls (48 women, 60%; 47.0 years). Plasma orexin-A levels were quantified by an enzyme-linked immunosorbent assay. Results: Mean orexin-A levels were significantly different across the four diagnostic groups (F=4.09; df=3; p=0.007, η2=0.06). In particular, the patients with BD showed significantly lower orexin-A levels than did the controls. When the median value of the control group (109.8 pg/ml) was set as a cut-off value, subjects whose orexin-A levels were below the cut-off were more common in all psychiatric groups (schizophrenia: 73.8%, x2=9.56, df=1, p=0.003, OR=2.81, 95% CI: 1.45 to 5.45, d=0.57; MDD: 78.5%, x2=14.02, df=1, p<0.001, OR=3.65, 95% CI: 1.82 to 7.29, d=0.72; BD: 87.5%, x2=16.0, df=1, p<0.001, OR=7.00, 95% CI: 2.49 to 19.70, d=1.07). We found no association between plasma orexin-A levels and any clinical symptoms, depression severity, or medication doses. Conclusion: Our results suggest that plasma orexin-A levels are reduced in patients with BD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The relationship between perinatal depressive symptoms, harm avoidance (HA), and a history of major depressive disorder (MDD) was examined in a prospective cohort study. Methods: This study was conducted from May 1, 2011, to December 31, 2016. A history of MDD was evaluated using the Inventory to Diagnose Depression, Lifetime version during pregnancy. Depressive state and HA were evaluated during pregnancy and at 1 month postnatal using the Edinburgh Postnatal Depression Scale (EPDS) and Temperament and Character Inventory, respectively. The relationship between these variances was examined using structural equation modeling. Results: A total of 338 participants with complete data were included in the present study. Pregnant women with compared with those without a history of MDD were observed to have a significantly higher intensity of HA and more severe depressive symptoms in both the prenatal and postnatal periods. A history of MDD affected the severity of depressive symptoms [standardized path coefficient (SPC) = 0.25, p < 0.001] and the intensity of HA during pregnancy (SPC = 0.36, p < 0.001). The intensity of HA during pregnancy affected that at 1 month postnatal (SPC = 0.78, p < 0.001), while the severity of depressive symptoms as assessed by the EPDS during pregnancy affected that at 1 month postnatal (SPC = 0.41, p < 0.001). The SPC for perinatal HA to postnatal depressive symptoms (SPC = 0.13, p = 0.014) was significant and higher than that for perinatal depressive symptoms to postnatal HA (SPC = 0.06, p = 0.087). Conclusion: The present results suggest that early intervention in pregnant women with a history of MDD or a high intensity of HA is important to prevent postnatal depressive symptoms. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the effects of medical fee revisions aimed to reduce psychotropic polypharmacy in Japan on the proportion of psychotropic polypharmacy in discharge prescriptions for patients with major depressive disorder (MDD) or bipolar disorder (BD) using a nationwide inpatient database., Methods: In this retrospective cohort study, we used the Diagnosis Procedure Combination database to identify patients with MDD or BD discharged between April 2012 and March 2021. We targeted medical fee revisions in October 2014, April 2016, and April 2018. The major outcome was the monthly proportion of psychotropic polypharmacy in prescription at discharge using the criteria following the April 2018 revision (antidepressants ≥3, antipsychotics ≥3, anxiolytics ≥3, hypnotics ≥3, or sum of anxiolytics and hypnotics ≥4). We performed interrupted time series analyses to evaluate the changes in level and trend between pre- and post-revisions., Results: We identified 63,289 and 33,780 patients with MDD and BD respectively in the entire study period. In both the patient groups, there were significant decreases in the proportion of psychotropic polypharmacy at revision in October 2014, and no significant trend and level change at revision were observed in April 2016 and April 2018, with a few exceptions., Conclusions: The medical fee revisions aimed to reduce psychotropic polypharmacy in Japan might have had a limited impact on discharge prescriptions for patients with MDD and BD., Competing Interests: Declaration of Competing Interest Shinsuke Kito reports grants and personal fees from Inter Reha CO., Ltd., Kyowa Pharmaceutical Industry CO., Ltd., Lundbeck Japan K.K., Sumitomo Pharma CO., Ltd., Otsuka Pharmaceutical CO., Ltd., Takeda Pharmaceutical CO., Ltd., Teijin Pharma Ltd., and Viatris Inc., outside the submitted work; the other authors have no competing interests to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: This study investigated whether the characteristic changes in hippocampal atrophy seen in coronal scans are useful for differentiating Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), and major depressive disorder (MDD). Methods: Subjects included 58 patients with AD, 33 with aMCI, 20 with MDD, and 22 normal controls, all aged 60 years or older. For each subject, eight coronal short TI inversion recovery images perpendicular to the hippocampal longitudinal axis were obtained. Images were manually measured using the conventional region of interest method of quantitative analysis. Results: The overall trend in the corrected volumes of the hippocampus was AD < aMCI < MDD < normal controls. We found atrophy in all slices in AD, atrophy centred on the hippocampal head in aMCI, and atrophy in the slice of the hippocampal body 12 mm from the amygdala in MDD. Conclusions: The present study suggested that our method of comparing hippocampal atrophy by region may be useful in distinguishing AD, aMCI, MDD, and normal controls. [ABSTRACT FROM AUTHOR]

Japan's prototype of depression was traditionally a melancholic depression based on the premorbid personality known as shũchaku-kishitsu proposed by Mitsuzo Shimoda in the 1930s. However, since around 2000, a novel form of depression has emerged among Japanese youth. Called 'modern type depression (MTD)' by the mass media, the term has quickly gained popularity among the general public, though it has not been regarded as an official medical term. Likewise, lack of consensus guidelines for its diagnosis and treatment, and a dearth of scientific literature on MTD has led to confusion when dealing with it in clinical practice in Japan. In this review article, we summarize and discuss the present situation and issues regarding MTD by focusing on historical, diagnostic, psychosocial, and cultural perspectives. We also draw on international perspectives that begin to suggest that MTD is a phenomenon that may exist not only in Japan but also in many other countries with different sociocultural and historical backgrounds. It is therefore of interest to establish whether MTD is a culture-specific phenomenon in Japan or a syndrome that can be classified using international diagnostic criteria as contained in the ICD or the DSM. We propose a novel diagnostic approach for depression that addresses MTD in order to combat the current confusion about depression under the present diagnostic systems. [ABSTRACT FROM AUTHOR]

Sickness absences are a significant public health and economic problem worldwide. However, sickness absence diagnoses and trends have not been reported in much detail in Japan. This study was a retrospective cohort study. We examined data on certified diagnoses and the durations of sickness absence lasting over 90 days (long-term sickness absence) from 2009-2018 among city public servants in Japan. We found that 1) "Mental and behavioral disorders" (495.0-780.6 per 100,000 employees) was the most prevalent reason for long-term sickness absence, and "Mood disorders" (318.6-584.3 per 100,000 employees) was the most prevalent mental disorders diagnosis in each study year; 2) the prevalence of long-term sickness absence for mental disorders showed decreasing trends (781/100,000 in 2009 to 622/100,000 in 2018; [p=0.005, for the trend test]); 3) the trends differed by gender (p<0.05) and age (p<0.001); and 4) the duration of long-term sickness absence related to mental disorders (13.2 ± 9.0 months) was longer than long-term sickness absence resulting from all physical disorders except for diseases of the circulatory system (15.1 ± 11.6 months). Increased focus on significant depressive and neurotic disorders is needed when promoting mental health in the workplace.

Objective.The aim of the study was to evaluate the association of transmembrane protein 132D (TMEM132D), catechol-O-methyltransferase (COMT), and gamma-aminobutyric acid (GABA) receptor alpha 6 subunit (GABRA6) genotypes with cingulate, frontal cortex and hippocampal emotional processing in panic disorder (PD) and major depressive disorder (MDD).Method.The single nucleotide polymorphisms (SNPs) in TMEM132D, COMT, and GABRA6 were examined in patients with MDD, PD, and healthy controls. Functional magnetic resonance imaging (fMRI) was performed in patients with MDD, PD, and healthy controls.Results.rs4680 in COMT and rs3219151 in GABRA6 showed positive associations with PD and MDD. A dynamic fearful face was shown to the participants during fMRI scanning. In PD patients, responses in the bilateral anterior cingulate were stronger in carriers of the AA genotype of SNP rs11060369 in TMEM132D compared with carriers of the AC + CC genotype, and stronger in CT + TT genotype carriers of SNP rs3219151 in GABRA6 compared with carriers of the CC genotype. The response in the medial orbital frontal cortex was stronger in carriers of the CT + TT genotypes of SNP rs3219151 in PD. In MDD patients, the response in the right parahippocampus of carriers of the GG genotype of rs4680 in COMT was stronger than that of carriers of the AA + AG genotype.Conclusion.These results suggest that TMEM132D, GABRA6, and COMT variants may increase vulnerability to panic. [ABSTRACT FROM AUTHOR]

Background: Approved doses of antidepressants in Japan are usually lower than those in the USA and European Union, but to date meta-analyses comparing antidepressants have all used the higher doses approved in the USA and European Union and often have used indirect comparisons. The purpose of this study was to conduct an integrated database analysis of patient level data to compare the effects of duloxetine with those of selective serotonin reuptake inhibitors (SSRIs) at the doses approved in Japan. Methods: Pooled data were analyzed from four randomized, double-blind, placebo-controlled studies that compared duloxetine at the dose range approved in Japan (40-60 mg/day) with other SSRIs (paroxetine 20 mg/day or escitalopram 10 mg/day) and placebo in patients with major depressive disorder. In total, 1,694 patients were included in the analysis (duloxetine, n=688; selective serotonin reuptake inhibitors, n=690; placebo, n=316). The primary outcome measure was the mean change from baseline at week 8 in 17-item Hamilton Rating Scale for Depression (HAMD17) total and subscale scores. Results: Duloxetine and both selective serotonin reuptake inhibitors were superior to placebo in HAMD17 total score at week 8 in both the all-randomized group and the more severe subgroup (HAMD17 total scores $19). Duloxetine was superior to SSRIs in improving the HAMD17 Retardation subscale score (least squares mean difference [95% confidence interval]): all-randomized group, -0.33 [-0.60, -0.07], P=0.015; severe subgroup, -0.45 [-0.83, -0.07], P=0.020). Conclusion: Within the dose range approved in Japan for patients with major depressive disorder, duloxetine and selective serotonin reuptake inhibitors demonstrated comparable overall efficacy, with a possible advantage for duloxetine in improving loss of energy and interest. To the best of our knowledge, this analysis is unique not only in evaluating dosages specific to Japan, but also in using individual patient data and the same endpoint across studies to allow for strictly direct head-to-head data comparisons as opposed to pooling direct and indirect comparisons. [ABSTRACT FROM AUTHOR]

Background A growing body of evidence shows that reducing the duration of untreated illness (DUI) correlates with improved clinical outcome and course of depression. However, the factors involved in delaying treatment contact after the first onset of lifetime depression are not fully understood. This cross-sectional study aims to identify the characteristics that may predict the delay in initial treatment contact after the first onset of lifetime depression by comparing the socio-demographics and clinical characteristics between those with longer and shorter DUI in a well-characterized Japanese clinical sample. Methods Ninety-five patients with depression with longer (>12 months) and shorter DUI (≤12 months) at three Japanese outpatient clinics were studied. Subjects received a comprehensive evaluation, including semi-structured clinical interviews and assessment battery, and their clinical charts were reviewed. Results Of the total sample, the median of DUI was 4 months (interquartile range (IQR) 25th-75th percentile, 2-13). We found that 72.6% of patients seek treatment contact within the first year of depression onset. Multivariate logistic regression analysis showed that longer DUI in patients was associated with marital status (never married). Further, the DSM-IV melancholic features approached significance. Conclusions Our findings suggest that most Japanese patients with depression are likely to seek treatment within 1 year of onset, and that marital status and melancholia may be potential predictors of the delay in the initial treatment contact after the first onset of lifetime depression. [ABSTRACT FROM AUTHOR]

No studies have compared mirtazapine with duloxetine in patients with major depressive disorder (MDD). Fifty-six patients were nonrandomly assigned to a 4-week treatment with either 15 to 45 mg/day of mirtazapine (n = 22) or 20 to 60 mg/day of duloxetine (n = 34). The primary efficacy measurements were the Hamilton Rating Scale for Depression (HRSD) and the Montgomery-Åsberg Depression 6-point Rating Scale (MADRS) scores. The second efficacy measurements were the response and remission rates of treatment. Tolerability assessments were also performed. Fifty-six patients (43 male; age, 43.6 years) were recruited. There was no significant difference in the discontinuation rate between the mirtazapine and duloxetine treatment groups (P = 0.867). Both mirtazapine and duloxetine significantly improved the HRSD and MADRS scores from baseline (P<0.0001-0.0004). While mirtazapine was superior to duloxetine in the reduction of HRSD scores (P = 0.0421), there was no significant change in MADRS scores in terms of between-group differences (P = 0.171). While more somnolence was observed with mirtazapine (P = 0.0399), more nausea was associated with duloxetine (P = 0.0089). No serious adverse events were observed for either antidepressant. Mirtazapine and duloxetine were safe and well-tolerated treatments for Japanese patients with MDD. Double-blind controlled studies are needed to further explore the efficacy and safety of mirtazapine and duloxetine in Japanese patients with MDD [ABSTRACT FROM AUTHOR]

Ten years after the Great East Japan Earthquake, thousands of residents of Fukushima Prefecture were still living as evacuees. Among them, unignorable numbers of people were living outside of the prefecture. A survey was conducted with evacuees to Ibaraki, the neighboring prefecture of Fukushima, to investigate their medium- to long-term mental care needs. A questionnaire was sent to 1,470 households that had been living in Fukushima on March 11, 2011, and who were evacuated to Ibaraki by October 2016. Binary logistic regression analyses were performed to identify risk factors for major depressive disorder, post-traumatic stress disorder (PTSD), and suicidal ideation. Of the participants, 16.5% had a high risk for major depressive disorder, 39.0% exhibited a high risk for PTSD, and 19.7% indicated suicidal ideation. "Own injuries and illnesses" and "Worries about the hometown" were risk factors for major depressive disorder, PTSD, and suicidal ideation. "Not receiving compensation for damages" was a risk factor common to major depressive disorder and suicidal ideation. There is a high possibility that many people who have evacuated to other prefectures might still be suffering from psychological symptoms after the disaster. Worries about their hometowns were highly related to their mental disorders.

Aim: The main purpose of this study was to evaluate the efficacy of paroxetine controlled-release (CR) formulation compared to placebo. A secondary objective was to test the hypothesis that the CR decreases selective-serotonin-reuptake-inhibitors-induced nausea as its formulation allows more distal gastrointestinal absorption than the paroxetine immediate-release (IR) formulation. Methods: We conducted this study in Japanese and Korean patients with major depressive disorder (MDD) in order to demonstrate the efficacy and safety of paroxetine CR compared with placebo. The primary efficacy end-point was the adjusted mean change from baseline in the 17-item Hamilton Rating Scale for Depression total score at Week 8. Results: A total of 416 patients with MDD were randomly assigned to the CR, IR and placebo groups. The mean change from baseline in the 17-item Hamilton Rating Scale for Depression was −12.8 in the CR group, −12.5 in the IR group, and −10.4 in the placebo group, which showed a statistically significant difference compared to placebo in CR ( P < 0.001) and IR ( P = 0.015). The incidence of adverse events was 65% in CR, 69% in IR and 55% in placebo. The adverse events were mostly mild or moderate in severity. In the early treatment period, when initiated from 12.5 mg, the incidence of nausea in the CR group was 6%, which was comparable with that of placebo (5%). Conclusion: Paroxetine CR is efficacious in the acute treatment of MDD and may have the potential benefit of decreasing the incidence of nausea in the early treatment period. [ABSTRACT FROM AUTHOR]

Background: Although often considered of minor significance in themselves, evidence exists that early-onset phobic disorders might be predictors of later more serious disorders, such as major depressive disorder (MDD). The purpose of this study is to investigate the association of phobic disorders with the onset of MDD in the community in Japan. Methods: Data from the World Mental Health Japan 2002–2004 Survey were analyzed. A total of 2,436 community residents aged 20 and older were interviewed using the WHO Composite International Diagnostic Interview 3.0 (response rate, 58.4%). A Cox proportional hazard model was used to predict the onset of MDD as a function of prior history of DSM-IV specific phobia, agoraphobia, or social phobia, adjusting for gender, birth-cohort, other anxiety disorders, education, and marital status at survey. Results: Social phobia was strongly associated with the subsequent onset of MDD (hazard ratio [HR]=4.1 [95% CI: 2.0–8.7]) after adjusting for sex, birth cohort, and the number of other anxiety disorders. The association between agoraphobia or specific phobia and MDD was not statistically significant after adjusting for these variables. Conclusions: Social phobia is a powerful predictor of the subsequent first onset of MDD in Japan. Although this finding argues against a simple neurobiological model and in favor of a model in which the cultural meanings of phobia play a part in promoting MDD, an elucidation of causal pathways will require more fine-grained comparative research. Depression and Anxiety, 2009. Published 2009 Wiley-liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Background: Several lines of evidence implicate abnormalities in glutamate neural transmission in the pathophysiology of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BP). Preclinical antidepressant effects were also reported for group II metabotropic glutamate receptor (Group II mGluRs) antagonists show dose-dependent antidepressant-like effects in murine models of depression. Also, it has been suggested that abnormalities in the hypothalamic-pituitary-adrenal axis and serotonergic neural transmission are important mechanisms in the pathophysiology of mood disorders. Group II mGluRs play an important role in regulating the function of these mechanisms. From these results, it has been suggested that abnormalities in Group II mGluRs might be involved in the pathophysiology of mood disorders, including MDD) and BP, and may influence the clinical response to treatment with SSRIs in MDD. Therefore, we studied the association between Group II mGluR genes (GRM2 and GRM3) and mood disorders and the efficacy of fluvoxamine treatment in Japanese MDD patients. Materials and methods: Using three tagging SNPs in GRM2 and an SNP (rs6465084) reported functional variant in GRM3, we conducted a genetic association analysis of case-control samples (325 MDD patients, 155 BP patients and 802 controls) in the Japanese population. In addition, we performed an association analysis of GRM2 and GRM3 and the efficacy of fluvoxamine treatment in 117 Japanese patients with MDD. 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. Results: We found an association between rs6465084 in GRM3 and MDD in the allele-wise analysis after Bonferroni''s correction (P-value=0.0371). However, we did not find any association between GRM3 and BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise analysis. We also did not detect any association between GRM2 and MDD, BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise or haplotype-wise analysis. Discussion: We detected an association between only one marker (rs6465084) in GRM3 and Japanese MDD patients. However, because we did not perform an association analysis based on LD and a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results. [Copyright &y& Elsevier]

Abstract: Several investigations have suggested that alterations in circadian rhythms may lay the foundation for the development of mood disorder (bipolar disorder and major depressive disorder). Recently, the nuclear receptor Rev-erb alpha was reported to be related to circadian rhythms, and was shown to be involved in the biological action of lithium in vitro. These evidences indicate that the nuclear receptor Rev-erb alpha gene (NR1D1) is a good candidate gene for the pathogenesis of mood disorders. To evaluate the association between NR1D1 and mood disorders, we conducted a case–control study of Japanese samples (147 bipolar patients, 322 major depressive disorder patients and 360 controls) with three tagging SNPs selected by HapMap database. One SNP showed an association with bipolar disorder in females. After Bonferroni correction for multiple testing, however, this significance disappeared. No significant association was found with major depressive disorder. In conclusion, our findings suggest that NR1D1 does not play a major role in the pathophysiology of mood disorders in the Japanese population. [Copyright &y& Elsevier]

Aims: Milnacipran, a new specific serotonin and norepinephrine re-uptake inhibitor, is as effective as tricyclic antidepressants. Symptomatological predictors of antidepressant response to milnacipran have not been studied until now. Methods: This study included 101 Japanese patients who fulfilled the DSM-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery and Åsberg Depression Rating Scale (MADRS) was ≥21. Eighty-three patients were finally included. Patients with a pretreatment MADRS score ≥31 points were defined as severe ( n = 28), and the rest as non-severe ( n = 55). The three-factor model of MADRS was used for analysis; the first factor was defined by three items, the second factor was defined by four items and the third factor was defined by three items representing dysphoria, retardation, and vegetative symptoms, respectively. Milnacipran was administered twice daily for 6 weeks. The initial dose was 50 mg/day; after a week it was increased to 100 mg/day. Results: No significant difference was observed in the mean score of first factor, second factor and third factor at pretreatment time between responders and non-responders in both severe and non-severe patients. Conclusions: No predictor of antidepressant response to milnacipran was obtained using the three-factor structures of the MADRS in Japanese patients with major depressive disorders. [ABSTRACT FROM AUTHOR]

Guidelines for treating depression often recommend continuing antidepressants at least for 6 months after remission. Whether this recommendation is implemented in daily practices represents a serious concern. We aimed to examine adequacy of continuation and maintenance treatment in Japan. A naturalistic prospective follow-up study with mood disorders was undertaken in 23 psychiatric departments from all over Japan. A total of 95 patients diagnosed with major depression were followed up every month until treatment termination and every 6 months thereafter. In this study, the cohort received 45.1 (SD = 64.7) mg of imipramine or equivalent per day during continuation phase, and about 74% were prescribed inadequate doses, i.e. less than 75 mg/day. At maintenance phase immediately before relapse, average dosage was 42.0 (SD = 74.7) mg/day and 83% were prescribed inadequate doses. There is gross under-treatment of depression during continuation and maintenance phases in Japan. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to clarify medical expenses in Japanese individuals before and after major depressive disorder (MDD) diagnosis, and to determine whether MDD treatment also reduces medical costs for comorbid physical conditions., Methods: This was an exploratory, descriptive, retrospective analysis of insurance claims data from JMDC Inc. Cohort A included individuals aged 18-64 years between January 2015 and December 2019. Cohorts B and C included Cohort A individuals with diabetes/hypertension ('chronic disease'), and sleep/anxiety disorders ('high depression risk'), respectively. Individuals in Cohorts A-C with an MDD diagnosis were analyzed by year of MDD onset (Cohorts A-C MDD2015-2019 ). Diagnoses and median medical costs were derived from International Classification of Diseases 10 codes., Results: Total medical and non-neuropsychiatric drug costs in MDD onset years were 170,390-182,120 and 8480-9586 yen higher, respectively, for Cohorts A MDD2015-2019 than for Cohort A. In Cohort A MDD2019 , total medical and non-neuropsychiatric drug costs increased incrementally from 2015 to 2019 (total changes: + 165,130 and + 7365 yen, respectively), to a greater degree than in Cohort A (+ 10,510 and + 1246 yen, respectively). Neuropsychiatric drug costs increased in the year of MDD onset only and decreased thereafter. After MDD onset, decreases in total medical and non-neuropsychiatric drug costs were observed (Cohorts A MDD2015-2019 ). Non-neuropsychiatric drug costs also decreased after MDD onset in the chronic disease groups (Cohorts C MDD 2015-2019 ), but not in patients with MDD recurrence., Conclusion: Treating MDD reduces medical costs for comorbid physical conditions and may be a useful strategy for improving healthcare efficiency in Japan., (© 2021. The Author(s).)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

This study attempted to determine whether patients with major depression and panic disorder could be differentiated by personality features, measured by the Munich Personality Test (MPT). One of the six MPT personality dimensions, `rigidity', was developed in relation to the `melancholic type of personality', which may be a specific personality feature of depressive subjects. We therefore hypothesized that the MPT might be sensitive to possible personality differences between patients with major depression and panic disorder. Sixty-six patients with major depression and 27 patients with panic disorder, taken from consecutive intakes at an outpatient unit, were compared in terms of six personality dimensions of the MPT. The results demonstrated that rigidity could significantly differentiate the two patient groups, even after the possible confounding effects on the personality assessments were statistically partialled out. The MPT was suggested to be powerful for describing distinctive personality features of depressive subjects from anxiety subjects. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to examine the cognitive performance of patients with bipolar disorder (BD) stratified by illness phase compared to that of patients with major depressive disorder (MDD) and healthy controls., Methods: Participants were 139 patients with BD (55 euthymic and 84 depressed), 311 patients with MDD (88 euthymic and 223 depressed), and 386 healthy controls who underwent the Wechsler Adult Intelligence Scale-Revised or the Third Edition. They were non-elderly Japanese individuals with normal estimated premorbid intelligence quotient (IQ; >90), group-matched for age, sex, and premorbid IQ., Results: The depressed BD group showed significantly lower scores on verbal IQ, performance IQ, full-scale IQ, and three group indexes of perceptual organization, working memory, and processing speed when compared with healthy controls (all P < 0.001). All IQs and working memory index were also significantly lower than those of the depressed MDD group. The depressed MDD group scored significantly lower than controls in performance IQ (P < 0.001), full-scale IQ, and only in the index of processing speed (P < 0.001). The euthymic BD group scored significantly lower than controls in performance IQ (P = 0.004), whereas the euthymic MDD group scored significantly lower than controls only in processing speed (P = 0.030)., Conclusion: Patients with BD appear to have global and more intense cognitive impairments in depressed states compared with those with MDD whose impairments seem to be apparent only in processing speed in the Wechsler Adult Intelligence Scale. Attenuated impairments appear to exist in euthymic states of both patients., (© 2020 The Authors Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Ethnopharmacological Relevance: Cognitive symptom is a "core" symptom of major depressive disorder (MDD) patients with clear deficit in memory, social and occupational function, and may persist during the remitting phase. Therefore, the remission of cognitive symptom has been considered as one of the main objectives in the treatment of MDD. Herbal antidepressants have been used to treat MDD, and there has been great advances in the understanding of the ability of these herbs to improve cognitive deficit linked to brain injury and various diseases including depression, Alzheimer disease, diabetes and age-related disorders. This systematic review summarizes the evidence from preclinical studies and clinical trials of herbal antidepressants with positive effects on cognitive deficit. The potential mechanisms by which herbal antidepressants prevent cognitive deficit are also reviewed. This review will facilitate further research and applications., Materials and Methods: We conducted an open-ended, English restricted search of MEDLINE (PubMed), Web of Science and Scopus for all available articles published or online before 31 December 2019, using terms pertaining to medical herb/phytomedicine/phytochemical/Chinese medicine and depression/major depressive disorder/antidepressant and/or cognitive impairment/cognitive deficit/cognitive dysfunction., Results: 7 prescriptions, more than 30 individual herbs and 50 phytochemicals from China, Japan, Korea and India with positive effects on the depressive state and cognitive deficit are reviewed herein. The evidence from preclinical studies and clinical trials proves that these herbal antidepressants exhibit positive effects on one or more aspects of cognitive defect including spatial, episodic, aversive, and short- and long-term memory. The action mode of the improvement of cognitive deficit by these herbal antidepressants is mediated mainly through two pathways. One pathway is to promote hippocampal neurogenesis through activating brain derived neurotrophic factor-tropomyosin-related kinase B signaling. The other pathway is to prevent neuronal apoptosis through the inhibition of neuro-inflammation and neuro-oxidation., Conclusion: These herbal antidepressants, having potential therapy for cognitive deficit, may prevent pathological processes of neurodegenerative diseases. Furthermore, these herbal medicines should provide a treasure trove, which will accelerate the development of new antidepressants that can effectively improve cognitive symptom in MDD. Studies on their molecular mechanisms may provide more potential targets and therapeutic approaches for new drug discovery., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Objectives: We aimed to investigate the risk factors for further sick leave episodes among Japanese workers returning to work after time off with a major depressive disorder., Design: A prospective study with 1 year of follow-up., Participants: We recruited 103 workers who had returned to work after taking sick leave with a major depressive disorder. Adjusted HRs with 95% CIs were calculated using Cox proportional hazard models to examine the risk of further sick leave., Results: In the adjusted analysis, we show that Social Adaptation Self-evaluation Scale scores (HR 0.95; p=0.019), 3-back correct response rate (N-back test) (HR 0.97; p<0.001) and benzodiazepine dosage (diazepam equivalent) (HR1.07; p=0.014) were associated with further episodes of sick leave., Conclusions: Poorer social and cognitive functioning, together with higher diazepam dosages, were associated with an increased likelihood of additional sick leave., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Epidemiologic studies have demonstrated that depression is a risk factor for dementia. In particular, dementia with Lewy bodies (DLB) has been noted to be highly relevant to depression. It has been suggested that α-synuclein (α-syn), a major component of Lewy bodies, is related to the onset and progression of DLB. To investigate the relationship between depression and DLB, we compared serum α-syn levels of patients with depression to those of healthy subjects., Methods: The subjects were 103 inpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), or DSM-5 major depressive disorder (MDD) and 132 healthy comparisons. Patients were recruited from Juntendo Koshigaya Hospital, Saitama, Japan, between June 2010 and November 2016. Serum α-syn levels were measured using an enzyme-linked immunosorbent assay kit. Serum α-syn levels were compared using a 2 (age group [<60 years versus ≥60 years]) × 2 (diagnosis [MDD versus comparison]) analysis of variance., Results: There was no significant main effect of age (F = 1.167, df = 1, 231, p = 0.281). There was a significant main effect of diagnosis (F = 44.657, df = 1, 231, p <0.001), with higher α-syn levels in the MDD group versus the healthy comparison group, regardless of age., Conclusion: The present results suggest that depression may affect the metabolism of α-syn; there is a possibility that depression is not only a prodromal symptom of DLB but also a causal risk factor for DLB., (Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Behavioral activation (BA) is receiving renewed interest as a stand-alone or as a component of cognitive-behavior therapy (CBT) for depression. However, few studies have examined which aspects of BA are most contributory to its efficacy., Methods: This is a secondary analysis of a 9-week randomized controlled trial of smartphone CBT for patients with major depression. Depression severity was measured at baseline and at end of treatment by the Patient Health Questionnaire-9. All aspects of behavioral activation tasks that the participants had engaged in, including their expected mastery and pleasure and obtained mastery and pleasure, were recorded in the web server. We examined their contribution to improvement in depression as simple correlations and in stepwise multivariable linear regression., Results: Among the 78 patients who completed at least one behavioral experiment, all aspects of expected or achieved mastery or pleasure correlated with change in depression severity. Discrepancy between the expectation and achievement, representing unexpected gain in mastery or pleasure, was not correlated. In stepwise regression, expected mastery and pleasure, especially the maximum level of the latter, emerged as the strongest contributing factors., Limitations: The study is observational and cannot deduce cause-effect relationships., Conclusions: It may be the expected and continued sense of pleasure in planning activities that are most meaningful and rewarding to individuals, and not the simple level or amount of obtained pleasure, that contributes to the efficacy of BA., (Copyright © 2018. Published by Elsevier B.V.)

A substantial and variable placebo response can cause unreliable findings in clinical trials designed to demonstrate the efficacy of antidepressants, and the high rate of failed trials represents a major obstacle in the development of new drugs for major depressive disorder (MDD). However, the influence of demographic and symptom factors on the antidepressant effect remains to be established. The purpose of this study was to estimate the magnitude of this influence. A patient-level meta-analysis of data from double-blind, randomized, placebo-controlled trials involving the use of antidepressants for adults with MDD was performed. Data from five confirmatory trials evaluating the efficacy of four antidepressants that were submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) to support new drug applications were pooled (n = 1898). The change in the total score of 17-item Hamilton Depression Rating Scale (HDRS 17 ) was the primary outcome of interest in our analysis. The changes in the total HDRS 17 score in both the antidepressant medication group (ADM) and the placebo group (PBO) increased in relation to baseline symptom severity. Among older patients and those with a history of prior treatment with antidepressants, the changes in the total HDRS 17 score decreased in ADM and remained static in PBO. There were no notable clinical symptoms that influenced the change in the total HDRS 17 score. Baseline symptom severity, participant age and a history of previous treatment with antidepressants were suggested as moderators of the antidepressant effect. The drug-placebo difference in the estimated changes as a function of baseline symptom severity varied depending on the regression models used, and further studies are required to investigate appropriate models., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aims: A review of the published work on treatments for major depressive disorder suggests that there is an alarming gap between guideline recommendations and actual clinical practices worldwide. The purpose of this study was to compare early-career psychiatrists' selections of treatment for mild to moderate major depression in Japan and the USA., Methods: The authors surveyed 120 early-career psychiatrists from two residency programs in Japan and the USA using web-based questionnaires. In response to two case vignettes of mild to moderate major depression, the subjects selected treatment modalities and first- and second-line pharmacotherapy., Results: Eighty-one psychiatrists (68%) returned surveys, of whom 42 (52%) were Japanese and 39 (48%) American. Fewer Japanese subjects selected psychotherapy than Americans. The Japanese psychiatrists favored benzodiazepine monotherapy for the treatment of mild depression, whereas the American psychiatrists favored antidepressant monotherapy. For the initial treatment of moderate depression, approximately half of the Japanese selected antidepressant monotherapy, and a quarter selected benzodiazepine monotherapy, whereas the Americans unanimously selected selective serotonin reuptake inhibitors monotherapy. As a second-line strategy, the Japanese were more likely to augment medication and less likely to increase dosage for moderate depression than their American counterparts., Conclusions: Differences were found between the treatment selections of early-career psychiatrists in Japan and the USA, despite comparable guidelines and postgraduate training. The results suggest that the gap between guidelines and practice may also be shaped by physician workload, attitudes toward side-effects, and the sociocultural contexts in which clinical decisions are made., (© 2015 The Authors. Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology.)