Hitoshi Sakurai

This study investigated the antisuicidal effects of repeated intravenous ketamine in patients with treatment-resistant depression and explored associations between suicidal ideation and temporal changes in selected plasma biomarkers to identify potential biomarkers. This secondary analysis of an open-label trial included outpatients with treatment-resistant depression who received four intravenous ketamine infusions (0.5 mg/kg) over 2 weeks. Suicidal ideation was assessed at baseline and post-intervention using the Montgomery–Åsberg Depression Rating Scale (item 10), Quick Inventory of Depressive Symptomatology–Self Report (item 12), and Columbia Suicide Severity Rating Scale. Eleven targeted plasma biomarkers were quantified via liquid chromatography–mass spectrometry. Associations between suicidal ideation scores and biomarker changes were evaluated using Pearson’s and Spearman’s correlation coefficients, with p-values adjusted for multiple comparisons using the false discovery rate procedure. Repeated ketamine infusions were associated with modest reductions in suicide-related item scores on the Montgomery–Åsberg Depression Rating Scale item 10 (1.5±1.5 to 1.0±1.3, p=0.01) and Quick Inventory of Depressive Symptomatology–Self Report item 12 (1.3±0.9 to 0.8±0.9, p=0.01). Columbia Suicide Severity Rating Scale scores numerically decreased (1.1±1.3 to 0.8±1.2, p=0.17) without reaching statistical significance. In unadjusted analyses, improved Columbia Suicide Severity Rating Scale scores showed nominal associations with increased levels of citric acid (r=− 0.40, p=0.03) and kynurenic acid (ρ=− 0.37, p=0.04), although these did not survive false discovery rate correction. Repeated ketamine infusions were associated with modest reductions in suicide-related item scores on the Montgomery–Åsberg Depression Rating Scale and Quick Inventory of Depressive Symptomatology–Self Report. While no definitive biomarkers were identified after false discovery rate correction, these nominal associations are purely hypothesis-generating and require larger validation trials.

Background: Rapidly evolving insomnia management with orexin receptor antagonists (ORAs) has outpaced current clinical guidelines. Objectives: This study aimed to provide a practical expert opinion reflecting specialists’ collective experience to bridge the gap between existing recommendations and contemporary clinical practice in Japan. Design: Cross-sectional web-based survey. Methods: A web-based questionnaire survey conducted in late 2025 targeted board-certified experts in clinical neuropsychopharmacology. Experts rated treatment options for 17 clinical scenarios using a nine-point Likert scale. Treatments were categorized as first-, second-, or third-line based on the 95% confidence interval (CI), with “treatments of choice” defined by ≥50% of respondents assigning the highest score. Results: A total of 152 responses were analyzed (response rate: 43.4%). ORAs occupied central positions across nearly all scenarios. Lemborexant was the treatment of choice for both sleep initiation and maintenance, while suvorexant and daridorexant were also first-line options. When ORA monotherapy was insufficient, switching to another ORA was the preferred strategy. In contrast, most benzodiazepine receptor agonists were relegated to lower-line treatments, with eszopiclone remaining a notable exception as a second-line option. Regarding treatment duration, experts showed an increased tendency for continuing pharmacotherapy, particularly when clinical stability was incomplete or relapse risk was high. Conclusions: This opinion survey demonstrates a clear shift toward ORA-based strategies in Japan and a growing acceptance of ORA continuation based on clinical stability. While representing a lower evidence level than formal guidelines, these practice-based insights offer a valuable reference for pharmacological decision-making in real-world scenarios where high-level evidence is limited.

The efficacy of antidepressants in mild depression remains debated. Despite guidelines recommending psychosocial interventions first, antidepressants are often initiated in real-world clinical practice. This study aimed to investigate the prescribing patterns of antidepressants at initial psychiatric consultations for patients with mild depression and to identify symptom-related factors influencing these prescribing decisions. A retrospective chart review was conducted on 1,508 outpatients diagnosed with depression at Kyorin University Hospital between 2020 and 2024. Among them, 171 patients met the criteria for mild depression, defined as a total score of 6–10 on the Quick Inventory of Depressive Symptomatology-Self Report. Independent t-tests and logistic regression analyses were performed to compare demographic and symptom-level characteristics between those who were prescribed antidepressants and those who were not. Of the 171 eligible patients, 28.1% were prescribed antidepressants at their first visit. No significant between-group differences were observed in demographics or overall symptom severity. The Quick Inventory of Depressive Symptomatology-Self Report item “increased weight” showed lower scores in the antidepressant group (0.1±0.4 vs 0.3±0.7, p=0.03), but this was not statistically significant after Benjamini–Hochberg false discovery rate correction and was also not statistically significant in logistic regression. Among participants prescribed monotherapy, no significant differences were found across antidepressant categories. Antidepressants were prescribed at the initial consultation in approximately 30% of patients with mild depression. No symptom item showed a clear, robust association with prescribing, suggesting that factors other than specific symptom profiles may play a more decisive role in real-world treatment selection.

Background: Self-management is essential for coping with depressive symptoms, yet little is known about its associations with depressive symptoms and personal recovery. Methods: We conducted a cross-sectional questionnaire survey of 183 outpatients with major depressive disorder in Japan between October 2024 and June 2025. Participants reported the use and perceived usefulness of 63 self-management strategies. Associations between the number of strategies and symptom severity and recovery were examined using Spearman’s rank correlation coefficients with the Japanese versions of the Quick Inventory of Depressive Symptomatology (QIDS-J) and the Questionnaire about the Process of Recovery (QPR-J). Results: Of the 183 respondents (mean age 43.6 ± 12.4 years; 54.1% female), the mean QIDS-J score was 9.55 ± 5.25 and 60.7% were in remission. Fourteen of the 63 strategies were used by at least half of the participants. The most frequently used strategies were “ensure enough rest to avoid exhaustion through overexertion” (88.0%), “engage in leisure activities (e.g. reading, watching TV, cooking, traveling, and driving)” (78.9%), and “eat a healthy diet” (65.0%). The strategies rated most useful included “discuss information about depression with a therapist” (86.7%), “meet with friends with whom I can be myself” (83.5%), and “avoid or minimize contact with people who tend to make me stressed or depressed” (83.3%). Participants reported using an average of 20.8 ± 13.5 strategies, of which 13.1 ± 9.16 were rated as useful. The number of strategies rated as useful was weakly negatively correlated with the QIDS-J scores (Spearman’s ρ = −0.207, p = 0.006) and moderately positively correlated with the QPR-J scores (Spearman’s ρ = 0.472, p < 0.001). Conclusion: The number of self-management strategies rated as useful showed a stronger correlation with personal recovery than with depressive symptom severity. The use of a greater number of self-management strategies may be associated with higher levels of personal recovery.

Background and Objectives The efficacy and safety of lemborexant, a dual orexin receptor antagonist, for treating insomnia associated with depressive episodes remain unclear. This pilot study aimed to evaluate the changes in clinical symptoms following the initiation of lemborexant treatment and its safety in patients with insomnia comorbid with depressive episodes. Methods The inclusion criteria for this multicenter, prospective, interventional, open-label pilot study conducted in Japan were adults (≥ 18 years) diagnosed with insomnia and either major depressive disorder (MDD) or bipolar disorder (BD) according to DSM-5, receiving treatment for a depressive episode for ≥ 4 weeks, and having a baseline Hamilton Depression Rating Scale (HAM-D-17) score of ≥ 8. Patients were classified into four cohorts on the basis of their MDD or BD diagnosis and concomitant insomnia medication use (lemborexant add-on or monotherapy). After a 2-week lead-in period with unchanged prior medications for insomnia MDD or BD, 12-week lemborexant treatment was administered. The primary endpoint was the change from baseline in the Insomnia Severity Index (ISI) total score at week 4, which was analyzed using paired t-tests with a two-sided significance level of 5%. For other endpoints, summary statistics and 95% confidence intervals (CIs) for observed values and changes from baseline were calculated by cohort. Safety outcomes included the evaluation of the safety and tolerability of lemborexant during the treatment period. Results A total of 83 patients with comorbid insomnia and depressive episodes were enrolled (MDD add-on cohort, n = 29; MDD monotherapy, n = 23; BD add-on, n = 16; and BD monotherapy, n = 15). The average age was 47.2 years and 64.6% were female. Mean baseline ISI total score (SD) was 14.5 (4.8), 13.2 (5.5), 13.5 (6.0), and 11.8 (4.6), respectively. At week 4, mean change from baseline in the ISI total score [95% CI, p-value] was − 2.3 [− 3.9, − 0.7, p = 0.0065], − 3.2 [− 5.0, − 1.3, p = 0.0018], − 5.2 [− 7.9, − 2.5, p = 0.0012], − 4.5 [− 6.3, − 2.6, p = 0.0001], respectively. Improvements were sustained through week 12. Sleep diary measures such as sleep onset latency and total sleep time improved in some cohorts, but the results were inconsistent. Mean baseline HAM-D-17 scores were 13.6 (5.1), 12.6 (5.1), 13.9 (4.3), and 11.4 (3.4), respectively, with mean changes at week 12 of − 6.4 [− 7.8, − 4.9], − 6.2 [− 7.7, − 4.6], − 5.2 [− 8.4, − 2.1], and − 5.4 [− 7.2, − 3.5], respectively. No serious treatment-emergent adverse events (TEAEs) were reported, with TEAE incidence ranging from 30% to 40%, all mild to moderate in severity. Somnolence was the most common adverse reaction, reported in 10.3–25.0% of cohorts except BD monotherapy. Nightmare followed, occurring in 4.3–12.5% across cohorts. Conclusions Lemborexant was associated with improvements in insomnia severity and depressive symptoms related to MDD or BD, with no new safety concerns. It may be a treatment option for residual insomnia following treatment for depression associated with MDD or BD, though somnolence and nightmares warrant attention. Confirmatory studies are needed to establish its therapeutic value. Study Registration Japan registry of clinical trials (jRCTs071220037; registered on 4 August 2022)

Aim: Assessing symptoms and daily functioning in individuals with attention‐deficit/hyperactivity disorder (ADHD) comorbid with major depressive disorder (MDD) is challenging because of their limited self‐monitoring abilities. This study aimed to determine whether specific occupational behaviors could differentiate patients with ADHD comorbid with MDD from those with MDD alone. Methods: This study included patients who underwent a comprehensive assessment for suspected difficult‐to‐treat depression at Kyorin University Hospital, Japan. During an artistic activity program, three therapists evaluated occupational performance characteristics to identify potential traits. Characteristics in patients with comorbid ADHD and MDD were compared to those in MDD alone using the chi‐square test. Key discriminators were selected based on significant characteristics ( p < 0.01). Discriminant analysis was conducted to enhance group differentiation, with prediction accuracy assessed via area under the curve (AUC). This study was approved by the Research Ethics Committee. Results: A total of 71 occupational performance characteristics were identified through retrospective analysis, of which 12 showed significant differences between 29 patients with comorbid ADHD and MDD and 35 patients with MDD alone. Four variables were selected as independent predictors in the discriminant analysis: “Have its own manners,” “Feel uncomfortable in groups,” “Work only at your own pace,” and “Ask questions and consult.” These variables contributed to the construction of a linear discriminant function. The discriminant model yielded a Wilks' λ of 0.631 ( p < 0.001) and achieved a classification accuracy of 81.3%. The receiver operating characteristic (ROC) curve showed an AUC of 0.857, with a sensitivity of 72.4% and a specificity of 88.6%. Conclusion: These findings highlight the role of occupational performance characteristics in differentiating comorbid ADHD and MDD from MDD alone. This approach may contribute to more tailored treatment strategies.

Aim: This study aims to investigate the acute and sustained antidepressant effects of repeated ketamine infusions in patients with treatment‐resistant depression (TRD), and to identify early metabolomic changes predictive of treatment outcomes using metabolome analyses.Methods: This open‐label study investigated the effects of four intravenous ketamine infusions (0.5 mg/kg) administered over 2 weeks in 30 patients with TRD. Clinical outcomes, including the Montgomery‐Åsberg Depression Rating Scale (MADRS), were evaluated at baseline, 1–2 h after each infusion, and monthly during a 12‐month follow‐up. Plasma levels of 11 depression‐associated metabolites were measured at baseline and 1.5–2 h after the first infusion. A general linear model was employed to analyze the association between metabolite changes after the first infusion and the MADRS score percent improvements after the fourth infusion and at 12 months. Remission was defined as a MADRS score of ≤10.Results: All participants completed the four infusions. The MADRS score decreased from 30.6 ± 6.1 at baseline to 20.3 ± 11.5 after the fourth infusion, with a remission rate of 26.7%. At 12 months, 13.3% of participants remained in remission. Changes in 3‐hydroxybutyrate levels after the first infusion predicted the MADRS score percent improvements after the fourth infusion (β = 1.35, 95% CI: 0.41–2.30, P = 0.005) and at 12 months (β = 1.38, 95% CI: 0.37–2.39, P = 0.007).Conclusion: While repeated ketamine infusions demonstrated rapid antidepressant effects, sustained remission was achieved in a minority of patients with TRD. 3‐Hydroxybutyrate may serve as a biomarker for predicting treatment response. These findings underscore the potential for individualized strategies using ketamine infusions.Clinical Trial Registration: jRCTs031210648 (Japan Registry of Clinical Trials).

Background: Mild depression lacks a consistent definition across diagnostic criteria and rating scales, posing challenges to standardizing treatment strategies. International guidelines predominantly recommend psychotherapy as the first‐line treatment for mild depression, while the use of antidepressants remains contentious. Supplements such as omega‐3 fatty acids, St. John's Wort, and magnesium have garnered attention as alternative therapeutic options for depression. This systematic review aims to assess the efficacy of pharmacological interventions, including supplements, in the treatment of mild depression. Methods: Comprehensive searches were performed in PubMed and Embase through November 2024 to identify randomized controlled trials (RCTs) investigating pharmacotherapy or supplements for mild depression diagnosed using standardized criteria. Eligible studies underwent screening and risk of bias assessment utilizing the ROB2 tool. Data on remission rates, symptom improvement, dropout rates, and adverse events were extracted, with meta‐analyses conducted where applicable. Results: Eight RCTs comprising 1049 participants met inclusion criteria. Among the agents studied, St. John's Wort was analyzed in two trials, both comparing it to fluoxetine. A meta‐analysis found no significant difference in response rates between the two treatments (risk ratio [RR] = 0.96, 95% CI: 0.78–1.18) or dropout rates (RR = 1.08, 95% CI: 0.62–1.88). For other agents, single studies evaluated their effects. Eicosapentaenoic acid and Rhodiola rosea demonstrated significant improvements in depressive symptoms compared to placebo. In non‐blinded trials, magnesium chloride showed efficacy in alleviating depressive symptoms. Other interventions, such as lavender, lemon balm, and transcranial electroacupuncture stimulation, were as effective as antidepressants. Conversely, S‐adenosylmethionine did not produce significant improvements relative to placebo. Conclusion: This review demonstrates that certain supplements, such as eicosapentaenoic acids and Rhodiola rosea , are therapeutic options for mild depression. However, no RCTs compared antidepressants directly to placebo for mild depression. The paucity of high‐quality RCTs exclusively targeting mild depression limits definitive conclusions, warranting further rigorous research.

Aim: Assessing symptoms and daily functioning in patients with major depressive disorder (MDD) can be challenging, as their limited self‐monitoring abilities may result in behavior observed during structured interviews not accurately reflecting their daily lives. This study aimed to determine if specific occupational behaviors could distinguish individuals with MDD from healthy individuals.Methods: Baseline data were collected from medical records and activity programs. Three occupational therapists conducted content analysis to assess occupational performance characteristics. Chi‐squared tests compared the prevalence of these characteristics between patients with MDD and healthy controls. Multivariable logistic regression controlled for potential confounders, with independent variables selected based on clinical relevance and sample size (p < 0.01). Discriminant analysis was used to enhance group differentiation, assessing prediction rates using area under the curve (AUC) values.Results: A total of 69 occupational performance characteristics were identified, with 12 showing significant differences between 27 patients with MDD and 43 healthy controls. Key discriminators included “Ask questions and consult” (p < 0.001, odds ratio [OR] = 0.051, 95% confidence interval [CI] = 0.009–0.283), “Concentrate on work” (p = 0.003, OR = 0.078, 95% CI = 0.015–0.416), “Choose simple work” (p = 0.004, OR = 17.803, 95% CI = 2.446–129.597), and “Punctual” (p = 0.017, OR = 0.030, 95% CI = 0.002–0.530). Discriminant analysis using these variables yielded a Wilks' λ of 0.493 (p < 0.001), achieving an 88.6% accuracy rate. The receiver operating characteristic curve's AUC value was 0.911 (sensitivity = 95.3%, specificity = 77.8%).Conclusion: This study highlights the importance of occupational performance characteristics in tailoring treatment strategies for MDD, providing insights beyond traditional assessment methods.

Background: Bipolar disorder often emerges from depressive episodes and is initially diagnosed as depression. This study aimed to explore the effects of a prior depression diagnosis on outcomes in patients diagnosed with bipolar disorder.Methods: This cohort study analyzed data of patients aged 18–64 years who received a new bipolar disorder diagnosis in Japan, using medical claims data from January 2005 to October 2020 provided by JMDC, Inc. The index month was defined as the time of the bipolar diagnosis. The study assessed the incidence of psychiatric hospitalization, all‐cause hospitalization, and mortality, stratified by the presence of a preceding depression diagnosis and its duration (≥1 or p‐values were estimated using Cox proportional hazards models, adjusted for potential confounders, and supported by log‐rank tests.Results: Of the 5595 patients analyzed, 2460 had a history of depression, with 1049 experiencing it for over a year and 1411 for less than a year. HRs for psychiatric hospitalization, all hospitalizations, and death in patients with a history of depression versus those without were 0.92 (95% CI = 0.78–1.08, p = 0.30), 0.87 (95% CI = 0.78–0.98, p = 0.017), and 0.61 (95% CI = 0.33–1.12, p = 0.11), respectively. In patients with preceding depression ≥1 year versus p = 0.43) for psychiatric hospitalization, 0.85 (95% CI = 0.71–1.00, p = 0.052) for all hospitalizations, and 0.25 (95% CI = 0.07–0.89, p = 0.03) for death.Conclusion: A prior history and duration of depression may not elevate psychiatric hospitalization risk after bipolar disorder diagnosis and might even correlate with reduced hospitalization and mortality rates.