Koichiro Watanabe

Background: The Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project is a nationwide Japanese educational program promoting guideline‐concordant pharmacotherapy for schizophrenia and major depressive disorder (MDD). Psychiatrists' self‐reported clinical behavior (CB) scores after EGUIDE training are partially associated with objective quality indicators of specific practices. However, their association with comprehensive objective measures of overall guideline adherence remains unclear. Methods: This multicenter observational study included 1897 EGUIDE‐trained psychiatrists. CB was assessed online immediately after training. The Guideline Adherence Rate (GAR) was calculated for 5328 patients with schizophrenia and 3538 patients with MDD whose discharge records were linked to their psychiatrist's CB score. Associations were evaluated using unadjusted patient‐level Spearman correlations, without modeling clustering within psychiatrists or institutions. Sensitivity analyses aggregated the data to the psychiatrist‐year level, adjusted for institution type, psychiatrist experience, and patient age, and used generalized estimating equations (GEE) to correct the patient‐level inference for clustering. Results: CB scores showed positive but very weak correlations with GAR (schizophrenia, ρ = 0.09–0.14; MDD, ρ = 0.08–0.11; all p < 0.001). Squared coefficients (approximately 0.006–0.020) indicated that CB scores accounted for < 2% of the rank‐order variation in GAR. These associations remained statistically significant in psychiatrist‐year‐level, covariate‐adjusted, and clustering‐corrected (GEE) sensitivity analyses. Conclusions: Post‐training self‐reported CB scores were weakly associated with patient‐level GAR. Given the cross‐sectional, unadjusted analysis and the non‐independence of patients treated by the same psychiatrist, these findings do not establish CB as a reliable proxy for actual clinical practice. Trial Registration: University Hospital Medical Information Network Clinical Trials Registry, UMIN000022645

Objectives: Research on predictors for consultations regarding obstructive sleep apnea (OSA) is limited, with few longitudinal studies examining how changes in disease status and work conditions influence these behaviors. This study tracked Japanese male workers in the construction and civil engineering sector for 1 year to determine whether individual changes could predict future OSA consultations. Methods: We conducted a longitudinal analysis using data from 16,279 male employees covered by the health insurance society of a construction and civil engineering company. The dataset comprised annual medical check-up findings, self-administered questionnaires, and medical claims data collected at two points, with a mean interval of 370 ± 34.3 days between assessments. Associations between time-varying factors and possible OSA consultation behavior were assessed using binary logistic regression with generalized estimating equations, while associations between changes in these factors and consultation behavior were evaluated using conventional binary logistic regression. This consultation behavior was defined as the occurrence of at least one of the following procedures in the medical insurance claims records: polysomnography, home sleep apnea testing, or pulse oximetry. Results: Possible OSA consultation behavior was positively associated with the presence of comorbidities and habitual snoring and/or witnessed apnea, but inversely associated with the number of working days. However, none of the changes observed during the follow-up period were significantly associated with consultation behavior. Additionally, a high risk for OSA alone was not significantly associated with the consultation behavior. Conclusion: Neither short-term within-person changes in symptoms or comorbidities nor high OSA risk prompted help-seeking, highlighting the need for proactive screening and streamlined referrals.

Background: Schizophrenia is characterized by positive symptoms, negative symptoms, and cognitive impairment and is primarily treated with antipsychotic medications. However, a subset of patients responds inadequately to treatment and is classified as having treatment‐resistant schizophrenia (TRS). The prevalence of TRS among patients with schizophrenia remains insufficiently characterized. This study aimed to determine the prevalence of TRS using nationwide data and standardized diagnostic criteria. Methods: This study included patients with schizophrenia who were discharged between 2016 and 2024 from 205 institutions participating in the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project and authorized to prescribe clozapine. TRS was defined according to standardized diagnostic criteria used in Japan. The prevalence of TRS was calculated among patients who underwent a TRS examination by their treating psychiatrist. Results: Among 18 914 patients, 9870 (52.2%) underwent a TRS examination. Among these 9870 patients, 2819 were classified as having TRS, corresponding to a prevalence of 28.6%. Among the 2819 patients with TRS, 1307 were prescribed clozapine at discharge, corresponding to a clozapine treatment rate of 46.4%. Conclusions: This study had the largest sample size among single‐cohort studies investigating the prevalence of TRS. The prevalence of TRS was 28.6% among patients with schizophrenia who underwent a TRS examination and was nearly identical to the pooled prevalence reported in studies at low risk of bias in a previous meta‐analysis. These findings may provide important evidence regarding the prevalence of TRS in routine clinical practice.

Tic disorders typically begin in childhood and often improve by adulthood, but some individuals continue to experience tic symptoms into adult life. Tic disorders frequently co‐occur with Attention‐deficit/hyperactivity disorder (ADHD), and in such cases α2‐adrenergic agonists are recommended as a treatment as they can address both conditions. However, evidence in adults with ADHD and comorbid tic disorders is limited, as most studies have focused on pediatric populations. Here, we present three adult male patients with childhood‐onset ADHD and chronic tic symptoms who showed a rapid and significant improvement in tics with low‐dose extended‐release guanfacine (GXR) monotherapy. These cases suggest that GXR can effectively treat both ADHD and tic symptoms in adults—a finding that has not been well documented in prior adult studies.

Major depressive disorder (MDD) is a leading cause of disability worldwide, with many patients experiencing inadequate response to standard antidepressants. Dysregulation of N-methyl-D-aspartate (NMDA) receptor activity is implicated in the pathophysiology of MDD. Satoprodil (BI 1569912), an oral NMDA subunit GluN2B-selective negative allosteric modulator, was evaluated for safety and efficacy in MDD in two multicenter, randomized, placebo-controlled Phase II dose-finding trials as an adjunctive or monotherapy. In each trial, patients (18–65 years old) were randomized 2:1:1:2 to placebo or satoprodil (5 mg, 10 mg, or 20 mg) once-daily for 6 weeks, with ongoing antidepressant treatment in the adjunctive trial. Primary endpoint was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6 (both trials). Safety and tolerability were also assessed. In the adjunctive trial ( N = 243; 60.9% female), the adjusted mean (standard error [SE]) change in MADRS total score at Week 6 was: placebo, –12.0 (1.1); satoprodil 5 mg, −7.8 (1.6); satoprodil 10 mg, −11.9 (1.6) and satoprodil 20 mg, −12.3 (1.2). In the monotherapy trial ( N = 225; 54.2% female), the adjusted mean (SE) change in MADRS total score at Week 6 was: placebo, –10.3 (1.4); satoprodil 5 mg, −13.6 (2.1); satoprodil 10 mg, −10.6 (2.0) and satoprodil 20 mg, −10.0 (1.4). In patients with MDD, satoprodil (all doses) over 6-weeks was well tolerated but did not reduce depressive symptoms beyond placebo in either trial in a relevant manner. These trials provide the most comprehensive clinical evidence to date on GluN2B-selective modulation in MDD and will inform future research on glutamatergic pathways.

This article relates to clinical relevance of venlafaxine ER for generalized anxiety disorder.

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: The current study investigated the superiority of anxiolytic effects of venlafaxine extended release (ER) compared with placebo and its safety and tolerability in Japanese adult outpatients with generalized anxiety disorder (GAD). Methods: In this placebo‐controlled, double‐blind study, 357 eligible participants were randomized to receive venlafaxine ER (75–225 mg/day) or placebo for 8 weeks. The primary endpoint was change from baseline to week 8 in Hamilton Anxiety Rating Scale (HAM‐A) total score. Secondary endpoints included changes from baseline to week 8 in scores of HAM‐A psychic anxiety factors, HAM‐A somatic anxiety factors, Clinical Global Impressions‐Severity of Illness (CGI‐S), Generalized Anxiety Disorder‐7 (GAD‐7), Zung Self‐Rating Anxiety Scale (Z‐SAS), Sheehan Disability Scale (SDS), and the absolute score of Clinical Global Impressions‐Global Improvement (CGI‐I). Results: Venlafaxine ER showed statistically significant reduction in HAM‐A total score at week 8 (difference versus placebo: P = 0.012). The results of all secondary endpoints were consistent with this finding and likewise demonstrated statistical significance in favor of venlafaxine ER in investigator‐ and patient‐rated scales. Venlafaxine ER further showed statistically significant remission in total HAM‐A score. These results showed that venlafaxine ER improved patients' functional disabilities along with symptoms more than placebo. Venlafaxine ER was well tolerated, and safety findings were generally consistent with the known safety profile of the drug. Conclusion: Venlafaxine ER has a favorable benefit–risk profile in adult Japanese patients with GAD, indicating its potential to improve GAD symptoms as well as patients' function and exert superior anxiolytic effects over placebo without any new safety concern. Trial Registration: Japan Registry of Clinical Trials Identifier jRCT2031220156.

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).