Yoshiteru Takekita

Background: Schizophrenia is a heterogeneous disorder in which affective symptoms commonly occur before the onset of frank psychosis. Depressive and anxiety symptoms preceding schizophrenia may complicate early diagnosis and influence subsequent clinical outcomes. This study aimed to describe psychiatric diagnostic patterns preceding first-recorded schizophrenia in Japan and examine clinical outcomes by the presence or absence of prior psychiatric diagnoses. Methods: This retrospective cohort study used a nationwide Japanese health insurance claims database. Patients with a first recorded schizophrenia diagnosis between January 2006 and November 2023 and continuous insurance enrollment for ≥ 1 year before and after the index month (earliest recorded schizophrenia diagnosis) were included. Outcomes included time from the earliest psychiatric diagnosis (recorded using ICD-10 F-category codes) to schizophrenia diagnosis, psychiatric inpatient admission, and sick leave after the index month. Outcomes were compared between patients with and without prior psychiatric diagnoses using inverse probability weighting and Cox models. Results: Among 21,590 eligible patients, 15,955 had ≥ 1 recorded psychiatric diagnosis before the index month and were evaluated for their earliest recorded psychiatric diagnosis. Of these patients, 5,788 were initially diagnosed with schizophrenia. In the other 10,167 patients, the most frequent diagnoses were depressive episodes (45.2%) and other anxiety disorders (21.6%). The mean ± standard deviation interval from the earliest recorded psychiatric diagnosis to the schizophrenia diagnosis was 12.8 ± 22.2 months overall and 20.2 ± 25.1 months among patients whose earliest recorded psychiatric diagnosis was not schizophrenia. The Cox regression model showed that patients with prior psychiatric diagnoses had a lower adjusted risk of psychiatric inpatient admission (HR, 0.87; 95% confidence interval [CI], 0.77–0.98; P = 0.020), although the Kaplan–Meier analysis and the patient-years analysis did not show significant differences between groups. The sick leave was higher at risk in patients with prior psychiatric diagnoses than those without by the Cox regression model (HR, 1.19; 95% CI, 1.11–1.27; P < 0.001), the Kaplan–Meier analysis (log-rank and Wilcoxon tests, both P < 0.001), and the patient-years analysis (the risk ratio 1.09 (95% CI, 1.04–1.15). Conclusions: Depressive and anxiety disorders commonly occur before the first recorded schizophrenia diagnosis in Japan. Patients with prior recorded psychiatric diagnoses showed different patterns of subsequent psychiatric inpatient admission and physician-certified sick leave. Because the mean interval between the earliest recorded non-schizophrenia psychiatric diagnosis and the first recorded schizophrenia diagnosis was approximately 20 months, continued clinical assessment may be warranted. Trial registration: Not registered.

Conventional schizophrenia treatment guidelines do not adequately address all clinically important issues in routine practice. This study aimed to update the 2021 expert consensus of the Japanese Society of Clinical Neuropsychopharmacology (JSCNP) to reflect the current clinical landscape. A total of 154 board-certified psychiatrists from the JSCNP and the Japanese Society of Neuropsychopharmacology (JSNP) evaluated treatment options across 21 clinically relevant situations using a 9-point Likert scale (1 = “strongly disagree”; 9 = “strongly agree”); the response rate was 44%. First-line antipsychotics varied by predominant symptoms: risperidone, brexpiprazole, olanzapine, paliperidone, and blonanserin for positive symptoms; aripiprazole and brexpiprazole for negative symptoms and cognitive impairment; aripiprazole, brexpiprazole, lurasidone, olanzapine, and quetiapine for depression and anxiety; brexpiprazole, aripiprazole, and olanzapine for disorganized thinking; olanzapine and risperidone for excitement and aggression; and aripiprazole, brexpiprazole, and lurasidone for social integration. Brexpiprazole, quetiapine, and aripiprazole were first-line options for patients at high risk of extrapyramidal side effects or diabetes mellitus. Dose reduction or switching was the treatment of choice for tardive dyskinesia. Repeated recurrence, patient request, and poor medication adherence were indications for introducing long-acting injectable antipsychotics. Switching to clozapine was the treatment of choice for treatment-resistant schizophrenia. Adverse effects were the highest-rated factor for both dose reduction and simplification to antipsychotic monotherapy. Second-generation antipsychotics were rated as first- or second-line options in most situations, whereas first-generation antipsychotics were generally rated as third-line. These recommendations provide practical guidance for treatment selection and shared decision-making in clinically challenging situations not adequately addressed by existing evidence alone.

Background: Impaired social functioning substantially affects the quality of life of patients with schizophrenia; however, it remains unclear whether the factors associated with social functioning differ according to relapse frequency. This study aimed to examine the differences in these factors among Japanese outpatients with schizophrenia, stratified by relapse frequency. Methods: This nationwide cross-sectional study, the Multicenter Treatment Survey and Assessments for Schizophrenia in Psychiatric Clinics (MUSASI), was conducted in 330 psychiatric clinics in Japan between September and October 2023. A total of 10,081 patients diagnosed with schizophrenia-related disorders were analyzed. Patients were categorized as nonrelapsers, low-frequency relapsers (1–2 relapses), or high-frequency relapsers (≥3 relapses). Social functioning was assessed using the Social and Occupational Functioning Assessment Scale, with scores ≥61 defined as high functioning. Results: This study included 3,670 nonrelapsers, 4,428 low-frequency relapsers, and 1,983 high-frequency relapsers. Overall, 55.8% ( n = 5,631) of patients were classified as having high social functioning. Across all groups, employment, shorter periods of instability during the past year, lower Clinical Global Impression–Severity scores, and fewer negative symptoms were significantly associated with higher social functioning. Group-specific associations were also observed: in nonrelapsers and low-frequency relapsers, positive symptoms and medication-related factors were relevant, whereas in low- and high-frequency relapsers, marital history was associated, and in high-frequency relapsers, the absence of tardive dyskinesia emerged as a factor. Conclusions: Factors associated with social functioning differed according to relapse frequency, highlighting the need for relapse frequency-based, stratified intervention strategies.

Aim: To determine the smallest worthwhile difference (SWD) for lecanemab, a disease‐modifying drug for Alzheimer's disease (AD), among the general Japanese population using a benefit‐harm trade‐off method. Methods: We conducted an online survey with 658 participants to evaluate their preferences for the treatment effect of lecanemab, given its associated risks and high cost. We calculated SWD as the minimum required increase in the possibility of maintaining cognitive function (relative to the 50% without lecanemab) that patients would accept in exchange for the burdens of treatment (adverse effects, costs, other inconveniences). We examined the median SWD for two scenarios: a family member (SWD‐families) and others (SWD‐others), and analyzed subgroup differences. Results: The median SWD revealed a 15% increase for SWD‐families and SWD‐others. This value exceeds the drug's actual efficacy of an 8% increase. Notably, 17% of respondents reported zero SWD, driven by an intense fear of AD and possibly high expectations from media coverage. Including these participants, nearly half of the respondents considered the current effect worthwhile. No noticeable difference was found between the SWD‐families and SWD‐others. Conclusion: Based on Japanese clinical scenarios, the public's median expectation for lecanemab exceeds its efficacy, though its current benefit remains acceptable to nearly half the population. These findings underscore that the SWD is shaped by psychological drivers, including fear and hope, rather than just reasoned evaluation. Clinicians must manage these expectations, accounting for highly heterogeneous treatment preferences. Future research should account for emotional factors that can overshadow a rational assessment of treatment value.

Background: Little is known about the optimal treatment for constipation in patients with schizophrenia or depression. Elobixibat is a laxative with a novel mechanism of action that inhibits the ileal bile acid transporter, acting as both an osmotic and a stimulant agent. Methods: We conducted a prospective, multicenter, postmarketing surveillance study to assess the safety and effectiveness of elobixibat for patients with chronic constipation in Japan (jRCT1080223950). The surveillance period was between June 2018 and May 2022. Patients were observed from the date of initial administration of elobixibat to 55 days thereafter (4-week treatment groups) or to 419 days thereafter (52-week treatment groups). Safety outcomes included adverse drug reactions (ADRs). Effectiveness outcomes included defecation frequency, Bristol Stool Form Scale (BSFS) scores, and constipation-related symptoms. Results: In the safety analysis set, the 4-week treatment groups comprised 105 patients with schizophrenia and 129 with depression; the 52-week treatment groups included 43 patients with schizophrenia and 55 with depression. Approximately 85% to 95% of patients used antipsychotics, and 40% to 55% used anxiolytics or sedative-hypnotics. The proportions of patients who experienced ADRs were 4.76% in the 4-week treatment group and 2.33% in the 52-week treatment group of patients with schizophrenia, and 3.88% and 9.09% of patients with depression. Diarrhea was the most common ADR in each group. There were no serious ADRs. In the 4-week treatment groups, the mean defecation frequency per week at baseline was 3.3 among patients with schizophrenia and 3.0 among patients with depression, which increased to 5.3 and 4.9, respectively, at week 4. In the 52-week treatment groups, the mean defecation frequency per week at week 52 was higher than that at baseline. After treatment, the proportion of patients with an ideal BSFS score of 4 increased in all groups by week 2 and reached approximately 60% by week 52. All constipation-related symptoms also improved by week 2 in all groups. Conclusions: Elobixibat improved chronic constipation with no new safety signal identified in patients with schizophrenia or depression and with available follow-up in real-world settings. Clinical trial registration: https://jrct.mhlw.go.jp/latest-detail/jRCT1080223950 , identifier jRCT1080223950.

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)

Background: Seizure threshold increases with age and the frequency of electroconvulsive therapy (ECT). Therefore, therapeutic seizures can be difficult to induce, even at maximum stimulus charge with available ECT devices. Such cases are known as difficult-to-induce-seizures electroconvulsive therapy cases (DECs). However, no clinical guidelines exist for DECs; thus, clinicians often face difficulties determining treatment strategies. This study aimed to obtain a consensus among clinical experts regarding the treatment of DECs. Methods: We asked Japanese ECT experts to rate 14 approaches under six conditions of DECs on a 9-point Likert scale (1 = “disagree” to 9 = “agree”). Based on responses from 195 experts, the approaches were classified as first-line (95% confidence interval mean ≥ 6.5), second-line (mean, 3.5–6.5), or third-line strategies (mean < 3.5). Approaches rated 9 points by at least 50% of the respondents were considered “treatments of choice.” Results: To avoid difficult seizure induction, dose reduction of benzodiazepine receptor agonist (BZRA) (8.33 ± 1.25), dose reduction or discontinuation of antiepileptic drugs (AEDs) or other drugs that may make seizure induction difficult (8.16 ± 1.18), and ensure hyperventilation (7.95 ± 1.47) were classified as treatments of choice. First-line treatment strategies were BRZA discontinuation (7.89 ± 1.45), stimulation timing adjustment (7.00 ± 2.00), and anesthetic dose reduction (6.93 ± 1.94). Dose reduction or discontinuation of AEDs or other drugs that might make seizure induction difficult and ensure hyperventilation were the treatments of choice across all patient conditions. The results of rating approaches for patients with mood disorders and schizophrenia were similar, with differences observed among the approaches for patients with catatonia, high risk of cognitive impairment, and cardiovascular events. Conclusions: ECT expert recommendations are useful and can assist in clinical decision-making. Our results suggest that while some strategies are applicable across all conditions, others should be tailored to meet the specific needs of patients. These recommendations should be further evaluated in future clinical studies.