岸 太郎

In clinical practice, theta burst stimulation (TBS) presents as a more efficient and potentially more effective therapeutic modality than conventional repetitive transcranial magnetic stimulation (rTMS), as it allows for the delivery of more stimuli in less time and at similar intensities. To date, accelerated treatment plans according to various continuous (cTBS) and intermittent TBS (iTBS) protocols for depression have been proposed. To investigate which of the TBS protocols provided a favorable risk-benefit balance for individuals with depression, this systematic review and random-effects model network meta-analysis was conducted. The study outcomes included response rate (primary), depression symptom improvement, remission rate, all-cause discontinuation rate, incidence of switch to mania, and incidence of headache/discomfort at treatment site. In this meta-analysis, a total of 23 randomized controlled trials (n = 960, mean age = 41.88 years, with 60.78% females) were included. Approximately 69.57% of the trials included individuals with an exclusive diagnosis of major depressive disorder. The following six TBS protocols (target) were evaluated: cTBS (right-dorsolateral prefrontal cortex [R-DLPFC]), cTBS (R-DLPFC) + iTBS (left-DLPFC [L-DLPFC]), iTBS (L-DLPFC), iTBS (L-DLPFC) + iTBS (R-DLPFC), iTBS (left-dorsomedial prefrontal cortex) + iTBS (right-dorsomedial prefrontal cortex), and iTBS (occipital lobe). Compared to sham, cTBS (R-DLPFC) + iTBS (L-DLPFC), iTBS (L-DLPFC), and iTBS (occipital lobe) had a higher response rate (k = 23); cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) dominated in the depression symptom improvement (k = 23); and iTBS (L-DLPFC) had a higher remission rate (k = 15). No significant differences were found for all-cause discontinuation rate (k = 17), incidence of switch to mania (k = 7), and incidence of headache/discomfort at treatment site (k = 10) between any TBS protocols and sham. Thus, cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) demonstrate favorable risk-benefit balance for the treatment of depression.

Background and Objective: Excellent generalizability is the precondition for the widespread practical implementation of machine learning models. In our previous study, we developed the schizophrenia classification model (SZ classifier) to identify potential schizophrenia patients in the Japanese population. The SZ classifier has exhibited impressive performance during internal validation. However, ensuring the robustness and generalizability of the SZ classifier requires external validation across independent sample sets. In this study, we aimed to present an external validation of the SZ classifier using outpatient data. Methods: The SZ classifier was trained by using online survey data, which incorporate demographic, health-related, and social comorbidity features. External validation was conducted using an outpatient sample set which is independent from the sample set during the model development phase. The model performance was assessed based on the sensitivity and misclassification rates for schizophrenia, bipolar disorder, and major depression patients. Results: The SZ classifier demonstrated a sensitivity of 0.75 when applied to schizophrenia patients. The misclassification rates were 59% and 55% for bipolar disorder and major depression patients, respectively. Conclusions: The SZ classifier currently encounters challenges in accurately determining the presence or absence of schizophrenia at the individual level. Prior to widespread practical implementation, enhancements are necessary to bolster the accuracy and diminish the misclassification rates. Despite the current limitations of the model, such as poor specificity for certain psychiatric disorders, there is potential for improvement if including multiple types of psychiatric disorders during model development.

Aim: This systematic review and frequentist network meta-analysis used random-effects models is conducted to determine whether there are differences in the efficacy, acceptability, tolerability, and safety profiles of brexpiprazole (BRE) and aripiprazole (ARI) for Japanese with major depressive disorder (MDD) who were inadequately responsive to antidepressants. Methods: Outcome measures were scores on the Montgomery Åsberg Depression Rating Scale (primary), the Clinical Global Impression severity scale, and social functioning scale; the non-response rate; the non-remission rate; all-cause discontinuation; discontinuation due to adverse events (DAE); at least one adverse event (1AE); serious adverse event, akathisia; tremor; weight gain. Results: A literature search identified three double-blind, randomized, placebo-controlled trials. These comprised one BRE study (with a 1 mg/day [BRE1] and a 2 mg/day [BRE2]) and two ARI studies (with a 3 mg/day arm and a flexible-dose arm[within the dosage range approved in Japan]) (n = 1736). Both BRE and ARI demonstrated better efficacy than the placebo. BRE but not ARI had a higher DAE than the placebo. ARI but not BRE had a higher 1AE than the placebo. BRE and ARI had a higher risk of akathisia and weight gain than the placebo. There were no significant differences between BRE and ARI for any of the outcomes. Although BRE1 had good efficacy, it carried risk of weight gain. Although BRE2 also had efficacy, it carried risks of DAE, akathisia, and weight gain. However, the risk of akathisia in BRE2 was reduced by an initial dose of 0.5 mg/day rather than 1.0 mg/day. Conclusions: Overall BRE showed similar utility to ARI and a good risk–benefit balance.

AIM: To update the major depressive disorder (MDD) treatment guidelines of the Japanese Society of Mood Disorders, we conducted a systematic review and pairwise meta-analysis of double-blind, randomized, placebo-controlled trials of available antidepressants in Japan for older adults with MDD. METHODS: Outcome measures included response rate (primary), improvement in depressive symptom scale score, remission rate, all-cause discontinuation, discontinuation due to adverse events, and at least one adverse event. A random-effects model was used to calculate the risk ratio (RR) and standardized mean difference (SMD) with a 95% confidence interval (95% CI). RESULTS: Nine double-blind, randomized, placebo-controlled trials (n = 2145) were identified. No study has been conducted in Japan. Our meta-analysis included the following antidepressants: duloxetine, escitalopram, imipramine, sertraline, venlafaxine, and vortioxetine. Antidepressants have significantly higher response rates than placebo (RR [95% CI] = 1.38 [1.04, 1.83], p = 0.02). Antidepressants outperformed placebo in terms of improving depressive symptom scale score (SMD [95% CI] = -0.62 [-0.92, -0.33], p < 0.0001). However, antidepressants were associated with a higher discontinuation rate due to adverse events (RR [95% CI] = 1.94 [1.30, 2.88], p = 0.001) and a higher incidence of at least one adverse event (RR [95% CI] = 1.11 [1.02, 1.21], p = 0.02) compared to placebo. The groups did not differ significantly in terms of remission rate or all-cause discontinuation. CONCLUSIONS: Our meta-analysis concluded that treatment with antidepressants available in Japan is only weakly recommended for moderate to severe MDD in older adults.

Background In Japan, challenges were reported in accurately estimating the prevalence of schizophrenia among the general population. Retrieving previous studies, we investigated that patients with schizophrenia were more likely to experience poor subjective well-being and various physical, psychiatric, and social comorbidities. These factors might have great potential for precisely classifying schizophrenia cases in order to estimate the prevalence. Machine learning has shown a positive impact on many fields, including epidemiology, due to its high-precision modeling capability. It has been applied in research on mental disorders. However, few studies have applied machine learning technology to the precise classification of schizophrenia cases by variables of demographic and health-related backgrounds, especially using large-scale web-based surveys. Objective The aim of the study is to construct an artificial neural network (ANN) model that can accurately classify schizophrenia cases from large-scale Japanese web-based survey data and to verify the generalizability of the model. Methods Data were obtained from a large Japanese internet research pooled panel (Rakuten Insight, Inc) in 2021. A total of 223 individuals, aged 20-75 years, having schizophrenia, and 1776 healthy controls were included. Answers to the questions in a web-based survey were formatted as 1 response variable (self-report diagnosed with schizophrenia) and multiple feature variables (demographic, health-related backgrounds, physical comorbidities, psychiatric comorbidities, and social comorbidities). An ANN was applied to construct a model for classifying schizophrenia cases. Logistic regression (LR) was used as a reference. The performances of the models and algorithms were then compared. Results The model trained by the ANN performed better than LR in terms of area under the receiver operating characteristic curve (0.86 vs 0.78), accuracy (0.93 vs 0.91), and specificity (0.96 vs 0.94), while the model trained by LR showed better sensitivity (0.63 vs 0.56). Comparing the performances of the ANN and LR, the ANN was better in terms of area under the receiver operating characteristic curve (bootstrapping: 0.847 vs 0.773 and cross-validation: 0.81 vs 0.72), while LR performed better in terms of accuracy (0.894 vs 0.856). Sleep medication use, age, household income, and employment type were the top 4 variables in terms of importance. Conclusions This study constructed an ANN model to classify schizophrenia cases using web-based survey data. Our model showed a high internal validity. The findings are expected to provide evidence for estimating the prevalence of schizophrenia in the Japanese population and informing future epidemiological studies.

The benefits of serotonin 3 receptor antagonists (5-HT3R-As) in obsessive-compulsive disorder (OCD) treatment remain unclear. Thus, this study aimed to perform a systematic review and a random-effects meta-analysis, including double-blind, randomized, placebo-controlled trials (DBRPCTs). The outcomes include the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score (primary), Y-BOCS obsession subscale score, Y-BOCS compulsive subscale score, treatment response, remission rate, all-cause discontinuation, and incidence of individual adverse events (nervousness/restlessness/anxiety, insomnia, headache, dizziness/lightheadedness, decreased appetite, constipation, nausea/vomiting, diarrhea, dry mouth, sweating/increased perspiration, itching/pruritus, tremor, and sexual dysfunction/decreased libido). The mean differences (MD) for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals (CIs) were calculated. Our study included 10 DBRPCTs (n = 628). Pooled 5-HT3R-As outperformed placebo regarding Y-BOCS total score (MD = -5.08, 95% CI = -7.04, -3.12, N = 9, n = 560), Y-BOCS obsession subscale score, Y-BOCS compulsive subscale score, treatment response, and remission rate. Individually, all 5-HT3R-As outperformed placebo regarding Y-BOCS total score (granisetron: MD = -5.59, 95% CI = -8.79, -2.39, N = 3, n = 178, ondansetron: MD = -5.72, 95% CI = -8.06, -3.37, N = 6, n = 331, tropisetron: MD = -2.87, 95% CI = -5.19, -0.550, N = 1, n = 96). However, all-cause discontinuation and incidence of individual adverse events between pooled 5-HT3R-As and placebo were not significantly different. In conclusion, our meta-analysis suggested 5-HT3R-As as efficacious for symptom improvement in individuals with OCD. However, the number of individuals included in each study was small; thus, a replication randomized trial of 5-HT3R-As should be conducted using a larger sample size.

INTRODUCTION: The question remains to be elucidated: "Is treatment with antidepressants at doses approved in Japan effective for Japanese patients with MDD?" It is crucial to confirm this in order to provide appropriate treatments for Japanese patients with major depressive disorder (MDD). Therefore, we conducted a systematic review and random-effects pairwise meta-analysis including these nine double-blind, randomized, placebo-controlled trials. METHODS: We calculated the standardized mean difference (SMD) and risk ratio (RR) with a 95% confidence interval (95% CI). RESULTS: Pooled newer antidepressants outperformed placebo regarding improvement of depressive symptom scale scores [SMD (95% CI) = -0.20 (-0.27, -0.12), p < 0.00001], response to treatment [RR (95% CI) = 1.23 (1.13, 1.32), p < 0.00001], and remission rate [RR (95% CI) = 1.30 (1.16, 1.45), p < 0.00001]. Although all-cause discontinuation was not significantly different between the treatment groups, the pooled antidepressant group showed a higher discontinuation rate due to adverse event [RR (95% CI) = 1.60 (1.13, 2.26), p = 0.007] and a higher incidence of at least one adverse event than the placebo group [RR (95% CI) = 1.13 (1.08, 1.18), p < 0.00001]. DISCUSSION: We concluded that newer antidepressants are effective for Japanese adults with MDD although the clinicians must monitor the health conditions of these individuals.

Our meta-analysis demonstrated that intermittent theta burst stimulation (iTBS)/bilateral-TBS (Bi-TBS) and high-frequency repetitive transcranial magnetic stimulation (HF-rTMS)/bilateral-rTMS (Bi-rTMS) had similar efficacy, acceptability, and safety profiles for antidepressant treatment-resistant major depressive disorder (AD-TRD). In our sensitivity analysis that excluded a study that compared Bi-TBS with Bi-rTMS for older adults, all efficacy outcomes were also comparable between iTBS and HF-rTMS. Because iTBS does not require higher stimulation intensity and a longer stimulus time than conventional HF-rTMS protocols, we speculated that for those with AD-TRD, iTBS/Bi-TBS is a more helpful therapeutic modality in clinical practice than HF-rTMS/Bi-rTMS.

The physical, psychiatric, and social comorbidities interfere with the everyday activities of community-dwelling individuals with schizophrenia and increase the risk of their readmission. However, these comorbidities have not been investigated comprehensively in Japan. We conducted a self-reported internet survey in February 2022 to identify individuals aged 20–75 years with and without schizophrenia using a prevalence case-control study. The survey compared physical comorbidities such as being overweight, hypertension, and diabetes; psychiatric comorbidities such as depressive symptoms and sleep disturbances; social comorbidities such as employment status, household income, and social support between participants with and without schizophrenia. A total of 223 participants with schizophrenia and 1776 participants without schizophrenia were identified. Participants with schizophrenia were more likely to be overweight and had a higher prevalence of hypertension, diabetes, and dyslipidemia than participants without schizophrenia. Additionally, depressive symptoms, unemployment, and non-regular employment were more prevalent in participants with schizophrenia than those without schizophrenia. These results highlight the necessity of comprehensive support and interventions addressing physical, psychiatric, and social comorbidities in individuals with schizophrenia in the community. In conclusion, effective interventions for managing comorbidities in individuals with schizophrenia are necessary to enable them to continue to live in the community.

双極性障害は躁病エピソードやうつ病エピソードに代表される急性期と急性期症状が改善し臨床的に安定した維持期に大別される。最新のメタ解析研究では,各病期に対して様々な薬物治療の使用が提案されているが,薬物の種類に加え,それら薬物の用量にも着目した診療が重要である。本稿では,2017年に発表されたThe International College of Neuro-Psychopharmacology(CINP)Treatment Guidelines for Bipolar Disorder in Adults(CINP-BD-2017)で推奨されている各薬剤の推奨用量を各病期別にまとめる。(著者抄録)

A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to treat adults with major depressive disorder (MDD) in the maintenance phase. This study searched the PubMed, Cochrane Library, and Embase databases and included only double-blind, randomized, placebo-controlled trials with an enrichment design: patients were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or placebo. The outcomes were the 6-month relapse rate (primary outcome, efficacy), all-cause discontinuation (acceptability), discontinuation due to adverse events (tolerability), and the incidence of individual adverse events. The risk ratio with a 95% credible interval was calculated. The meta-analysis comprised 34 studies (n = 9384, mean age = 43.80 years, and %females = 68.10%) on 20 antidepressants (agomelatine, amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, vilazodone, and vortioxetine) and a placebo. In terms of the 6-month relapse rate, amitriptyline, citalopram, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, and vortioxetine outperformed placebo. Compared to placebo, desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had lower all-cause discontinuation; however, sertraline had a higher discontinuation rate due to adverse events. Compared to placebo, venlafaxine was associated with a lower incidence of dizziness, while desvenlafaxine, sertraline, and vortioxetine were associated with a higher incidence of nausea/vomiting. In conclusion, desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had reasonable efficacy, acceptability, and tolerability in the treatment of adults with stable MDD.

The amygdala is a prominent region of the brain that plays a critical role in the pathophysiology of major depressive disorder (MDD). The amygdala is formed from a collection of interconnected substructures (nuclei) that relay signals from multiple brain areas, which suggests that the amygdala has different functions depending on its subregion. There are two main alleles of serotonin transporter gene polymorphism (5-HTTLPR): a 44-bp insertion (l-allele) or deletion (s-allele). The transcriptional activity of the l-allele of the gene is twice that of the s-allele. The present study aimed to investigate the association between the volume of the whole amygdala and subregions of the amygdala in 25 first-episode and drug-naive patients with MDD and 46 healthy controls (HCs) with the s/s genotype of 5-HTTLPR and plasma levels of brain-derived neurotrophic factor (BDNF) or cortisol. No significant difference was observed in the amygdala total and subregion volumes between the HC and MDD groups. No significant difference was found in the plasma levels of BDNF and cortisol between the two groups. In addition, no correlations were found between the total and subregion amygdala volume and plasma levels of cortisol or BDNF.

＜Key Point＞・統合失調症治療の大黒柱は抗精神病薬を用いた薬物治療である・各抗精神病薬間で、有効性に大差はないが、安全性には大きな違いがある・維持期を見据えて患者さんと一緒に急性期に用いる抗精神病薬を選択することが望まれる(著者抄録)

A systematic review and random-effects model network meta-analysis was conducted to compare the efficacy, acceptability, tolerability, and safety of pharmacological interventions for adults with acute bipolar mania. We searched PubMed, the Cochrane Library, and Embase databases for eligible studies published before March 14, 2021. Randomized controlled trials (RCTs) of oral medication monotherapy lasting ≥10 days in adults with mania were included, and studies that allowed the use of antipsychotics as a rescue medication during a trial were excluded. The primary outcomes were response to treatment (efficacy) and all-cause discontinuation (acceptability). The secondary outcomes were the improvement of mania symptoms and discontinuation due to inefficacy. Of the 79 eligible RCTs, 72 double-blind RCTs of 23 drugs and a placebo were included in the meta-analysis (mean study duration = 3.96 ± 2.39 weeks, n = 16442, mean age = 39.55 years, with 50.93% males). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed response to treatment (N = 56, n = 14503); aripiprazole, olanzapine, quetiapine, and risperidone had lower all-cause discontinuation; however, topiramate had higher all-cause discontinuation (N = 70, n = 16324). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed the improvement of mania symptoms (N = 61, n = 15466), and aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, valproate, and ziprasidone had lower discontinuation due to inefficacy (N = 50, n = 14284). In conclusions, these antipsychotics, carbamazepine, lithium, tamoxifen, and valproate were effective for acute mania. However, only aripiprazole, olanzapine, quetiapine, and risperidone had better acceptability than the placebo.

AIM: Globally, evidence from short-term studies is insufficient for the guidelines to uniformly recommend a particular antipsychotic(s) for the maintenance treatment of schizophrenia. Therefore, long-term comprehensive evaluation of antipsychotics is required from a social rehabilitation perspective, especially for drugs that have not yet been studied. The Japan Useful Medication Program for Schizophrenia (JUMPs) is a large-scale, long-term naturalistic study to present pivotal 52-week data on the continuity of second-generation antipsychotics (SGA: aripiprazole, blonanserin, and paliperidone). METHODS: JUMPs was an open-label, three-arm, randomized, parallel-group, 52-week study. Enrolled patients had schizophrenia, were ≥ 20 years old, and required antipsychotic treatment or switched from previous therapy. The primary endpoint was treatment discontinuation rate over 52 weeks. Secondary outcomes included remission rate, social functioning and quality-of-life scores (Personal and Social Performance Scale [PSP] and EuroQol-5 dimensions), and safety. RESULTS: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). The discontinuation rate (P = 0.9771) and remission rates (P > 0.05) over 52 weeks did not differ significantly between the three treatment groups. The discontinuation rates were 68.3%, 68.2%, and 65.5% in the aripiprazole, blonanserin, and paliperidone groups, respectively. Significant improvements (all P < 0.05) from baseline in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favored blonanserin. CONCLUSION: All three SGAs evaluated in this study showed similar treatment discontinuation rates in patients with chronic schizophrenia in Japan. TRIAL REGISTRATION: UMIN-Clinical Trials Registry 000007942. This article is protected by copyright. All rights reserved.

Most conventional insomnia medications are gamma-aminobutylic acid receptor agonists. However, physical dependence is a concern and one of the major limiting factors for long-term treatment. The dual orexin receptor antagonists, suvorexant and lemborexant, were recently approved for treating chronic insomnia, giving a novel pharmacotherapeutic option. Because there are no comparative studies on these drugs, a network meta-analysis was conducted, which is suitable for comparing interventions. According to this analysis, 5- and 10-mg lemborexant were superior to 20-mg suvorexant because of the greater improvement in initiating sleep after 1-week administration. Furthermore, 5-mg lemborexant (not 10 mg) and suvorexant were similarly well tolerated, without requiring discontinuation due to adverse events. We also overviewed the pharmacological and pharmacokinetic properties of lemborexant and suvorexant that may support these clinical outcomes. When compared to suvorexant, lemborexant quickly binds to the orexin receptors. The time to reach the maximum concentration after multiple administrations is shorter for lemborexant than for suvorexant. Considering these results, we recommend 5-mg lemborexant as an initial treatment for insomnia, followed by 10-mg lemborexant or suvorexant.

RATIONALE: We conducted a meta-analysis of double-blind, randomized placebo-controlled trials of lurasidone (LUR) to examine the difference in the risk ratios (RRs) for adverse events (AEs) between depressive disorders (bipolar depression and major depressive disorders) and schizophrenia. OBJECTIVES: Three trials for depressive disorders (n = 1,239) were used for flexible-dose LUR 20-60 (LUR20-60) and/or 80-120 (LUR80-120) mg/day. Nine schizophrenia trials (n = 2,684) were used for fixed-dose LUR. The RRs of LUR20-60 and LUR80-120 for depressive disorders were compared with those of LUR 40 (LUR40) and LUR 80 (LUR80) mg/day for schizophrenia, respectively, to match LUR dose. RESULTS: LUR20-60 caused a higher incidence of akathisia (RR = 2.28; p = 0.003) and weight gain (RR = 4.11; p = 0.05) than placebo in patients with depressive disorders, and LUR40 caused a higher incidence of akathisia (RR = 2.39; p = 0.0001), extrapyramidal symptoms (RR = 1.88; p = 0.02), anticholinergic drug use (RR = 1.58; p = 0.005), somnolence (RR = 2.19; p = 0.002), and dizziness (RR = 2.06; p = 0.05) than placebo in patients with schizophrenia. However, no significant differences in the RRs for all outcomes were found between depressive disorders and schizophrenia. LUR80-120 caused a higher incidence of akathisia (RR = 3.90; p < 0.0001), extrapyramidal symptoms (RR = 2.26; p = 0.04), anticholinergic use (RR = 4.70; p < 0.0001), and nausea (RR = 2.15; p = 0.001) than placebo in patients with depressive disorders. LUR80 caused a higher incidence of akathisia (RR = 2.99; p < 0.0001), extrapyramidal symptoms (RR = 2.55; p = 0.01), anticholinergic use (RR = 1.86; p = 0.01), somnolence (RR = 2.46; p = 0.001), and nausea (RR = 1.64; p = 0.04) than placebo in patients with schizophrenia. Depressive disorders had a higher RR for anticholinergic use than schizophrenia (p = 0.04). CONCLUSIONS: The incidence of AEs did not differ between schizophrenia and depressive disorders.

AIM: We conducted a chart review to investigate the detailed outcomes of patients with schizophrenia who discontinued long-acting injectable second-generation antipsychotic (LAI-SGA) therapy due to adverse events (AEs). METHODS: The study included patients with schizophrenia and related psychotic disorders who commenced LAI-SGA therapy between January/1//2009 and March/31/2020 at Fujita Health University Hospital in Toyoake, Japan. RESULTS: We conducted a chart review of 157 patients with schizophrenia. At the time of this survey, 4 (6.9%), 5 (12.2%), and 10 (17.2%) of the patients in the aripiprazole once monthly, paliperidone palmitate, and risperidone-LAI groups, respectively, discontinued due to AEs since the start of LAI-SGA therapy. Three patients required hospitalization for AE treatment. CONCLUSION: The severity of these AEs in most patients is moderate (ie, no hospital treatment required). Due to the small sample size, a larger study is needed to confirm/replicate our study results.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) has been employed worldwide for therapy-resistant depression. The Food and Drug Administration has approved a number of therapeutic devices for treating major depressive disorder; however, no studies have examined the differences in efficacy and acceptability among commercially available stimulation devices. The aim of our study was to compare the efficacy and acceptability of 3 stimulation devices (NeuroStar, MagPro, and Magstim) for depressive disorders. METHODS: Our study included 31 randomized sham-controlled trials of high-frequency rTMS included in the network meta-analysis by Brunoni. We calculated the risk ratio and 95% confidence intervals, comparing each device with sham for the endpoints of response rate, remission rate, and all-cause discontinuation. We then analyzed the differences among the devices in effect size for those endpoints. RESULTS: After determining the effect sizes for the endpoints, we found no statistically significant subgroup differences in the response rates, all-cause discontinuation, or remission rates among the devices (p = 0.12, p = 0.84, and p = 0.07, respectively). CONCLUSION: Our results suggest similar efficacy and acceptability for the 3 stimulation devices. Future studies need to perform head-to-head comparisons of the efficacy and acceptability of the stimulation devices for treating depression using the same stimulation protocols.

アセナピン(商品名:シクレスト)は、本邦初となる舌下錠の非定型抗精神病薬である。アセナピンは幅広い受容体に高い親和性を有し、多元受容体作用抗精神病薬(multi-acting receptor targeted antipsychotics:MARTA)に属するが、従来のMARTAとは異なる薬理学的特徴を有し、D2受容体への親和性は比較的高く、ムスカリン受容体への親和性は極めて低い。また、アセナピンは急性期統合失調症患者の興奮に対する速やかな効果が期待できるが、一方で、口の感覚鈍麻といった舌下錠に特有の副作用に注意が必要である。さらに、最新の系統的レビューとネットワークメタ解析によると、アセナピンは急性期統合失調症患者に対して、益と害のバランスの良い薬の1つであることが示されている。舌下錠という新しい剤型は、統合失調症の薬物治療における新たな治療選択肢となるかもしれない。(著者抄録)

BACKGROUND: We examined the efficacy and safety of using antipsychotic medication for schizophrenia using only randomized trials of antipsychotic for schizophrenia conducted in Japan to avoid the biological and environmental heterogeneities caused by pooling data from various races and ethnicities. METHODS: We searched for eligible studies on Embase, PubMed, and CENTRAL. Primary outcomes were improvement in Positive and Negative Syndrome Scale total score (PANSS-T) and all-cause discontinuation. Other outcomes were improvement in PANSS subscale scores, discontinuation due to adverse events or inefficacy, and the incidence of 16 adverse events. RESULTS: We calculated mean difference or risk ratios and 95% credible intervals. We identified 34 RCTs (6798 patients; mean study duration, 9.0 ± 4.24 weeks; proportion of male patients, 53.7%; mean age, 43.3 years). Besides placebo, studies included aripiprazole, asenapine, blonanserin, blonanserin-patch, brexpiprazole, clocapramine (no PANSS data), clozapine (no PANSS data), haloperidol, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, and risperidone. Efficacy and safety profiles differed for antipsychotics used with schizophrenia in Japanese patients. All active treatments other than haloperidol and quetiapine outperformed placebo to improve PANSS-T. Asenapine, olanzapine, paliperidone, and risperidone outperformed placebo for all-cause discontinuation. Asenapine, blonanserin, blonanserin-patch, haloperidol, lurasidone, mosapramine, olanzapine, paliperidone, and risperidone outperformed placebo to improve PANSS positive subscale scores. Aripiprazole, asenapine, blonanserin, blonanserin-patch, brexpiprazole, lurasidone, olanzapine, paliperidone, perospirone, and risperidone outperformed placebo to improve PANSS negative subscale scores. The confidence in evidence of most outcomes was low or very low. CONCLUSION: Our results are similar to those of previous network meta-analysis involving various races and ethnicities.

AIM: This study aimed to investigate body composition in Japanese patients with psychiatric disorders. METHODS: A cross-sectional study was conducted to assess the body composition in Japanese patients with psychiatric disorders and healthy controls. InBody470 was used to measure the body composition of the participants. For the primary analysis, measures of body composition between patients and healthy controls were compared. Moreover, the following patient subgroups were also compared with the healthy controls: (a) patients with psychotic disorders only, (b) patients with mood disorders only, (c) patients receiving antipsychotics, (d) patients receiving conventional mood stabilizers, (e) patients receiving antidepressants only but not any antipsychotics and/or mood stabilizers, and (f) patients receiving hypnotics/anxiolytics. RESULTS: This study included 205 individuals (105 patients and 100 healthy controls). It was found that patients had a significantly higher body mass index, waist-hip ratio, body fat mass, and percent body fat compared with the healthy controls. Moreover, significant differences were noted in the waist-hip ratio, body fat mass, and percent body fat between all patient subgroups other than patients receiving conventional mood stabilizers subgroup and healthy controls. CONCLUSION: This is the first cross-sectional study to examine body composition in Japanese patients with psychiatric disorders. No difference in the skeletal muscle volume was noted although patients had higher body fat than healthy controls. A longitudinal and large cohort study in the future, controlling for medication and diagnosis, will need to determine why body fat is increased in Japanese patients with psychiatric disorders.

OBJECTIVES: A systematic review and meta-analysis of double-blind, randomized placebo-controlled trials were conducted to examine how soon an increase in recurrence risk could be observed among bipolar I disorder (BDI) patients who were clinically stable with the combination therapy of mood stabilizers with second-generation antipsychotics (SGA+MS) treatment following second-generation antipsychotics discontinuation (i.e., MS alone) compared with SGA+MS maintenance. METHODS: Embase, PubMed, and CENTRAL databases were used for systematic literature searches until May/22/2020. The primary outcome was the recurrence rate of any mood episode at 6 months. The secondary outcomes were the recurrence rates of manic/hypomanic/mixed and depressive episodes and all-cause discontinuation at 6 months. The recurrence rates at 1, 2, 3, 9, and 12 months were also investigated. RESULTS: Eight studies (mean study duration = 58.25 ± 33.63 weeks) were identified (SGA+MS group [n = 1,456: 3 aripiprazole+MS studies, 1 lurasidone+MS study, 1 olanzapine+MS study, 2 quetiapine+MS studies, 1 ziprasidone+MS study] and placebo+MS group [n = 1,476]). Pooled SGA+MS exhibited lower recurrence rates of any mood episode, manic/hypomanic/mixed episodes, and depressive episodes as well as reduced all-cause discontinuation at every observational point. The risk ratios (95% confidence interval) of the recurrence rate at 6 months were 0.51 (0.39-0.86) for any mood episode, 0.42 (0.30-0.59) for manic/hypomanic/mixed episodes, and 0.39 (0.28-0.54) for depressive episodes. The RR for all-cause discontinuation was 0.67 (0.50-0.89). Both aripiprazole+MS and quetiapine+MS outperformed placebo+MS in the recurrence of any mood, manic/hypomanic/mixed, and depressive episodes at 6 months. CONCLUSIONS: SGA+MS prevented recurrence for up to 12 months for BDI compared with placebo+MS.

現代の医療現場では、医師は科学的根拠に基づいた医療(evidence-based medicine:EBM)を実践することが求められている。特に精神科医療において、科学的根拠に基づいた精神科医療(evidence-based mental health:EBMH)が注目されており、個々の患者の病状や合併症、患者の価値観や社会的要因も取り入れ、患者と共に診療方針を決定することが求められている(shared decision making:SDM)。本稿では、最もエビデンスレベルが高い研究手法であるシステマティックレビューとメタアナリシスの意義や研究手順について述べ、具体的に2019年にHahnらが報告したネットワークメタアナリシスの論文を用いて、連続変数および二値変数のアウトカムの見方を解説する。また、効果量や異質性などのメタアナリシスの結果を理解する上で必要な専門用語や、近年報告数が増えてきているアンブレラレビューについて解説する。(著者抄録)

We investigated the association between discontinuation due to withdrawal of consent (DWC) in schizophrenia trials and the use of long-acting injectable antipsychotics (LAI-APs). In two categorical meta-analyses of randomized controlled trials, we compared DWC: individual and pooled LAI-APs vs. (1) placebo and (2) oral antipsychotics (OAPs). We also performed conducted a single-group meta-analysis to calculate the average DWC and a meta-regression analysis to examine the association between the results of the meta-analyses and factors related to study design, treatment, and patients. We identified 52 studies (total adult patients = 18,675, LAI-APs = 12,613, placebo = 2,083, and OAPs = 3,979; median study duration = 32 weeks). DWC was higher for LAI-aripiprazole than for the placebo [risk ratio (95% confidence interval) = 1.70 (1.23-2.39)]. Neither pooled nor individual LAI-APs differed from the placebo for fluphenazine, olanzapine, paliperidone, and risperidone or from the OAPs for aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, risperidone, and zuclopenthixol. The average DWC of each LAI-AP was as follows: LAI-aripiprazole = 10.98%, LAI-fluphenazine = 7.65%, LAI-flupenthixol = 3.33%, LAI-haloperidol = 6.71%, LAI-olanzapine = 10.50%, LAI-paliperidone = 10.38%, LAI-perphenazine = 7.06%, LAI-risperidone = 10.39%, LAI-zuclopenthixol = 4.45%, pooled LAI-APs = 9.88%, and placebo = 11.17%. Meta-regression analysis demonstrated that publication year (β = 0.02), percentage of males (β = 0.02), and mean age (β = 0.05) were associated with an average DWC for pooled LAI-APs. Study duration (β = -0.03), percentage of males (β = 0.08), and patient status (β = -0.85) were associated with an average DWC for LAI-aripiprazole. Presence of a placebo arm (β = 1.60) was associated with an average DWC for LAI-fluphenazine. LAI-AP use was unlikely to be associated with DWC. Although the LAI-aripiprazole had a higher DWC than did the placebo, its average DWC was similar to other those of LAI-APs.

AIM: This systematic review and random-effect model, network meta-analysis of the phase 3 trials in Japan assessed the efficacy and safety profile of lurasidone compared with olanzapine and quetiapine extended-release (QUE-XR) for the treatment of bipolar depression. METHODS: The study included double-blind, randomized, placebo-controlled, phase 3 trials in Japan that included patients with bipolar depression. Outcomes included response rate (primary), remission rate (secondary), improvement of Montgomery-Åsberg Depression Rating Scale (MADRS) total score, discontinuation rates, and incidence of individual adverse events. RESULTS: Three studies were included (n = 1223). Lurasidone and olanzapine but not QUE-XR were superior to placebo in response rate [risk ratio (95% credible interval): lurasidone = 0.78 (0.66, 0.92); olanzapine = 0.84 (0.71, 0.99); QUE-XR = 0.87 (0.73, 1.03)]. Lurasidone, olanzapine and QUE-XR were superior to placebo in remission rate [lurasidone = 0.90 (0.83, 0.98); olanzapine = 0.87 (0.77, 0.99); QUE-XR = 0.84 (0.73, 0.98)] and the improvement of MADRS total score. There were not differences in discontinuation rates between each antipsychotic and placebo. Compared with placebo, lurasidone was higher incidence of akathisia, and increased body weight and blood prolactin level; olanzapine was higher incidence of somnolence and ≥7% weight gain, and increased body weight, blood total cholesterol level, blood LDL cholesterol level, and blood triglyceride levels; QUE-XR was higher incidence of extrapyramidal symptoms, akathisia, somnolence, dry mouth, constipation and ≥7% weight gain, and increased body weight, blood total cholesterol level, blood LDL cholesterol level, and blood triglyceride levels. CONCLUSIONS: Our results suggested although the efficacy of three SGAs was similar, there were the differences in the safety profile among the SGAs.

We searched Embase, PubMed, and CENTRAL from inception until 22 May 2020 to investigate which antipsychotics and/or mood stabilizers are better for patients with bipolar disorder in the maintenance phase. We performed two categorical network meta-analyses. The first included monotherapy studies and studies in which the two drugs used were specified (i.e., aripiprazole, aripiprazole once monthly, aripiprazole+lamotrigine, aripiprazole+valproate, asenapine, carbamazepine, lamotrigine, lamotrigine+valproate, lithium, lithium+oxcarbazepine, lithium+valproate, olanzapine, paliperidone, quetiapine, risperidone long-acting injection, valproate, and placebo). The second included studies on second-generation antipsychotic combination therapies (SGAs) (i.e., aripiprazole, lurasidone, olanzapine, quetiapine, and ziprasidone) with lithium or valproate (LIT/VAL) compared with placebo with LIT/VAL. Outcomes were recurrence/relapse rate of any mood episode (RR-any, primary), depressive episode (RR-dep) and manic/hypomanic/mixed episode (RR-mania), discontinuation, mortality, and individual adverse events. Risk ratios and 95% credible interval were calculated. Forty-one randomized controlled trials were identified (n = 9821; mean study duration, 70.5 ± 36.6 weeks; percent female, 54.1%; mean age, 40.7 years). All active treatments other than carbamazepine, lamotrigine+valproate (no data) and paliperidone outperformed the placebo for RR-any. Aripiprazole+valproate, lamotrigine, lamotrigine+valproate, lithium, olanzapine, and quetiapine outperformed placebo for RR-dep. All active treatments, other than aripiprazole+valproate, carbamazepine, lamotrigine, and lamotrigine+valproate, outperformed placebo for RR-mania. Asenapine, lithium, olanzapine, quetiapine, and valproate outperformed placebo for all-cause discontinuation. All SGAs+LIT/VALs other than olanzapine+LIT/VAL outperformed placebo+LIT/VAL for RR-any. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-dep. Aripiprazole+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-mania. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for all-cause discontinuation. Treatment efficacy, tolerability, and safety profiles differed among treatments.

背景:ボルチオキセチン(商品名:トリンテリックス)は、2019年9月に国内承認を得た新規抗うつ薬である。目的:海外で行われた臨床試験も包括した系統的レビューとメタ解析のエビデンスを基に、成人大うつ病性障害に対するボルチオキセチンの「急性期治療における有効性と忍容性」「身体症状に対する有効性」および「最適な投与量」を検討する。結果:ボルチオキセチンは、急性期うつ症状やそれに合併した身体症状に対する有効性を認めた。しかしながら、そのエビデンスレベルは低かった。急性期治療におけるボルチオキセチンの忍容性はプラセボに勝ったが、一部の新規抗うつ薬には劣っていた。また、忍容性不良は用量依存的であった。結論:ボルチオキセチンは大うつ病性障害に対する第1選択薬の1つと考えられるかもしれない。20mg/日へ増量した際は、副作用に注意が必要である。(著者抄録)

BACKGROUND: This random-effects model meta-analysis of double-blind, randomized placebo-controlled trials compared recurrence rates in bipolar disorder (BD) patients between antipsychotic/mood stabilizer discontinuation and maintenance groups. METHODS: We conducted systematic literature search of Embase, PubMed, and CENTRAL databases without language restriction from inception until 22 May 2020. Independent investigators assessed studies and extracted data. We calculated risk ratios (RRs) and numbers needed to benefit or harm (NNTB/NNTH). Primary outcome was the recurrence rate of any mood episode at 6 months. Secondary outcomes were recurrence rates of depressive episodes and manic/hypomanic/mixed episodes and all-cause discontinuation at 6 months. We also investigated these outcomes at 1, 3, 9, 12, 18, and 24 months. RESULTS: We identified 22 studies (n = 5462) receiving aripiprazole, asenapine, divalproex, long-acting injectable (LAI)-aripiprazole, LAI-risperidone, lamotrigine, lithium, olanzapine, paliperidone, or quetiapine. Mean study duration was 64.50 ± 69.35 weeks. The maintenance group demonstrated lower recurrence rates of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes as well as reduced all-cause discontinuation at every observational point. The RRs (95% confidence interval, NNTB/NNTH) of recurrence rate at 6 months were 0.61 (0.54-0.70, 5) for any mood episode, 0.72 (0.60-0.87, 13) for depressive episodes, and 0.45 (0.36-0.57, 6) for manic/hypomanic/mixed episodes. The RR for all-cause discontinuation at 6 months was 0.71 (0.61-0.82, 6). CONCLUSIONS: Maintaining drug treatment during clinically stable BD prevented recurrence for up to 24 months. Discontinuation of medications for ⩾1 month significantly increased recurrence risk. However, 47.3% of patients who discontinued drugs for 6 months did not experience recurrence.

＜Key Point＞・(1)系統的レビューとメタ解析はもっともエビデンスレベルが高い研究手法である・(2)エキスパートコンセンサスガイドラインは(1)で対応できない場合に参考となる・実臨床では(1)と(2)を柔軟に組み合わせて治療方針を決定する(著者抄録)