佐久間 健二

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.

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.

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.

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.

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.

＜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)

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.

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.

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.

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.

<title>Abstract</title> 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 (<italic>n</italic> = 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)

RATIONALE: It remains unclear whether using N-acetylcysteine as an adjunctive treatment has any benefit for bipolar depression and major depressive disorder. OBJECTIVES: A systematic review and random-effect meta-analysis of double-blind, randomized placebo-controlled trials was conducted to explore the clinical question. METHODS: Outcomes included improvement in depression scale scores (primary), Young Mania Rating Scale score, Hamilton Anxiety Rating Scale score, Clinical Global Impression-Severity Scale (CGI-S) score, Global Assessment of Functioning Scale score, Social and Occupational Functioning Assessment Scale score, Range of Impaired Functioning Tool score, Streamed Longitudinal Interval Clinical Evaluation for the Longitudinal Interview Follow-Up Evaluation score, quality of life scales scores, and the incidence of all-cause discontinuation and individual adverse events. RESULTS: Seven studies (n = 728, 8-24 weeks, mean age = 46.81, % female = 58.45%) were included. N-acetylcysteine did not improve depressive symptoms compared with placebo (N = 7, n = 579, standardized mean difference (SMD) = - 0.12, 95% confidence interval (95% CI) = - 0.38, 0.14, p = 0.38, I2 = 52.74%). The meta-regression analysis detected an association between effect size and publication year (coefficient = 0.06, 95% CI = 0.00, 0.11, p = 0.04, I2 = 27.56%). Although N-acetylcysteine was superior to placebo in CGI-S score (N = 6, n = 563, SMD = - 0.28, 95% CI = - 0.47, - 0.10, p < 0.01, I2 = 14.88%), there was no significant difference in the other efficacy outcomes between the treatment groups. Although N-acetylcysteine was associated with a higher incidence of gastrointestinal adverse events compared with placebo (N = 4, n = 537, risk ratio = 1.79, 95% CI = 1.37, 2.32, p < 0.01, I2 = 0.00%, number needed to treat to harm = 7), there was no significant difference in all-cause discontinuation and other safety outcomes between the treatments. CONCLUSIONS: Although N-acetylcysteine decreased CGI-S score, no specific improvements in symptoms were identified.

This study investigated factors associated with discontinuation in double-blind, randomized, placebo-controlled trials (DBRPCTs) of second-generation antipsychotics (SGAs) for acute schizophrenia, with a view to establishing what factors were associated with all-cause discontinuation. 77 eligible studies (96 comparisons; n = 22,678) were included in this study. Thirty-one factors potentially affecting all-cause discontinuation, related to the participants, study design, and drugs, were included in a meta-regression analysis that examined the factors associated with discontinuation rates in treatment and placebo groups and/or the treatment-placebo group difference in discontinuation. Smaller improvements in Positive and Negative Syndrome Scale total scores from baseline to endpoint were associated with higher discontinuation rates in both the treatment and placebo groups, and smaller response rates in the treatment group were associated with higher discontinuation rates in the treatment group. These factors were also associated with the treatment-placebo group difference in discontinuation. Although the risk of weight gain from SGA use was not associated with discontinuation rates in either the treatment or placebo groups, SGAs with a risk of weight gain were associated with a larger treatment-placebo group difference in discontinuation, although the reason is unknown. Factors associated with discontinuation rates in both treatment and placebo groups did not influence the treatment-placebo group difference in discontinuation. The efficacy and the risk of weight gain of SGAs seemed to influence treatment-placebo group difference in discontinuation in DBRPCTs of SGAs for acute schizophrenia.

<title>Abstract</title> <sec id="S0033291720003505_sec_a1"> <title>Background</title> 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. </sec> <sec id="S0033291720003505_sec_a2" sec-type="methods"> <title>Methods</title> 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. </sec> <sec id="S0033291720003505_sec_a3" sec-type="results"> <title>Results</title> We identified 22 studies (<italic>n</italic> = 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). </sec> <sec id="S0033291720003505_sec_a4" sec-type="conclusions"> <title>Conclusions</title> 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. </sec>

＜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)

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 conducted a random-effects model network meta-analysis to examine differences between lemborexant and suvorexant in efficacy and safety outcomes for treating patients with insomnia. We searched Embase, MEDLINE, and CENTRAL from their inception until April/28/2020. Primary outcomes were subjective time to sleep onset (sTSO), subjective total sleep time (sTST), and subjective wake-after-sleep onset (sWASO) at week 1. Four double-blind, randomized controlled trials were identified (n = 3237; 72.4% female; mean age 58.0 years). The treatment arm consisted of lemborexant 10 mg/d (LEM10, n = 592), lemborexant 5 mg/d (LEM5, n = 589), suvorexant 20/15 mg/d (SUV20/15, n = 493), zolpidem tartrate extended release 6.25 mg/d (ZOL6.25, n = 263), and placebo (n = 1300). All active treatments outperformed placebo regarding sTSO at week 1; standardized mean differences (95% credible interval): LEM10 = -0.51 (-0.63, -0.39), LEM5 = -0.48 (-0.60, -0.36), SUV20/15 = -0.21 (-0.33, -0.10), and ZOL6.25 = -0.30 (-0.46, -0.14); sTST at week 1: LEM10 = -0.58 (-0.70, -0.45), LEM5 = -0.33 (-0.46, -0.21), SUV20/15 = -0.34 (-0.46, -0.23), and ZOL6.25 = -0.42 (-0.59, -0.25); and sWASO at week 1: LEM10 = -0.42 (-0.57, -0.28), LEM5 = -0.26 (-0.40, -0.11), SUV20/15 = -0.18 (-0.32, -0.05), and ZOL6.25 = -0.37 (-0.56, -0.18). Although no significant differences were found in discontinuation due to adverse events between each active drug and placebo, LEM10 and SUV20/15 were associated with greater somnolence compared with placebo. LEM10 had the largest effect size compared with placebo for all primary outcomes, although with a risk of somnolence.

Background The exact recurrence rate of bipolar disorder in patients receiving lithium maintenance phase treatment and the modifiers associated with recurrence are still unknown. Methods We searched Embase, PubMed, and CENTRAL from inception until April 28, 2020. Outcomes included recurrence rate of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes; all-cause discontinuation rate; and discontinuation rate due to adverse events. A random-effects model, single-group summary meta-analysis was conducted. A meta-regression analysis to examine whether the modifiers (total number of patients, %female, mean age, duration of study, duration of preliminary phase, publication year, bipolar disorder type, mood status at recruitment, presence of a placebo arm, sponsorship, enrichment design, number of treatment arms, and risk of bias for blinding or randomization) were associated with the event rate of the outcomes was also performed. Results We identified 21 randomized trials (n = 1,415; mean study duration, 78.40 +/- 32.10 weeks; %female, 54.85%; mean age, 43.47 +/- 4.88 years). The event rates (95% confidence interval [CI]) were as follows: recurrence of any mood episode, 39.8% (32.8%, 47.1%); depressive episodes, 25.6% (18.8%, 34.0%); manic/hypomanic/mixed episodes, 18.5% (13.7%, 24.7%); all-cause discontinuation rate, 67.0% (57.2%, 75.5%); and discontinuation rate due to adverse events, 8.7% (5.1%, 14.7%). After adjusting for multiple testing, our meta-regression analysis showed association only between the all-cause discontinuation rate and presence of a placebo arm. Conclusions The recurrence rate of depressive episodes seemed to be higher than the recurrence rate of manic/hypomanic/mixed episodes. The all-cause discontinuation rate was high. However, the studies included in our meta-analysis were of short duration.

INTRODUCTION: Considering that the efficacy results of the Japan lurasidone phase 3 trials for acute schizophrenia were inconsistent, we conducted a systematic review and a random-effect model network meta-analysis of those trials to examine whether lurasidone was beneficial for the treatment of Japanese patients with acute schizophrenia. METHODS: The study included the double-blind, randomized trial in Japan that included patients with acute schizophrenia. Efficacy outcomes were improvement of the Positive and Negative Syndrome Scale total score (PANSS-T, primary), positive (PANSS-P), negative (PANSS-N), and general (PANSS-G) subscale scores; and Clinical Global Impression-Severity Scale (CGI-S) score and response rate. Other outcomes were discontinuation rates and incidence of individual adverse events. RESULTS: We included four studies (n = 1,608). Although both lurasidone 40 mg/d (LUR40) and 80 mg/d (LUR80) outperformed placebo in PANSS-T [standardized mean difference (95% credible interval): LUR40 = -0.298 (-0.420, -0.176), LUR80 = -0.170 (-0.320, -0.019)], PANSS-P, and CGI-S scores, LUR40 but not LUR80 outperformed placebo in PANSS-N and PANSS-G scores and response rate. LUR40 outperformed LUR80 regarding PANSS-G score. Both LUR40 and LUR80 were associated with a higher incidence of akathisia, somnolence, and increased body weight compared with placebo. Compared with placebo, LUR40 was associated with a higher incidence of weight gain (≥7%), and LUR80 was associated with a higher incidence of dystonia and weight loss (≥7%) and higher Drug-Induced Extrapyramidal Symptoms Scale score. CONCLUSIONS: Both LUR40 and LUR80 improved overall symptoms in Japanese patients with acute schizophrenia. However, LUR80 seemed to have a risk of extrapyramidal symptoms.

<title>Abstract</title> Introduction Several reports of the effectiveness of the use of psychostimulants for the treatment of Alzheimer’s disease (AD) are available. Methods A systematic review and meta-analysis was conducted including double-blind, randomized, placebo-controlled trials. Outcomes were the improvement of apathy scales score (primary), mini-mental state examination (MMSE) score, activities of daily living scale score, Zarit burden interview score, all-cause discontinuation, discontinuation due to adverse events, and incidence of at least 1 adverse event. Results Three methylphenidate studies and 1 modafinil study were identified (n=156). Results from combined psychostimulants were superior to placebo in the improvement of apathy scales score (standardized mean differences [SMD]=−0.63 (−1.22, −0.04), p=0.04, all studies) and the MMSE score (SMD=−0.58 (−1.14, −0.02), p=0.04, 3 methylphenidate studies). The modafinil study was excluded from the meta-analysis for the improvement of apathy scales score; therefore, the effect size increased (SMD=−0.82 (−1.43, −0.20), p=0.009). However, no significant differences were observed in terms of other outcomes, including safety outcomes between the treatment groups. Discussion Methylphenidate would be effective in treating apathy and cognitive impairment in AD patients.

<title>Abstract</title> Introduction The use of the blonanserin patch (BLO-P) for schizophrenia treatment was approved in Japan in 2019. This systematic review of trials in Japan assessed the efficacy and safety profile of BLO-P compared with other antipsychotics. Methods The systematic review included 6-week, double-blind, randomized, placebo-controlled, phase 3 trials in Japan that included patients with acute schizophrenia. Pooled data for patients receiving BLO-P 40 and 80 mg/day (BLO-P40+80) were compared with pooled data for patients receiving asenapine 10 and 20 mg/day (ASE10+20) and data for those receiving brexpiprazole 2 mg/day (BRE2) and paliperidone extended-release 6 mg/day (PAL-ER6). Results All the investigated treatments were superior to placebo in reducing the Positive and Negative Syndrome Scale (PANSS) total score; the Hedges’ g values (95% confidence interval) for BLO-P40+80, ASE10+20, BRE2, and PAL-ER6 were−0.40 (−0.58,−0.22),−0.61 (−0.79,−0.42),−0.33 (−0.60,−0.07), and−0.69 (−0.93,−0.45), respectively. There were differences among the antipsychotics in the incidence of various individual adverse events. Discussion BLO-P40+80 may have a good efficacy/safety/tolerability profile for the treatment of patients with acute schizophrenia.

RATIONALE: What is the difference between aripiprazole and brexpiprazole? OBJECTIVES: This systematic review, network meta-analysis of randomized trials evaluated the efficacy and safety/tolerability of aripiprazole and brexpiprazole for treating acute schizophrenia. METHODS: We searched Scopus, MEDLINE, and Cochrane Library from inception until May 22, 2019. The response rate was set as the primary outcome. Other outcomes were discontinuation rate and incidence of individual adverse events. The risk ratio (RR) and 95% credible interval (95%CrI) were calculated. RESULTS: Fourteen studies were identified (n = 3925). Response rates of both aripiprazole and brexpiprazole were superior to that of the placebo (RR [95%CrI]: aripiprazole = 0.84 [0.78, 0.92], brexpiprazole = 0.84 [0.77, 0.92]). Aripiprazole and brexpiprazole were associated with a lower incidence of all-cause discontinuation (0.80 [0.71, 0.89], 0.83 [0.72, 0.95]), adverse events (0.67 [0.47, 0.97], 0.64 [0.46, 0.94]), and inefficacy (0.56 [0.40, 0.77], 0.68 [0.48, 0.99]) compared with the placebo. Although brexpiprazole was associated with a lower incidence of schizophrenia as an adverse event compared with the placebo (0.57 [0.37, 0.85]), aripiprazole and brexpiprazole were associated with a higher incidence of weight gain compared with the placebo (2.12 [1.28, 3.68], 2.14 [1.35, 3.42]). No significant differences were found in other individual adverse events, such as somnolence, akathisia, extrapyramidal symptoms, and dizziness between aripiprazole or brexpiprazole and placebo. Any outcome between aripiprazole and brexpiprazole were not different. CONCLUSIONS: Differences in short-term efficacy and safety for acute schizophrenia were not apparent between aripiprazole and brexpiprazole. Future studies are warranted to evaluate whether there are differences in the long-term outcome between treatments.

<title>Abstract</title> <sec> <title>Background</title> This systematic review and meta-analysis included double-blind, randomized, placebo-controlled trials of brexpiprazole adjunctive treatment (0.5–3 mg/d) for major depressive disorder where antidepressant treatment had failed. </sec> <sec> <title>Methods</title> The outcomes were the response rate (primary), remission rate (secondary), Montgomery Åsberg Depression Rating Scale score (secondary), Sheehan Disability Scale scores (secondary), Clinical Global Impression–Improvement/Severity scores, discontinuation rate, and individual adverse events. A subgroup meta-analysis of the data at week 6 compared outcomes by dose &gt;2 mg/d or ≤2 mg/d (2 mg/d is the recommended dose). </sec> <sec> <title>Results</title> We identified 9 studies (n = 3391). Compared with placebo, brexpiprazole (any dose) was superior for response rate (risk ratio [RR] = 0.93, 95% confidence interval [95% CI] = 0.89−0.97, number needed to treat = 17), remission rate (RR = 0.95, 95% CI = 0.93−0.98, number needed to treat = 25), Montgomery Åsberg Depression Rating Scale score (standardized mean difference = −0.20, 95% CI = −0.29, −0.11), Sheehan Disability Scale score (standardized mean difference = −0.12, 95% CI = −0.21, −0.04), and Clinical Global Impression–Improvement/Severity scores but was associated with a higher discontinuation rate, akathisia, insomnia, restlessness, somnolence, and weight increase. Doses &gt;2 mg/d had a significantly higher RR for response rate than ≤2 mg/d (0.96 vs 0.89); moreover, compared with placebo, doses &gt;2 mg/d were associated with higher incidences of akathisia (RR = 4.58) and somnolence (RR = 7.56) as well as were marginally associated with a higher incidence of weight increase (RR = 3.14, P = .06). Compared with placebo, doses ≤2 mg/d were associated with higher incidences of akathisia (RR = 2.28) and weight increase (RR = 4.50). </sec> <sec> <title>Conclusions</title> Brexpiprazole adjunctive treatment is effective for major depressive disorder when antidepressant treatment fails. At 6 weeks, doses ≤2 mg/d presented a better risk/benefit balance than &gt;2 mg/d. </sec>

AIM: There have been no previous reports on the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders. METHODS: This one-week, prospective, single-arm, clinical trial of fixed dose of suvorexant (20 mg if ages 18-64 or 15 mg if age ≥ 65 years) for insomnia included 57 patients with psychiatric disorders who had experienced any of the following insomnia symptoms for four or more nights during the week prior to the start of the study: total sleep time (TST) <6 hours, time to sleep onset (TSO) ≥30 minutes, or two or more episodes of wake after sleep onset. RESULTS: The mean age of the patients was 49.4 ± 17.3 years; 54.4% were women, 49.1% had a major depressive disorder, and 77.2% completed the trial. Compared with the baseline scores (the mean scores for the two days before the start of the study), taking suvorexant was associated with significant improvements in TST, TSO, wake time after sleep onset, and the patients' sleep satisfaction level at week 1. Adverse events included at least one adverse event (43.9%), sleepiness (28.8%), fatigue (11.5%), nightmares (5.8%), headache (3.8%), dizziness (3.8%), and vomiting (1.9%). CONCLUSION: Suvorexant was beneficial for the treatment of insomnia in people with psychiatric disorders. However, this study was of short duration and included only a relatively small number of patients. A larger, long-term study is needed to investigate the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders.

AIM: Whether patients with adult bipolar disorder (BD) who have been clinically stabilized with lithium or lamotrigine should continue this medication is not established fully. This systematic review and meta-analysis evaluated the efficacy and safety of lithium and lamotrigine for maintenance treatment in clinically stable patients with adult BD. METHODS: This meta-analysis included only double-blind, randomized, placebo-controlled trials with an enrichment design that selected patients who responded acutely to lithium or lamotrigine. Reports prior to November 15, 2018, were retrieved from the PubMed/Cochrane Library/Embase. The primary outcome was the relapse rate due to any mood episode at the study endpoint. Other outcomes were relapse rates due to a manic/hypomanic/mixed episode or depression at the study endpoint, discontinuation rate, death, and death by suicide. Risk ratios (RRs) (95% confidence intervals) were calculated. When the random-effects model showed significant differences between groups, the number-needed-to-treat (NNT) was estimated. RESULTS: The search retrieved two studies regarding lithium (N = 218) and four evaluating lamotrigine (N = 706). Both drugs were superior to placebo for reducing the relapse rate due to any mood episode [lithium: RR = 0.52 (0.41-0.66), P < 0.00001, I2  = 0%, NNT = 2.3 (1.6-4.2); lamotrigine: RR = 0.81 (0.70-0.93), P = 0.004, I2  = 0%, NNT = 8.3 (5.0-25.0)] and all-cause discontinuation. There were no significant differences in other outcomes between lithium or lamotrigine and the placebo groups. CONCLUSION: Both drugs showed benefit for preventing relapse in clinically stable patients with adult BD. However, the number of studies and patients in this analysis was small.

This study evaluated the efficacy and safety/tolerability of quetiapine extended-release 300 mg/day (QUEXR300), quetiapine immediate-release 600 mg/day (QUEIR600), and quetiapine immediate-release 300 mg/day (QUEIR300) formulations for treating bipolar depression. A random-effect network meta-analysis of 8-week, double-blind, randomized placebo-controlled trials was used to determine the most optimal agent for intervention. Remission rate was set as the primary outcome. Secondary outcomes were response rate, improvement in the Montgomery-Åsberg Depression Rating Scale score, discontinuation rate, and the incidence of individual adverse events. Seven eligible studies including 3267 participants were included in the meta-analysis. The QUEIR600, QUEIR300, and QUEXR300 groups were superior to the placebo group in every efficacy outcome; however, there were no significant differences in the efficacy outcomes among the treatment groups. All treatment groups exhibited higher incidences of extrapyramidal symptoms, dry mouth, somnolence, constipation, and increase in body weight than the placebo group. The QUEIR600 and QUEIR300 groups had higher incidences of dizziness than the placebo group. The QUEIR600 group had a higher discontinuation rate due to adverse events than the placebo group, and the QUEIR300 group had higher blood HbA1c levels than the placebo group. The QUEIR600 and QUEXR300 groups had higher incidences of ≥7% weight gain than the placebo group. The QUEXR300 group had a higher incidence of fatigue than the QURIR300 and placebo groups. In conclusion, there were no significant differences in the efficacies of QUEIR600, QUEIR300, and QUEXR300 in treating bipolar depression; moreover, tolerance to QUEIR600 might be worse than the other treatments.