松田 勇紀

INTRODUCTION: The clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) in Japan has not been adequately investigated. Furthermore, the relationship between stimulation-site pain and the antidepressant effects of rTMS has not been thoroughly examined. Therefore, this study aimed to clarify (1) the real-world efficacy and safety of rTMS for TRD in Japan and (2) the relationship between stimulation-site pain and clinical improvement of depressive symptoms. METHODS: We conducted a retrospective observational study involving 50 right-handed patients with TRD. All patients received high-frequency rTMS for up to 6 weeks. Depressive symptoms were assessed using the Montgomery-Åsberg depression rating scale (MADRS). Pain at the stimulation site was reported by the patients using a visual analog scale (VAS) after each session. Remission and response rates at 3 and 6 weeks were calculated based on the MADRS scores. The correlation between changes in the MADRS and VAS scores was examined. RESULTS: Remission and response rates were 36% and 46%, respectively, at the end of 3 weeks, and 60% and 70%, respectively, at 6 weeks. At the end of the treatment, there was significant correlation between the reduction of MADRS and VAS scores (r = 0.42, p = 0.003). CONCLUSION: This study demonstrates the clinical efficacy of rTMS in Japan and the correlation between its antidepressant effects and stimulation-site pain.

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.

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.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a widely used treatment for major depressive disorder (MDD), and its effectiveness in preventing relapse/recurrence of MDD has been explored. Although few small sample controlled studies exist, the protocols of maintenance rTMS therapy were heterogeneous and evidence of its effectiveness is not sufficient. Thus, this study aims to evaluate whether maintenance rTMS is effective in maintaining the treatment response in patients with MDD with a large sample size and feasible study design. METHODS: In this multicenter open-labelled parallel-group trial we plan to recruit 300 patients with MDD who have responded or remitted to acute rTMS therapy. Participants would be classified into two groups according to their preference; the maintenance rTMS and pharmacotherapy group, and the pharmacotherapy only group. The protocol of maintenance rTMS therapy is once a week for the first six months and once biweekly for the second six months. The primary outcome is the relapse/recurrence rates during 12 months following enrollment. Other measures of depressive symptoms and recurrence/relapse rates at different time points are the secondary outcomes. The primary analysis is the between-group comparison adjusted for background factors using a logistic regression model. We will perform the group comparison with inverse probability of treatment weighting as the sensitivity analysis to ensure the comparability of the two groups. DISCUSSION: We hypothesize that maintenance rTMS therapy could be an effective and safe treatment for preventing depressive relapse/recurrence. Considering the limitation of potential bias owing to the study design, we plan to use statistical approaches and external data to avoid overestimation of the efficacy. TRIAL REGISTRATION: Japan Registry of Clinical Trials, ID: jRCT1032220048 . Registered 1 May 2022.

BACKGROUND: This study aimed to evaluate the effects of medical fee revisions aimed to reduce psychotropic polypharmacy in Japan on the proportion of psychotropic polypharmacy in discharge prescriptions for patients with major depressive disorder (MDD) or bipolar disorder (BD) using a nationwide inpatient database. METHODS: In this retrospective cohort study, we used the Diagnosis Procedure Combination database to identify patients with MDD or BD discharged between April 2012 and March 2021. We targeted medical fee revisions in October 2014, April 2016, and April 2018. The major outcome was the monthly proportion of psychotropic polypharmacy in prescription at discharge using the criteria following the April 2018 revision (antidepressants ≥3, antipsychotics ≥3, anxiolytics ≥3, hypnotics ≥3, or sum of anxiolytics and hypnotics ≥4). We performed interrupted time series analyses to evaluate the changes in level and trend between pre- and post-revisions. RESULTS: We identified 63,289 and 33,780 patients with MDD and BD respectively in the entire study period. In both the patient groups, there were significant decreases in the proportion of psychotropic polypharmacy at revision in October 2014, and no significant trend and level change at revision were observed in April 2016 and April 2018, with a few exceptions. CONCLUSIONS: The medical fee revisions aimed to reduce psychotropic polypharmacy in Japan might have had a limited impact on discharge prescriptions for patients with MDD and BD.

Patients with major depressive disorder (MDD) exhibit several clinical symptoms including difficulties in flexible thinking. Flexible thinking mainly relies on a cognitive ability called shifting; however, the mechanisms underlying shifting in patients with MDD have not yet been clarified. Therefore, we conducted a preliminary intervention study to clarify the association between depression and shifting ability. We examined the hemodynamic responses in the frontal regions during the shifting task using functional near-infrared spectroscopy (fNIRS) in 21 patients with MDD who were treated using high-frequency repetitive transcranial magnetic stimulation (rTMS). Behavioral performance on the shifting task did not change between pre- and posttreatments, whereas patients who responded well to rTMS treatment showed a significant decrease in hemodynamic responses posttreatment. On the other hand, the poor responders did not show significant changes in the hemodynamic responses between pre- and posttreatments. These results suggest that the good responders were successfully remedied with rTMS treatment and did not need effortful activity in frontal regions for shifting, which made their brain activity more efficient.

OBJECTIVES: Electroconvulsive therapy (ECT) is a widely used treatment for bipolar depression; however, evidence of its effectiveness is not sufficient. This study therefore aimed to evaluate whether early ECT is associated with reduced length of hospital stay. METHODS: In this retrospective cohort study using the Japanese Diagnosis Procedure Combination database, we identified patients admitted for bipolar depression between April 2010 and March 2018. The primary outcome was length of hospital stay, and the secondary outcome was clinical outcomes and total hospitalization costs. Propensity score-matched analyses were performed to compare the outcomes between patients who received ECT within 8 days of admission (early ECT group) and those who did not (control group). RESULTS: We identified 5941 eligible patients, comprising 219 in the early ECT group and 5722 in the control group. After 1:4 propensity score matching, patients in the early ECT group had significantly shorter lengths of hospital stay than those in the control group (53 days in the early ECT group and 73 days in the control group; difference: -20.2 days; 95 % confidence interval: -29.2 to -11.2 days). There was no significant difference in total hospitalization costs between the two groups. In-hospital mortality and fatal complications were rare in both groups. The result was similar in the sensitivity analysis using inverse probability of treatment weighting. LIMITATIONS: Our study was limited by retrospective design and the possibility of unmeasured confounders. CONCLUSIONS: Early ECT was associated with reduced length of hospital stay without increasing total hospitalization costs in patients with bipolar depression.

The factors associated with the clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) in patients with major depressive disorder (MDD) remain largely unexplored. Therefore, this study aimed to examine whether rTMS can change the functional laterality of the prefrontal hemodynamic response and whether baseline functional laterality can predict the clinical outcomes of rTMS using functional near-infrared spectroscopy (fNIRS). We included 19 patients with MDD who were treated with high-frequency rTMS. The verbal fluency task was used as the activation task. We calculated the laterality index (LI) based on the task-related oxygenation response in the frontal region. First, the LI was compared before and after rTMS treatment. Second, the reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) score was compared between the rightward dominance group (pre-LI < 0) and the leftward dominance group (pre-LI ≥ 0). The findings showed a significant change in the LI after rTMS treatment. The rightward dominance group had a significantly greater reduction in MADRS score than the leftward dominance group. Subsequently, the laterality of the task-related hemodynamic response of the prefrontal region shifted leftward following left high-frequency rTMS treatment. Thus, the pre-LI calculated using fNIRS data is a possible predictor of rTMS outcomes in patients with MDD.

AIM: Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that shows potential for treating psychiatric disorders. Although several studies have sought to investigate new TMS modalities for the treatment of various psychiatric disorders, no study has yet examined publication trends in research on TMS modalities for psychiatric disorders. This study investigated publication trends in TMS research for 13 psychiatric disorders, including addiction, dementia, major depressive disorder (MDD), and obsessive-compulsive disorder (OCD), and schizophrenia, as well as 9 TMS modalities, including bilateral stimulation, deep TMS, high-frequency stimulation, low-frequency stimulation, and theta burst stimulation. METHODS: Articles published in PubMed from 1985 to 2019 were searched to determine the number of published articles for each year in each category using the "Results by year" tool from the PubMed database. RESULTS: Over the past 30 years, an increasing number of articles were published regarding TMS research for the treatment of MDD, addiction, and dementia, which were among those most commonly investigated psychiatric disorders, whereas the number of articles addressing schizophrenia and OCD treated via TMS remained steady since 2015. Regarding TMS modalities, previous high-frequency stimulation, low-frequency stimulation, and bilateral stimulation were the most common topics, with research regarding deep TMS and theta burst stimulation having increased since 2000 and 2005, respectively. CONCLUSION: TMS applications are rapidly developing and becoming increasingly ubiquitous in various psychiatric disorders. Determining publication trends in TMS research can be a useful method for monitoring TMS research interests and applications of new TMS modalities for psychiatric disorders.

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.

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.

OBJECTIVES: This study aimed to evaluate whether early electroconvulsive therapy (ECT) can reduce length of hospital stay and total hospitalization costs in major depressive disorder (MDD) patients. METHODS: Using the Japanese Diagnosis Procedure Combination inpatient database from April 2011 to March 2018 linked with the Annual Report for Functions of Medical Institutions, we identified patients admitted for MDD. Patients who received ECT within 8 days of admission were assigned to the early ECT group and the remaining patients to the control group. The primary outcomes were length of hospital stay and total hospitalization costs. The secondary outcomes were in-hospital mortality and fatal adverse events. Propensity score-matched analyses were performed to compare the outcomes between the 2 groups. RESULTS: We identified 41,248 eligible patients, comprising 1169 in the early ECT group and 40,079 in the control group. After 1:1 propensity score matching, patients in the early ECT group had significantly shorter length of hospital stay than those in the control group (difference: -12.6 days; 95% confidence interval: -17.4 to -7.7 days). There was no significant difference in total hospitalization costs between the 2 groups. Early ECT was not significantly associated with increased in-hospital mortality or fatal adverse events. CONCLUSIONS: Early ECT may reduce length of hospital stay without increasing total hospitalization costs or fatal adverse events in patients with MDD.

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.

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.

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.

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.

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.

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.

<title>Abstract</title><sec><title>Introduction</title>Recent studies have shown a high frequency of abnormal electrocardiograms in patients with schizophrenia. The objective of this study was to associate schizophrenia diagnoses with early repolarization patterns in a sample of hospitalized patients from a single hospital in Japan. </sec><sec><title>Methods</title>We conducted a retrospective age, sex and coronary risk factors matched case-control study on 85 patients with schizophrenia and 89 controls from medical checkups. First, we compared the presence of early repolarization patterns in both groups. Secondly, we elucidated an association between the presence of an early repolarization pattern and clinical findings in the patients’ groups. We also evaluated J-point elevation patterns. </sec><sec><title>Results</title>As a result, we found that both early repolarization patterns and J-point elevation patterns observed were significantly higher in the schizophrenic group than in the matched control group (early repolarization pattern 23;6 P &lt; 0.001; J-point elevation pattern 34:12; P = 0.001). After multivariable logistic regression among the patients and controls, schizophrenia was the independent predictor for early repolarization pattern (P = 0.001) and J-point elevation (P &lt; 0.001). Among the patients, the independent predictor for early repolarization pattern was psychiatric family history (P = 0.006), while older age (P = 0.038) and psychiatric family history (P = 0.014) were predictors for J-point elevation patterns. </sec><sec><title>Conclusion</title>These findings suggest that an association between early repolarization pattern or J-point elevation pattern and schizophrenia in a single Japanese center. </sec>

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.

OBJECTIVES: Major depression is a highly prevalent disorder that causes economic burden in office workers. We conducted a randomized, double-blind, sham-controlled trial to evaluate the efficacy and safety of deep transcranial magnetic stimulation (dTMS) in office workers with treatment-resistant depression. METHODS: In this study, we randomized office workers taking administrative leave for treatment-resistant major depressive disorder or bipolar disorder with current major depressive episode. dTMS treatment was applied at 120% resting motor threshold with 18 Hz over the left dorsolateral prefrontal cortex. The treatment sessions delivered a total of 1,980 pulses a day, 5 days a week, for 4-6 weeks. The primary outcome was change in the total score on the 21-item Hamilton Depression Rating Scale (HDRS-21) from baseline to the end of study in an intent-to-treat analysis. The secondary outcomes were the response and remission rates. We also assessed changes in cognitive function and adverse events. RESULTS: Forty patients were randomized to active or sham dTMS groups (1:1). The change in the total score on the HDRS-21 was more significantly improved in the active group than in the sham group at 6 weeks (p = 0.045). There were no significant differences in the response and remission rates or cognitive measures between the active and sham groups. No serious adverse events were observed in either group. CONCLUSIONS: These results suggest that dTMS might be effective and safe in office workers with treatment-resistant depression. Further well-designed studies are needed.

BACKGROUND: 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. METHODS: 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 >2 mg/d or ≤2 mg/d (2 mg/d is the recommended dose). RESULTS: 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 >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 >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). CONCLUSIONS: 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 >2 mg/d.

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.

AIM: Clinical trials and meta-analyses have demonstrated the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left prefrontal cortex in treatment-resistant depression. The aim of this study was to prospectively evaluate the effectiveness of the conventional 37.5-minute vs 18.75-minute rTMS protocol over the left prefrontal cortex in patients with treatment-resistant depressive episode. METHODS: Thirty patients with treatment-resistant depression or bipolar disorder depressive episode were randomized 1:1 to either 37.5-minute or 18.75-minute rTMS protocol groups. rTMS treatment was applied at 120% resting motor threshold with 10 Hz over the left prefrontal cortex. Treatment sessions were delivered for a total of 3000 pulses/d, 5 days a week, for 4-6 weeks. Patients received a 75 trains with "4 sec on and 26 sec off" for 37.5 minutes or a 75 trains with "4 sec on and 11 sec off" for 18.75 minutes. Severity of depression was rated with the Quick Inventory of Depressive Symptomatology (QIDS) and Patient Health Questionnaire (PHQ-9). Remission was defined as a total score of 5 or less on the QIDS. The primary outcome measure was to compare the remission rate between the both groups. RESULTS: Thirteen of 30 patients (43.3%) showed remission at week 6. There were no significant differences in the remission rate between the conventional 37.5- and 18.75-minute protocol groups (46.7% and 40.0%, respectively). No seizures or treatment-emergent mania/hypomania were occurred. CONCLUSION: These findings suggest that, compared with the conventional one, rTMS with 18.75-minute protocol might be equally effective and clinically beneficial in saving the treatment session length. Further well-designed studies are needed.

OBJECTIVE: It is unknown whether there are differences in efficacy and safety between quetiapine extended-release, 300 mg/d (QUEXR300), and olanzapine, 5-20 mg/d (OLA), for Japanese patients with bipolar depression. METHODS: We conducted a Bayesian analysis of data from phase 3 studies in Japan of QUEXR300 and OLA. Outcomes were remission rate (primary), response rate, improvement on the Montgomery-Åsberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale scores, discontinuation rate, and incidence of individual adverse events. We calculated the standardized mean difference (SMD) and the risk ratio (RR) and 95% credible interval (95% CrI) for continuous and dichotomous data, respectively. RESULTS: There were no significant differences between QUEXR300 and OLA for any of the efficacy outcomes. QUEXR300 was associated with a higher incidence of somnolence than OLA (RR = 5.517; 95% CrI = 1.563, 19.787), while OLA was associated with greater increase body weight (SMD = -0.488; 95% CrI = -0.881, -0.089) and blood prolactin levels (SMD = -0.642; 95% CrI = -1.073, -0.213) than QUEXR300, and a greater decrease in high-density lipoprotein cholesterol levels (SMD = -0.408; 95% CrI = -0.785, -0.030) than QUEXR300. CONCLUSION: Although the two drugs' efficacy did not differ, OLA increased the risk of metabolic syndrome and QUEXR300 the risk of somnolence. A large scale, long-term, head-to-head comparison study of QUEXR300 vs OLA for Japanese patients with bipolar depression is needed to confirm the results of the current study.

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.

BACKGROUND: Discontinuation of antipsychotics predisposes patients with remitted/stable first-episode psychosis (FEP) to a higher risk of relapse, but it remains unclear how long discontinuation increases the relapse rate in these patients compared with maintenance. METHODS: This meta-analysis of randomized controlled trials (RCTs) compared relapse rates in FEP patients between antipsychotic treatment discontinuation and maintenance groups at 1, 2, 3, 6, 9, 12 (primary), and 18-24 months. The risk ratio (RR) and numbers needed to treat/harm (NNT/NNH) were calculated using a random-effects model. RESULTS: Ten RCTs were identified (n = 776; mean study duration, 18.6 ± 6.0 months). The antipsychotics were discontinued abruptly in four RCTs (which reported data only at 12 months) and after tapering off gradually over several months (mean length, 3 months) in six RCTs. Compared with the discontinuation group, the maintenance group experienced significantly fewer relapses at all time points except 1 month [RR (NNT): 2 months, 0.49 (13); 3 months, 0.46 (9); 6 months, 0.55 (6); 9 months, 0.48 (3); 12 months, 0.47 (3); and 18-24 months, 0.57 (4)]. The maintenance group was associated with higher discontinuation due to adverse events (RR, 2.61; NNH, not significant). CONCLUSIONS: Maintaining antipsychotic treatment prevented relapse for up to 24 months in FEP patients. Discontinuation of antipsychotics for ⩾2 months significantly increased the risk of relapse. However, 45.7% of patients who discontinued antipsychotics for 12 months (39.4% after 18-24 months) did not experience a relapse.

INTRODUCTION: We conducted an updated systematic review and meta-analysis of randomized controlled trials (RCTs) comparing blonanserin with other antipsychotics (amisulpride, aripiprazole, haloperidol, paliperidone, and risperidone). METHODS: Weighted mean difference (WMD), risk ratio, and number needed to harm (NNH) with 95% confidence intervals (95% CIs) were calculated using random-effects model. RESULTS: Ten RCTs (n=1521) were included in this study. Blonanserin was superior to aripiprazole in improvement of Positive and Negative Syndrome Scale total scores (WMD=-10.62, 95% CI=-17.67 to -3.560, p=0.003). Blonanserin was associated with a higher incidence of all-cause discontinuation (RR=1.373, 95% CI=1.088-1.734, p=0.008, NNH=11), akathisia, extrapyramidal disorder, and agitation/excitement and a lower risk of hyperprolactinemia compared with risperidone + paliperidone. DISCUSSION: The current meta-analytic study did not update the comparison of blonanserin vs. haloperidol because there were no new RCTs. Our results suggest that the efficacy of blonanserin for schizophrenia is comparable with that of other antipsychotics, and blonanserin seems to be well tolerated.

We performed a meta-analysis to determine whether combination therapy with serotonin reuptake inhibitors (SRIs) and memantine (MEM) was beneficial for the treatment of obsessive- compulsive disorder. This study included three double-blind, randomized, placebo-controlled trials. MEM+SRI was superior to placebo+SRI with regard to response rate [primary outcome, n = 97 risk ratio = 0.22 95% confidence intervals (CI) = 0.12-0.42 p &lt 0.00001 I 2 = 0% number needed to treat = 2], the Yale- Brown Obsessive- Compulsive Scale total [standardized mean difference (SMD) = - 4.56 95% CI = - 8.50, - 0.62 p = 0.02], obsession subscale (SMD = - 4.39 95% CI = - 5.94, - 2.85 p &lt 0.00001), and compulsion subscale score (SMD = - 4.60 95% CI = - 7.64, - 1.55 p = 0.003). No significant differences in any safety outcome were found between the groups.