Association between Stimulation-Site Pain and Clinical Improvement during Repetitive Transcranial Magnetic Stimulation for Patients with Major Depressive Disorders: A Prospective Observational Study at Two Sites.

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.

Longitudinal reduction in brain volume in patients with schizophrenia and its association with cognitive function.

Establishing a brain biomarker for schizophrenia is strongly desirable not only to support diagnosis by psychiatrists but also to help track the progressive changes in the brain over the course of the illness. A brain morphological signature of schizophrenia was reported in a recent study and is defined by clusters of brain regions with reduced volume in schizophrenia patients compared to healthy individuals. This signature was proven to be effective at differentiating patients with schizophrenia from healthy individuals, suggesting that it is a good candidate brain biomarker of schizophrenia. However, the longitudinal characteristics of this signature have remained unclear. In this study, we examined whether these changes occurred over time and whether they were associated with clinical outcomes. We found a significant change in the brain morphological signature in schizophrenia patients with more brain volume loss than the natural, age-related reduction in healthy individuals, suggesting that this change can capture a progressive morphological change in the brain. We further found a significant association between changes in the brain morphological signature and changes in the full-scale intelligence quotient (IQ). The patients with IQ improvement showed preserved brain morphological signatures, whereas the patients without IQ improvement showed progressive changes in the brain morphological signature, suggesting a link between potential recovery of intellectual abilities and the speed of brain pathology progression. We conclude that the brain morphological signature is a brain biomarker that can be used to evaluate progressive changes in the brain that are associated with cognitive impairment due to schizophrenia.

Characteristics of patients with anxiety disorder without selective serotonin reuptake inhibitor prescription over a two-year period of pharmacotherapy.

INTRODUCTION: Pharmacotherapy such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake inhibitors is recommended for the treatment of anxiety disorders. Although there are patients with persisted symptoms of anxiety disorders who are treated with monotherapy of benzodiazepine anxiolytics without SSRIs, the characteristics of these patients are unclear. In the present study, we investigated the characteristics of patients with persisted symptoms of anxiety disorder without SSRI prescription. METHODS: From a prescription dataset covering 2018 and 2020, the prescriptions of 243 patients with anxiety disorder were analyzed. Patients were classified into two groups: SSRI non-prescription and prescription groups. RESULTS: The SSRI non-prescription group had a higher ratio of females than did the SSRI prescription group (60.1% vs. 44.6%, respectively, p = 3.12 × 10-2 ), but statistically not significant after the Bonferroni correction. No significant differences in age, body mass index, or duration of outpatient visits were found between groups. Among the independent variables, sex (female) was the only variable identified that predicted SSRI non-prescription. CONCLUSION: The present study showed that among patients with anxiety disorders, sex (female) was the only variable that predicted SSRI non-prescription.

Cerebral cortical structural alteration patterns across four major psychiatric disorders in 5549 individuals.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.

Maintenance repetitive transcranial magnetic stimulation (rTMS) therapy for treatment-resistant depression: a study protocol of a multisite, prospective, non-randomized longitudinal study.

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.

Effectiveness of medical fee revisions for psychotropic polypharmacy in patients with mood disorders in Japan: An interrupted time-series analysis using a nationwide inpatient database.

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.

Repetitive transcranial magnetic stimulation decreased effortful frontal activity for shifting in patients with major depressive disorder.

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.

Early electroconvulsive therapy in patients with bipolar depression: A propensity score-matched analysis using a nationwide inpatient database.

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.

Laterality of prefrontal hemodynamic response measured by functional near-infrared spectroscopy before and after repetitive transcranial magnetic stimulation: A potential biomarker of clinical outcome.

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.

Comparative Efficacy and Acceptability of 3 Repetitive Transcranial Magnetic Stimulation Devices for Depression: A Meta-Analysis of Randomized, Sham-Controlled Trials.

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.

Transcranial magnetic stimulation modalities for psychiatric disorders: Publication trends from 1985 to 2019.

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.

Early Electroconvulsive Therapy in Patients With Major Depressive Disorder: A Propensity Score-Matched Analysis Using a Nationwide Inpatient Database in Japan.

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.

Psycho-educational interventions focused on maternal or infant sleep for pregnant women to prevent the onset of antenatal and postnatal depression: A systematic review.

AIMS: This systematic review aimed to evaluate randomized controlled trials (RCTs) to examine the effect of maternal and infant sleep intervention during women's pregnancy for the purpose of preventing perinatal depression. METHOD: A systematic search (from inception to January 28, 2019) for RCTs using five electronic databases-the Cochrane Controlled Register of Trials (CENTRAL), Embase, PubMed, PsycINFO, and Ichushi Web (Japan Medical Abstracts Society)-was conducted. Twelve investigators independently conducted initial screenings based on title and abstract, and then, two researchers performed full-text reviews one by one. A meta-analysis would be conducted if at least three studies were found. However, only two articles that met inclusion criteria, and narrative data synthesis was conducted for these two articles. The study protocol has been registered at PROSPERO (CRD42019119999). RESULT: A total of 13 654 studies were initially searched. After removing duplicates, 10 547 studies were screened, and finally, two studies met the inclusion criteria. In both studies, the intervention was a one-time face-to-face session during pregnancy to deliver the behavioral knowledge and skills for optimizing sleep hygiene for both infant and mother. Effectiveness of the intervention in improving maternal mood was not significant in one study. In the other, there was a significant difference in maternal mood between the intervention and control group. No mood comparison was made between baseline and postintervention. CONCLUSION: This study found limited evidence to support the effectiveness of sleep intervention for all pregnant women, which means "universal intervention," to protect maternal mental health. Further well-designed RCTs are needed to confirm these findings.