論文 - 菊地　俊暁

Dynamic neural network modulation associated with rumination in major depressive disorder: a prospective observational comparative analysis of cognitive behavioral therapy and pharmacotherapy

Katayama N., Shinagawa K., Hirano J., Kobayashi Y., Nakagawa A., Umeda S., Kamiya K., Tajima M., Amano M., Nogami W., Ihara S., Noda S., Terasawa Y., Kikuchi T., Mimura M., Uchida H.

Translational Psychiatry 15 （ 1 ）  2025年12月

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Cognitive behavioral therapy (CBT) and pharmacotherapy are primary treatments for major depressive disorder (MDD). However, their differential effects on the neural networks associated with rumination, or repetitive negative thinking, remain poorly understood. This study included 135 participants, whose rumination severity was measured using the rumination response scale (RRS) and whose resting brain activity was measured using functional magnetic resonance imaging (fMRI) at baseline and after 16 weeks. MDD patients received either standard CBT based on Beck’s manual (n = 28) or pharmacotherapy (n = 32). Using a hidden Markov model, we observed that MDD patients exhibited increased activity in the default mode network (DMN) and decreased occupancies in the sensorimotor and central executive networks (CEN). The DMN occurrence rate correlated positively with rumination severity. CBT, while not specifically designed to target rumination, reduced DMN occurrence rate and facilitated transitions toward a CEN-dominant brain state as part of broader therapeutic effects. Pharmacotherapy shifted DMN activity to the posterior region of the brain. These findings suggest that CBT and pharmacotherapy modulate brain network dynamics related to rumination through distinct therapeutic pathways.

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Long-term effectiveness of vortioxetine on achievement of personal goals and work productivity in patients with major depressive disorder: The VGOAL-J study

Watanabe K., Sumiyoshi T., Kato M., Kikuchi T., Moriguchi Y., Åström D.O., Christensen M.C.

Journal of Affective Disorders Reports 21 2025年07月

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Background: The long-term effectiveness of vortioxetine for facilitating progress toward personal recovery goals and improving productivity at work was assessed in patients with major depressive disorder (MDD). Methods: Single-arm, prospective, 24-week cohort study in employed patients with MDD initiating treatment with vortioxetine (n = 121) in outpatient settings in Japan. The Goal Attainment Scale for Depression (GAS-D) was used to evaluate progress toward personal recovery goals. At baseline, a combination of patient-defined and pre-specified goals was established collaboratively with the treating psychiatrist, followed by longitudinal assessments at baseline and weeks 4, 8, 12, and 24. Work-related productivity was assessed using the Work Productivity and Activity Impairment (WPAI) questionnaire. Co-primary endpoints were the proportion of patients achieving their pre-specified personal recovery goals at week 12 and the change in work productivity from baseline. Results: In all, 45/107 patients (42.1%) had achieved their personal recovery goals at week 12, increasing to 62/100 (62.0%) at week 24. Significant improvement was observed across all WPAI domains (i.e., absenteeism, presenteeism, productivity loss, and activity impairment) at week 24. Depressive symptoms, global patient functioning, emotional and cognitive symptoms, cognitive performance, and quality of life also significantly improved over the 24 weeks of follow-up. At week 24, 80/102 patients (78.4%) remained on vortioxetine; 49 of these patients (61.3%) were receiving vortioxetine 20 mg/day. Limitations: Open-label study. Conclusions: Vortioxetine was found to be effective in helping to achieve personal recovery goals and in enhancing workplace productivity over the 6-month study period in patients with MDD. Trial registration: Japan Primary Registries Network: JRCT1031210200.

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Impact of Emotional Blunting on Patient Social Function and Depressive Symptoms: A Post Hoc Analysis of a Web-Based Survey in Japanese Patients with Major Depressive Disorder

Kikuchi T., Iga J.I., Hattori A., Tokuda F., Moriguchi Y., Hoshino T.

Neuropsychiatric Disease and Treatment 21   841 - 854 2025年

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Background: Emotional blunting (EB), defined as a flattening of emotions and emotional indifference, is reported by many patients with major depressive disorder (MDD) taking antidepressants. Severity of EB correlates with depressive symptoms, as well as deficits in social function, anxiety and health-related quality of life. However, awareness and understanding of EB and its impact on treatment of MDD remain poorly understood. Methods: This was a post hoc analysis of data from a web-based survey of 3376 adults with MDD in Japan. The primary endpoint was the correlation between total and subdomain scores of the Oxford Depression Questionnaire (ODQ; a validated instrument to assess EB) and total and individual domain/item scores of the Work and Social Adjustment Scale (WSAS) and Patient Health Questionnaire 9-item (PHQ-9). The secondary endpoint explored which patients had a discrepancy between EB symptoms (assessed by the ODQ) and their own evaluation of EB (using a validated screening question). Results: There was a moderate correlation between the ODQ total score and the WSAS total score (Spearman’s rank correlation coefficient [r<inf>s</inf> ] = 0.578) and a strong correlation between the ODQ total score and PHQ-9 total score (r<inf>s</inf> = 0.670). Multiple regression analyses showed that the ODQ subdomains “not caring” (NC) and “reduction in positive emotions” (PR) had the greatest impact on both the WSAS total score (partial regression coefficients = 1.034 and 0.501, respectively) and PHQ-9 total score (partial regression coefficients = 0.548 and 0.592, respectively). A higher proportion of men (versus women) and unemployed individuals (versus employed individuals) underestimated their EB severity compared with their ODQ score. Conclusion: The ODQ subdomains of NC and PR are important factors when evaluating the impact of EB on social function and severity of depressive symptoms in patients with MDD. Physicians should assess EB symptoms for each patient, considering the patient’s background.

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Network meta-analysis of the effectiveness of psychotherapies with or without medication for treating adult depression

Fukumori M., Kikuchi T., Zhou Y., Hattori S., Kudo T.

Acta Neuropsychiatrica 36 （ 6 ） 423 - 437 2024年12月

ISSN  09242708

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Objective: To ascertain whether psychotherapies combined with medication are more efficacious than those without medication and determine which combinations yield the best results. Methods: We conducted a network meta-analysis of randomised controlled trials (RCTs) comparing behavioural activation (BA), psychoanalytic/psychodynamic psychotherapy (DYN), interpersonal psychotherapy (IPT), individual face-to-face cognitive behavioural therapy (CBT (ftf)), group cognitive behavioural therapy (gCBT), and computerised or internet cognitive behavioural therapy (iCBT) with each other, or with treatment-as-usual (TAU) and wait list control (WLC) among adults formally diagnosed with depression. The psychotherapy arms were categorised as either psychotherapy alone or psychotherapy combined with medication (+ p). Treatment efficacy was assessed based on depression severity. We used a random-effects model to conduct a pairwise meta-analysis. Results: A total of 100 RCTs with 9,873 participants were included. The most common treatment was CBT (ftf) alone. All treatment arms were compared with TAU. Most psychotherapies combined with medication were superior to psychotherapy alone. In the subgroup analyses according to the baseline severity of depression, most psychotherapies combined with medication were more effective than psychotherapy alone in moderate-to-severe depression, whereas in mild depression, such differences were not observed. Among psychotherapies with medication, gCBT + p was significantly more effective than TAU and other psychotherapies in both the main and subgroup analyses. Conclusion: The efficacy of depression treatment varied depending on the severity of the depressive condition. Notably, gCBT + p was identified as the most effective approach for treating adult depression.

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Gender differences and mental distress during COVID-19: a cross-sectional study in Japan

Kanata T., Takeda K., Fujii T., Iwata R., Hiyoshi F., Iijima Y., Nakao T., Murayama K., Watanabe K., Kikuchi T., Mimura M., Yoshimi A., Hishimoto A., Hirata H., Ozaki N., Kito S., Kuga H., Oba M., Oi H., Nakagome K.

BMC Psychiatry 24 （ 1 ）  2024年12月

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Background: To identify risk factors for mental distress and investigate whether the factors were different between men and women during the coronavirus disease 2019 (COVID-19), using KOKOROBO data, which is an online platform that aims to facilitate access to mental health services. Methods: We used baseline data on KOKOROBO users 13 years of age or older in Japan who accessed it from October 11, 2021, to April 6, 2023, excluding those receiving treatment for mental health problems. Global severity, based on the most severe measure on Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Insomnia Severity Index (ISI), was analyzed using multivariable logistic regression with baseline characteristics for each gender, and for under 30 and 30 years of age or older in women. We conducted the same analysis of suicidal ideation for each gender. Results: In the 686 men and 1274 women, 117 (17.1%) and 100 (7.8%) had minimal global severity respectively, and the rest suffered from mental distress to some extent. For women, ages under 30 years (adjusted OR (aOR): 0.352, 95%CI: 0.231–0.539, P < 0.001), marriage (aOR: 0.453, 95%CI: 0.274–0.746, P = 0.002), and concerns about COVID-19 infection were associated with global severity, while having children (aOR: 0.509, 95% CI: 0.284–0.909, P = 0.023) and decrease of going out during the COVID-19 pandemic had a protective effect on global severity and suicidal ideation for men, respectively. Living with family was a risk factor for mental distress in unmarried women over 30 years of age. Less communication with family or others and responding to the questionnaire late at night (00:00–05:59) were associated with severe global severity in both genders. Conclusions: Age, living arrangement, marriage, having children, concerns about COVID-19 infection, and lifestyle changes during the COVID-19 pandemic had gender-specific effects on mental distress, while frequent communication and regular life rhythm maintained mental health in both genders. Young women and, unmarried middle-aged women living with their families tended to experience mental distress during the COVID-19 pandemic. Trial registration: The Ethics Committee of the National Center of Neurology and Psychiatry approved this study (approval number B2020141) on April 15, 2021.

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A web-based survey on the occurrence of emotional blunting in patients with major depressive disorder in Japan: Patient perceptions and attitudes

Kikuchi T., Iga J.i., Oosawa M., Hoshino T., Moriguchi Y., Izutsu M.

Neuropsychopharmacology Reports 44 （ 2 ） 321 - 332 2024年06月

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Aims: To determine the prevalence and impact of emotional blunting (EB) in patients with major depressive disorder (MDD) in Japan, and identify treatment needs for EB using patients' perceptions and attitudes. Methods: Eligible patients in Japan (aged 18–59 years) who reported a diagnosis of MDD and antidepressant medication use for >3 months were eligible to complete an online survey. The primary outcome was the prevalence of EB, self-reported using a validated screening question. Secondary outcomes included the correlation between EB symptoms (measured by the Oxford Depression Questionnaire [ODQ]) and scores on the Patient Health Questionnaire 9-item (PHQ-9), Generalized Anxiety Disorder 7-item (GAD-7), Work and Social Adjustment Scale (WSAS), and the EuroQol 5-Dimension 5-Levels questionnaire (EQ-5D-5L). Descriptive questions were used to explore patients' perceptions and attitudes toward EB. Results: In total, 3376 patients were included in the analysis (56% male; 48% aged 50–59 years). Overall, 67.1% of patients self-reported symptoms of EB, with 10% rating these as severe. The mean (SD) ODQ total score was 78.2 (21.5), which increased with worsening EB symptoms. There were correlations between ODQ total scores and the PHQ-9, GAD-7, WSAS, and EQ-5D-5L scores (correlation coefficients: 0.67, 0.55, 0.56, −0.51, respectively; all p < 0.0001). Descriptive analyses showed that one-third of patients reporting EB symptoms did not tell their physician, with two-thirds finding these symptoms distressing and likely to affect recovery. Conclusion: EB is an important clinical issue in Japan that needs to be considered alongside functional recovery when managing treatment of patients with MDD.

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Live two-way video versus face-to-face treatment for depression, anxiety, and obsessive-compulsive disorder: A 24-week randomized controlled trial

Kishimoto T., Kinoshita S., Kitazawa M., Hishimoto A., Asami T., Suda A., Bun S., Kikuchi T., Sado M., Takamiya A., Mimura M., Sato Y., Takemura R., Nagashima K., Nakamae T., Abe Y., Kanazawa T., Kawabata Y., Tomita H., Abe K., Hongo S., Kimura H., Sato A., Kida H., Sakuma K., Funayama M., Sugiyama N., Hino K., Amagai T., Takamiya M., Kodama H., Goto K., Fujiwara S., Kaiya H., Nagao K.

Psychiatry and Clinical Neurosciences 78 （ 4 ） 220 - 228 2024年04月

ISSN  13231316

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Aim: Live two-way video, easily accessible from home via smartphones and other devices, is becoming a new way of providing psychiatric treatment. However, lack of evidence for real-world clinical setting effectiveness hampers its approval by medical insurance in some countries. Here, we conducted the first large-scale pragmatic, randomized controlled trial to determine the effectiveness of long-term treatment for multiple psychiatric disorders via two-way video using smartphones and other devices, which are currently the primary means of telecommunication. Methods: This randomized controlled trial compared two-way video versus face-to-face treatment for depressive disorder, anxiety disorder, and obsessive-compulsive disorder in the subacute/maintenance phase during a 24-week period. Adult patients with the above-mentioned disorders were allocated to either a two-way video group (≥50% video sessions) or a face-to-face group (100% in-person sessions) and received standard treatment covered by public medical insurance. The primary outcome was the 36-Item Short-Form Health Survey Mental Component Summary (SF-36 MCS) score. Secondary outcomes included all-cause discontinuation, working alliance, adverse events, and the severity rating scales for each disorder. Results: A total of 199 patients participated in this study. After 24 weeks of treatment, two-way video treatment was found to be noninferior to face-to-face treatment regarding SF-36 MCS score (48.50 vs 46.68, respectively; p < 0.001). There were no significant differences between the groups regarding most secondary end points, including all-cause discontinuation, treatment efficacy, and satisfaction. Conclusion: Two-way video treatment using smartphones and other devices, was noninferior to face-to-face treatment in real-world clinical settings. Modern telemedicine, easily accessible from home, can be used as a form of health care.

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Conversation Analysis of Remote Dialogue System for Mental Health Interventions

Yi S., Kikuchi T., Yamasaki T.

Lecture Notes in Computer Science Including Subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics 14975 LNCS   278 - 291 2024年

ISSN  03029743

　概要を見る

Mental health conditions significantly impact all aspects of life, highlighting the need for innovative and accessible interventions. Remote automatic dialogue systems are increasingly used in mental health interventions to help individuals express their concerns and relieve stress. We used NLP technologies to address three key challenges in mental health intervention dialogue systems: identifying user concern topics, predicting concern severity, and optimizing dialogue flow. First, we introduced a new topic clustering method to classify samples into customized categories without the need for large labeled datasets, achieving an accuracy of 73.8%. Next, we created a dataset containing user concerns and severity labels to train models for detecting severe concerns. In our evaluation, BERT achieved a Pearson correlation coefficient of 0.83 in predicting concern severity. We also used language models for dialogue flow optimization. BERT achieved an F-score of 0.752 in predicting user satisfaction. We continuously monitored and predicted user satisfaction based on conversation content, identifying flows that negatively impacted satisfaction. We believe that our AI-supported dialogue system, capable of continuous adaptation and improvement, can significantly contribute to mental health interventions.

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Real-world clinical determinants of alcohol dependence in outpatients with bipolar disorder: a multicenter treatment survey for bipolar disorder in psychiatric outpatient clinics with 2,392 participants

Tokumitsu K., Sugawara N., Adachi N., Kubota Y., Watanabe Y., Miki K., Azekawa T., Edagawa K., Katsumoto E., Hongo S., Goto E., Ueda H., Kato M., Yoshimura R., Nakagawa A., Kikuchi T., Tsuboi T., Watanabe K., Yasui-Furukori N.

Frontiers in Psychiatry 15 2024年

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Background: Bipolar disorder is a psychiatric disorder characterized by mood swings between manic and depressed states that causes psychosocial problems. Cognitive function deteriorates with each recurrence, making it important to maintain remission through continued treatment. Bipolar disorder often co-occurs with alcohol dependence, which is known to lead to decreased treatment adherence and increased suicide risk. However, the real-world clinical determinants of alcohol dependence in outpatients with bipolar disorder in Japan remain unclear. Methods: We conducted an observational study targeting 2392 patients with bipolar disorder using data from the MUSUBI study, a joint project of the Japanese Association of Neuro-Psychiatric Clinics and the Japanese Society of Clinical Neuropsychopharmacology. After determining the prevalence of alcohol dependence and the sociodemographic characteristics of patients with bipolar disorder, multivariate analysis was performed to identify risk factors for alcohol comorbidity. Results: The prevalence of alcohol dependence among outpatients with bipolar disorder in this study was 5.7%. The prevalence was 7.6% for males and 3.1% for females. The results of the binomial logistic regression analysis revealed that bipolar I disorder, manic state, comorbidities with other psychiatric disorders, male sex, and suicidal ideation were significantly associated with alcohol dependence. Stratified analysis by gender showed that alcohol dependence was more strongly associated with the presence of suicidal ideation in women than in men. Limitation: First, because this was an observational study with a cross-sectional design, causal relationships between factors cannot be determined. In addition, this study included outpatients in Japan but lacked information on inpatients. Therefore, it was considered necessary to conduct the study on a larger population in order to generate more robust evidence. Conclusions: We found that outpatients with bipolar disorder, especially men, had higher rates of alcohol dependence overall than the general population in Japan. In addition, the relationship between alcohol dependence and suicidal ideation was stronger in women than in men with bipolar disorder. There was a strong association between manic states and alcohol dependence in outpatients with bipolar disorder. These results are useful to clinicians because they reinforce real-world clinical evidence for the treatment of bipolar disorder and co-occurring alcohol dependence.

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Goal Attainment Scaling for Depression: Validation of the Japanese GAS-D Tool in Patients with Major Depressive Disorder

Kato M., Kikuchi T., Watanabe K., Sumiyoshi T., Moriguchi Y., Åström D.O., Christensen M.C.

Neuropsychiatric Disease and Treatment 20   49 - 60 2024年

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Purpose: Goal attainment scaling (GAS) has been proposed as a person-centric, semi-quantitative measure that assimilates achievement of individually set goals into a single standardized “goal attainment score” that can be compared at the population level. We aimed to examine the reliability and validity of the Japanese version of the GAS for depression (GAS-D) tool in assessing goal attainment in people living with major depressive disorder (MDD). Patients and Methods: This was a prespecified analysis of a prospective, 24-week, multicenter, observational cohort study of employed Japanese outpatients with MDD initiating treatment with vortioxetine according to the Japanese label (JRCT1031210200). Participants were assessed using the Japanese version of the GAS-D and other clinical rating scales at baseline and Weeks 8, 12 and 24. Results: Goal attainment was significantly associated with symptom severity as assessed by the Montgomery–Åsberg Depression Rating Scale (MADRS) scale, confirming convergent validity. In particular, GAS-D scores were significantly related to MADRS total score at Weeks 12 and 24, indicating that improvements in overall symptom severity with vortioxetine treatment were likely to be reflected in the achievement of individualized treatment goals. With an intraclass correlation coefficient of 0.67 (95% CI 0.45–0.82), the GAS-D also showed moderate test–retest reliability between Weeks 8 and 12 while proving independent of demographic characteristics. Conclusion: The results of this open-label study support the use of the GAS-D as a valid and sensitive outcome measure in the assessment of treatment response in MDD.

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Clinical characteristics and potential association to Parkinson’s disease and dementia with Lewy bodies in patients with major depressive disorder who received maintenance electroconvulsive therapy: a retrospective chart review study

Kudo S., Uchida T., Nishida H., Takamiya A., Kikuchi T., Yamagata B., Mimura M., Hirano J.

BMC Psychiatry 23 （ 1 ）  2023年12月

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Background: Maintaining remission after electroconvulsive therapy (ECT) is clinically relevant in patients with depression, and maintenance ECT has been introduced in patients who fail to maintain remission after ECT. However, the clinical characteristics and biological background of patients who receive maintenance ECT are poorly understood. Thus, this study aimed to examine the clinical background of patients who underwent maintenance ECT. Methods: Patients with major depressive disorder who underwent ECT followed by maintenance ECT (mECT group) and those who did not (acute ECT [aECT] group) were included. Clinical characteristics, including the results of neuroimaging examinations for Parkinson’s disease (PD) and dementia with Levy body (DLB) such as myocardial 123I-metaiodobenzylguanidine (MIBG) scintigraphy and dopamine transporter imaging single-photon emission computerized tomography (DaT-SPECT), were compared between the groups. Results: In total, 13 and 146 patients were included in the mECT and aECT groups, respectively. Compared to the aECT group, the mECT group showed a significantly higher prevalence of melancholic features (92.3% vs. 27.4%, p < 0.001) and catatonic features (46.2% vs. 9.6%, p = 0.002). Overall, 8 of the 13 patients in the mECT group and 22 of the 146 patients in the aECT group underwent neuroimaging examinations for PD/DLB. The rate of patients examined is significantly higher in the mECT group than in the aECT group (61.5% vs. 11.2%, p < 0.001). Among the groups examined, 7/8 patients in the mECT group and 16/22 patients in the aECT group showed relevant neuroimaging findings for PD/DLB; the positive rate was not significantly different between the two groups (87.5% vs. 72.7%, p = 0.638). Conclusions: Patients who receive acute and maintenance ECT may have underlying neurodegenerative diseases, including PD/DLB. Investigating the neurobiology of patients who receive maintenance ECT is important for developing appropriate treatments for depression.

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Real-world predictors of divorce among outpatients with bipolar disorder: sex differences and clinical implications

Tokumitsu K., Sugawara N., Adachi N., Kubota Y., Watanabe Y., Miki K., Azekawa T., Edagawa K., Katsumoto E., Hongo S., Goto E., Ueda H., Kato M., Yoshimura R., Nakagawa A., Kikuchi T., Tsuboi T., Watanabe K., Yasui-Furukori N.

Annals of General Psychiatry 22 （ 1 ）  2023年12月

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Background: Bipolar disorder is a mental illness characterized by recurring episodes of mania and depression and is known to cause social impairment. Additionally, it has been revealed that bipolar disorder increases the risk of divorce and loss of family member support, which can worsen the prognosis. However, there is limited evidence regarding the predictive factors of divorce among patients with bipolar disorder in real-world settings. Methods: This study utilized an observational approach and involved psychiatrists from 176 member clinics of the Japanese Association of Neuro-Psychiatric Clinics. They were requested to conduct a retrospective review of medical records and complete a questionnaire focused on patients diagnosed with bipolar disorder. The data collection period for baseline patient characteristics spanned from September to October 2017. Next, we investigated the incidence of divorce over a 2-year period, ranging from baseline to September to October 2019. Results: A total of 1071 outpatients with bipolar disorder were included in the analysis, and 2.8% (30/1071) experienced divorce during the first 2 years of observation. The incidence of divorce in this population was considerably higher than that in the general Japanese population. Binomial logistic regression analysis confirmed that a younger baseline age and lower BMI values were statistically significant predictors of divorce occurrence for all study participants. The predictors of divorce were then examined separately by sex. The results revealed that for men, a younger age at baseline and having bipolar I disorder compared to bipolar II disorder were statistically significant predictors of divorce. In contrast, for women, having a lower BMI and using anxiolytics emerged as statistically significant predictors of divorce. Conclusions: In this study, a younger baseline age and lower BMI values were statistically significant predictors of divorce in patients with bipolar disorder. Notably, the predictors of divorce varied significantly between men and women. These findings provide important insights from a family perspective regarding social support for individuals with bipolar disorder in real-world clinical settings.

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Functional connectivity changes between frontopolar cortex and nucleus accumbens following cognitive behavioral therapy in major depression: A randomized clinical trial

Katayama N., Nakagawa A., Umeda S., Terasawa Y., Shinagawa K., Kikuchi T., Tabuchi H., Abe T., Mimura M.

Psychiatry Research Neuroimaging 332 2023年07月

ISSN  09254927

　概要を見る

Cognitive behavioral therapy (CBT) is a psychotherapy that challenges distorted cognitions; however, the neural mechanisms that underpin CBT remain unclear. Hence, we aimed to assess the treatment-related resting-state functional connectivity (rsFC) changes in the brain regions associated with future thinking and the associations between rsFC changes and clinical improvements. Thirty-eight adult patients with MDD were randomly assigned with equal likelihood to receive 16-week individual CBT or talking control with a 12-month follow-up period. We evaluated the rsFC changes in the frontal regions, nucleus accumbens, amygdala, and limbic structures key to the depression pathophysiology and future thinking with 2 × 2 mixed ANOVA interaction analysis. Pearson's correlation analysis with Bonferroni's correction was also performed to examine the associations with clinical symptoms, such as depression severity and automatic thoughts in follow-up evaluations. Treatment-specific changes include enhancement in frontopolar connectivity with the nucleus accumbens. An increased rsFC was associated with lower negative automatic thoughts postoperatively, together with lower depressive symptoms and higher positive automatic thoughts at follow-up. Conclusively, rsFC changes in the fronto-limbic neural control circuit after CBT, particularly between the frontal pole and nucleus accumbens, may be clinically meaningful functional changes related to the depression recovery process.

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The effect of cognitive behavioral therapy on future thinking in patients with major depressive disorder: A randomized controlled trial

Amano M., Katayama N., Umeda S., Terasawa Y., Tabuchi H., Kikuchi T., Abe T., Mimura M., Nakagawa A.

Frontiers in Psychiatry 14 2023年01月

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Background: Pessimistic thinking about the future is one of the cardinal symptoms of major depression. Few studies have assessed changes in pessimistic thinking after undergoing cognitive behavioral therapy (CBT). A randomized clinical trial (RCT) was conducted with patients diagnosed with major depressive disorder (MDD) to determine whether receiving a course of CBT affects pessimistic future thinking using a future thinking task. Methods: Thirty-one patients with MDD were randomly assigned to either CBT (n = 16) or a talking control (TC) (n = 15) for a 16-week intervention. The main outcomes were the change in response time (RT) and the ratio of the responses for positive valence, measured by the future thinking task. Secondary outcomes included the GRID-Hamilton Depression Rating Scale, the Beck Depression Inventory-Second Edition (BDI-II), the Dysfunctional Attitude Scale (DAS), and the word fluency test (WFT). Results: Regarding the main outcomes, the CBT group showed reduced RT for the positive valence (within-group Cohen’s d = 0.7, p = 0.012) and negative valence (within-group Cohen’s d = 0.6, p = 0.03) in the distant future condition. The ratio of positive valence responses in both groups for all temporal conditions except for the distant past condition increased within group (distant future: CBT: Cohen’s d = 0.5, p = 0.04; TC: Cohen’s d = 0.8, p = 0.008; near future: CBT: Cohen’s d = 1.0, p < 0.001; TC: Cohen’s d = 1.1, p = 0.001; near past: CBT: Cohen’s d = 0.8, p = 0.005; TC: Cohen’s d = 1.0, p = 0.002). As for secondary outcomes, the CBT group showed greater improvement than the TC group regarding the need for social approval as measured by the DAS (p = 0.012). Conclusion: Patients with MDD who received CBT showed a reduced RT for the positive and negative valence in the distant future condition. RT in the future thinking task for depressed patients may be a potential objective measure for the CBT treatment process. Because the present RCT is positioned as a pilot RCT, a confirmatory trial with a larger number of patients is warranted to elucidate the CBT treatment process that influences future thinking. Clinical trial registration: https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000021028, identifier UMIN000018155.

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Assessing Reliability and Validity of the Oxford Depression Questionnaire (ODQ) in a Japanese Clinical Population

Kato M., Kikuchi T., Watanabe K., Sumiyoshi T., Moriguchi Y., Åström D.O., Christensen M.C.

Neuropsychiatric Disease and Treatment 19   2401 - 2412 2023年

　概要を見る

Purpose: Originally developed in English, the Oxford Depression Questionnaire (ODQ) is a patient-reported scale specifically developed for assessing emotional blunting in people with major depressive disorder (MDD). We aimed to examine the reliability and validity of the Japanese version of the ODQ. Patients and methods: This was a prespecified analysis of a prospective, 24-week, multicenter, observational cohort study of employed Japanese outpatients with MDD initiating treatment with vortioxetine according to the Japanese label (JRCT1031210200). Participants were assessed using the Japanese version of the ODQ and other clinical rating scales at baseline and Weeks 8, 12 and 24. Results: One hundred and sixteen patients initiated vortioxetine and had ≥1 post-baseline visit. Directionally, the associations between ODQ scores and other clinical measures were as expected and demonstrated good concurrent validity. Factor analysis shows that the scale has a good fit for three factors. The Cronbach’s α coefficient was 0.912, and the scale also showed good test–retest reliability with intraclass correlation coefficients for the ODQ total score and domains ranging between 0.69 and 0.82. ODQ scores had strong positive correlations with symptom severity assessed using the Montgomery and Åsberg Depression Rating Scale and were moderately correlated with work productivity, overall functioning, and quality of life scales. Conclusion: Data from this prospective analysis confirm that the Japanese version of the ODQ retains the good validity and reliability of the original English scale and is suitable for use in prospective studies wanting to capture treatment effects on emotional blunting in MDD.

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Predictors of psychiatric hospitalization among outpatients with bipolar disorder in the real-world clinical setting

Tokumitsu K., Yasui-Furukori N., Adachi N., Kubota Y., Watanabe Y., Miki K., Azekawa T., Edagawa K., Katsumoto E., Hongo S., Goto E., Ueda H., Kato M., Nakagawa A., Kikuchi T., Tsuboi T., Watanabe K., Shimoda K., Yoshimura R.

Frontiers in Psychiatry 14 2023年

　概要を見る

Background: Bipolar disorder is a psychiatric disorder that causes recurrent manic and depressive episodes, leading to decreased levels of social functioning and suicide. Patients who require hospitalization due to exacerbation of bipolar disorder have been reported to subsequently have poor psychosocial functioning, and so there is a need to prevent hospitalization. On the other hand, there is a lack of evidence regarding predictors of hospitalization in real-world clinical practice. Methods: The multicenter treatment survey on bipolar disorder (MUSUBI) in Japanese psychiatric clinics was an observational study conducted to provide evidence regarding bipolar disorder in real-world clinical practice. Psychiatrists were asked, as part of a retrospective medical record survey, to fill out a questionnaire about patients with bipolar disorder who visited 176 member clinics of the Japanese Association of Neuro-Psychiatric Clinics. Our study extracted baseline patient characteristics from records dated between September and October 2016, including comorbidities, mental status, duration of treatment, Global Assessment of Functioning (GAF) score, and pharmacological treatment details. The incidence and predictors of hospitalization among patients with bipolar disorder over a 1-year period extending from that baseline to September–October 2017 were examined. Results: In total, 2,389 participants were included in our study, 3.06% of whom experienced psychiatric hospitalization over the course of 1 year from baseline. Binomial logistic regression analysis revealed that the presence of psychiatric hospitalization was correlated with bipolar I disorder, lower baseline GAF scores, unemployment, substance abuse and manic state. Conclusions: Our study revealed that 3.06% of outpatients with bipolar disorder were subjected to psychiatric hospitalization during a 1-year period that extended to September–October 2017. Our study suggested that bipolar I disorder, lower baseline GAF scores, unemployment, substance abuse and baseline mood state could be predictors of psychiatric hospitalization. These results may be useful for clinicians seeking to prevent psychiatric hospitalization for bipolar disorder.

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Development and acceptability of a decision aid for anxiety disorder considering discontinuation of benzodiazepine anxiolytic

Aoki Y., Takaesu Y., Inada K., Yamada H., Murao T., Kikuchi T., Takeshima M., Tani M., Mishima K., Otsubo T.

Frontiers in Psychiatry 14 2023年

　概要を見る

Aim: We aimed to develop a decision aid (DA) for individuals with anxiety disorders who consider tapering benzodiazepine (BZD) anxiolytics, and if tapering, tapering BZD anxiolytics with or without cognitive behavioral therapy (CBT) for anxiety. We also assessed its acceptability among stakeholders. Methods: First, we conducted a literature review regarding anxiety disorders to determine treatment options. We cited the results of the systematic review and meta-analysis, which we conducted previously, to describe the related outcomes of two options: tapering BZD anxiolytics with CBT and tapering BZD anxiolytics without CBT. Second, we developed a DA prototype in accordance with the International Patient Decision Aid Standards. We carried out a mixed methods survey to assess the acceptability among stakeholders including those with anxiety disorders and healthcare providers. Results: Our DA provided information such as explanation of anxiety disorders, options of tapering or not tapering BZD anxiolytics (if tapering, the options of tapering BZD anxiolytics with or without CBT) for anxiety disorder, benefits and risks of each option, and a worksheet for value clarification. For patients (n = 21), the DA appeared to be acceptable language (86%), adequate information (81%), and well-balanced presentation (86%). The developed DA was also acceptable for healthcare providers (n = 10). Conclusion: We successfully created a DA for individuals with anxiety disorders who consider tapering BZD anxiolytics, which was acceptable for both patients and healthcare providers. Our DA was designed to assist patients and healthcare providers to involve decision-making about whether to taper BZD anxiolytics or not.

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Costs of psychotropics for outpatients with bipolar disorder in Japan; the MUSUBI 2016 survey

Adachi N., Kubota Y., Goto E., Watanabe K., Yoshimura R., Tsuboi T., Yasui-Furukori N., Kato M., Hongo S., Azekawa T., Katsumoto E., Edagawa K., Nakagawa A., Kikuchi T., Ueda H., Miki K.

Annals of Medicine 55 （ 1 ）  2023年

ISSN  07853890

　概要を見る

Background: Although the costs of bipolar disorder (BD) treatments are associated with local and universal factors, data from non-Western countries remain limited. The associations between clinical features and costs of outpatient pharmacotherapy have not been well characterize. To estimate the costs of outpatient BD treatments and their associations with clinical features in a Japanese population, we investigated with special reference to the costs of medicines constituted the bulk of the total healthcare expense and were steadily increasing. Methods: The Multicenter Treatment Survey for Bipolar Disorder (MUSUBI) retrospectively evaluated 3130 patients with BD who visited 176 Japanese psychiatric outpatient clinics in 2016. Clinical features and drug prescriptions were recorded, and the total daily costs of psychotropic drug treatment were calculated. The annual medical costs related to outpatient BD treatments in Japan were estimated based on the corresponding demographics. The associations between daily medical costs and patients’ clinical features were analyzed using multiple regression analysis. Results: The daily costs of psychotropic drugs ranged from zero to JPY3245 (mean, JPY349 equivalent to USD32.5) and were exponentially distributed. The annual costs for outpatients BD treatments were approximately 51.9 billion Japanese yens (519 million US dollars). Subsequent multiple regression analysis revealed that social adjustment, depressive symptoms, age, rapid cycling, psychotic symptoms, and comorbid mental disorders correlated strongly with the daily cost of psychotropic drugs. Conclusion: The estimated annual costs for outpatient BD treatment in Japan were equivalent to those in OECD countries (except for the US) and higher than those in some Asian countries. The cost of psychotropic treatments was associated with individual characteristics and psychopathological conditions.Key Messages Psychotropic treatment for an outpatient with bipolar disorder has a daily cost approximately JPY350. The annual outpatient treatment cost for bipolar disorder in Japan was estimated to 51.9 billion Japanese yen in 2016. Individual characteristics and psychopathological conditions affected the cost of drug treatment.

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Clinical characteristics and prescriptions associated with a 2-year course of rapid cycling and euthymia in bipolar disorder: a multicenter treatment survey for bipolar disorder in psychiatric clinics

Takano C., Kato M., Adachi N., Kubota Y., Azekawa T., Ueda H., Edagawa K., Katsumoto E., Goto E., Hongo S., Miki K., Tsuboi T., Yasui-Furukori N., Nakagawa A., Kikuchi T., Watanabe K., Kinoshita T., Yoshimura R.

Frontiers in Psychiatry 14 2023年

　概要を見る

Objective: In patients with bipolar disorder (BD), rapid cycling (RC) presents a risk for a more severe illness, while euthymia (EUT) has a better prognosis. This study focused on the progression of RC and EUT, which are contrasting phenomenology, and aimed to clarify the influence of patient backgrounds and prescription patterns on these different progressions, using a large sample from the first and second iterations of a multicenter treatment survey for BD in psychiatric clinics (MUSUBI). Methods: In the cross-sectional study (MUSUBI), a questionnaire based on a retrospective medical record survey of consecutive BD cases (N = 2,650) was distributed. The first survey was conducted in 2016, and the second one in 2017. The questionnaire collected information on patient backgrounds, current episodes, and clinical and prescribing characteristics. Results: In the first survey, 10.6% of the participants had RC and 3.6% had RC for two consecutive years, which correlated with BP I (Bipolar disorder type I), suicidal ideation, duration of illness, and the use of lithium carbonate and antipsychotic medications. Possible risk factors for switching to RC were comorbid developmental disorders and the prescription of anxiolytics and sleep medication. Moreover, 16.4% of the participants presented EUT in the first survey, and 11.0% presented EUT for two consecutive years. Possible factors for achieving EUT included older age; employment; fewer psychotic symptoms and comorbid personality disorders; fewer antidepressants, antipsychotics, and anxiolytics, and more lithium prescriptions. Conclusion: RC and EUT generally exhibit conflicting characteristics, and the conflicting social backgrounds and factors contributing to their outcomes were distinctive. Understanding these clinical characteristics may be helpful in clinical practice for management of patients with BD.

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Development of medical device software for the screening and assessment of depression severity using data collected from a wristband-type wearable device: SWIFT study protocol

Kishimoto T., Kinoshita S., Kikuchi T., Bun S., Kitazawa M., Horigome T., Tazawa Y., Takamiya A., Hirano J., Mimura M., Liang K.C., Koga N., Ochiai Y., Ito H., Miyamae Y., Tsujimoto Y., Sakuma K., Kida H., Miura G., Kawade Y., Goto A., Yoshino F.

Frontiers in Psychiatry 13 2022年12月

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Introduction: Few biomarkers can be used clinically to diagnose and assess the severity of depression. However, a decrease in activity and sleep efficiency can be observed in depressed patients, and recent technological developments have made it possible to measure these changes. In addition, physiological changes, such as heart rate variability, can be used to distinguish depressed patients from normal persons; these parameters can be used to improve diagnostic accuracy. The proposed research will explore and construct machine learning models capable of detecting depressive episodes and assessing their severity using data collected from wristband-type wearable devices. Methods and analysis: Patients with depressive symptoms and healthy subjects will wear a wristband-type wearable device for 7 days; data on triaxial acceleration, pulse rate, skin temperature, and ultraviolet light will be collected. On the seventh day of wearing, the severity of depressive episodes will be assessed using Structured Clinical Interview for DSM-5 (SCID-5), Hamilton Depression Rating Scale (HAMD), and other scales. Data for up to five 7-day periods of device wearing will be collected from each subject. Using wearable device data associated with clinical symptoms as supervisory data, we will explore and build a machine learning model capable of identifying the presence or absence of depressive episodes and predicting the HAMD scores for an unknown data set. Discussion: Our machine learning model could improve the clinical diagnosis and management of depression through the use of a wearable medical device. Clinical trial registration: [https://jrct.niph.go.jp/latest-detail/jRCT1031210478], identifier [jRCT1031210478].

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Understanding psychiatric illness through natural language processing (UNDERPIN): Rationale, design, and methodology

Kishimoto T., Nakamura H., Kano Y., Eguchi Y., Kitazawa M., Liang K.C., Kudo K., Sento A., Takamiya A., Horigome T., Yamasaki T., Sunami Y., Kikuchi T., Nakajima K., Tomita M., Bun S., Momota Y., Sawada K., Murakami J., Takahashi H., Mimura M.

Frontiers in Psychiatry 13 2022年12月

　概要を見る

Introduction: Psychiatric disorders are diagnosed through observations of psychiatrists according to diagnostic criteria such as the DSM-5. Such observations, however, are mainly based on each psychiatrist's level of experience and often lack objectivity, potentially leading to disagreements among psychiatrists. In contrast, specific linguistic features can be observed in some psychiatric disorders, such as a loosening of associations in schizophrenia. Some studies explored biomarkers, but biomarkers have yet to be used in clinical practice. Aim: The purposes of this study are to create a large dataset of Japanese speech data labeled with detailed information on psychiatric disorders and neurocognitive disorders to quantify the linguistic features of those disorders using natural language processing and, finally, to develop objective and easy-to-use biomarkers for diagnosing and assessing the severity of them. Methods: This study will have a multi-center prospective design. The DSM-5 or ICD-11 criteria for major depressive disorder, bipolar disorder, schizophrenia, and anxiety disorder and for major and minor neurocognitive disorders will be regarded as the inclusion criteria for the psychiatric disorder samples. For the healthy subjects, the absence of a history of psychiatric disorders will be confirmed using the Mini-International Neuropsychiatric Interview (M.I.N.I.). The absence of current cognitive decline will be confirmed using the Mini-Mental State Examination (MMSE). A psychiatrist or psychologist will conduct 30-to-60-min interviews with each participant; these interviews will include free conversation, picture-description task, and story-telling task, all of which will be recorded using a microphone headset. In addition, the severity of disorders will be assessed using clinical rating scales. Data will be collected from each participant at least twice during the study period and up to a maximum of five times at an interval of at least one month. Discussion: This study is unique in its large sample size and the novelty of its method, and has potential for applications in many fields. We have some challenges regarding inter-rater reliability and the linguistic peculiarities of Japanese. As of September 2022, we have collected a total of >1000 records from >400 participants. To the best of our knowledge, this data sample is one of the largest in this field. Clinical Trial Registration: Identifier: UMIN000032141.

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Central monitoring of depression and anxiety symptoms reduces placebo responses in depression clinical trials: A post hoc exploratory analysis of data from the phase III CCT-004 trial of vortioxetine

Watanabe Y., Nishimura A., Kikuchi T., Sawada N., Imazaki M., Inada I., Watanabe K.

Neuropsychopharmacology Reports 42 （ 4 ） 468 - 477 2022年12月

　概要を見る

Aim: Clinical trials of antidepressants often fail to demonstrate their efficacy versus placebo, suggesting that patient selection based on physician ratings of depression may contribute to a high placebo response. Methods: In the CCT-004 trial of vortioxetine, central monitoring was employed to compare physician and patient ratings of depression and anxiety at baseline and over time to identify factors contributing to a large placebo response, as well as to explore the potential of a unique patient-rated clinical measure combining QIDS-J and Himorogi Self-rating Anxiety Scale (HSAS), to contribute to optimal patient selection at baseline and patient monitoring over time. Results: The CCT-004 trial showed similar trends between the QIDS-J and MADRS (Montgomery-Åsberg Depression Rating Scale) ratings. It was suggested that central monitoring of the QIDS-J and MADRS ratings of depression and anxiety symptoms helped reduce the baseline score inflation by calling the study sites' attention to discrepancies between these ratings at baseline; it also allowed these ratings to be assessed for their concordance over time. Of note, MDD patients with baseline QIDS-J scores ≥11/HSAS ≤19 were associated with the smallest placebo response, with the effect size being larger than that for those with QIDS-J scores ≤10/HSAS ≥20. Conclusion: The use of both physician and patient ratings of depression and anxiety symptoms at baseline and over time, as well as their central monitoring, helped minimize the baseline score inflation and optimize patient monitoring over time, and allowed the antidepressant to be evaluated for its full therapeutic potential.

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Effect of age and sex on prescriptions for outpatients with bipolar disorder in the MUSUBI study: a cross‑sectional study

Kawamata Y., Yasui-Furukori N., Adachi N., Ueda H., Hongo S., Azekawa T., Kubota Y., Katsumoto E., Edagawa K., Goto E., Miki K., Kato M., Nakagawa A., Kikuchi T., Tsuboi T., Yoshimura R., Shimoda K., Watanabe K.

Annals of General Psychiatry 21 （ 1 ）  2022年12月

　概要を見る

Background: Childbearing-aged female patients and elderly patients with bipolar disorder need special attention for pharmacological treatments, but current guidelines provide little information on their pharmacological treatment. In particular, the risk/benefit balance of pharmacological treatment for childbearing-aged females with bipolar disorder is a growing concern. Therefore, we aimed to address the effect of age and sex on psychotropic drug prescription for outpatients with bipolar disorder. Methods: The MUlticenter treatment SUrvey for BIpolar disorder in Japanese psychiatric clinics (MUSUBI) study was conducted, and data on age, sex, and details of pharmacological treatment were collected. Results: A total of 3106 outpatients were included in this study. Among young females (age ≤ 39), 25% were prescribed valproate. There was no significant difference in the frequency and daily dose of valproate prescription for young females among all groups. Valproate prescriptions were significantly less frequent among young males and more frequent among middle-aged males. Lithium prescriptions were significantly less frequent among young females and more frequent among older males (age ≥ 65) and older females. Lamotrigine prescriptions were significantly more frequent among young males and young females and less frequent among older males and older females. Carbamazepine prescriptions were significantly less frequent among young males and more frequent among older males. Conclusions: Biased information about the risk and safety of valproate and lithium for young females was suggested, and further study to correct this bias is needed. Older patients were prescribed lithium more commonly than lamotrigine. Further studies are needed to determine the actual pharmacotherapy for elderly individuals.

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Determinants of three-year clinical outcomes in real-world outpatients with bipolar disorder: The multicenter treatment survey for bipolar disorder in psychiatric outpatient clinics (MUSUBI)

Sugawara N., Adachi N., Kubota Y., Watanabe Y., Miki K., Azekawa T., Edagawa K., Katsumoto E., Hongo S., Goto E., Ueda H., Kato M., Yoshimura R., Nakagawa A., Kikuchi T., Tsuboi T., Watanabe K., Shimoda K., Yasui-Furukori N.

Journal of Psychiatric Research 151   683 - 692 2022年07月

ISSN  00223956

　概要を見る

Background: There is limited evidence regarding predictors of long-term clinical outcomes in patients with bipolar disorder (BD). The objective of this study was to describe 3-year clinical outcomes and identify their predictors from participants in the multicenter treatment survey for BD in psychiatric outpatient clinics (MUSUBI). Methods: The MUSUBI was a naturalistic study investigating patients with BD in real-world clinical practice. Our study extracted data regarding 1647 outpatients with BD from 2016, 2017, and 2019 as baseline, 1-year, and 3-year assessments. As clinical outcomes, we assessed the presence of time ill (depressive and manic) during the 1 year prior to the 3-year assessment and durable remission (53 weeks or more) prior to the 3-year assessment. Results: Participants with durable remission prior to the 3-year assessment had significant associations with diagnosis of a personality disorder and duration of continuous remission at baseline. Regarding the presence of depressive symptoms during the 1 year prior to the 3-year assessment, work status, Global Assessment of Functioning (GAF) scores, suicidal ideation, and duration of continuous remission at baseline had significant associations with this outcome. Conclusions: At the 3-year assessment, 19.3% of participants (318/1647) achieved durable remission, while 47.5% of them (782/1647) were not remitted. Our findings can help clinicians predict the illness course of BD by understanding demographic and clinical characteristics.

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Cognitive behavioral therapy effects on frontopolar cortex function during future thinking in major depressive disorder: A randomized clinical trial

Katayama N., Nakagawa A., Umeda S., Terasawa Y., Abe T., Kurata C., Sasaki Y., Mitsuda D., Kikuchi T., Tabuchi H., Mimura M.

Journal of Affective Disorders 298   644 - 655 2022年02月

ISSN  01650327

　概要を見る

Background: Despite the importance of Beck's theoretical cognitive model of psychopathology, the neural mechanisms underlying future thinking in cognitive behavioral therapy (CBT) remain elusive. Recent neuroimaging studies have shown that the function of the frontopolar cortex (Brodmann area 10 [BA10]) is associated with future thinking. We hypothesized that, compared with unstructured psychotherapy (talking control: TC), CBT may involve different neural responses in BA10 associated with future thinking. Methods: This randomized clinical trial included 38 adult patients with moderate-to-severe major depressive disorder who underwent up to 16 weeks of CBT or TC with a 6-month follow-up period. We evaluated changes in BA10 activation during distant future thinking using functional magnetic resonance imaging with a future-thinking task. We assessed frontal neurocognitive function and clinical symptoms at baseline and post-treatment. Depression severity and automatic thoughts were assessed at the 6-month follow-up. Results: We found decreased activation in the frontopolar cortex during distant future thinking after CBT (t = 3.00, df=15, p = 0.009) and no changes after TC. Further, the reduction in BA10 activity significantly correlated with changes in frontal cognitive function after the treatment (r = 0.48, p = 0.007), and in positive automatic thought after 6 months of treatments (r = 0.39; p = 0.03). Limitations: Relatively small sample size and homogenous clinical profile could limit the generalizability. Patients received pharmacotherapy including antidepressant. Conclusions: CBT appears to improve frontopolar cortex function during future thinking in a manner distinct from TC. Larger clinical trials are necessary to provide firm evidence whether BA10 activity may serve as a neuro-marker for monitoring successful depression treatment with CBT.

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Differences in prescription patterns between real-world outpatients with bipolar I and II disorders in the MUSUBI survey

Shinozaki M., Yasui-Furukori N., Adachi N., Ueda H., Hongo S., Azekawa T., Kubota Y., Katsumoto E., Edagawa K., Goto E., Miki K., Kato M., Nakagawa A., Kikuchi T., Tsuboi T., Watanabe K., Shimoda K., Yoshimura R.

Asian Journal of Psychiatry 67 2022年01月

ISSN  18762018

　概要を見る

Objective: There is limited information available on the prescription of psychotropic agents to patients with bipolar I (BD-I) and bipolar II disorder (BD-II). The purpose of this study was to investigate the characteristics of drug therapy in BD-I and BD-II outpatients, particularly with regard to antidepressants. Methods: In 2017, the MUlticenter treatment SUrvey for BIpolar disorder in Japanese psychiatric clinics (MUSUBI) study collected data on current mental status, medications, and other factors from 2774 outpatients with BD-I or BD-II. Results: There were significant differences in the rates of prescriptions for mood stabilizers, antipsychotics and antidepressants. Mood stabilizers and antipsychotics were prescribed at higher rates to patients with BD-I (mood stabilizers; BD-I 86.0%, BD-II 80.8%, p < 0.001; antipsychotics; BD-I 61.5%, BD-II 47.8%, p < 0.001), and antidepressants were prescribed at higher rates to patients with BD-II (BD-I 32.1%, BD-II 46.4%, p < 0.001). The most commonly prescribed antidepressants were escitalopram for patients with BD-I and duloxetine for patients with BD-II. Selective serotonin reuptake inhibitors (SSRIs) were the most common class of antidepressants prescribed to patients with BD. With regard to combination therapy, combinations containing antidepressants were often prescribed to patients with BD-II. Conclusion: There was a difference in the prescription of psychotropic agents between patients with BD-I and BD-II. The outpatient prescriptions for BD in Japan were mood stabilizers and antipsychotics, which generally followed the guidelines. There is insufficient evidence regarding the effects of the prescribed antidepressants and the risk of manic episodes, and further evidence needs to be collected.

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Relationship Between Employment Status and Unstable Periods in Outpatients with Bipolar Disorder: A Multicenter Treatment Survey for Bipolar Disorder in Psychiatric Outpatient Clinics (MUSUBI) Study

Ikenouchi A., Konno Y., Fujino Y., Adachi N., Kubota Y., Azekawa T., Ueda H., Edagawa K., Katsumoto E., Goto E., Hongo S., Kato M., Tsuboi T., Yasui-Furukori N., Nakagawa A., Kikuchi T., Watanabe K., Yoshimura R.

Neuropsychiatric Disease and Treatment 18   801 - 809 2022年

　概要を見る

Purpose: To clarify the relationship between the length of unstable periods and employment status of patients with bipolar disorder. Patients and Methods: Medical records of outpatients with bipolar disorder who visited 176 member clinics of the Japanese Association of Neuro-Psychiatric Clinics were investigated during September–October 2016, and details of their medical care and employment were surveyed using a questionnaire. The odds ratios (ORs) of length of unstable period and unemployment were analyzed with a logistic regression model. Results: The study included 816 patients, of whom 707 were employed full-time (continuous employment) and 70 were unemployed (loss of employment). Univariate analysis showed that ORs were statistically significant for patients who were unstable for “almost all” of the year (OR = 10.4 [4.48–24.28] p < 0.001), but not for “few” unstable periods (OR = 1.06 [0.56–1.98] p = 0.849) and for “significant” unstable periods (OR = 1.65 [0.73–3.74] p = 0.231) were not significantly different. Multivariate analysis showed that ORs were statistically “significant” for patients who were unstable for “almost all” (OR = 12.1 [4.37–33.3] p < 0.001), but not for “few” unstable periods (OR = 1.07 [0.55–2.07] p = 0.846) and for “significant” unstable periods (OR = 1.62 [0.66–3.98] p = 0.290) did not differ significantly. Conclusion: Patients with bipolar disorder with a long unstable period were associated with a higher risk of unemployment.

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Japanese project for telepsychiatry evaluation during COVID-19: Treatment comparison trial (J-PROTECT): Rationale, design, and methodology

Kishimoto T., Kinoshita S., Bun S., Sato Y., Kitazawa M., Kikuchi T., Sado M., Takamiya A., Mimura M., Nakamae T., Abe Y., Kanazawa T., Kawabata Y., Tomita H., Abe K., Hishimoto A., Asami T., Suda A., Watanabe Y., Amagai T., Sakuma K., Kida H., Funayama M., Kimura H., Sato A., Fujiwara S., Nagao K., Sugiyama N., Takamiya M., Kodama H., Azekawa T.

Contemporary Clinical Trials 111 2021年12月

ISSN  15517144

　概要を見る

Introduction: The COVID-19 pandemic has had a profound impact on the mental health of people around the world. Anxiety related to infection, stress and stigma caused by the forced changes in daily life have reportedly increased the incidence and symptoms of depression, anxiety disorder and obsessive-compulsive disorder. Under such circumstances, telepsychiatry is gaining importance and attracting a great deal of attention. However, few large pragmatic clinical trials on the use of telepsychiatry targeting multiple psychiatric disorders have been conducted to date. Methods: The targeted study cohort will consist of adults (>18 years) who meet the DSM-5 diagnostic criteria for either (1) depressive disorders, (2) anxiety disorders, or (3) obsessive-compulsive and related disorders. Patients will be assigned in a 1:1 ratio to either a “telepsychiatry group” (at least 50% of treatments to be conducted using telemedicine, with at least one face-to-face treatment [FTF] within six months) or an “FTF group” (all treatments to be conducted FTF, with no telemedicine). Both groups will receive the usual treatment covered by public medical insurance. The study will utilize a master protocol design in that there will be primary and secondary outcomes for the entire group regardless of diagnosis, as well as the outcomes for each individual disorder group. Discussion: This study will be a non-inferiority trial to test that the treatment effect of telepsychiatry is not inferior to that of FTF alone. This study will provide useful insights into the effect of the COVID-19 pandemic on the practice of psychiatry. Trial Registration: jRCT1030210037, Japan Registry of Clinical Trials (jRCT).

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Real-world clinical predictors of manic/hypomanic episodes among outpatients with bipolar disorder

Tokumitsu K., Norio Y.F., Adachi N., Kubota Y., Watanabe Y., Miki K., Azekawa T., Edagawa K., Katsumoto E., Hongo S., Goto E., Ueda H., Kato M., Nakagawa A., Kikuchi T., Tsuboi T., Watanabe K., Shimoda K., Yoshimura R.

Plos One 16 （ 12 December ）  2021年12月

　概要を見る

Background Bipolar disorder is a mental illness in which manic and depressive states are repeated, causing psychosocial dysfunction. Manic/hypomanic episodes cause problems with interpersonal, social and financial activities, but there is limited evidence regarding the predictors of manic/hypomanic episodes in real-world clinical practice. Methods The multicenter treatment survey on bipolar disorder (MUSUBI) in Japanese psychiatric clinics was administered in an observational study that was conducted to accumulate evidence regarding bipolar disorder in real-world clinical practice. Psychiatrists were asked to complete a questionnaire about patients with bipolar disorder who visited 176 member clinics of the Japanese Association of Neuro-Psychiatric Clinics by conducting a retrospective medical record survey. Our study extracted baseline patient characteristics from September to October 2016, including comorbidities, mental status, duration of treatment, Global Assessment of Functioning (GAF) score, and pharmacological treatment details. We investigated the presence or absence of manic/hypomanic episodes over the course of one year from baseline to September-October 2017. Results In total, 2231 participants were included in our study, 29.1% of whom had manic/hypomanic episodes over the course of one year from baseline. Binomial logistic regression analysis revealed that the presence of manic/hypomanic episodes was correlated with lower baseline GAF scores, rapid cycling, personality disorder, bipolar I disorder, and a mood state with manic or mixed features. Substance abuse was also a risk factor for manic episodes. There was no significant association between a baseline antidepressant prescription and manic/hypomanic episodes. Conclusions In Japan, 29.1% of outpatients with bipolar disorder had manic/hypomanic episodes over the course of one year. Our study suggested that a low GAF score, rapid cycling, personality disorder, bipolar I disorder, substance abuse, and baseline mood state could be predictors of manic/hypomanic episodes. Based on our findings, an antidepressant prescription is not a predictor of manic/hypomanic episodes.

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Association of electroconvulsive therapy-induced structural plasticity with clinical remission

Takamiya A., Kishimoto T., Hirano J., Kikuchi T., Yamagata B., Mimura M.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry）  110 2021年08月

ISSN  02785846

　概要を見る

Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe depression. Recent neuroimaging studies have consistently reported that ECT induces volume increases in widely distributed brain regions. However, it still remains unclear about ECT-induced volume changes associated with clinical improvement. Methods: Longitudinal assessments of structural magnetic resonance imaging were conducted in 48 participants. Twenty-seven elderly melancholic depressed individuals (mean 67.5 ± 8.1 years old; 19 female) were scanned before (TP1) and after (TP2) ECT. Twenty-one healthy controls were also scanned twice. Whole-brain gray matter volume (GMV) was analyzed via group (remitters, nonremitters, and controls) by time (TP1 and TP2) analysis of covariance to identify ECT-related GMV changes and GMV changes specific to remitters. Within-subject and between-subjects correlation analyses were conducted to investigate the associations between clinical improvement and GMV changes. Depressive symptoms were evaluated using the 17-item Hamilton Depression Rating Scale (HAM-D), and remission was defined as HAM-D total score ≤ 7. Results: Bilateral ECT increased GMV in multiple brain regions bilaterally regardless of clinical improvement. Remitters showed a larger GMV increase in the right-lateralized frontolimbic brain regions compared to nonremitters and healthy controls. GMV changes in the right hippocampus/amygdala and right middle frontal gyrus showed correlations with clinical improvement in within−/between-subjects correlation analyses. Conclusions: ECT-induced GMV increase in the right frontolimbic regions was associated with clinical remission.

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Antipsychotic Polypharmacy Is Associated with Adverse Drug Events in Psychiatric Inpatients: The Japan Adverse Drug Events Study

Ayani N., Morimoto T., Sakuma M., Kikuchi T., Watanabe K., Narumoto J.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology）  41 （ 4 ） 397 - 402 2021年07月

ISSN  02710749

　概要を見る

Background Antipsychotic (AP) polypharmacy (APP), the coprescription of more than 1 AP, is frequently practiced in psychiatric inpatients and is considered to be a risk factor for adverse drug events (ADEs). However, the association between APP and ADEs among psychiatric inpatients has not been well investigated. Methods The Japan Adverse Drug Events (JADE) study was a series of cohort studies conducted in several clinical settings. In particular, the JADE study for psychiatric inpatients was a retrospective cohort study of 448 psychiatric inpatients with a cumulative 22,733 patient-days. We investigated the relationship between APP, defined as a concurrent prescription of 2 or more APs and ADEs. We also assessed the relationship between potential risk factors for ADEs due to APs. Results Among the 448 patients included in this study, 106 patients (24%) had APP and the remaining 342 patients were prescribed 1 AP or none. Risperidone was the most frequent drug (25%, 109/442 AP prescriptions) used, and levomepromazine was most frequently prescribed as a concurrent medication with other APs (91%, 29/32). The median number of ADEs among the patients with APP was significantly higher than in those without APP (P = 0.001). Antipsychotic polypharmacy was a risk factor for the occurrence of first (adjusted hazard ratio, 1.54; 95% confidence interval, 1.15-2.04) and second (adjusted hazard ratio, 1.99; 95% confidence interval, 1.40-2.79) ADEs. Conclusions Antipsychotic polypharmacy was a risk factor for the occurrence of single and multiple ADEs. Antipsychotic polypharmacy should be conservatively and minimally practiced.

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Does cognitive behavioral therapy for anxiety disorders assist the discontinuation of benzodiazepines among patients with anxiety disorders? A systematic review and meta-analysis

Takeshima M., Otsubo T., Funada D., Murakami M., Usami T., Maeda Y., Yamamoto T., Matsumoto T., Shimane T., Aoki Y., Otowa T., Tani M., Yamanaka G., Sakai Y., Murao T., Inada K., Yamada H., Kikuchi T., Sasaki T., Watanabe N., Mishima K., Takaesu Y.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences）  75 （ 4 ） 119 - 127 2021年04月

ISSN  13231316

　概要を見る

Long-term use of benzodiazepines (BZD) is not recommended for the treatment of anxiety disorders. Cognitive behavioral therapy (CBT) is an effective treatment option for discontinuation of BZD in patients with anxiety disorders. This systematic review and meta-analysis sought to clarify whether CBT is effective for discontinuing BZD anxiolytics in patients with anxiety disorders. This study was preregistered with PROSPERO (registration number: CRD42019125263). A literature search of major electronic databases was conducted in December 2018. Three randomized controlled trials were included in this review, and meta-analyses were performed. The proportion of discontinuing BZD anxiolytics was significantly higher in the CBT plus gradual tapering group than in the gradual tapering alone group, both in the short term (3 months after allocation; number needed to treat: 3.2, 95% confidence interval [CI]: 2.1 to 7.1; risk ratio: 1.96, 95%CI: 1.29 to 2.98, P = 0.002, three studies) and long term (6 to 12 months after allocation; number needed to treat: 2.8, 95%CI: 1.9 to 5.3; risk ratio: 2.16, 95%CI: 1.41 to 3.32, P = 0.0004, three studies). CBT may be effective for discontinuing BZD anxiolytics, both in the short term and in the long term after the allocation. Further studies with larger sample sizes are necessary to draw definitive conclusions regarding the efficacy and safety of CBT for discontinuing BZD anxiolytics in patients with anxiety disorders.

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Pharmacological Treatment of Schizophrenia: Japanese Expert Consensus

Sakurai H., Yasui-Furukori N., Suzuki T., Uchida H., Baba H., Watanabe K., Inada K., Kikuchi Y.S., Kikuchi T., Katsuki A., Kishida I., Kato M.

Pharmacopsychiatry （Pharmacopsychiatry）  54 （ 2 ） 60 - 67 2021年03月

ISSN  01763679

　概要を見る

Introduction Conventional treatment guidelines of schizophrenia do not necessarily provide solutions on clinically important issues. Methods A total of 141 certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology evaluated treatment options regarding 19 clinically relevant situations in the treatment of schizophrenia with a 9-point scale (1=disagree and 9=agree). Results First-line antipsychotics varied depending on predominant symptoms: risperidone (mean±standard deviation score, 7.9±1.4), olanzapine (7.5±1.6), and aripiprazole (6.9±1.9) were more likely selected for positive symptoms; aripiprazole (7.6±1.6) for negative symptoms; aripiprazole (7.3±1.9), olanzapine (7.2±1.9), and quetiapine (6.9±1.9) for depression and anxiety; and olanzapine (7.9±1.5) and risperidone (7.5±1.5) for excitement and aggression. While only aripiprazole was categorized as a first-line treatment for relapse prevention (7.6±1.0) in patients without noticeable symptoms, aripiprazole (8.0±1.6) and brexpiprazole (6.9±2.3) were categorized as such for social integration. First-line treatments in patients who are vulnerable to extrapyramidal symptoms include quetiapine (7.5±2.0) and aripiprazole (6.9±2.1). Discussion These clinical recommendations represent the expert consensus on the use of a particular antipsychotic medication for a particular situation, filling a current gap in the literature.

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Estimated model of psychotropic polypharmacy for bipolar disorder: Analysis using patients' and practitioners' parameters in the MUSUBI study

Adachi N., Azekawa T., Edagawa K., Goto E., Hongo S., Kato M., Katsumoto E., Kikuchi T., Kubota Y., Miki K., Nakagawa A., Tsuboi T., Ueda H., Watanabe K., Watanabe Y., Yasui-Furukori N., Yoshimura R.

Human Psychopharmacology （Human Psychopharmacology）  36 （ 2 ）  2021年03月

ISSN  08856222

　概要を見る

Objective: This study aims to clarify the relevant factors influencing practitioners' methods of prescribing medications for bipolar disorder, in a nation-wide survey in Japan. Methods: The clinical records of 3130 outpatients with bipolar disorder were consecutively reviewed from 176 psychiatric outpatient clinics. Fifteen parameters, that is, five patients' including five general characteristics (sex, age, education, occupation, and social adjustment), five patients' aspects of mental functioning (onset age, comorbid mental illness, rapid-cycling, psychopathologic severity, and followed-up years), and five practitioners' characteristics (sex, age, specialist experience, clinic standing years, and location), were evaluated. The number of psychotropic drugs (mood stabilizers, antidepressants, antipsychotic drugs, anxiolytics, and hypnotics) was used as an index of pharmacotherapy. Converted data from each practitioner-unit were analyzed. Results: Seven factors (patient's social adjustment, patient's psychopathology, patient's comorbid mental disorders, patient's followed-up years, doctor's age, clinic running years, and patient's education years) were correlated to the number of psychotropic drugs. Multiple regression analysis showed that the severity of illness (poor social adjustment, and comorbid mental illness) and an intractable disease course (long followed-up years), were significantly associated with the number of psychotropic drugs. Conclusion: Our findings indicated that patient-related conditions affected psychotropic polypharmacy more strongly than did practitioner-related conditions.

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Relationship between mood episode and employment status of outpatients with bipolar disorder: Retrospective cohort study from the multicenter treatment survey for bipolar disorder in psychiatric clinics (musubi) project

Konno Y., Fujino Y., Ikenouchi A., Adachi N., Kubota Y., Azekawa T., Ueda H., Edagawa K., Katsumoto E., Goto E., Hongo S., Kato M., Tsuboi T., Yasui-Furukori N., Nakagawa A., Kikuchi T., Watanabe K., Yoshimura R.

Neuropsychiatric Disease and Treatment （Neuropsychiatric Disease and Treatment）  17   2867 - 2876 2021年

ISSN  11766328

　概要を見る

Objective: The objective of this study was to clarify the relationship between mood episode and employment in patients with bipolar disorder to help improve their employment status. Methods: All medical records of patients with bipolar disorder who visited 176 member clinics of the Japanese Association of Neuro-Psychiatric Clinics in September-October 2016 were investigated in September-October 2017. Details of the medical care received were investigated using a survey sheet, which included employment status. Odds ratios of mood episodes for employment status were analyzed using a logistic regression model. Results: Among patients aged 60 years or less, 2292 described their occupation. On univariate analysis, odds ratios were statistically significant for depressive episode (OR=2.68 [1.50-4.78] p=0.001) and manic episode (OR=2.64 [1.07-6.47] p=0.034), whereas no significant difference was noted for mixed episode (OR=1.72 [0.69-4.33] p=0.246). On multivariate analysis, odds ratios were statistically significant for depressive episode (OR=2.16 [1.13-4.13], p=0.020) and manic episode (OR=3.55 [1.36-9.25], p=0.010), whereas no significant difference was noted for mixed episode (OR=1.83 [0.65-5.14] p=0.254). Conclusion: Employment status among these patients with bipolar disorder receiving outpatient treatment was 43.5%. Compared to remission episodes, manic and depressive episodes were associated with a higher risk of unemployment.

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How significant is the assessment of the DSM-5 'anxious distress' specifier in patients with major depressive disorder without comorbid anxiety disorders in the continuation/maintenance phase?

Otsubo T., Hokama C., Sano N., Watanabe Y., Kikuchi T., Tanaka K.

International Journal of Psychiatry in Clinical Practice （International Journal of Psychiatry in Clinical Practice）  25 （ 4 ） 385 - 392 2021年

ISSN  13651501

　概要を見る

Objective: Anxious distress (ANXD), which is common in major depressive disorder (MDD), is associated with poor outcomes. We investigated clinical characteristics of MDD patients with the DSM-5 ANXD specifier and only mild residual symptoms without comorbid anxiety disorders in the continuation/maintenance phase. Methods: We recruited 110 outpatients with MDD without comorbid anxiety disorders. They were interviewed; the presence of the DSM-5 ANXD specifier was assessed. They completed the Quick Inventory of Depressive Symptomatology (QIDS), the Eysenck Personality Questionnaire (S-EPQ), the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Autoquestionnaire (TEMPS-A). Results: The mean QIDS total score was 9.7 ± 5.5. The DSM-5 ANXD specifier was identified in 73 patients (66.4%). A univariate analysis indicated ANXD was significantly associated with younger age; unmarried status; living alone; higher QIDS total score; higher S-EPQ neuroticism score; and higher TEMPS-A cyclothymic, depressive and irritable scores. After covariate adjustment, a multivariable linear regression analysis revealed a significant association between the QIDS total score and ANXD (three different models). Conclusion: The DSM-5 ANXD was also common among MDD patients without comorbid anxiety disorders in the continuation/maintenance phase; it was significantly associated with greater depression severity and might be related to temperament associated with bipolar disorder.Key points DSM-5 anxious distress is common among MDD patients without comorbid anxiety disorders in the continuation/maintenance phase and correlated with some of their socio-demographic and clinical characteristics. • The presence of DSM-5 anxious distress was significantly associated with greater severity of depression and might be related to temperament associated with bipolar disorder. • The evaluation of the DSM-5 anxiety distress was revealed to have some significance not only in the acute phase but also in the continuation/maintenance phase of MDD.

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Cost-effectiveness analyses of augmented cognitive behavioral therapy for pharmacotherapy-resistant depression at secondary mental health care settings

Sado M., Koreki A., Ninomiya A., Kurata C., Mitsuda D., Sato Y., Kikuchi T., Fujisawa D., Ono Y., Mimura M., Nakagawa A.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences）  75 （ 11 ） 341 - 350 2021年

ISSN  13231316

　概要を見る

Aim: Pharmacotherapy is the primary treatment strategy in major depression. However, two-thirds of patients remain depressed after the initial antidepressant treatment. Augmented cognitive behavioral therapy (CBT) for pharmacotherapy-resistant depression in primary mental health care settings proved effective and cost-effective. Although we reported the clinical effectiveness of augmented CBT in secondary mental health care, its cost-effectiveness has not been evaluated. Therefore, we aimed to compare the cost-effectiveness of augmented CBT adjunctive to treatment as usual (TAU) and TAU alone for pharmacotherapy-resistant depression at secondary mental health care settings. Methods: We performed a cost-effectiveness analysis at 64 weeks, alongside a randomized controlled trial involving 80 patients who sought depression treatment at a university hospital and psychiatric hospital (one each). The cost-effectiveness was assessed by the incremental cost-effectiveness ratio (ICER) that compared the difference in costs and quality-adjusted life years, and other clinical scales, between the groups. Results: The ICERs were JPY −15 278 322 and 2 026 865 for pharmacotherapy-resistant depression for all samples and those with moderate/severe symptoms at baseline, respectively. The acceptability curve demonstrates a 0.221 and 0.701 probability of the augmented CBT being cost-effective for all samples and moderate/severe depression, respectively, at the threshold of JPY 4.57 million (GBP 30 000). The sensitivity analysis supported the robustness of our results restricting for moderate/severe depression. Conclusion: Augmented CBT for pharmacotherapy-resistant depression is not cost-effective for all samples including mild depression. In contrast, it appeared to be cost-effective for the patients currently manifesting moderate/severe symptoms under secondary mental health care.

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Clinical features related to rapid cycling and one-year euthymia in bipolar disorder patients: A multicenter treatment survey for bipolar disorder in psychiatric clinics (MUSUBI)

Kato M., Adachi N., Kubota Y., Azekawa T., Ueda H., Edagawa K., Katsumoto E., Goto E., Hongo S., Tsuboi T., Yasui-Furukori N., Yoshimura R., Nakagawa A., Kikuchi T., Kinoshita T., Watanabe Y., Miki K., Watanabe K.

Journal of Psychiatric Research （Journal of Psychiatric Research）  131   228 - 234 2020年12月

ISSN  00223956

　概要を見る

Objective: Rapid cycling (RC) presents a risk of greater severity in bipolar disorder (BD), whereas patients with one-year euthymia (OYE) have better prognosis. The purpose of this study was to identify the clinical background and prescription characteristics of patients in the two opposing states of current RC and OYE from a large sample (N = 2609) in a multicenter treatment survey on BD in psychiatric clinics (MUSUBI). Methods: MUSIBI was a cross-sectional study wherein questionnaires, based on a retrospective medical record survey of consecutive cases of BD, were distributed to 176 outpatient clinics. The questionnaire collected information on patient background, current episode, and clinical and prescription characteristics. OYE was defined as the presence of a euthymic state for at least 12 months. Results: In this study, current RC (9.7% frequency) was significantly higher in females, had a younger age of onset, functional impairments, and a higher rate of neurodevelopmental disorder and physical comorbidity compared to non-RC patients. OYE (19.4% frequency) was associated with a lower proportion of females, older age, higher occupational status, and lower rate of suicide ideation, psychotic symptoms, personality disorder, and alcohol or substance abuse. Mood stabilizers were prescribed in ≥80% of cases, while antipsychotics were prescribed in half of the cases (more in RC and less in OYE). Antidepressant prescription rates were lower in OYE than in RC. Conclusions: RC and OYE generally show opposing characteristics, but the details of the opposite parameters are distinctive. Clinicians can help predict the progression of BD by understanding the clinical background and characteristics of these opposing clinical features.

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Real-world clinical features of and antidepressant prescribing patterns for outpatients with bipolar disorder

Tokumitsu K., Yasui-Furukori N., Adachi N., Kubota Y., Watanabe Y., Miki K., Azekawa T., Edagawa K., Katsumoto E., Hongo S., Goto E., Ueda H., Kato M., Yoshimura R., Nakagawa A., Kikuchi T., Tsuboi T., Shimoda K., Watanabe K.

BMC Psychiatry （BMC Psychiatry）  20 （ 1 ）  2020年12月

　概要を見る

Background: Several evidence-based practice guidelines have been developed to better treat bipolar disorder. However, the articles cited in these guidelines were not sufficiently based on real-world clinical practice. Methods: The MUlticenter treatment SUrvey on BIpolar disorder in Japanese psychiatric clinics (MUSUBI) is a study conducted to accumulate evidence on the real-world practical treatment of bipolar disorder. Psychiatrists were asked to complete a questionnaire about patients with bipolar disorder by performing a retrospective medical record survey. The questionnaire included patient characteristics (age, gender, height, weight, academic background, and occupational status), comorbidities, mental status, treatment period, Global Assessment of Functioning (GAF) score, and details of pharmacological treatment. Results: Data on 2705 patients were included in this study. The proportion of patients receiving antidepressant prescriptions was 40.9%. The most commonly used antidepressant was duloxetine, and the most frequently used antidepressant class was selective serotonin reuptake inhibitors (SSRIs). Binomial logistic regression analysis and bivariate analysis revealed that the usage of antidepressants was correlated with low prescription rates for mood stabilizers, high prescription rates for anxiolytics and hypnotics, and low GAF scores. In addition, patients in a depressive state had a significantly higher rate of antidepressant prescriptions than patients with other mental states. Conclusions: Approximately 40% of patients in Japan with a diagnosis of bipolar disorder have received antidepressants. Antidepressants were most often prescribed in combination with mood stabilizers, antipsychotics or both. Patients who were prescribed antidepressants received fewer mood stabilizers, more anxiolytics, and more hypnotics than those who did not receive antidepressant prescriptions.

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Pharmacological management of bipolar disorder: Japanese expert consensus

Sakurai H., Kato M., Yasui-Furukori N., Suzuki T., Baba H., Watanabe K., Inada K., Kishida I., Sugawara Kikuchi Y., Kikuchi T., Katsuki A., Uchida H.

Bipolar Disorders （Bipolar Disorders）  22 （ 8 ） 822 - 830 2020年12月

ISSN  13985647

　概要を見る

Objectives: The aim of this study was to develop a consensus guideline by certified experts of the Japanese Society of Clinical Neuropsychopharmacology on the psychopharmacological treatment for bipolar disorders I and II (BP-I and BP-II), in order to fill the gap in the literature and provide more concrete guidance for challenging and controversial real-world situations. Methods: Experts were asked to assess treatment options regarding 19 clinical situations of bipolar disorder with a nine-point Likert scale (one = “disagree” and nine = “agree”). According to the responses from 119 experts, the options were categorized into the first-, second-, and third-line treatments. Results: For the treatment of BP-I, lithium monotherapy was categorized as a first-line treatment for manic episodes (mean ± standard deviation score, 7.0 ± 2.2), depressive episodes (7.1 ± 2.0), and the maintenance phase (7.8 ± 1.8). Combination therapy of lithium and an atypical antipsychotic was endorsed for manic episodes (7.7 ± 1.7), depressive episodes with (7.1 ± 2.0) and without mixed features (6.9 ± 2.2), and the maintenance phase (6.9 ± 2.1). Similarly, in BP-II, lithium monotherapy was categorized as a first-line treatment for hypomanic episodes (7.3 ± 2.2), depressive episodes (7.0 ± 2.2), and the maintenance phase (7.3 ± 2.3), while combination therapy of lithium and an atypical antipsychotic was recommended for hypomanic episodes (6.9 ± 2.4).No antipsychotic monotherapy or antidepressant treatment was categorized as a first-line treatment for any type of episode. Conclusions: These recommendations reflect the current evidence and represent the experts' consensus on using lithium for the treatment of bipolar disorder. Clinicians should consider the effectiveness and adverse effects of antipsychotic and antidepressant medications for the treatment of bipolar disorder.

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Factors Associated with Doses of Mood Stabilizers in Real-world Outpatients with Bipolar Disorder

Yasui-Furukori N., Adachi N., Kubota Y., Azekawa T., Goto E., Edagawa K., Katsumoto E., Hongo S., Ueda H., Miki K., Kato M., Yoshimura R., Nakagawa A., Kikuchi T., Tsuboi T., Watanabe K., Shimoda K.

Clinical Psychopharmacology and Neuroscience （Clinical Psychopharmacology and Neuroscience）  18 （ 4 ）  2020年11月

ISSN  17381088

　概要を見る

Objective: Several evidence-based practice guidelines have been developed to better treat bipolar disorder. However, the articles cited in these guidelines were based on clinical or basic studies with specific conditional settings and were not sufficiently based on real-world clinical practice. In particular, there was little information on the doses of mood stabilizers. Methods: The MUlticenter treatment SUrvey on BIpolar disorder in Japanese psychiatric clinics (MUSUBI) is a study conducted to accumulate evidence on the real-world practical treatment of bipolar disorder. The questionnaire included patient characteristics such as comorbidities, mental status, treatment period, Global Assessment of Functioning (GAF) score, and details of pharmacological treatment. Results: Most patients received mood stabilizers such as lithium (n = 1,317), valproic acid (n = 808), carbamazepine (n = 136), and lamotrigine (n = 665). The dose of lithium was correlated with age, body weight, number of episodes, depression and GAF. The dose of valproic acid was correlated with body weight, number of episodes, presence of a rapid cycle and GAF. The dose of carbamazepine was correlated with age, mania, and the presence of a rapid cycle. The dose of lamotrigine was correlated with the number of episodes, depression, mania, psychotic features, and the presence of a rapid cycle. Doses of coadministered mood stabilizers were significantly correlated, except for the combination of valproic acid and lamotrigine. Conclusion: The dose of mood stabilizers was selectively administered based on several factors, such as age, body composition, current mood status and functioning. Further prospective studies are required to confirm these findings.

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The project for objective measures using computational psychiatry technology (PROMPT): Rationale, design, and methodology

Kishimoto T., Takamiya A., Liang K.c., Funaki K., Fujita T., Kitazawa M., Yoshimura M., Tazawa Y., Horigome T., Eguchi Y., Kikuchi T., Tomita M., Bun S., Murakami J., Sumali B., Warnita T., Kishi A., Yotsui M., Toyoshiba H., Mitsukura Y., Shinoda K., Sakakibara Y., Mimura M.

Contemporary Clinical Trials Communications （Contemporary Clinical Trials Communications）  19 2020年09月

ISSN  24518654

　概要を見る

Introduction: Depressive and neurocognitive disorders are debilitating conditions that account for the leading causes of years lived with disability worldwide. However, there are no biomarkers that are objective or easy-to-obtain in daily clinical practice, which leads to difficulties in assessing treatment response and developing new drugs. New technology allows quantification of features that clinicians perceive as reflective of disorder severity, such as facial expressions, phonic/speech information, body motion, daily activity, and sleep. Methods: Major depressive disorder, bipolar disorder, and major and minor neurocognitive disorders as well as healthy controls are recruited for the study. A psychiatrist/psychologist conducts conversational 10-min interviews with participants ≤10 times within up to five years of follow-up. Interviews are recorded using RGB and infrared cameras, and an array microphone. As an option, participants are asked to wear wrist-band type devices during the observational period. Various software is used to process the raw video, voice, infrared, and wearable device data. A machine learning approach is used to predict the presence of symptoms, severity, and the improvement/deterioration of symptoms. Discussion: The overall goal of this proposed study, the Project for Objective Measures Using Computational Psychiatry Technology (PROMPT), is to develop objective, noninvasive, and easy-to-use biomarkers for assessing the severity of depressive and neurocognitive disorders in the hopes of guiding decision-making in clinical settings as well as reducing the risk of clinical trial failure. Challenges may include the large variability of samples, which makes it difficult to extract the features that commonly reflect disorder severity. Trial Registration: UMIN000021396, University Hospital Medical Information Network (UMIN).

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Pharmacological management of depression: Japanese expert consensus

Sakurai H., Uchida H., Kato M., Suzuki T., Baba H., Watanabe K., Inada K., Kikuchi T., Katsuki A., Kishida I., Sugawara Kikuchi Y., Yasui-Furukori N.

Journal of Affective Disorders （Journal of Affective Disorders）  266   626 - 632 2020年04月

ISSN  01650327

　概要を見る

Background: Clinically relevant issues in the real-world treatment of depression have not always been captured by conventional treatment guidelines. Methods: Certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology were asked to evaluate treatment options regarding 23 clinical situations in the treatment of depression using a 9-point Likert scale (1=“disagree” and 9=“agree”). According to the responses of 114 experts, the options were categorized into first-, second-, and third-line treatments. Results: First-line antidepressants varied depending on predominant symptoms: escitalopram (mean ± standard deviation score, 7.8 ± 1.7) and sertraline (7.3 ± 1.7) were likely selected for anxiety; duloxetine (7.6 ± 1.9) and venlafaxine (7.2 ± 2.1) for loss of interest; mirtazapine for insomnia (8.2 ± 1.6), loss of appetite (7.9 ± 1.9), agitation and severe irritation (7.4 ± 2.0), and suicidal ideation (7.5 ± 1.9). While first-line treatment was switched to either an SNRI (7.7 ± 1.9) or mirtazapine (7.4 ± 2.0) in the case of non-response to an SSRI, switching to mirtazapine (7.1 ± 2.2) was recommended in the case of non-response to an SNRI, and vice versa (switching to an SNRI (7.0 ± 2.0) in the case of non-response to mirtazapine). Augmentation with aripiprazole was considered the first-line treatment for partial response to an SSRI (7.1 ± 2.3) or SNRI (7.0 ± 2.5). Limitations: The evidence level of expert consensus is considered low. All included experts were Japanese. Conclusions: Recommendations made by experts in the field are useful and can supplement guidelines and informed decision making in real-world clinical practice. We suggest that pharmacological strategies for depression be flexible and that each patient's situational needs as well as the pharmacotherapeutic profile of medications be considered.

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Neural and clinical changes of cognitive behavioural therapy versus talking control in patients with major depression: A study protocol for a randomised clinical trial

Katayama N., Nakagawa A., Abe T., Kurata C., Sasaki Y., Mitsuda D., Nakao S., Mizuno S., Ozawa M., Nakagawa Y., Ishikawa N., Umeda S., Terasawa Y., Tabuchi H., Kikuchi T., Mimura M.

BMJ Open （BMJ Open）  10 （ 2 ）  2020年02月

　概要を見る

While major depression causes substantial distress and impairment for affected individuals and society, the effectiveness of cognitive behavioural therapy (CBT) in treating the condition has been established. However, the therapeutic mechanism underlying the efficacy of CBT remains unknown. This study aimed to describe a protocol for a randomised controlled trial that will measure the CBT-induced clinical and neural changes in patients with non-psychotic major depression. Methods and analysis The current study is a 16-week assessor-blinded, randomised, parallel-group trial with a 12-month follow-up as part of usual depression care at an outpatient clinic. Patients aged 20-69 years with major depressive disorder will be randomly assigned to receive either CBT in addition to their usual treatment or talking control in addition to their usual treatment for 16 weeks. The primary outcome is the functional changes in the brain areas that have been associated with future-oriented thinking at 16 weeks; secondary outcomes include changes in functional brain connectivity, severity and changes in the scores of objective and subjective clinical depression symptoms, proportion of responders and remitters and quality of life. The intention-to-treat analysis will be used. Ethics and dissemination All protocols and the informed consent form are compliant with the Ethics Guideline for Clinical Research (Japanese Ministry of Health, Labour and Welfare). Ethical Review Committees at the Keio University School of Medicine have approved the study protocol (version 3, 11 September 2017). We will disseminate research findings to scientific and general audiences through national and international conference presentations as well as lay summaries to the general public, including mental health consumer and publications in international peer-reviewed psychiatry and brain imaging journals. Trial registration number UMIN Clinical Trials Registry (UMIN000018155); Pre-results.

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Neuronal network mechanisms associated with depressive symptom improvement following electroconvulsive therapy

Takamiya A., Kishimoto T., Hirano J., Nishikata S., Sawada K., Kurokawa S., Yamagata B., Kikuchi T., Mimura M.

Psychological Medicine （Psychological Medicine）  51 （ 16 ） 2856 - 2863 2020年

ISSN  00332917

　概要を見る

BackgroundElectroconvulsive therapy (ECT) is the most effective antidepressant treatment for severe depression. Although recent structural magnetic resonance imaging (MRI) studies have consistently reported ECT-induced hippocampal volume increases, most studies did not find the association of the hippocampal volume changes with clinical improvement. To understand the underlying mechanisms of ECT action, we aimed to identify the longitudinal effects of ECT on hippocampal functional connectivity (FC) and their associations with clinical improvement.MethodsResting-state functional MRI was acquired before and after bilateral ECT in 27 depressed individuals. A priori hippocampal seed-based FC analysis and a data-driven multivoxel pattern analysis (MVPA) were conducted to investigate FC changes associated with clinical improvement. The statistical threshold was set at cluster-level false discovery rate-corrected p < 0.05.ResultsDepressive symptom improvement after ECT was positively associated with the change in the right hippocampus-ventromedial prefrontal cortex FC, and negatively associated with the right hippocampus-superior frontal gyrus FC. MVPA confirmed the results of hippocampal seed-based analyses and identified the following additional clusters associated with clinical improvement following ECT: the thalamus, the sensorimotor cortex, and the precuneus.ConclusionsECT-induced change in the right frontotemporal connectivity and thalamocortical connectivity, and changes in the nodes of the default mode network were associated with clinical improvement. Modulation of these networks may explain the underlying mechanisms by which ECT exert its potent and rapid antidepressant effect.

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Factors associated with non-remission in bipolar disorder: The multicenter treatment survey for bipolar disorder in psychiatric outpatient clinics (musubi)

Tsuboi T., Suzuki T., Azekawa T., Adachi N., Ueda H., Edagawa K., Katsumoto E., Kubota Y., Goto E., Hongo S., Watanabe Y., Kato M., Yasui-Furukori N., Yoshimura R., Nakagawa A., Kikuchi T., Watanabe K.

Neuropsychiatric Disease and Treatment （Neuropsychiatric Disease and Treatment）  16   881 - 890 2020年

ISSN  11766328

　概要を見る

Purpose: The aim of this study was to identify factors associated with non-remission in bipolar disorder. Patients and Methods: The multicenter treatment survey for bipolar disorder in psychiatric outpatient clinics (MUSUBI) study used a questionnaire administered at 176 clinics throughout Japan from September to October 2016. Clinic psychiatrists performed a retrospective medical record survey of consecutive cases with bipolar disorder. Patients were considered to be in remission if they met all of the following criteria: they were not in a mixed state, their manic or depressive symptoms were either borderline or nonexistent (corresponding to 2 or 1 points on the Clinical Global Impressions Scale, Bipolar Version), and their psychiatrists clinically considered them to be in remission. Enrolled patients were classified into remitters group and non-remitters group and demographic and clinical characteristics were contrasted between the groups. Non-remitters were compared with remitters, using a series of logistic regression analyses. Results: A total of 3130 patients (1420 men; mean age: 50.3 years) were included in this study; 1307 patients (41.8%) were in remission. Of the remaining 1823 patients, 1260 (40.3%) had mild to severe depression, 261 (8.3%) suffered from manic or hypomanic episodes, and 302 (9.6%) were in a mixed state. Logistic regression analyses found the following eight factors to be significantly correlated with non-remission in patients with bipolar disorder: female gender, younger age, unemployed status, rapid cycling pattern, comorbid alcohol/substance abuse, poorer social function, lithium non-use, and antidepressant use. Conclusion: The MUSUBI study, the largest nationwide investigation on bipolar disorder, identified eight clinically relevant factors associated with non-remission in bipolar patients. They have important clinical implications; further prospective studies are necessary to replicate these findings and to guide better managements for those in serious needs.

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Brexpiprazole for the treatment of schizophrenia in adults: An overview of its clinical efficacy and safety and a psychiatrist’s perspective

Watanabe Y., Yamada S., Otsubo T., Kikuchi T.

Drug Design, Development and Therapy （Drug Design, Development and Therapy）  14   5559 - 5574 2020年

　概要を見る

While the prognosis of patients with schizophrenia has dramatically improved after the advent of chlorpromazine, the antipsychotics currently available are so numerous that it has become a challenge for psychiatrists to choose from among these drugs for each patient presenting for care. In addition, while numerous studies show that an effective antipsychotic should be continued indefinitely to prevent relapses or worsening, many patients appear to have difficulty remaining on any drug thus initiated. Brexpiprazole, a dopamine D 2 receptor partial agonist, appears to provide a unique profile that has much to offer in this light. Specifically, this novel drug is potentially better suited for long-term use, with decreased risk of extrapyramidal side effects, hyperprolactinemia, weight gain, psychosis, insomnia, akathisia, nausea/vomiting or restlessness, thus potentially facilitating patients’ reintegration into society. Indeed, brexpiprazole has been shown in randomized, double-blind, placebo-controlled trials to have proven efficacy not only in improving the symptoms of schizophrenia but in preventing relapses. It is also suggested in both short- and long-term studies that brexpiprazole offers a favorable safety and tolerability profile. This review also includes a proposed treatment algorithm incorporating brexpiprazole, based on the clinical trial results available, as well as on the authors’ clinical experience, where brexpiprazole may be best used as a drug of first choice for the treatment of schizophrenia. Thus, overall, brexpiprazole appears to play a more significant role in the treatment of schizophrenia than other antipsychotics.

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Effectiveness and safety of long-term benzodiazepine use in anxiety disorders: A systematic review and meta-analysis

Shinfuku M., Kishimoto T., Uchida H., Suzuki T., Mimura M., Kikuchi T.

International Clinical Psychopharmacology （International Clinical Psychopharmacology）  34 （ 5 ） 211 - 221 2019年09月

ISSN  02681315

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Long-term benzodiazepines (BZDs) use is not endorsed in the treatment guidelines for anxiety disorders, but is prevalent in the real-world clinical settings. A systematic literature review was performed by using PubMed (last search: May 2019) to identify randomized controlled trials (RCTs) or maintenance studies following RCT that examined the effectiveness of BZDs in patients with anxiety disorders for a duration of 13 weeks or more. Meta-analyses were then conducted regarding changes in the Hamilton Anxiety Rating Scale (HAM-A) scores from baseline through endpoint, all-cause discontinuation, side effects, and the numbers of panic attacks at endpoint. Eight studies were identified (N = 1228). There were no significant differences in all outcomes between BZDs and antidepressants after the initial 8-week treatment. While no significant difference was noted in the HAM-A score changes between BZDs and placebo, BZDs resulted in a lower discontinuation rate and more frequent constipation and dry mouth than placebo. Our study indicates that for those who respond to an initial 8-week treatment, continuing BZDs is equivalent to antidepressants in efficacy and safety. However, the limited number of studies warranted further investigations of the long-term effectiveness and safety of BZDs.

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Frontopolar cortex activation associated with pessimistic future-thinking in adults with major depressive disorder

Katayama N., Nakagawa A., Umeda S., Terasawa Y., Kurata C., Tabuchi H., Kikuchi T., Mimura M.

NeuroImage: Clinical （NeuroImage: Clinical）  23 2019年

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Background: Pessimistic thinking about the future is one of the cardinal symptoms of major depressive disorder (MDD) and is an important domain of cognitive functioning associated with hopelessness. Neuroimaging studies have shown that the frontopolar cortex (Brodmann area [BA] 10) is involved in thinking about the future and demonstrated that patients with MDD have dysfunctions in BA10. However, the relationship between pessimistic thinking about the future and brain activity is unclear. Hence, we aimed to compare brain activity during future-thinking between patients with MDD and healthy individuals. Methods: We assessed 23 patients with current MDD and 23 healthy individuals. Participants were instructed to imagine the future or to recall the past using the future-thinking paradigm with four distinct temporal conditions (distant future, near future, distant past, and near past) during functional MRI. Resting-state functional MRI was also performed to explore the functional connectivity of BA10. Results: Compared with healthy individuals, patients with MDD had greater negative thinking about the distant future and exhibited increased activation in the medial BA10 when imagining the distant future, following small-volume correction focusing on the frontopolar a priori region of interest (family-wise error correction p < 0.05). Increased positive functional correlation between the right BA10 seed region and the posterior cingulate cortex was also observed. Conclusion: Patients with MDD who show greater pessimistic thinking about the distant future demonstrate increased activation in the frontopolar cortex. These findings are consistent with the hypothesis that frontopolar cortical dysfunction plays a key role in the hopelessness that manifests in patients with MDD.

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Dysconnectivity of the agency network in schizophrenia: A functional magnetic resonance imaging study

Koreki A., Maeda T., Okimura T., Terasawa Y., Kikuchi T., Umeda S., Nishikata S., Yagihashi T., Kasahara M., Nagai C., Moriyama Y., Den R., Watanabe T., Kikumoto H., Kato M., Mimura M.

Frontiers in Psychiatry （Frontiers in Psychiatry）  10 （ APR ）  2019年

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Background: Self-disturbances in schizophrenia have recently been explained by an abnormality in the sense of agency (SoA). The cerebral structures of SoA in healthy people are considered to mainly include the insula and inferior parietal lobule. In contrast, the functional lesion of aberrant SoA in schizophrenia is not yet fully understood. Considering the recent explanation of establishing SoA from the standpoint of associative learning, the “agency network” may include not only the insula and inferior parietal lobule but also the striatum. We hypothesized that aberrant SoA in schizophrenia is based on a deficit in the “agency network.” Methods: Functional magnetic resonance imaging data were acquired while patients with schizophrenia (n = 15) and matched controls (n = 15) performed our adaptation method of agency attribution task on a trial-by-trial basis to assess participants' explicit experience of the temporal causal relationship between an action and an external event with temporal biases. Analysis of functional connectivity was done using the right supramarginal gyrus and the right middle frontal gyrus as seed regions. Results: In healthy controls, analyses revealed increased activation of the right inferior parietal lobule (mainly the supramarginal gyrus), right insula, and right middle frontal gyrus as an activation of the agency condition. We defined activated Brodmann areas shown in the agency condition of healthy controls as the seed region for connectivity analysis. The connectivity analysis revealed lower connectivity between the head of the left caudate nucleus and right supramarginal gyrus in the patients compared to healthy controls. Conclusions: This dysconnectivity of the agency network in schizophrenia may lead to self-disturbance through deficits in associative learning of SoA. These findings may explain why pathological function of the striatum in schizophrenia leads to self-disturbance.

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Comparative effectiveness of switching paroxetine formulation for treatment of major depressive disorder: An open-label multicenter study

Otsubo T., Watanabe Y., Hongo S., Inoue M., Akimoto K., Murakami K., Takahashi R., Kikuchi T.

Neuropsychiatric Disease and Treatment （Neuropsychiatric Disease and Treatment）  14   955 - 966 2018年04月

ISSN  11766328

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Aim: To assess the effectiveness and safety of switching the antidepressant formulation from immediate-release (IR) to controlled-release (CR) paroxetine in patients with major depressive disorder (MDD). Patients and methods: A total of 113 outpatients with MDD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, and treated with a stable dose of IR paroxetine for at least 6 months were enrolled. Patients were then switched to CR paroxetine for 8 weeks. Effectiveness was evaluated by scores on the Himorogi Self-Rating Depression/Anxiety Scales (HSDS/HSAS) and the Clinical Global Impression – Severity (CGI-S). Safety was evaluated based on the reported adverse drug reactions (ADRs). Medication satisfaction and preference were assessed based on questionnaire responses using Likert-type scales. Results: The overall patient HSDS/HSAS scores significantly improved after switching from IR to CR paroxetine (P<0.001). Furthermore, CR paroxetine was superior to IR paroxetine (P<0.001) according to the results of the CGI-S evaluation. ADRs were experienced by 14 (12.4%) patients, including dry mouth, nausea/vomiting, somnolence/drowsiness, and wakefulness/arousal during sleep. Satisfaction and preference for paroxetine improved after switching to the CR formulation (P<0.001; chi-square test). Conclusion: These results suggest that switching the treatment from IR to CR paroxetine could improve depressive symptoms and decrease ADRs. However, these results may have been caused by the psychological effect of drug switching. Hence, future studies with blinded evaluation methods are required to confirm and expand our findings.

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