Published papers

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.