Published papers

Aims The aim of this cross-sectional study was to examine the prevalence of psychological dependence on benzodiazepines in outpatients with panic disorder and elucidate demographic and clinical characteristics associated with this condition. Methods Subjects were eligible if they were outpatients in four clinics in Tokyo, Japan, aged 18 years or older and met the diagnostic criteria for panic disorder according to the ICD-10. The subjects received the following assessments: the Severity of Dependence Scale, Japanese Version (SDS), the Self-Report Version of Panic Disorder Severity Scale, Japanese Version (PDSS-SR), and the Quick Inventory of Depressive Symptomatology-Self Report, Japanese Version. The following information was also collected: age, sex, ethnicity, duration of illness, physical and psychiatric comorbidities, and details of prescribed psychotropic medications. Results The data from 51 outpatients showed that 31 patients (60.8%) showed psychological dependence (i.e. a total score of ≥5 in the SDS). The proportion of patients with dependence was significantly lower in remitted patients (i.e. a total score of ≤4 in the PDSS) (44.1%, n-=-15/34) than those who were not (94.1%, n-=-16/17) (Pearson χ2-=-11.9, P-<-0.001). A multiple regression analysis showed that the PDSS scores showed a positive correlation with the SDS total scores (β-=-0.60, 95% confidence interval-=-0.30-0.90, P-=-0.0001). Conclusion These findings emphasize the need for enhanced awareness about benzodiazepine dependence in patients and psychiatrists, as well as especially close attention to patients with panic disorder who present severe symptomatology.

Objectives: Improving Quality of Life (QoL) is an important objective in the treatment of bipolar disorder. The aim of the current study was to examine to which extent resilience, internalized stigma, and psychopathology are correlated to QoL. Methods: We recruited 60 outpatients diagnosed with bipolar I disorder according to DSM-IV criteria and 77 healthy control subjects from the general community. In patients, symptoms were quantified by the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS) and internalized stigma by the Internalized Stigma of Mental Illness (ISMI) scale. In order to assess QoL and resilience, the Berliner Lebensqualitätsprofil (BELP) and the Resilience Scale (RS-25) were used in both patients and control subjects. Results: Despite presenting with a very mild symptom level and relatively low internalized stigma, patients with bipolar I disorder indicated significantly lower QoL and resilience as compared to healthy control subjects. In patients, QoL correlated significantly with resilience, internalized stigma, and residual symptoms of depression. No significant correlations were observed between QoL and residual manic symptoms. Limitations: The cross-sectional design and the relatively small sample size limit the generalizability of our results. Furthermore, levels of resilience and internalized stigma may change over the course of the illness and have different impacts on the long-term outcome of patients with bipolar disorder. Conclusion: Our results show that QoL of patients suffering from bipolar I disorder, even when only mildly ill, is strongly associated with the degree of resilience and internalized stigma, and that particularly residual depressive symptoms have a negative impact on QoL. In addition to drug treatment, psychotherapeutic approaches should be applied to strengthen resilience, to reduce internalized stigma, and, ultimately, to improve quality of life.

Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.

Introduction Kampo is a Japanese traditional medicinal system and is represented by unity of mind and body. It is originally based upon Chinese traditional medicine but has uniquely developed in Japan. Methods A narrative review on the use of Kampo for psychiatric conditions is provided. Results Kampo formula is a combination of several crude ingredients; most derive from natural plants and some from animals and minerals. These Kampo formulae are widely prescribed in almost all medical disciplines, including psychiatry, in Japan; they have been used for various psychiatric disorders such as dementia, schizophrenia spectrum disorders, mood disorders, anxiety disorders, and personality disorders. Kampo is a versatile traditional medicine with a variety of positive effects on mental states with relatively benign side effect profiles. Kampo formulae can be adjunctively combined with or substituted for the Western psychotropic drugs, which will provide more treatment options to patients with psychiatric conditions. Discussion This review summarizes the current knowledge on Kampo for psychiatric conditions, highlighting a paucity of data and a need for further good-quality evidence on these medications.

Introduction Data on the knowledge about antipsychotic medications prescribed in patients with schizophrenia are very limited. Moreover, it remains unclear how patients’ knowledge about prescribed antipsychotics affects medication adherence. Methods ighty-one Japanese outpatients with schizophrenia according to the International Classification of Diseases, 10th edition, were included. Patients’ knowledge of the primary antipsychotics prescribed to them in terms of therapeutic effects, type, and implicated neurotransmitters was assessed with a multiple-choice questionnaire developed for this study. Medication possession ratios (MPRs) were compared between patients who answered correctly and those who did not in each category. Results The percentages of subjects who answered correctly regarding antipsychotic effects, type, and implicated neurotransmitters were low at 30.9%, 30.9%, and 7.4%, respectively. No differences were found in MPRs between subjects who answered correctly and those who did not. Discussion Our preliminary results indicate that patients lack knowledge about their antipsychotic medications. More concerning, they suggest that knowledge about prescribed antipsychotics may not directly translate into actual medication adherence in patients with schizophrenia.

Objective: To compare symptom trajectories between placebo and active drug responders and to examine whether early placebo improvement would be associated with subsequent placebo response in the treatment of patients with behavioral and psychological symptoms of dementia. Methods: A post hoc analysis of data from 371 patients with DSM-IV Alzheimer’s disease in Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness for Alzheimer’s disease (CATIE-AD) (April 2001 to November 2004) was conducted. Patients were randomly assigned to double-blind treatment with olanzapine, quetiapine, risperidone, or placebo. Trajectories of change in Brief Psychiatric Rating Scale (BPRS) total scores were compared between placebo and active drug responders. The predictive power of improvement at week 2 for response at week 8 was investigated, and sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in BPRS total score at week 2 were calculated. Results: There were no significant differences in symptom trajectories between placebo and active drug responders. BPRS score reduction at week 2 was significantly associated with placebo response at week 8 (odds ratio = 1.13; P< .001). Use of a cutoff of 10% showed the highest accuracy of 0.67 (sensitivity, 0.63; specificity, 0.70). Conclusions: Symptom trajectories of improvement of behavioral and psychological symptoms of dementia follow the same pattern irrespective of treatment. A 10% improvement at week 2 was the most appropriate predictor of subsequent placebo response at week 8, which may indicate utility for the placebo lead-in phase to minimize future trial failures of treatment for noncognitive symptoms of Alzheimer’s disease.

Introduction Since falls may lead to fractures and have serious, potentially fatal outcomes, prevention of falls is an urgent public health issue. We examined the effects of chair yoga therapy on physical fitness among psychiatric patients in order to reduce the risk of falls, which has not been previously reported in the literature. Methods In this 12-week single-blind randomized controlled trial with a 6-week follow-up, inpatients with mixed psychiatric diagnoses were randomly assigned to either chair yoga therapy in addition to ongoing treatment, or treatment-as-usual. Chair yoga therapy was conducted as twice-weekly 20-min sessions over 12 weeks. Assessments included anteflexion in sitting, degree of muscle strength, and Modified Falls Efficacy Scale (MFES) as well as QOL, psychopathology and functioning. Results Fifty-six inpatients participated in this study (36 men; mean ± SD age, 55.3 ± 13.7 years; schizophrenia 87.5%). In the chair yoga group, significant improvements were observed in flexibility, hand-grip, lower limb muscle endurance, and MFES at week 12 (mean ± SD: 55.1 ± 16.6 to 67.2 ± 14.0 cm, 23.6 ± 10.6 to 26.8 ± 9.7 kg, 4.9 ± 4.0 to 7.0 ± 3.9 kg, and 114.9 ± 29.2 to 134.1 ± 11.6, respectively). Additionally, these improvements were observable six weeks after the intervention was over. The QOL-VAS improved in the intervention group while no differences were noted in psychopathology and functioning between the groups. The intervention appeared to be highly tolerable without any notable adverse effects. Conclusions The results indicated sustainable effects of 20-min, 12-week, 24-session chair yoga therapy on physical fitness. Chair yoga therapy may contribute to reduce the risk of falls and their unwanted consequences in psychiatric patients.

For most antipsychotics, positron emission tomography studies have demonstrated that a therapeutic window of striatal D2 receptor occupancy (65-80%) is associated with clinical response in young adults with schizophrenia. On the other hand, the dopamine D2 receptor occupancy required for the maintenance of remission may be lower than that for acute phase treatment. A series of our modeling work has shown that the dose needed to achieve a target dopamine D2/3 receptor occupancy at peak and trough can be estimated for each individual. First, striatal dopamine D2 receptor occupancy levels with antipsychotics such as risperidone and olanzapine can be predicted from plasma antipsychotic concentrations. Second, doses that result in any given target plasma levels at any point in time can be estimated, using plasma levels of those drugs with two sparsely collected plasma samples with population pharmacokinetic techniques. Furthermore, we demonstrated that by combining these two models, doses that correspond to any given dopamine D2/3 receptor occupancy with risperidone and olanzapine can be reliably estimated for each individual. Thus, in practice, the dose needed to achieve a target D2 receptor blockade at peak and trough can be estimated for each individual and therefore could be used as a target dose.

Purpose: The purpose of the study was to evaluate subjective (self-rated), family-rated, and objective (researcher-rated) cognitive functions in patients with breast cancer after chemotherapy. Method: We conducted a prospective study to trace self-rated cognitive functions in 30 patients with breast cancer at the completion of chemotherapy (T0) and 6 months later (T1). Subjective cognitive functions were assessed with Cognitive Failures Questionnaire (CFQ), Dysexecutive Questionnaire (DEX-S), and Everyday Memory Checklist (EMC-S) for attention, executive function, and episodic memory, respectively. Their family members also completed DEX-I and EMC-I for executive function and episodic memory, respectively. We also examined objective cognitive functions. Self-rated cognitive functions were compared with the normative data. They were compared between T0 and T1. We calculated correlation coefficients between self-rated and other cognitive functions. Results: At T0, 6 (20.0%) and 2 (6.7%) participants showed higher DEX-S and EMC-S scores than the normative data, respectively, while no participant had abnormal CFQ scores. At T1, DEX-S and EMC-S scores were normalized in 3 (50.0%) and 2 (100.0%) participants, respectively. No participant showed increases in CFQ scores. No changes were found in objective cognitive functions from T0 to T1. DEX-S and DEX-I or EMC-S and EMC-I scores were correlated at both T0 and T1, which did not survive multiple corrections. There was no association between subjective and objective cognitive functions. Conclusion: Impairments in subjective cognition may be transient after chemotherapy in patients with breast cancer. Furthermore, patients and their families appear to share similar prospects on their cognitive functions.

Background Health-related quality of life (HRQOL) is significantly affected in individuals with schizophrenia or bipolar I disorder (BD-I). The current study investigated whether symptomatic remission and resilience might differently impact HRQOL in these patients. Methods Fifty-two patients with schizophrenia and 60 patients suffering from BD-I from outpatient mental health services as well as 77 healthy control subjects from the general community were included into a cross-sectional study. HRQOL and resilience were assessed using the WHOQOL-BREF and the Resilience Scale. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale or the Montgomery Asberg Depression Rating Scale and the Young Mania Rating Scale, respectively. Results Notably, both patient groups showed lower HRQOL and resilience compared to control subjects, non-remitted patients indicated lower HRQOL than remitted ones. The effect of remission on HRQOL was significantly larger in patients with BD-I than in those with schizophrenia but did not explain the difference in HRQOL between groups. Resilience predicted HRQOL in all three groups. When accounting for the effect of resilience among remitted patients, only the difference in HRQOL between schizophrenia patients and control subjects was significant. Conclusion These findings demonstrate the impact of symptomatic remission and resilience on HRQOL of both patients suffering from schizophrenia and BD-I and indicate that these factors are especially relevant for HRQOL of patients with BD-I.

Objective The degree and quality of resilience in patients with depression have never been investigated in the context of remission status, spirituality/religiosity, and family members' resilience levels, which was addressed in this study. Methods This cross-sectional study recruited Japanese outpatients with depressive disorder according to ICD-10 and cohabitant family members who were free from psychiatric diagnoses. Resilience was assessed using the 25-item Resilience Scale (RS). Other assessments included the Montgomery-Asberg Depression Rating Scale (MADRS); the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT) and Kasen et al.'s (2012) scale for spirituality/religiosity; and the Rosenberg Self-Esteem Scale (RSES). Results One hundred outpatients with depression (mean ± SD age, 50.8 ± 14.5 years; 44 men; MADRS total score 9.8 ± 9.0) and 36 healthy family members (mean ± SD age, 56.5 ± 15.0 years; 18 men) were included. Symptom severity, attendance at religious/spiritual services, and self-esteem were significantly associated with RS scores in the patient group. RS total scores were significantly higher in remitted patients compared to non-remitted patients (mean ± SD, 112.3 ± 17.1 vs. 84.8 ± 27.7, p < 0.001). No correlation was found in RS total scores between patients and their family members (p = 0.265), regardless of patients' remission status. Conclusions Resilience may be influenced by individual characteristics rather than familial environment; furthermore, self-esteem or spirituality/religiosity may represent reinforcing elements. While caution is necessary in extrapolating these findings to other patient populations, our results suggest that resilience may be considered a state marker in depression.

While the efficacy and tolerability of electroconvulsive therapy (ECT) for depression has been well established, the acute effects of ECT on brain function remain unclear. Particularly, although cognitive dysfunction has been consistently observed after ECT, little is known about the extent and time course of ECT-induced brain functional changes, as observed during cognitive tasks. Considering the acute antidepressant effects of ECT on depression, aberrant brain functional responses during cognitive tasks in patients with depression may improve immediately after this treatment. To clarify changes in cortical functional responses to cognitive tasks following ECT, we used task-related functional near-infrared spectroscopy (NIRS) to assess 30 patients with major depressive disorder or bipolar depression before and after an ECT series, as well as 108 healthy controls. Prior to ECT, patients exhibited significantly smaller [oxy-Hb] values in the bilateral frontal cortex during a letter verbal fluency task (VFT) compared with healthy controls. We found a significant increase in [oxy-Hb] values in the bilateral frontal cortex during the VFT after ECT in the patient group. A decrease in depression severity was significantly correlated with an increase in [oxy-Hb] values in the right ventrolateral prefrontal cortex following ECT. This is the first NIRS study to evaluate brain functional changes before vs. after ECT. Impaired functional responses, observed during the cognitive task in depressed patients, were normalized after ECT. Thus, recovery from abnormal functional responses to cognitive tasks in the frontal brain regions may be associated with the acute therapeutic effects of ECT for depression.

Background: Antipsychotic switching is routine in clinical practice, although it remains unclear which is the preferable switching method: immediate discontinuation of the current antipsychotic or a gradual tapering approach. The first strategy has been implicated in rebound/withdrawal symptoms and emergence/exacerbation of symptoms, whereas the gradual approach is thought to pose a risk of additive or synergistic side effects if employed in the context of a crossover approach. Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched. Randomized controlled trials examining immediate vs gradual antipsychotic discontinuation in antipsychotic switching in patients with schizophrenia and/or schizoaffective disorder were selected. Data on clinical outcomes, including study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events, were extracted. Results: A total of 9 studies involving 1416 patients that met eligibility criteria were included in the meta-analysis. No significant differences in any clinical outcomes were found between the 2 approaches (all Ps >.05). Sensitivity analyses revealed that the findings remained unchanged in the studies where switching to aripiprazole was performed or where immediate initiation of the next antipsychotic was adopted, while some significant differences were observed in switching to olanzapine or ziprasidone. Conclusions: These findings indicate that either immediate or gradual discontinuation of the current antipsychotic medication represents a viable treatment option. Clinicians are advised to choose an antipsychotic switching strategy according to individual patient needs. This said, immediate discontinuation may be advantageous both for simplicity and because a stalled cross-titration process in antipsychotic switching could end up in antipsychotic polypharmacy.

Background: Residual symptoms are detrimental to prognosis in major depressive disorder (MDD); however, little is known about the contribution of each residual symptom in predicting outcomes. The objective of this analysis was to identify which individual symptoms, based on self-report and clinician interview, could predict subsequent relapse. Methods: The data of 1133 outpatients with nonpsychotic MDD who entered a 12-month naturalistic follow-up phase after achieving remission with level 1 treatment (i.e., citalopram for up to 14 weeks) and had at least one post-baseline contact in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were analyzed. Specific residual symptoms in the 16-item Quick Inventory of Depressive Symptomatology, self-report (QIDS-SR16) and clinician rating (QIDS-C16), at the follow-up entry that predicted relapse were identified, using a Cox proportional hazards model. Results: The following three QIDS-SR16 symptoms were significantly associated with subsequent relapse: restlessness (HR = 1.197, p = 0.018), hypersomnia (HR = 1.190, p = 0.009), and weight change (HR = 1.127, p = 0.041). On the other hand, the following three symptoms in the QIDS-C16 at the follow-up entry were significantly associated with relapse in the follow-up phase: restlessness (HR = 1.328, p = 0.001), sleep onset insomnia (HR = 1.129, p = 0.047), and weight change (HR = 1.125, p = 0.045). Limitations: The original trial was not designed to evaluate the issue addressed herein. Individual symptoms may be associated with each other and functional status was not addressed. Conclusions: Some residual symptoms, including restlessness, insomnia, and weight change, may help better identify patients with MDD vulnerable to relapse. Contribution of individual residual symptoms to subsequent relapse was similar between self-report and clinician-rated symptoms.

While positron emission tomography (PET) studies have provided invaluable data on antipsychotic effects, selection bias remains a serious concern. A systematic review of PET studies that measured dopamine D2 receptor blockade with antipsychotics was conducted to examine their inclusion/exclusion criteria, using PubMed, EMBASE, and ClinicalTrials.gov (last search, September 2016). PET studies were included if they measured D2 receptor occupancy in patients with schizophrenia and included introduction of antipsychotic treatment or antipsychotic regimen change in a systematic manner. Twenty-six studies were identified. Age limit was included in 13 studies; one study solely included geriatric patients while others targeted younger adults. Eleven, 6, and 3 studies specifically targeted clinically stable patients, patients with severe psychopathology, and antipsychotic-free patients, respectively. Nineteen and 18 studies excluded patients with physical comorbidity and substance abuse, respectively. As a result, the mean age of subjects ranged from 23 to 42 years when one study that targeted geriatric patients was excluded. Mean Positive and Negative Syndrome Scale total scores ranged from 54 to 95. No comparison active-drug or placebo arm was employed in 24 studies. Blind assessment of symptomatology was performed in 5 studies. In general, subjects participating in clinical PET studies were relatively young, presented with mild symptomatology, and were free from substance abuse or physical comorbidities. These characteristics need to be taken into account when clinical PET data are interpreted. On the other hand, it should also be noted that this study was only qualitative and conservative interpretation is necessary for possibility of subjective bias.

Little is known about the influence of D2 receptor occupancy on impaired insight into illness (III)—a core feature of schizophrenia. III is associated with illness severity and cognitive dysfunction. Comparably, supratherapeutic D2 receptor occupancy can impair cognition. However, it is unclear how illness severity, cognition, and D2 receptor occupancy interact to influence III in schizophrenia. The aim of this study was to explore the influence of antipsychotic dose reduction on the relationships of illness severity and cognition to III. III was assessed at baseline and 28 weeks post-antipsychotic dose reduction in 16 participants with schizophrenia and plasma antipsychotic concentrations. III was assessed primarily with the Schedule for the Assessment of Insight–Japanese version, and secondarily with the Positive and Negative Syndrome Scale item G12. Correlation and regression analyses were performed to explore III's relationship to illness severity, cognition, and estimated D2 receptor occupancy (Est.D2). Cognition and Est.D2 predicted III at baseline. At 28 weeks post-reduction, illness severity and Est.D2 predicted III. Our findings suggest a complex relationship may exist among III, illness severity, cognition and Est.D2. At higher D2 receptor occupancies, III is influenced by cognitive dysfunction, whereas, at lower occupancies, illness severity has a stronger effect on III.