Published papers

© 2014 American Association for Geriatric Psychiatry. Objective In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D2/3 receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D2/3 relative receptor occupancy (RRO) on clinical outcomes in this population. Design Open-label intervention. Setting Centre for Addiction and Mental Health, Toronto. Participants Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for more than 6 months. Intervention A dose reduction of risperidone of up to 40%, followed by a 3-month follow-up. Measurements Dopamine D2/3 RRO in dorsal putamen was assessed, using the region of interest analysis of [11C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale. Results Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D2/3 RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D2/3 RRO. Conclusion EPS diminished less than 70% D2/3 RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.

© Copyright 2016 Physicians Postgraduate Press, Inc. Objective: Although hyperprolactinemia carries a long-Term risk of morbidity, the threshold of dopamine D2/3 receptor (D2/3R) occupancy for hyperprolactinemia has not been investigated in older patients with schizophrenia. Data were taken from a positron emission tomography (PET) study conducted between August 2007 and August 2015. The present post hoc study included 42 clinically stable outpatients with schizophrenia (DSM-IV) (mean SD age = 60.2 6.7 years) taking olanzapine or risperidone. Subjects underwent [11C]-raclopride PET scans to measure D2/3R occupancy before and after reducing their dose of antipsychotic by up to 40%. Blood samples were collected before each PET scan to measure prolactin levels. Methods: The relationship between prolactin levels and D2/3R occupancy was examined using stepwise linear regression analyses. The D2/3R occupancy thresholds for hyperprolactinemia were explored using Fisher exact tests. Results: Prolactin levels decreased following dose reduction (mean SD = 24.1 30.2 ng/mL to 17.2 15.1 ng/mL; P < .001). Prolactin levels were associated with female gender (β = .32, P = .006, vs male), antipsychotics (β = .23, P = .02, risperidone vs olanzapine), and D2/3R occupancy (β = .23, P = .04). Those with D2/3R occupancy of 66% or higher were more likely to have hyperprolactinemia than those with D2/3R occupancy lower than 66% (P = .03). Sensitivity, specificity, positive predictive value, and negative predictive value of this threshold were 0.44, 0.81, 0.78, and 0.48, respectively. We identified a D2/3R occupancy threshold for hyperprolactinemia of 66% in older patients with schizophrenia, which is lower than that reported in younger patients (73%) by other researchers. Conclusions: Our results suggest a higher sensitivity to antipsychotics in older patients. Prolactin levels could assist in the determination of appropriate antipsychotic dosing to minimize adverse effects.

© Georg Thieme Verlag KG. Introduction: The objective of this study was to examine the evolution of antidepressant switch and adjunctive therapy. Methods: This chart review was conducted at 6 primary psychiatric clinics or hospitals, in Tokyo, Japan. A chart review of longitudinal prescriptions was conducted regarding 633 outpatients with major depressive disorder for up to 2 years after their first visit. Patients who had already received antidepressants prior to the visit were excluded. Results: 22.6% (N=143) of the patients completed or continued the outpatient treatment over the 2 years while 27 (4.3%), 23 (3.6%), and 439 (69.4%) patients discontinued it due to hospitalization, referral to another clinic, and loss to follow-up, respectively. A total of 597 episodes of antidepressant treatment were identified. Among them, 482 episodes (80.7%) were associated with the suggested dose ranges while antidepressant drugs were under-dosed in 19.3% (N=115) of the episodes. 50 patients (7.9%) received adjunctive therapy; it was employed after a median of only one antidepressant had been tried. Conclusion: Psychiatrists may be hasty in prescribing an adjunctive therapy in the treatment of depression.

Antipsychotic polypharmacy has been empirically used and a recent trend in favour of that mode of therapy has been suggested for the treatment of schizophrenia. The clinical efficacy, however, still remains to be clarified. In order to critically evaluate the usefulness of such kind of psychopharmacotherapy, antipsychotic combination regimen (polypharmacy) was switched to a treatment with the single main antipsychotic (monotherapy) in cross-tapered fashion, while approximately maintaining the total amount, for patients with chronic schizophrenia. Patients had been treated with an average of three antipsychotics and maintained with the same antipsychotic polypharmacy regimen for more than 6 months before the entry. They were followed up with an antipsychotic monopharmacy and evaluated at 24 wk after completion of switching. Forty-seven patients were recruited for this study. Of 44 patients for whom evaluation was possible, 24 (54.5%) remained stable, while 10 (22.7%) showed improvement and the same number of patients ended in a deleterious status. Twenty-two patients were converted to antipsychotic monotherapy, while another 12 needed minimal dosing of low-potency agents. Overall, social functioning, evaluated by the Global Assessment of Functioning and the Clinical Global Impression, remained unchanged. Eighteen of 34 successful patients showed adverse effects of the main antipsychotic medication, which necessitated a significant dose reduction. Nine out of 10 deteriorating patients had been treated with a combination of low- and high-potency antipsychotics. It is suggested that many instances of antipsychotic polypharmacy is avoidable. The result is compatible with the current treatment recommendations, which dictate the use of a single antipsychotic agent.

Antipsychotics have been sporadically reported to induce the brief recurrent episodes characterized by hypersensitivity of the visual perception, which is known as paroxysmal perceptual alteration (PPA) mainly in Japan. PPA is characterized by hypersensitivity of perception mainly in visual modalities, which could occur in patients treated with antipsychotics. PPA is occasionally known to be accompanied by an oculogyric crisis (OGC). In this study, we examine the prevalence and the characteristics of patients with PPA. Three hundred thirty-eight patients who were treated with antipsychotics and diagnosed with schizophrenia, mood disorders, or neurotic disorders (International Classification of Disease, or ICD-10) were interviewed. We compared the characteristics between subjects with and without PPA. The mean overall prevalence of PPA was 3.25%, which was higher among patients treated with high-potency antipsychotics (3.91%) than in subjects treated with mid-potency or low-potency drugs (1.16%). PPA occurred simultaneously with OGC at the rate of 36.4%. We also found much similarity between PPA and OGC in terms of phenomenology. We suggest that PPA could manifest itself as an undesirable effect of antipsychotics, especially those of high potency. PPA and OGC may a share common underlying mechanism.

OBJECTIVE: To report on a patient who was successfully rechallenged with cloza - pine after perforation of the large intestine and pulmonary embolism post opera - tively, and provide a literature review on clozapine rechallenge. CASE SUMMARY: A 46-year-old Japanese man with treatment-resistant schizo - phrenia developed constipation and slight abdominal discomfort while taking clozapine 275 mg/day. He developed appendicitis, leading to perforation of the large intestine. During the postsurgery period, a partial embolism of the pulmonary artery was revealed. The patient's constipation was relieved when clozapine was discontinued, but other antipsychotics failed to control his delusions well. After thorough discussion, it was decided to rechallenge with clozapine. The low dose of clozapine 200 mg/day was tolerable for his delusion, and his constipation was managed with laxatives and exercises until 8 months after the accident. DISCUSSION: Clozapine is a gold standard medication in treatment-resistant schizophrenia but is associated with various adverse effects, some of which are life-threatening. Reintroduction of clozapine after severe adverse drug effects when other medications are not effective almost always poses a clinical dilemma for mental health professionals. A PubMed search (to January 25, 2013) using the key words clozapine and rechallenge found 50 articles. There were only sporadic positive case reports regarding the rechallenge after clozapine-related serious gastrointestinal problems. CONCLUSIONS: From the currently available evidence, most psychiatrists appear to avoid reintroduction of clozapine. However, the evidence is too weak to draw a definitive conclusion about reintroduction of this drug. Reintroduction of clozapine after initial adverse effects in patients with treatment-resistant schizophrenia may warrant case-by-case judgment, but needs to be further investigated.

Objective: Improving quality of life (QoL) is an important objective in the treatment of schizophrenia. The aim of the current study was to examine to what extent resilience, self-esteem, hopelessness, and psychopathology are correlated with QoL. Method: We recruited 52 out-patients diagnosed with schizophrenia according to DSM-IV criteria and 77 healthy control subjects from the general community. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale. The following scales were used in both patients and control subjects: the Berliner Lebensqualitätsprofil, the Resilience Scale, the Rosenberg Self-Esteem Scale, and the Beck Hopelessness Scale to assess QoL, resilience, self-esteem, and hopelessness respectively. Results: Patients with schizophrenia presented with significantly less QoL, resilience, self-esteem, and hope compared to healthy control subjects. In patients, QoL correlated moderately with resilience, self-esteem, and hopelessness and weakly with symptoms. With respect to the latter, particularly depression and positive symptoms were negatively correlated with QoL. Conclusion: Our results highlight the complex nature of QoL in patients suffering from schizophrenia. They underscore that significant efforts are necessary to enhance resilience and self-esteem and to diminish hopelessness as well as affective and positive symptoms in patients with schizophrenia.

The relationship between the Global Assessment of Functioning (GAF) with other scales in schizophrenia has rarely been investigated. A systematic literature search was conducted to identify articles that reported the GAF score together with scores in the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) or Brief Psychiatric Rating Scale (BPRS), using MEDLINE, EMBASE and PsycINFO, with keywords of schizophrenia, clinical trial and global assessment of functioning (last search 30 June 2013). Correlational analyses with weighting by the study participant numbers across these rating scales were performed. In 40 clinical trials (. n=8000) that reported cross-sectional data on the GAF and PANSS, a significant but modest correlation was noted (Pearson[U+05F3]s r=-0.401, p<0.0001). Furthermore, a correlation between the GAF and CGI-severity (CGI-S) at study baseline in 38 studies ( n=11,315) was robust ( r=-0.893, p<0.0001). In longitudinal studies, changes in the GAF scores were negatively correlated with those in the PANSS as well as CGI-S scores ( p<0.0001 for both). Data on the BPRS were all statistically significant although relatively scarce. While optimal degree of concordance is undetermined among psychiatric scales that are presumed to be measuring different but overlapping constructs, this study found significant correlations in the GAF and CGI-S or PANSS, both cross-sectionally and longitudinally. The GAF-CGI-S relationship was especially tighter, making it a reliable clinical indicator.

© 2018 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.

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: The impact of religious/spiritual activities on clinical outcomes in patients with serious mental illnesses remains controversial, which was addressed in this international cross-sectional study. Method: Three-hundred sixty-nine subjects were recruited from Austria (n = 189) and Japan (n = 180), consisting of 112 outpatients with paranoid schizophrenia, 120 with bipolar I disorder (DSM-IV), and 137 healthy controls. Religiosity was assessed in terms of attendance and importance of religious/spiritual activities, while resilience was assessed using the 25-item Resilience Scale. General linear models were used to test whether higher religiosity will be associated with higher resilience, higher social functioning, and lower psychopathology. The association between levels of spiritual well-being and resilience was also examined. Results: Attendance of religious services (F [4,365] = 0.827, P = 0.509) and importance of religion/spirituality (F [3,365] = 1.513, P = 0.211) did not show significant associations with resilience. Regarding clinical measures, a modest association between higher importance of religion/spirituality and residual manic symptoms was observed in bipolar patients (F [3,118] = 3.120, P = 0.029). In contrast to the findings regarding religiosity, spiritual well-being showed a strong positive correlation with resilience (r = 0.584, P < 0.001). Conclusion: The protective effect of religiosity in terms of resilience, social functioning, and psychopathology was not evident in our sample. Spiritual well-being appears more relevant to resilience than religiosity.

© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: Synthetic glucocorticoids cause various psychiatric symptoms. Prescription of psychotropic drugs could be considered to be a proxy for manifestation of psychiatric symptoms. The aim of this study was to investigate the prescriptions of psychotropics in outpatients receiving synthetic glucocorticoids. Methods: We used the claims sampling data during January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan made by the Ministry of Health, Labor, and Welfare in Japan. We compared the prescription rates of psychotropics between outpatients receiving oral synthetic glucocorticoids and age- and sex-matched controls and the prescription rates of psychotropics among the eight dosage groups of synthetic glucocorticoids by chi-squared test, and chlorpromazine/imipramine/diazepam equivalent doses (or daily defined doses) of respective psychotropics among these groups using Welch's t-test. Results: Synthetic glucocorticoids were prescribed to 3.1% (n = 18 122) of 581 990 patients. The prescription rates of psychotropics were significantly higher among the synthetic glucocorticoid recipients than among the non-recipients: antipsychotics, 1.8% (n = 321) vs. 1.1% (n = 201) (P = 1.4 × 10−7); antidepressants, 4.0% (n = 724) vs. 2.0% (n = 359) (P = 8.7 × 10−30); anxiolytics/hypnotics, 16.7% (n = 3029) vs. 10.2% (n = 1841) (P = 2.7 × 10−75); and mood stabilizers, 1.3% (n = 238) vs. 0.7% (n = 120) (P = 3.6 × 10−10) respectively. There was no significant difference in the prescription rates of any psychotropic drugs, other than anxiolytics/hypnotics, among the eight synthetic glucocorticoid dosage groups. Conclusion: Prescriptions of oral synthetic glucocorticoids were found to be associated with the use of any of the types of psychotropic drugs, other than anxiolytics/hypnotics, although a causal relationship could not be confirmed due to the retrospective and cross-sectional nature of this study.

© 2014 Elsevier Inc. Objective: Physical restraint sometimes causes deep vein thrombosis (DVT) and pulmonary embolism. Although unfractionated heparin (UFH) is used for the prophylaxis of DVT, its effectiveness remained unknown for restrained patients. Method: We conducted a chart review of restrained inpatients at Sakuragaoka Memorial Hospital in Japan. Restrained patients received subcutaneous injection of UFH 5000 IU bid from December 2008 to September 2010 [heparin (+) period] while UFH was not used from December 2010 to September 2012 [heparin (-) period]. A Doppler ultrasound scanning was performed to examine the presence of DVT. The incidence of DVT was compared between the two periods by chi-square test. A multiple logistic regression model was used to examine effects of demographic and clinical characteristics on the incidence of DVT. Results: No significant difference was found in the incidence of DVT between the heparin (+) and (-) periods [11.8% (11/93) vs. 11.1% (13/117)]. Sedation [odds ratio (OR)=3.78], physical comorbidities (OR=6.29) and a longer duration of restraint (OR=1.22) were associated with the incidence of DVT. Conclusion: The use of UFH was not associated with any reduction in the incidence of DVT in restrained psychiatric patients.

© 2016 Wolters Kluwer Health, Inc. No study has investigated psychological dependence on antidepressants in patients with panic disorder, which was addressed in this study. This study was carried out in four psychiatric clinics in Tokyo, Japan. Individuals were eligible if they were outpatients aged 18 years or older and fulfilled the diagnostic criteria for panic disorder (ICD-10). Assessments included the Japanese Versions of the Severity of Dependence Scale (SDS), the Self-Report Version of Panic Disorder Severity Scale (PDSS-SR), and the Quick Inventory of Depressive Symptomatology-Self Report. Eighty-four individuals were included; of these, 30 patients (35.7%) showed psychological dependence on antidepressants (i.e. a total score of ≥5 in the SDS). A multiple regression analysis showed that PDSS scores and illness duration were correlated positively with SDS total scores. A binary regression model showed that absence of remission (i.e. a total score of ≥5 in the PDSS) and longer duration of illness increased the risk of dependence on antidepressants. Approximately one-third of the patients with panic disorder, receiving antidepressants, fulfilled the criteria for psychological dependence on these drugs. The results underscore the need for close monitoring, especially for those who present severe symptomatology or have a chronic course of the illness.

© 2017 Elsevier Masson SAS 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.