Published papers

Objective: Antipsychotic dose reduction is generally recommended to occur after six months of clinical stabilization despite inadequate evidence. This timing issue was addressed in this study. Methods: This is an observational, retrospective and medical chart-based study. Inclusion criteria were (1) diagnosis of schizophrenia (DSM-IV), (2) being acutely psychotic at their first outpatient visit from May, 2002 to April, 2003, (3) having responded to antipsychotics and achieved clinical stabilization of acute symptoms, indexed as a fixation of regimen for four or more weeks, and (4) having one or more years of follow-up. Patients who had their antipsychotic doses reduced were then identified, and they were divided into two groups based on the waiting period before dose reduction: <24 weeks (Early Group) and ≥24 weeks (Standard Group). The rate of dose escalation for ≥20% during follow-up period was investigated as a proxy of clinical worsening. Results: After excluding stable patients at baseline, 211 patients met inclusion criteria. The mean ± SD waiting period before reducing antipsychotics was 122 ± 102 days. The rates of patients needing dose escalation were not significantly different between patients whose dose was reduced (N = 83) and those who was not (N = 128) (57.8% vs. 59.4%), and between Early Group (N = 59) and Standard Group (N = 24) (61.0% vs. 50.0%) although the reduction rate in antipsychotic dosage was significantly greater in Early Group (58.7% vs. 43.3%, p < 0.05). Conclusion: These findings may indicate that timeline until antipsychotic reduction in stable patients with schizophrenia could be earlier than recommended, although caution is needed in interpreting our retrospective results.

Rationale: Evidence on sequential trial with atypical antipsychotics has been scarce. Objectives: We conducted an algorithm-based antipsychotic pharmacotherapy. Materials and methods: In this open-label study, patients with schizophrenia (DSM-IV) were treated with antipsychotic monotherapy, step-by-step, with each trial lasting up to 8 weeks. At baseline, they were highly symptomatic to score more than 54 in the total Brief Psychiatric Rating Scale (BPRS1-7) score. When the posttreatment BPRS score was above 70% of the baseline, they were subsequently treated with another and up to three atypicals. Basically, anticholinergics were prohibited, and only adjunctive allowed was lorazepam. The secondary endpoint was a clinical status good enough to be discharged for 66 inpatients and a successful continuation therapy with the same antipsychotic agent for more than 6 months for 12 outpatients. Results: Three groups of 26 patients each were randomized to Olanzapine, Quetiapine, or Risperidone. Thirty-nine (50%) responded to the first agent (Olanzapine16, Quetiapine9, Risperidone14), and 14 responded to the second. Only two showed response to the third, and 16 failed to respond to all three antipsychotics, with only 7 dropouts. Overall, there were 22 Olanzapine, 14 Quetiapine, and 19 Risperidone responders. Based on the secondary outcome, 20 Olanzapine-treated (average maximum dose, 15.4 mg), 10 Quetiapine-treated (418 mg), and 20 Risperidone-treated (4.10 mg) patients responded. The difference in response as the first choice was significant (p<0.05). Relative doses of those failing to respond were comparable (Olanzapine 18.3 mg, Quetiapine 564 mg, Risperidone5.47 mg). Extrapyramidal symptoms did not change significantly. Conclusions: When the first atypical antipsychotic is inadequate, switching to the second is worth trying, although some remain treatment-refractory. Quetiapine may be inferior to Olanzapine and Risperidone in symptomatic patients.

Psychophysiological markers have been focused to investigate the psychopathology of psychiatric disorders and personality subtypes. In order to understand neurobiological mechanisms underlying these conditions, fear-conditioning model has been widely used. However, simple aversive stimuli are too simplistic to understand mechanisms because most patients with psychiatric disorders are affected by social stressors. The objective of this study was to test the feasibility of a newly-designed conditioning experiment using a stimulus to cause interpersonal conflicts and examine associations between personality traits and response to that stimulus. Twenty-nine healthy individuals underwent the fear conditioning and extinction experiments in response to three types of stimuli: a simple aversive sound, disgusting pictures, and pictures of an actors' face with unpleasant verbal messages that were designed to cause interpersonal conflicts. Conditioned response was quantified by the skin conductance response (SCR). Correlations between the SCR changes, and personality traits measured by the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) and Revised NEO Personality Inventory were explored. The interpersonal conflict stimulus resulted in successful conditioning, which was subsequently extinguished, in a similar manner as the other two stimuli. Moreover, a greater degree of conditioned response to the interpersonal conflict stimulus correlated with a higher ZANBPD total score. Fear conditioning and extinction can be successfully achieved, using interpersonal conflicts as a stimulus. Given that conditioned fear caused by the interpersonal conflicts is likely associated with borderline personality traits, this paradigm could contribute to further understanding of underlying mechanisms of interpersonal fear implicated in borderline personality disorder.

© 2019 Wolters Kluwer Health, Inc. All rights reserved. Objectives Delirium following electroconvulsive therapy (ECT) has been a clinical challenge, which, however, has not been investigated through a systematic literature review. The objective of this study was to systematically synthesize available evidence regarding factors associated with post-ECT delirium. Methods We conducted a systematic literature search for any type of original investigations that reported risk factors of post-ECT delirium, using PubMed. Results The literature search identified 43 relevant articles. One study found an association between catatonic feature and increased risk of postictal delirium. Five studies reported that the presence of cerebrovascular disease, Parkinson disease, or dementia was related to higher incidence of post-ECT delirium. Incidence of post-ECT course delirium was increased with bitemporal stimulation (3 studies). One study showed that ultrabrief pulse ECT reduced reorientation time following seizure compared with brief pulse ECT. High stimulus intensity resulted in more prolonged reorientation time after ECT than lower stimulus intensity (2 studies). Longer seizure length was significantly associated with post-ECT delirium in 1 study. Eight studies that examined postictal delirium in association with medications used, including lithium, did not show any consistent finding in their relationships. Four studies showed decreased incidence of postictal delirium in those receiving dexmedetomidine. Conclusions Limited evidence suggests that catatonic feature, cerebrovascular disease, Parkinson disease, dementia, bitemporal electrode placement, high stimulus intensity, or longer seizure length are associated with an increased risk of post-ECT delirium. Moreover, dexmedetomidine and ultrabrief pulse ECT seem to have preventive effects of post-ECT delirium.

Background: Clozapine has been serving as the gold standard medication for patients with treatment-resistant schizophrenia who failed to respond to other antipsychotics. However, factors affecting response to this medication have not been comprehensively reviewed recently. Methods: In order to find factors associated with response to clozapine in schizophrenia, a literature search was conducted using PubMed through January 2011 with keywords of clozapine, response, and schizophrenia. Cross-referencing of relevant articles was also performed. Factors were arbitrarily classified into the following: demographic/clinical, oral dosage/pharmacokinetic, biochemical, (electro)physiological, genetic, imaging, and combinations. Results: A synthesis from 280 articles indicated that demographic and clinical variables such as high baseline symptoms and low premorbid functioning have not been particularly useful in predicting response to clozapine. Pharmacokinetic evidence points to a threshold clozapine level of 350 ng/ml but in a context of significant inter- as well as intra-individual variability. Pharmacokinetic perspectives appear to have more implication in special situations including poor response, suspected toxicity and nonadherence. A number of laboratory-based studies have reported on many potential candidates for response prediction to clozapine, however, reproducibility, specificity, robustness of the findings, as well as clinical feasibility and cost-effectiveness all pose a significant practical challenge, in relation with the fact that pathophysiological bases of treatment resistance in schizophrenia largely remain to be elucidated. Conclusions: No unequivocal factors to clozapine response were found despite a relatively rich body of the literature, which calls for more works on this important topic. Clozapine level of 350 ng/ml appears to be useful in case of nonresponse.

© 2019, The Author(s), under exclusive licence to American College of Neuropsychopharmacology. This systematic review and meta-analysis examined predictors of successful antipsychotic dose reduction in schizophrenia. Prospective clinical trials and randomized controlled trials (RCTs) investigating antipsychotic dose reduction in schizophrenia were selected for systematic review and meta-analysis, respectively. In total, 37 trials were identified. Only 8 studies focused on second-generation antipsychotics (SGAs); no studies investigated long-acting injectable SGAs. Of 24 studies evaluating relapse or symptom changes, 20 (83.3%) met the criteria for successful dose reduction. Factors associated with successful dose reduction were study duration < 1 year, age > 40 years, duration of illness > 10 years, and post-reduction chlorpromazine equivalent (CPZE) dose > 200 mg/day. Clinical deterioration was mostly re-stabilized by increasing the dose to the baseline level (N = 7/8, 87.5%). A meta-analysis of 18 RCTs revealed that relapse rate was significantly higher in the reduction group than the maintenance group (risk ratio [RR] = 1.96; 95% confidence interval [CI], 1.23–3.12), whereas neurocognition was significantly improved (standardized mean difference = 0.69; 95% CI, 0.25–1.12). A subgroup analysis indicated that only a post-reduction CPZE dose ≤ 200 mg/day was associated with an increased risk of relapse (RR = 2.79; 95% CI, 1.29–6.03). Thus, when reducing antipsychotic doses, clinicians should consider the long-term risk of relapse in younger patients with a relatively short illness duration and keep the final doses higher than CPZE 200 mg/day. Further studies, particularly those involving SGAs, are warranted to determine the optimal strategies for successful antipsychotic dose reduction in schizophrenia.

© 2017 Elsevier Ltd 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.

© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology. Aim: Psychopharmacological treatment is indispensable in patients with schizophrenia but data on needs, preferences, and complaints about their medications are limited. Moreover, there has been no study to assess the degree of awareness of their psychiatrists (gap in needs) regarding these issues. Methods: Ninety-seven Japanese patients with schizophrenia (ICD-10) were asked to fill in the questionnaire consisting of multiple-choice questions regarding (a) their needs and complaints about psychopharmacological treatment that they were receiving, and (b) their preference of dosage form, dosing frequency, and timing of dosing. Additionally, their psychiatrists in charge were asked to predict their patients’ response to the above questions. Results: Both the most frequently endorsed need and complaints about the current psychopharmacological treatment were “nothing in particular” (n = 14, 16.7% and n = 17, 20.2%); merely 23.1% and 15.4% of their psychiatrists correctly predicted these responses, respectively. “Once a day” (n = 56, 65.1%), “at bedtime” (n = 53, 61.6%), and “tablet” (n = 51, 59.3%) were the patients’ most favorite dosing frequency, timing, and dosage form, respectively; 59.8% (n = 49), 54.9% (n = 45), and 64.6% (n = 53) of their psychiatrists predicted them. Conclusions: These findings suggest that there is substantial room for improvement on the side of psychiatrists to capture their patients’ needs and complaints about psychopharmacological treatment.

© 2020 Elsevier Ltd The unpredictability and uncertainty of the COVID-19 pandemic; the associated lockdowns, physical distancing, and other containment strategies; and the resulting economic breakdown could increase the risk of mental health problems and exacerbate health inequalities. Preliminary findings suggest adverse mental health effects in previously healthy people and especially in people with pre-existing mental health disorders. Despite the heterogeneity of worldwide health systems, efforts have been made to adapt the delivery of mental health care to the demands of COVID-19. Mental health concerns have been addressed via the public mental health response and by adapting mental health services, mostly focusing on infection control, modifying access to diagnosis and treatment, ensuring continuity of care for mental health service users, and paying attention to new cases of mental ill health and populations at high risk of mental health problems. Sustainable adaptations of delivery systems for mental health care should be developed by experts, clinicians, and service users, and should be specifically designed to mitigate disparities in health-care provision. Thorough and continuous assessment of health and service-use outcomes in mental health clinical practice will be crucial for defining which practices should be further developed and which discontinued. For this Position Paper, an international group of clinicians, mental health experts, and users of mental health services has come together to reflect on the challenges for mental health that COVID-19 poses. The interconnectedness of the world made society vulnerable to this infection, but it also provides the infrastructure to address previous system failings by disseminating good practices that can result in sustained, efficient, and equitable delivery of mental health-care delivery. Thus, the COVID-19 pandemic could be an opportunity to improve mental health services.

Introduction: While patients with schizophrenia are often treated with psychotropic polypharmacy, how and when polypharmacy begins is not well documented. Methods: A systematic chart review of 300 patients, 100 of whom were psychotropic-free prior to their first visit, was conducted to examine 2-year longitudinal prescription patterns of concomitant psychotropics, in addition to a primary antipsychotic. Results: Overall polypharmacy occurred in 79% patients, with 2-year rates of the use of hypnotics, benzodiazepine derivative anxiolytics, anticholinergic drugs, antidepressants, and mood stabilizers were 56.7, 49.7, 38.3, 21.3, and 14.0%, respectively. Once polypharmacy had started, it was continued until their final visit in >70% of the patients. In a subgroup of 100 psychotropic-free patients, mood stabilizers, antidepressants, anticholinergic antiparkinsonian drugs, anxiolytics, and hypnotics were initiated after 2.3, 2.3, 2.1, 1.6, and 1.5 antipsychotics had been prescribed, respectively (mean duration before the introduction of a concomitant drug in days: 17.7, 121.6, 86.4, 32.1, and, 57.7, respectively). Conclusion: Routine practice deviates significantly from algorithms - with polypharmacy often being initiated early, often a without trial of other options, and once started commonly stays. © Georg Thieme Verlag KG Stuttgart · New York.

Background: Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics. Methods: The dataset from 481 subjects (risperidone, N = 172, olanzapine, N= 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated. Results: The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68-70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.). Conclusion: The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65-80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia. © 2013 The Authors.