Published papers

© 2017 Japanese Society of Neuropsychopharmacology. All rights reserved. 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.

Positron emission tomography (PET) studies proposed a therapeutic window of D2 receptor occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET studies that measured D2 occupancy levels and assessed extrapyramidal side effects (EPS) and/or treatment response induced by antipsychotics (excluding partial agonists) were identified, using MEDLINE and EMBASE (last search: March 2010). Individual subjects were divided into 2 groups based on EPS status (ie, presence or lack of newly emergent EPS) and treatment response (ie, a ≥ 25% or ≥ 50% reduction in the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale). To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cutoff points in the D2 occupancy were calculated: Accuracy = (True Positive + True Negative)/Total N. Twelve studies, including a total of 82 subjects, were included in our analyses. The cutoff points associated with 0.5 or greater in both sensitivity and specificity with the greatest accuracy were 77% to 78% for EPS, 60% for a 25% or greater symptom reduction, and 72% for a 50% or greater symptom reduction. These findings support the presence of a therapeutic window of 60% to 78% D2 occupancy of antipsychotics in young adults with schizophrenia and may suggest the presence of a continuum of effectiveness with increasing occupancy within this therapeutic window. © 2011 Lippincott Williams & Wilkins.

Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions. Results: D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment. © 2012 The Author.

Patients with depression may not well be aware of antidepressant adverse events (AEs); however, no studies have assessed how these AEs affect their daily function. Therefore, to evaluate the relationship between the quality of AEs and functional impairment, we studied 482 outpatients with depressive disorders who were not receiving any antidepressant treatment prior to the baseline visit and started it thereafter in usual clinical settings. The Quick Inventory for Depressive Symptomatology Self-Report Japanese version and antidepressant AEs for subjective assessment (antiAS) were performed at baseline and 10 days after antidepressant initiation (i.e. second visit). Functional impairment was evaluated with the Sheehan Disability Scale (SDS) on the second visit. As a result, the SDS was positively associated with the number of AEs (β=0.089, p=0.022) in multiple linear regression analysis (adjusted R2=0.357, p<0.001). Subjects who experienced vertigo, nausea and insomnia had significantly more functional impairment than those who did not. Additionally, the number of severe AEs (β=0.151, p<0.001) was associated with a higher SDS score, and those AEs with a negative causal attribution to antidepressants in the antiAS significantly affected the SDS (β=0.105, p=0.008). AEs of antidepressants should be carefully monitored since they could negatively affect their daily function.

Objective: The use of an algorithm may facilitate measurement-based treatment and result in more rational therapy. We conducted a 1-year, open-label study to compare various outcomes of algorithm-based treatment (ALGO) for schizophrenia versus treatment-as-usual (TAU), for which evidence has been very scarce. Methods: In ALGO, patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were treated with an algorithm consisting of a series of antipsychotic monotherapies that was guided by the total scores in the positive and negative syndrome scale (PANSS). When posttreatment PANSS total scores were above 70% of those at baseline in the first and second stages, or above 80% in the 3rd stage, patients proceeded to the next treatment stage with different antipsychotics. In contrast, TAU represented the best clinical judgment by treating psychiatrists. Results: Forty-two patients (21 females, 39.0 10.9 years-old) participated in this study. The baseline PANSS total score indicated the presence of severe psychopathology and was significantly higher in the ALGO group (n=25; 106.9 ± 20.0) than in the TAU group (n = 17; 92.2 ± 18.3) (P = 0.021). As a result of treatment, there were no significant differences in the PANSS reduction rates, premature attrition rates, as well as in a variety of other clinical measures between the groups. Despite an effort to make each group unique in pharmacologic treatment, it was found that pharmacotherapy in the TAU group eventually became similar in quality to that of the ALGO group. Conclusion: While the results need to be carefully interpreted in light of a hard-to-distinguish treatment manner between the two groups and more studies are necessary, algorithm-based antipsychotic treatments for schizophrenia compared well to treatment-as-usual in this study.

BACKGROUND: Although clozapine is primarily used in a younger to mid-life population of patients with psychosis, there are limited data on the clinical pharmacology of clozapine later in life. The objective of this study was to assess the magnitude and variability of plasma concentrations of clozapine and norclozapine across the lifespan in a real-world clinical setting. DESIGN: A population pharmacokinetic study using nonlinear mixed effect modeling (NONMEM). Age, sex, height, weight, and dosage formulation were covariates. SETTING: Inpatients and outpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007. PARTICIPANTS: Patients ranging in ages from 11 to 79 with schizophrenia spectrum disorders and prescribed clozapine (Clozaril). MEASUREMENTS: A total of 1142 plasma clozapine and norclozapine concentrations (2,284 concentration measurements) from 391 patients with schizophrenia spectrum disorder. RESULTS: A one-compartment model with first-order absorption and elimination best described the data. The population predicted clearance of clozapine for females was 27.1 L/h (SE 11.1%) and 36.7 L/h (SE 9.7%) for males. For norclozapine, clearance in females was 48.6 L/h (SE 10.8%) and 63.1 L/h (SE 9.3%) in males. The only covariates with a significant effect on clearance were age and sex: clearance for both parent and metabolite decreased exponentially with age at least 39 years. CONCLUSIONS: Decreased clearance of clozapine and norclozapine with age results in increased blood concentrations and, hence, the potential for adverse drug reactions. These findings have particular clinical relevance for the dosing and safety monitoring of clozapine in older adults, highlighting a need for increased vigilance.

As people with schizophrenia grow older, prevention of falls in this older population has become a public health priority. It is therefore critically important to identify risk factors to effectively prevent falls. For this purpose, the degree of postural sway can serve as a convenient index of risk assessment. The objective of this study was to find clinical and demographic characteristics associated with postural instability. Inpatients and outpatients with schizophrenia or related psychosis were recruited at 2 hospitals in Japan. The clinical stabilometric platform, which measured a range of the trunk motion, and extrapyramidal side effects were evaluated between 9 and 11 a.m. Four hundred two subjects were enrolled (age: mean, 55.5 [SD, 14.4] years). A univariate general linear model showed that the use of antipsychotic drugs with a chlorpromazine equivalent of 10 or greater, being overweight, and inpatient treatment setting were associated with a greater degree of the range of postural sway. Another general linear model, including a subgroup of 300 subjects who did not present any extrapyramidal side effects, not only consolidated these findings, but also revealed a great degree of postural sway in older subjects. In addition, quetiapine was found to be associated with a greater range of postural sway among atypical antipsychotics. Schizophrenia patients generally showed a greater degree of postural instability, compared with the reference data of healthy people. These findings highlight truncal instability as a risk factor of falls in patients with schizophrenia, especially when they are overweight, old, and/or receiving antipsychotics with a chlorpromazine equivalent of 10 or greater, including quetiapine.

Objective: Most difficult inpatients with schizophrenia are in serious needs but obviously underrepresented in clinical trials. Methods: Very challenging patients received open-label treatment with atypical antipsychotics concurrently augmented with valproic acid. The primary outcome was the newly developed Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz). Patients improving more than 20 points were classified as responders. Results: Mean age and illness duration of 28 participants (22male) were 42 y.o. and 20 years, respectively. They had spent a half of their life admitted after the onset. The average Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) were very severe at 79 and 6.1, respectively, with the baseline Global Assessment of Functioning (GAF) of as low as 21. As a result of augmentation, there were nine responders, 12 partial responders, and seven non-responders including only two patients who got worse. The main antipsychotics were mostly either risperidone or olanzapine. Mean maximum oral dose and blood level of valproic acid were 1907 mg and 91.7μg/ml, respectively. Overall significant improvements whilst to an inadequate degree were noted in clinical parameters. Valproate augmentation was generally well tolerated but serious adverse effects included thrombocytopenia, anaemia and sedation/falls. Conclusions: While these preliminary results need to be tested against tenacious monotherapy or polypharmacy involving clozapine, augmenting atypical antipsychotics with valproic acid can be useful for very severe schizophrenia.

© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd. Background and Objectives: Altered trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors has been reported in postmortem studies and suggested the involvement of AMPA receptors in the pathophysiology underpinning addictive disorders. However, these findings seemed mixed. Methods: A systematic literature search was conducted, using PubMed and Embase (last search, August 2018), to identify human postmortem studies that examined the expression of proteins and mRNA of AMPA receptor subunits in patients with addictive disorders in comparison with healthy controls. Results: Twelve (18 studies) out of 954 articles were identified to be relevant. Eight studies included alcohol use disorders, and four studies included heroin/cocaine abusers. The most frequently investigated regions were the hippocampus (three studies), amygdala (three studies), and putamen (three studies). In summary, two out of the three studies showed an increase in the expression of AMPA receptors in the hippocampus, while the other study found no change. Two studies to examine the amygdala demonstrated either a decreased or no change in receptor expression or binding. Concerning putamen, two studies showed no significant change whereas an overexpression of receptors was observed in the other. Conclusions and Scientific Significance: The hippocampus and amygdala may be pertinent to addictive disorders through their functions on learning and memory, whereas findings in other regions were inconsistent across the studies. Human postmortem studies are prone to degenerative changes after death. Moreover, only qualitative assessment was conducted because of the limited, heterogenous data. These limitations emphasize the need to investigate AMPA receptors in the living human brains.

© 2019 Elsevier Ltd The objective of this study was to investigate possible circadian pattern of psychotic symptoms in patients with schizophrenia, which could be reflected on the dosing schedule/regimen, i.e. chrono-pharmacology. Patients with schizophrenia (ICD-10) who reported having auditory hallucination, receiving monotherapy with risperidone, olanzapine or paliperidone for at least two weeks were included. The subjects were provided a diary and asked to record the time and duration of auditory hallucinations during the eight time periods (i.e. 00:00–03:00, 03:00–06:00, 06:00–09:00, 09:00–12:00, 12:00–15:00, 15:00–18:00, 18:00–21:00, and 21:00–24:00). In the diary, times of medication doses and sleep were also recorded. Time and degree of peak and trough dopamine D2 receptor blockade with antipsychotics were estimated from 2 sparsely collected plasma drug concentrations. The prevalence and duration of auditory hallucinations were statistically examined among the eight time periods, respectively. Forty-nine patients participated in this study (mean ± SD age, 50.7 ± 14.8 years; 36 men (73.5%); 34 inpatients (69.4%)). Auditory hallucinations occurred most frequently and lasted for the longest duration in the period of 18:00–21:00 (75.5% (37/49) and 1.37 ± 1.67 h). This happened despite the fact that the difference in D2 receptor occupancy between the peak and trough was less than 2%, indicating a stable drug delivery. Since the dopamine D2 receptor blockade by antipsychotics was stable, the nocturnal circadian pattern found in this study may reflect intrinsic dopaminergic fluctuation or generally quieter environments at night. These circadian patterns may be considered to devise individualized treatment approach in the context of “chrono-pharmacology” for patients with schizophrenia.

© 2015 Elsevier Ltd. The aim of this study is to evaluate whether an adjunct antidepressant therapy at a higher dose to a mood stabilizer would make a difference in the treatment of bipolar depression. This is a post-hoc analysis of the data from the randomized treatment for acute depression of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment with a mood stabilizer plus adjunctive antidepressant drugs or placebo. According to the highest dose received in the course of treatment, the subjects were divided into one of the following three groups: high-dose, low-dose and placebo groups. The primary and secondary outcomes were durable recovery (which was operationally defined as eight consecutive weeks with =2 symptoms) and treatment-emergent affective switch (i.e. transition to mania or hypomania), respectively. In the evaluable 333 subjects, subjects in both the high-dose (n=102) and placebo groups (n=169) more significantly achieved durable recovery than the low-dose group (n=62) (odds ratio=3.013 [p=0.009], 2.899 [p=0.008], respectively). No significant association was found between the dose status and treatment-emergent affective switch (p=0.614). The allocation to either high- and low-dose antidepressants was not randomized and the dose was guided by a case-by-case decision, which hampers to draw a firm conclusion on dose-response issues and renders the findings as preliminary. Nevertheless, higher doses of adjunctive antidepressant drugs seem to have potential for yielding greater clinical improvement without increasing any risk of manic switch compared to lower doses, at least in carefully selected patients.

Objective: It remains unclear whether antipsychotic polypharmacy, a common clinical practice, is related to an increased risk of corrected time between start of Q wave and end of T wave (QTc) interval prolongation. We conducted a systematic review of the literature to address this important issue. Method: A systematic literature search was conducted in October 2014, using MEDLINE, Embase, and PsycINFO. Studies and case reports were included if they reported QTc intervals or QTc interval changes before and after antipsychotic polypharmacy or QTc intervals in both antipsychotic polypharmacy and monotherapy groups. Results: A total of 21 articles (10 clinical trials, 4 observational studies, and 7 case reports) met inclusion criteria. The clinical trials have shown that a combination treatment with risperidone or pimozide is not obviously related to an increase in QTc interval, whereas ziprasidone or sertindole combined with clozapine may prolong QTc interval. Among the 4 observational studies, antipsychotic polypharmacy was not clearly associated with QTc prolongation in 3 studies, each cross-sectional. In contrast, one prospective study showed a significant increase in QTc interval following antipsychotic coadministration. The case reports indicated an increased risk of QTc prolongation in at least some patients receiving antipsychotic polypharmacy. Conclusions: Currently available evidence fails to confirm that antipsychotic polypharmacy worsens QTc prolongation in general, although the evidence is scarce and inconsistent. Clinicians are advised to remain conservative in resorting to antipsychotic polypharmacy, as a combination of some QTc-prolongation liable antipsychotics may further prolong QTc interval, and efficacy supporting the clinical benefits of antipsychotic polypharmacy is equivocal, at best.

While combining antipsychotics is common in schizophrenia treatment, the literature on the reasons for antipsychotic polypharmacy (APP) is limited. We aimed to identify prescriber attitudes and rationales for APP in Japan where high APP utilization is reported. Two-hundred and seventeen psychiatrists participated in the survey, which assessed APP attitudes and behaviors. Prescribing APP to 47.7±24.7% (mean±S.D.) of their patients, psychiatrists reported that they were "moderately" concerned about APP. The most APP-justifiable factors were (1="not at all" to 5="extreme") cross titration (4.50±0.67), randomized controlled evidence (3.67±0.83), and treatment of comorbid conditions (3.31±0.83). Conversely, APP-discouraging factors were chronic side effects (4.14±0.64), difficulty determining cause and effect (4.07±0.74), and acute side effects (3.99±0.81). Comparing high to low APP prescribers (>50% vs. ≤50% of patients), no differences emerged regarding APP justification and concerns. In multivariate analyses, high APP use was associated with practice at a psychiatric hospital (OR: 2.70, 95% CI: 1.29-5.67, p=0.009), concern about potential drug-drug interactions (OR: 1.56, 95% CI: 1.04-2.35, p=0.031), and less reliance on case reports of APP showing efficacy (OR: 0.64, 95% CI: 0.44-0.92, p=0.017) (r2=0.111, p=0.001). High and low APP prescribers shared a comparable degree of justifications and concerns. Future research should examine the impact of cultural determinants on APP. © 2013 Elsevier Ireland Ltd.

Objective: Antipsychotic treatment strategy for the maintenance phase of schizophrenia has been inconsistent in the literature. The purpose of this systematic review is to overview recommendations in various guidelines and algorithms. Methods: The guidelines and algorithms for schizophrenia that were published or updated in English after 2000 were searched, using Medline, PubMed, EMBASE, and PsycINFO with the following key words: guideline, algorithm, schizophrenia, and psychosis (last search: July 2011). The reference lists of the relevant reports were also examined. Results: Fourteen guidelines and algorithms were identified; only five of them clearly defined terms about the maintenance phase and treatment. Ten of 11 guidelines and algorithms did not recommend discontinuation of antipsychotics within five years; six of them partially recommended antipsychotic discontinuation for patients with first-episode schizophrenia exclusive. All nine guidelines and algorithms that referred to intermittent or targeted antipsychotic strategy endorsed against this strategy. Although being a hot topic of controversy, dose reduction of antipsychotics or lower dose therapy in the maintenance phase compared to the acute dosage is not recommended on the whole concerning atypical antipsychotics, whereas dose reduction appears sometimes considered acceptable for typical antipsychotics. Conclusion: What constitutes maintenance phase and its treatment in schizophrenia has not yet been established in the literature. While discontinuation and intermittent or targeted strategies are not generally recommended, there is controversy regarding dose reduction or lower dose therapy, especially with regards to atypical antipsychotics. Further evidence is needed in order to derive treatment recommendations on antipsychotics in this critical treatment phase of schizophrenia. © 2011 Elsevier B.V.