Published papers

Objective: The concept of resilience is relevant in understanding the heterogeneous outcomes noted in schizophrenia and bipolar disorder. However, clinical and biological correlates of resilience in these populations have rarely been investigated. We aimed to identify key correlates of subjective resilience in such patients using comprehensive assessments and to explore associations between resilience levels and peripheral biomarkers. Method: 180 subjects with DSM-IV schizophrenia, bipolar disorder, and healthy controls (60 per group) were included. Demographic and clinical variables were assessed by means of interview and various psychometric scales. Furthermore, blood and saliva samples were obtained for the assessment of brain-derived neurotrophic factor, adrenocorticotropic hormone, cortisol, high sensitivity C-reactive protein, and alpha-amylase levels. Cross-sectional associations with resilience, as assessed by the 25-item Resilience Scale were sought. Results: Resilience Scale total scores were significantly higher in healthy individuals (130.1, 95% confidence intervals (CI): 124.8-135.4) compared to subjects with schizophrenia (109.9, 95% CI: 104.6-115.2, p.

IMPORTANCE Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D2/3 receptor (D2/3R) occupancies remain largely unexplored in patients with LLS. OBJECTIVE To evaluate effects of antipsychotic dose reduction on striatal dopamine D2/3R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS. DESIGN, SETTING, AND PARTICIPANTS An open-label, single-arm prospective study with a 3- To 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015. INTERVENTIONS Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction. MAIN OUTCOMES AND MEASURES Striatal dopamine D2/3R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels). RESULTS Dopamine D2/3R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D2/3R occupancy associated with clinical stabilitywas 50%. Extrapyramidal symptoms (EPSs)were more likely to occur with D2/3R occupancies higher than 60%: 90.5%(19 of 21) of the participants with baseline EPSs and 76.9%(10 of 13) of the participants with postreduction EPSs had striatal D2/3R occupancies higher than 60%. The baseline D2/3R occupancieswere lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58%[15%] vs 72%[10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased. CONCLUSIONS AND RELEVANCE Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D2/3R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

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

Objective: The objective of this study was to synthesize the available evidence regarding the impact of patients' language proficiency on access to psychiatric care. Methods: A systematic literature search of PubMed, EMBASE, Medline, and PsycINFO was performed to identify studies published between January 1950 and July 2014 that examined the impact of language proficiency on access to and utilization of psychiatric services in the general population or among patients with psychiatric disorders. The keywords were psychiatry, language, utilization, access, and mental health care. Only articles in English were included. Cross-referencing of the identified articles was also performed. Results: Eighteen articles from four countries were identified, including 13 from the United States, two from Australia, two from Canada, and one from the Netherlands. These reports were generally consistent in showing a clear association between insufficient language proficiency and underutilization of psychiatric services; 15 studies reported that limited language proficiency was significantly associated with less frequent mental health care visits.Only one article showed an inverse relationship between limited language proficiency and use of mental health services, and two articles reported no association. No published data were found on the effects of linguistic interventions on access to mental health care among people with limited language proficiency. Conclusions: It is plausible that limited language proficiency is closely associated with underutilization of psychiatric services. Still, the lack of prospective interventional data clearly highlights the need for further investigations of the impact of language barriers on access to psychiatric care.

Introduction: There is no consensus regarding whether a previously prescribed, that is, failed, antidepressant should be continued or switched after a successful electroconvulsive therapy (ECT) for the maintenance of clinical remission in patients with treatment-resistant depression (TRD). In this study, we conducted a chart review to examine impacts of the antidepressant switch after the successful ECT on 1-year outcome in patients with TRD. MATERIALS AND Methods: This retrospective chart review included inpatients with TRD (ie, those who failed to respond to adequate trials of 2 distinctly different classes of antidepressants) who showed clinical remission after ECT. Readmission rate and social functioning 6 months and 1 year after the successful ECT were compared between patients who experienced an antidepressant switch and those who continued prior regimen. Results: Twenty-eight patients (mean age, 59 years; 9 men) were followed-up for 1 year. The patients who changed antidepressants after ECT (n = 7) experienced a readmission significantly less frequent than the others (n = 21) in 1 year (0% vs 43%, P = 0.043). In addition, the former showed significantly better social contacts at 6 months (P = 0.022) and 1 year (P = 0.015). There were no significant differences in baseline characteristics between the 2 groups. Conclusions: The patients who experienced an antidepressant switch after ECT required a readmission less frequently in 1 year than those who were maintained with the same antidepressant. The findings of this preliminary study suggest that a switch to another antidepressant after successful ECT may be encouraged for the maintenance of clinical remission in patients with TRD.

Age effects on dosing of antipsychotics in schizophrenia and mechanisms underlying those effects have not been well understood. The objective of this article is to review the literature regarding effects of age on antipsychotic dosing in schizophrenia and potential mechanisms underlying the age-related antipsychotic sensitivity. According to prescription surveys, age appears to have biphasic effects on prescribed antipsychotic dose. The dose increased with age through the third decade, subsequently plateaued, and decreased after the fifth decade. The first half of this inverted U-shaped relationship may be attributable to a deterioration process in the early phase of schizophrenia and the contribution of 'tachyphylaxis' of antipsychotics on the dopaminergic system. The following age-related decline in prescribed dose is likely associated with physiological aging. Recent data suggest that this increased antipsychotic sensitivity with age comes from age-related functional decline in the dopaminergic system, including endogenous dopamine level and dopamine receptor density. Although the evidence on potential mechanisms underlying age effects on antipsychotic dosing is still limited, alterations in the dopaminergic system due to aging and chronic exposure to this drug may contribute to the inverted U-shaped relationship between dose and age. This age-related antipsychotic sensitivity highlights the importance of finding the lowest possible effective dose of antipsychotic drugs as patients age to enhance therapeutic effects as well as minimize their side effects.

Background: Position emission tomography (PET) imaging using [18F]-setoperone to quantify cortical 5-HT2A receptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT2A receptor (5HT2AR) binding potential. The purpose of this study was to assess the test-retest variability of [18F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT2AR availability in subjects greater than 60 years old. Methods: Six healthy subjects (age range = 65-78 years) completed two [18F]-setoperone PET scans on two separate occasions 5-16 weeks apart. Results: The average difference in the binding potential (BPND) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions. Conclusion: We conclude that the test-retest variability of [18F]-setoperone PET in elderly subjects is comparable to that of [18F]-setoperone and other 5HT2AR radiotracers in younger subject samples.

The primary objective of this study was to evaluate the magnitude and variability of concentration exposure to clozapine and norclozapine in a real-world clinical setting, with a focus on smoking status, using population pharmacokinetic methodologies. A retrospective review of plasma clozapine and norclozapine concentrations taken from inpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007 was conducted. A nonlinear mixed-effects model was developed using NONMEM, including age, gender, weight, smoking status, and dosage formulation as covariates. Pharmacokinetic parameters and interindividual and residual variabilities were estimated with 1- and 2-compartment models. A total of 519 plasma clozapine concentrations from 197 patients (138 males; mean ± SD age, 38 ± 13 years; schizophrenia spectrum disorder 98.2%) were included for the analysis. A 1-compartment model with first-order absorption and elimination best described the data. Apparent volume of distribution was fixed to a previously reported value in the literature of 7 L/kg.The population-predicted oral clearance of clozapine and norclozapine was 18.0 and 39.0 L/h, respectively; both the predicted clearance values vary nearly 6-fold (range, 9.18-59.06 and 16.29-97.84 L/h, respectively). For clozapine, smokers and males showed increased oral clearance by 6.0 and 4.5 L/h, respectively. For norclozapine, smokers and male gender were associated with an increased oral clearance of 11.3 and 7.6 L/h, respectively. The formulation of clozapine administered had an impact on the absorption rate with a Ka of 0.14/h for tablet and 10.3/h for the suspension form.The data suggest that smoking and male gender are associated with lower exposure to clozapine and norclozapine due to the higher oral clearance. These findings may account for some of the variability in clozapine exposure and have important implications for individualized drug dosing and therapeutic drug monitoring.

Background: Adherence has recently been suggested to be divided into these two components: persistence (i.e., whether patients continue treatment or not) and compliance (i.e., whether patients take doses as instructed). However, no study has yet assessed these two clinically relevant components at the same time in adherence to antidepressant treatment in the clinical outpatient setting. Methods: In this retrospective chart-review, 6-month adherence to antidepressants was examined in 367 outpatients with a major depressive disorder (ICD-10) (170 males; mean ± SD age 37.6 ± 13.9 years), who started antidepressant treatment from April 2006 through March 2007. Additionally, we evaluated Medication Possession Rate (MPR), defined as the total days a medication was dispensed to patients divided by the treatment period. Results: Only 161 patients (44.3%) continued antidepressant treatment for 6 months. Among 252 patients who discontinued their initial antidepressant, 63.1% of these patients did so without consulting their physicians. Sertraline use was associated with a higher persistence rate at month 6 (odds ratio 2.59 in comparison with sulpiride), and the use of anxiolytic benzodiazepines had a positive effect on persistence to antidepressant treatment only at month 1 (odds ratio 2.14). An overall MPR was 0.77; 55.6% of patients were considered compliant (i.e., a MPR of ≥ 0.8). Conclusion: Given a high rate of antidepressant discontinuation without consulting their physicians, closer communication between patients and their physicians should be encouraged. Although the use of anxiolytic benzodiazepines was associated with a higher persistence to antidepressant treatment at month 1, the use of these drugs should be avoided as a rule, given their well-known serious adverse effects.

Since the literature on benzodiazepine use in elderly patients with anxiety disorders is limited, a large cross-sectional review of psychotropic prescriptions in 796 patients with neurotic disorders (ICD-10) (age range = 11-91 years) was conducted across 30 sites in Japan. Use of benzodiazepine-derivative anxiolytics was approximately 70% in all decades without a group difference. The proportion of subjects who received prescriptions for benzodiazepine-derivative anxiolytics in the absence of antidepressants was higher in older age groups (e.g., 27.7% and 43.2% in the third and sixth decades, respectively). On the other hand, antidepressants were less frequently prescribed in older age groups (e.g., 59.8% and 41.5% in the third and sixth decades, respectively). The very high use of anxiolytics in the elderly, especially in the absence of concomitant antidepressant use, is a cause for concern since they are not a preferred long-term treatment strategy given their adverse effects in the elderly.

Background: While antipsychotic-free schizophrenia patients showed a high degree of within-subject variability in dopamine D2 receptor density over 6-24 months, no study has examined the long-term stability of D2 receptor measures in medicated patients. Methods: Four schizophrenia patients receiving a stable dose of risperidone underwent [11C]raclopride positron emission tomography scans on two occasions 5-14 months apart. Results: Plasma risperidone levels were found to be consistent between scans, and consistencies of nondisplaceable D2 binding potential and D2 occupancy were good. Conclusions: The finding supports the validity of quantification of D2 receptor binding in longitudinal PET studies of medicated patients with schizophrenia.

OBJECTIVE:: It is generally held that the elderly are more sensitive to motor side effects of antipsychotics, although the mechanisms for such an effect are not fully understood. The objective of this study was to examine whether this sensitivity is due to a central pharmacokinetic (i.e., higher occupancy for a given plasma level) or pharmacodynamic (i.e., greater functional effects for a given occupancy) effect. DESIGN:: Crosssectional. SETTING:: Centre for Addiction and Mental Health, Toronto, Ontario, Canada. PARTICIPANTS:: Thirteen subjects aged 50 (mean ± standard deviation age: 62 ± 9 years) with schizophrenia or schizoaffective disorder who were receiving risperidone. MEASUREMENTS:: Dopamine D2 binding potential in the striatum, using [C]raclopride positron emission tomography scan. D2 receptor occupancy was calculated, using age-corrected measure from healthy individuals and region of interest analysis. RESULTS:: The authors observed the expected nonlinear relationship between total risperidone and 9-hydroxyrisperidone plasma level and striatal D2 receptor occupancy. The estimated plasma level of risperidone plus 9-hydroxyrisperidone associated with 50% maximal receptor occupancy was 7.3 ng/mL, which is similar to what has been reported in younger patients. However, extrapyramidal side effects (EPS) were observed in seven subjects at D2 occupancy of 34%-79%, occupancy levels that are lower than previously reported for younger patients in whom EPS are rare at occupancies lower than 80%. CONCLUSION:: The observation of greater functional effect (EPS in this case) for a given drug occupancy than the younger patients supports a pharmacodynamic mechanism for age-related antipsychotic drug sensitivity. This finding has important implications for dosing of antipsychotics in older patients with schizophrenia.

Objective: The primary objective of this article is to review the literature regarding clinical effects, pharmacokinetics, and pharmacodynamics of antipsychotics in older people and to examine potential mechanisms underlying the age-related antipsychotic sensitivity. Data Sources: Data for this review were identified by searches of PubMed (1950-2007) and references from relevant articles and books. Search terms included antipsychotic, neuroleptic, elderly, aging, pharmacokinetics, pharmacodynamics, and dopamine, and only articles written in English or Japanese were consulted. Data Selection: Studies, reviews, and books pertaining to the clinical effects, pharmacokinetics, and pharmacodynamics with regard to the use of antipsychotics in older patients were selected. Data Synthesis: The prevailing practices and clinical guidelines suggest that elderly patients can obtain therapeutic benefits at a lower dose and experience adverse effects from antipsychotics more often than younger patients, although there are still few trials that have directly compared elderly patients with the young. The literature suggests an age-related increase in brain access of drugs and demonstrates a decrease with age in the principal components in the dopaminergic system, including endogenous dopamine level and dopamine receptor density. Conclusions: While clinicians conclusively hold that patients become more sensitive to antipsychotics as they become older, this proposition has only modest empirical support and warrants further investigation. Age-related functional decline in the dopaminergic system predicts lower antipsychotic doses for older patients. We propose a hierarchical series of testable hypotheses to address the relative contribution of age-related pharmacokinetic and pharmacodynamic changes to antipsychotic drug sensitivity.

Patients with schizophrenia have many problems as well as symptoms, and various rating scales have been in use to address them. The authors review past representative rating scales and some pivotal studies to focus on treatment target in schizophrenia. Traditionally, positive symptoms have been the main target of treatment. However, other crucial domains such as negative and cognitive symptoms, and subjective perspectives are drawing due attention because of their clinical relevance. Given many domains to be addressed, there have eventually been too many assessment scales to be selected and widely utilized in real-world clinical settings, and there has been still no concrete consensus on which scales to utilize in a given situation, which is currently decided at the discretion of the investigators. Measurement is frequently difficult even with the existing assessments, especially as what constitutes an acceptable clinical status is hard to define, considering highly hetero generous nature of the illness. Many rating scales are met with limitations especially in time and in pragmatic comprehensiveness, which often hinder their routine application in time-limited busy settings. Still, problems and functioning of patients are the reasonable target to evaluate for measurement-based treatment. The authors suggest assessment of problems resulting from symptoms together with objective functioning, which clinical psychiatrists are actually doing in everyday practice, would serve as a minimum set of standardized assessment in schizophrenia, and the newly developed TIP-Sz and FACT-Sz would serve for that purpose. Other crucial viewpoints could be supplemented with (subjective) assessment scales as appropriate.