Switching from 2 antipsychotics to 1 antipsychotic in schizophrenia: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: Antipsychotic polypharmacy (APP) is employed routinely, although it remains controversial because robust evidence supporting its efficacy is lacking. In addition, it is associated with increased costs, higher antipsychotic dosing, and greater risk of side effects. Surprisingly, no prospective, randomized, double-blind studies have addressed this issue; the present investigation set out to fill this gap in knowledge. METHOD: A 12-week, double-blind, randomized, placebo-controlled, single-site study was carried out in individuals with schizophrenia or schizoaffective disorder (DSM-IV) receiving a designated primary antipsychotic plus a secondary antipsychotic, with doses stabilized for each. Individuals were randomly assigned to APP (N = 17), reflecting current treatment, or antipsychotic monotherapy (APM) (N = 18), in which the secondary antipsychotic was discontinued. Assessments occurred weekly during month 1 and every 2 weeks during months 2 and 3; the primary outcome measure was the Brief Psychiatric Rating Scale (BPRS) total score. Other measures included the Clinical Global Impressions (CGI) scale, Simpson-Angus Scale, and Barnes Akathisia Scale. The study was carried out between August 2006 and March 2011. RESULTS: Withdrawal due to clinical deterioration occurred in 1 individual receiving APP (5.8%) and in 4 individuals in the APM group (22.2%). Overall, however, there was no indication of clinical worsening with APM, as measured using BPRS and CGI scale. CONCLUSIONS: Almost 80% (n = 14) of individuals with schizophrenia or schizoaffective disorder currently receiving APP could be safely transitioned to APM with no clinical deterioration. For those who do deteriorate, risk appears greatest in the first several months. From another perspective, results also indicate that a minority of individuals benefit from APP, and research focusing on identifying this group may represent the best strategy to curb excessive use of APP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00493233.

Helmet-Wearing Practices and Barriers in Toronto Bike-Share Users: a Case-Control Study.

BACKGROUND: Helmet use among bike-share users is low. We sought to characterize helmet-use patterns, barriers to helmet use, and cycling safety practices among bike-share users in Toronto. METHODS: A standardized survey of public bike-share program (PBSP) users at semi-random distribution of PBSP stations was undertaken. By maintaining a ratio of one helmet-wearer (HW): two non-helmet-wearers (NHW) per survey period, we controlled for location, day, time, and weather. RESULTS: Surveys were completed on 545 (180 HW, 365 NHW) unique users at 48/80 PBSP locations, from November 2012 to August 2013. More females wore helmets (F: 41.1%, M: 30.9%, p=0.0423). NHWs were slightly younger than HWs (NHW mean age 34.4 years vs HW 37.3, p=0.0018). The groups did not differ by employment status, education, or income. Helmet ownership was lower among NHWs (NHW: 62.4% vs HW: 99.4%, p<0.0001), as was personal bike ownership (NHW: 65.8%, vs HW: 78.3%, p=0.0026). NHWs were less likely to always wear a helmet on personal bikes (NHW: 22.2% vs HW: 66.7%, p<0.0001), and less likely to wear a helmet always or most of the time on PBSP (NHW: 5.8% vs HW: 92.3%, p<0.0001). Both groups, but more HWs, had planned to use PBSP when leaving their houses (HW: 97.2% vs NHW: 85.2%, p<0.0001), primarily to get to work (HW: 88.3% vs NHW: 84.1%, p=0.19). NHWs were more likely to report that they would wear a helmet more (NHW: 61.4% vs HW: 13.9%, p<0.0001), and/or cycle less (NHW: 22.5% vs HW: 4.4%) if helmet use was mandatory. CONCLUSIONS: PBSP users surveyed appear to make deliberate decisions regarding helmet use. NHWs tended to be male, slightly younger, and less likely to use helmets on their personal bikes. As Toronto cyclists who do not wear helmets on PBSP generally do not wear helmets on their personal bikes, interventions to increase helmet use should target both personal and bike-share users. Legislating helmet use and provision of rental helmets could improve helmet use among bike-share users, but our results suggest some risk of reduced cycling with legislation.

A knowledge translation intervention to improve tuberculosis care and outcomes in Malawi: a pragmatic cluster randomized controlled trial.

BACKGROUND: Lay health workers (LHWs) play a pivotal role in addressing the high TB burden in Malawi. LHWs report lack of training to be a key barrier to their role as TB care providers. Given the cost of traditional off-site training, an alternative approach is needed. Our objective was to evaluate the effectiveness of a KT intervention tailored to LHWs needs. METHODS: The study design is a pragmatic cluster randomized trial. The study was embedded within a larger trial, PALMPLUS, and compared three arms which included 28 health centers in Zomba district, Malawi. The control arm included 14 health centers randomized as controls in the larger trial and maintained as control sites. Seven of 14 PALMPLUS intervention sites were randomized to the LHW intervention (PALM/LHW intervention arm), and the remaining 7 PALMPLUS sites maintained as a PALM only arm. PALMPLUS intervention sites received an educational outreach program targeting mid-level health workers. LHW intervention sites received both the PALMPLUS intervention and the LHW intervention employing on-site peer-led educational outreach and a point-of-care tool tailored to LHWs identified needs. Control sites received no intervention. The main outcome measure is the proportion of treatment successes. RESULTS: Among the 28 sites, there were 178 incident TB cases with 46/80 (0.58) successes in the control group, 44/68 (0.65) successes in the PALMPLUS group, and 21/30 (0.70) successes in the PALM/LHW intervention group. There was no significant effect of the intervention on treatment success in the univariate analysis adjusted for cluster randomization (p = 0.578) or multivariate analysis controlling for covariates with significant model effects (p = 0.760). The overall test of the intervention-arm by TB-type interaction approached but did not achieve significance (p = 0.056), with the interaction significant only in the control arm [RR of treatment success for pulmonary TB relative to non-pulmonary TB, 1.18, 95% CI 1.05-1.31]. CONCLUSIONS: We found no significant treatment effect of our intervention. Given the identified trend for effectiveness and urgent need for low-cost approaches to LHW training, further evaluation of tailored KT strategies as a means of LHW training in Malawi and other LMICs is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01356095 .

Associations of medical comorbidity, psychosis, pain, and capacity with psychiatric hospital length of stay in geriatric inpatients with and without dementia.

ABSTRACT Background: Geriatric psychiatry hospital beds are a limited resource. Our aim was to determine predictors of hospital length of stay (LOS) for geriatric patients with dementia admitted to inpatient psychiatric beds. Methods: Admission and discharge data from a large urban mental health center, from 2005 to 2010 inclusive, were retrospectively analyzed. Using the resident assessment instrument - mental health (RAI-MH), an assessment that is used to collect demographic and clinical information within 72 hours of hospital admission, 169 geriatric patients with dementia were compared with 308 geriatric patients without dementia. Predictors of hospital LOS were determined using a series of general linear models. Results: A diagnosis of dementia did not predict a longer LOS in this geriatric psychiatry inpatient population. The presence of multiple medical co-morbidities had an inverse relationship to length of hospital LOS - a greater number of co-morbidities predicted a shorter hospital LOS in the group of geriatric patients who had dementia compared to the without dementia study group. The presence of incapacity and positive psychotic symptoms predicted longer hospital LOS, irrespective of admission group (patients with dementia compared with those without). Conversely, pain on admission predicted shorter hospital LOS. Conclusions: Specific clinical characteristics generally determined at the time of admission are predictive of hospital LOS in geriatric psychiatry inpatients. Addressing these factors early on during admission and in the community may result in shorter hospital LOS and more optimal use of resources.

Therapeutic window for striatal dopamine D(2/3) receptor occupancy in older patients with schizophrenia: a pilot PET study.

OBJECTIVE: In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D(2/3) 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 D(2/3) 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 D(2/3) 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 D(2/3) 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% D(2/3) RRO. CONCLUSION: EPS diminished less than 70% D(2/3) 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.

Perceptions of positive contributions and burnout in community developmental disability workers.

Research on staff supporting individuals with intellectual and developmental disabilities (IDD) tends to focus on negative aspects of the work. This study expanded on previous research on the positive consequences that work in the IDD field has on staff using a brief version of the Staff Positive Contributions Questionnaire with 926 staff. Factor analysis suggested two factors: General positive contributions and Positive work motivation. Positive work motivation was associated with high levels of personal accomplishment, but shared limited variance with the other two burnout dimensions (emotional exhaustion, depersonalization). Findings lend support to the idea that we need to consider both positive and negative aspects of work life. This brief scale may be a useful index of how staff benefit from their work.

Low maternal sensitivity at 6 months of age predicts higher BMI in 48 month old girls but not boys.

BACKGROUND: Large population-based studies suggest that systematic measures of maternal sensitivity predict later risk for overweight and obesity. More work is needed to establish the developmental timing and potential moderators of this association. The current study examined the association between maternal sensitivity at 6 months of age and BMI z score measures at 48 months of age, and whether sex moderated this association. DESIGN: Longitudinal Canadian cohort of children from birth (the MAVAN project). METHODS: This analysis was based on a dataset of 223 children (115 boys, 108 girls) who had structured assessments of maternal sensitivity at 6 months of age and 48-month BMI data available. Mother-child interactions were videotaped and systematically scored using the Maternal Behaviour Q-Sort (MBQS)-25 items, a standardized measure of maternal sensitivity. Linear mixed-effects models and logistic regression examined whether MBQS scores at 6 months predicted BMI at 48 months, controlling for other covariates. RESULTS: After controlling for weight-relevant covariates, there was a significant sex by MBQS interaction (P=0.015) in predicting 48 month BMI z. Further analysis revealed a strong negative association between MBQS scores and BMI in girls (P=0.01) but not boys (P=0.72). Logistic regression confirmed that in girls only, low maternal sensitivity was associated with the higher BMI categories as defined by the WHO (i.e. "at risk for overweight" or above). CONCLUSIONS: A significant association between low maternal sensitivity at 6 months of age and high body mass indices was found in girls but not boys at 48 months of age. These data suggest for the first time that the link between low maternal sensitivity and early BMI z may differ between boys and girls.

Effects of intracerebroventricular (ICV) olanzapine on insulin sensitivity and secretion in vivo: an animal model.

The atypical antipsychotics (AAPs) have been associated with an increased risk of type 2 diabetes. While weight gain associated with AAPs is a risk factor for diabetes, preclinical work suggests that among these medications, olanzapine, when given peripherally in a single dose, causes pronounced effects on insulin sensitivity and secretion. Given a critical role of the hypothalamus in control of glucose metabolism, we examined the effect of central administration of olanzapine. Sprague-Dawley rats were treated with a single 75 µg intracerebroventricular (ICV) dose of olanzapine and tested using separate hyperinsulinemic-euglycemic and hyperglycemic clamps. Dosing of olanzapine was established based on inhibition of amphetamine-induced locomotion. In contrast to the single dosing peripheral paradigm, there was no effect of central olanzapine on insulin sensitivity, either with respect to hepatic glucose production or peripheral glucose uptake. Analogous to the peripheral model, a single ICV dose of olanzapine followed by the hyperglycemic clamp decreased insulin (p=0.0041) and C-peptide response (p=0.0039) to glucose challenge as compared to vehicle, mirrored also by a decrease in the steady state glucose infusion rate required to maintain hyperglycemia (p=0.002). In conclusion, we demonstrate novel findings that at least part of the effect of olanzapine on beta-cell function in vivo is central.

Acute effects of single-dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls.

Atypical antipsychotics may "directly" influence glucose homeostasis, increasing risk of type 2 diabetes independently of changes in adiposity. Animal models suggest direct effects after even a single dose of certain atypical antipsychotics on glucose dysregulation. Here, we investigated effects of a single-dose olanzapine (OLA) on glucose metabolism in healthy volunteers, thereby minimizing confounding effects of the illness of schizophrenia and adiposity. In a randomized double-blind crossover design, 15 subjects were administered 10 mg of OLA or placebo at 7:00 A.M. on separate study dates. A frequently sampled intravenous glucose tolerance test was initiated 4.25 hours later to assess changes in glucose homeostasis, including an index of insulin sensitivity, disposition index, glucose effectiveness, and acute insulin response to glucose. We also examined effects on cortisol, prolactin, fasting free fatty acids (FFAs), insulin-mediated suppression of FFAs, and adipocytokines (leptin, adiponectin, C-reactive protein, interleukin 6, and tumor necrosis factor α). Complete data for both visits were analyzed for 12 subjects. Olanzapine treatment significantly decreased glucose effectiveness (P = 0.041) and raised fasting glucose over 4.25 hours (P = 0.03) as compared to placebo. Olanzapine was associated with lower serum cortisol (P = 0.003), lower fasting FFA (P = 0.042), and increased prolactin levels (P < 0.0001). We therefore suggest that a single dose of OLA may invoke early changes in some parameters of glucose and lipid metabolism, as well as endocrine indices.

Childhood maltreatment and aggressive behaviour in violent offenders with psychopathy.

OBJECTIVE: To document experiences of childhood maltreatment among violent offenders with antisocial personality disorder (ASPD) distinguishing between those with and without the syndrome of psychopathy (+P and -P), and to determine whether maltreatment is associated with proactive and reactive aggression. METHOD: The sample included 10 violent offenders with ASPD+P, 15 violent offenders with ASPD-P, and 15 non offenders. All participants completed interviews with the same forensic psychiatrist focusing on physical, sexual, and emotional abuse prior to age 18 using the Early Trauma Inventory. Aggression was assessed using the Reactive-Proactive Questionnaire. RESULTS: Violent offenders with ASPD+P reported significantly more severe childhood physical abuse, but not more sexual or emotional abuse, than violent offenders with ASPD-P and non offenders. Psychopathy Checklist-Revised (PCL-R) scores, but not childhood physical abuse, were associated with proactive aggression. Childhood physical abuse was associated with reactive aggression, as was an interaction term indicating that when both PCL-R scores and childhood physical abuse were high, so was reactive aggression. CONCLUSIONS: Among violent offenders, PCL-R scores were positively associated with proactive aggression, while experiences of childhood maltreatment were not. This finding concurs with previous studies of children and adults and suggests that proactive aggression may be a behavioural marker of psychopathic traits. By contrast, childhood physical abuse was associated with reactive aggression, even among violent offenders with high PCL-R scores. This latter finding suggests a strong influence of childhood physical abuse on the development of reactive aggression that persists over the lifespan.

Objectif : Documenter les expériences de maltraitance dans l'enfance chez les délinquants violents souffrant du trouble de la personnalité antisociale (TPA) en distinguant entre ceux avec syndrome de psychopathie et sans (+P et ­P), et déterminer si la maltraitance est associée à l'agressivité proactive et réactive. Méthode : L'échantillon comprenait 10 délinquants violents souffrant du TPA+P, 15 délinquants violents souffrant du TPA­P, et 15 non-délinquants. Tous les participants ont été interviewés par le même psychiatre légiste à propos des abus physiques, sexuels, et émotionnels subis avant l'âge de 18 ans, à l'aide de l'inventaire des traumatismes précoces. L'agressivité a été évaluée par le questionnaire de l'agressivité réactive­proactive. Résultats : Les délinquants violents souffrant du TPA+P rapportaient des abus physiques dans l'enfance significativement plus graves, mais pas plus d'abus sexuels ou émotionnels que les délinquants violents souffrant du TPA­P et que les non-délinquants. Les scores à la liste de contrôle révisée de la psychopathie (PCL-R), mais pas l'abus physique dans l'enfance, étaient associés à l'agressivité proactive. L'abus physique dans l'enfance était associé à l'agressivité réactive, comme l'était une interaction qui indiquait que lorsque les scores à la PCL-R et l'abus physique dans l'enfance étaient élevés, l'agressivité réactive l'était aussi. Conclusions : Chez les délinquants violents, les scores à la PCL-R étaient positivement associés à l'agressivité proactive, alors que les expériences de maltraitance dans l'enfance ne l'étaient pas. Ce résultat est en conformité avec les études précédentes d'enfants et d'adultes et suggère que l'agressivité proactive peut être un marqueur comportemental de traits psychopathiques. Par contre, l'abus physique dans l'enfance était associé à l'agressivité réactive, même chez les délinquants violents ayant des scores élevés à la PCL-R. Ce dernier résultat suggère une forte influence de l'abus physique dans l'enfance sur le développement de l'agressivité réactive qui persiste durant la vie.

Pathways into the criminal justice system for individuals with intellectual disability.

BACKGROUND: Studies focusing on pathways in the criminal justice system for individuals with intellectual disability are limited in that they only study individuals once they are involved in the system and do not consider the pathways into it. The purpose of this study is to examine predisposing factors that lead to various outcomes for individuals with intellectual disability when police are called to respond to their behavioural crises. METHOD: The current study examined the outcome of police response to 138 individuals with intellectual disability in crisis. Following police intervention, 15 individuals were arrested, 76 were taken to the emergency department and 47 received on-scene resolution. Comparisons between the three groups were conducted. RESULTS: The three groups differed in terms of residence at the time of crisis, history of forensic involvement and type of crisis. Police intervention with adults with intellectual disability can happen for different reasons. Both individual and situational predictors explained this outcome.

Antipsychotic response in first-episode schizophrenia: efficacy of high doses and switching.

Clinicians treating schizophrenia routinely employ high doses and/or antipsychotic switching to achieve response. However, little is actually known regarding the value of these interventions in early schizophrenia. Data were gathered from a treatment algorithm implemented in patients with first-episode schizophrenia that employs two antipsychotic trials at increasing doses before clozapine. Patients were initially treated with either olanzapine or risperidone across three dose ranges, (low, full, high), and in the case of suboptimal response were switched to the alternate antipsychotic. We were interested in the value of (a) high dose treatment and (b) antipsychotic switching. A total of 244 patients were evaluated, with 74.5% (184/244) responsive to Trial 1, and only 16.7% (10/60) responsive to Trial 2. Percentage of response for subjects switched from olanzapine to risperidone was 4.0% (1/25) vs. 25.7% (9/35) for those switched from risperidone to olanzapine. High doses yielded a 15.5% response (14.6% for risperidone vs. 16.7% for olanzapine).The present findings concur with other research indicating that response rate to the initial antipsychotic trial in first-episode schizophrenia is robust; thereafter it declines notably. In general, the proportion of responders to antipsychotic switching and high dose interventions was low. For both strategies olanzapine proved superior to risperidone, particularly in the case of antipsychotic switching (i.e. risperidone to olanzapine vs. vice versa). It remains to be established whether further antipsychotic trials are associated with even greater decrements in rate of response. Findings underscore the importance of moving to clozapine when treatment resistance has been established.

Atypical antipsychotics and effects of adrenergic and serotonergic receptor binding on insulin secretion in-vivo: an animal model.

Atypical antipsychotics (AAPs) are associated with several metabolic sequelae including increased risk of type 2 diabetes. Growing evidence points to a direct drug effect of these compounds on glucose homeostasis, independent of weight gain. While the responsible mechanisms have yet to be elucidated, the heterogeneous binding profiles of AAPs likely include receptors involved in glucose metabolism. This study aimed to clarify weight-gain independent mechanisms of AAP-induced alterations in insulin secretion. Deconstruction of the receptor binding profiles of these agents was done using representative antagonists. Healthy rats were pre-treated with a single subcutaneous dose of prazosin 0.25mg/kg (n = 16), a selective α1 antagonist; idazoxan 0.5mg/kg (n = 10), a selective α2 antagonist; SB242084 0.5mg/kg (n = 10), a selective 5HT2C antagonist; WAY100635 0.1mg/kg (n = 10), a selective 5HT1A antagonist; MDL100907 0.5mg/kg (n = 8), a selective 5HT2A antagonist; or vehicle: 0.9% NaCl saline (n = 8), DMSO (n = 8), or cyclodextrin (n = 5). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic ß-cells. Treatment with prazosin and MDL100907 resulted in significant decreases in both insulin and C-peptide secretion compared to their respective controls, DMSO and saline. These findings were corroborated with decreased glucose infusion rate and disposition index in the prazosin group. Results suggest that α1 and 5HT2A receptor antagonism may be involved in glucose dysregulation with AAP treatment, however, the exact mechanisms involved remain unknown.

Effects of tobacco smoking on neuropsychological function in schizophrenia in comparison to other psychiatric disorders and non-psychiatric controls.

BACKGROUND AND OBJECTIVES: Compared to the general population cigarette smoking prevalence is elevated in psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). These disorders are also associated with neurocognitive impairments. Cigarette smoking is associated with improved cognition in SZ. The effects of smoking on cognition in BD and MDD are less well studied. METHODS: We used a cross-sectional design to study neuropsychological performance in these disorders as a function of smoking status. Subjects (N = 108) were SZ smokers (n = 32), SZ non-smokers (n = 15), BD smokers (n = 10), BD non-smokers (n = 6), MDD smokers (n = 6), MDD non-smokers (n = 10), control smokers (n = 12), and control non-smokers (n = 17). Participants completed a neuropsychological battery; smokers were non-deprived. RESULTS: SZ subjects performed significantly worse than controls in select domains, while BD and MDD subjects did not differ from controls. Three verbal memory outcomes were improved in SZ smokers compared with non-smokers; smoking status did not alter performance in BD or MDD. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These data suggest that smoking is associated with neurocognitive improvements in SZ, but not BD or MDD. Our data may suggest specificity of cigarette-smoking modulation of neurocognitive deficits in SZ.

Cognitive performance of individuals with schizophrenia across seven decades: a study using the MATRICS consensus cognitive battery.

OBJECTIVES: The objectives of this study were to determine the effect of aging, schizophrenia, and their interaction on cognitive function. DESIGN: Cross-sectional controlled study. SETTING: Community living. PARTICIPANTS: A total of 235 subjects with schizophrenia age 19-79 and 333 comparison subjects age 20-81. MEASUREMENTS: The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). RESULTS: Older age was associated with poorer performance on 9 of 10 MCCB tests in both subjects with schizophrenia and comparison subjects. Subjects with schizophrenia were impaired relative to comparison subjects on each of the 10 tests. However, there was no interaction between aging and schizophrenia on any test. Essentially the same results were observed when analyzing performance on the seven MCCB cognitive domains and MCCB global composite score. CONCLUSIONS: Consistent with other reports, schizophrenia appears to be a disorder marked by generalized cognitive dysfunction. However, the rate of cognitive decline appears to be similar to that observed in healthy comparison subjects. They do not experience acceleration in cognitive aging, which supports the hypothesis that schizophrenia is a syndrome of premature aging. Longitudinal studies including very old patients are needed to confirm and extend these findings.

Analysis of 34 candidate genes in bupropion and placebo remission.

There is considerable variability in the rate of response and remission following treatment with antidepressant drugs or placebo in depression patients. No pharmacogenetic studies of bupropion response have been done. We investigated 532 tagging single nucleotide polymorphisms (SNPs) in 34 candidate genes for association with remission and response to either bupropion (n=319) or placebo (n=257) in patients with major depressive disorder. Analyses were performed using conditional logistic regression. Significant association (gene-wide correction) was observed for remission following treatment with bupropion for a SNP within the serotonin receptor 2A gene (HTR2A rs2770296, p(corrected)=0.02). Response to bupropion treatment was significantly associated with a SNP in the dopamine transporter gene (rs6347, p(corrected)=0.013). Among the patients who received placebo, marginal association for remission was observed between a SNP in HTR2A (rs2296972, p(corrected)=0.055) as well as in the serotonin transporter gene (5-HTT or SLC6A4 rs4251417, p(corrected)=0.050). Placebo response was associated with SNPs in the glucocorticoid receptor gene (NR3C1; rs1048261, p(corrected)=0.040) and monoamine oxidase A gene (MAOA; rs6609257, p corrected=0.046). Although the above observations were significant after gene-wide corrections, none of these would be significant after a more conservative study-wide correction for multiple tests. These results suggest a possible role for HTR2A in remission to bupropion treatment. In accordance with bupropion pharmacology, dopamine transporter may play a role in response. The MAOA gene may be involved in placebo response.

Can repetitive magnetic stimulation improve cognition in schizophrenia? Pilot data from a randomized controlled trial.

BACKGROUND: Working memory represents a core cognitive domain that is impaired in schizophrenia for which there are currently no satisfactory treatments. Repetitive transcranial magnetic stimulation (rTMS) targeted over the dorsolateral prefrontal cortex has been shown to modulate neurophysiological mechanisms linked to working memory in schizophrenia and improves working memory performance in healthy subjects and might therefore represent a treatment modality for schizophrenia patients. The objectives were to evaluate the effects of rTMS on working memory performance in schizophrenia patients and evaluate whether rTMS normalizes performance to healthy subject levels. METHODS: In a 4-week randomized double-blind sham-controlled pilot study design, 27 medicated schizophrenia patients were tested at the Centre for Addiction and Mental Health (a university teaching hospital that provides psychiatric care to a large urban catchment area and serves as a tertiary referral center for the province of Ontario). Patients performed the verbal working memory n-back task before and after rTMS magnetic resonance image targeted bilaterally sequentially to left and right dorsolateral prefrontal cortex 750 pulses/side at 20 Hz for 20 treatments. The main outcome measure was mean magnitude of change in the n-back accuracy for target responses with active (n = 13) or sham (n = 12) rTMS treatment course. RESULTS: The rTMS significantly improved 3-back accuracy for targets compared with placebo sham (Cohen's d = .92). The improvement in 3-back accuracy was also found to be at a level comparable to healthy subjects. CONCLUSIONS: These pilot data suggest that bilateral rTMS might be a novel, efficacious, and safe treatment for working memory deficits in patients with schizophrenia.

Therapeutic Window for Striatal Dopamine D2/3 Receptor Occupancy in Older Patients With Schizophrenia: A Pilot PET Study.

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 [C]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.

Predicting hospital length of stay for geriatric patients with mood disorders.

OBJECTIVE: To determine predictors of hospital length of stay (LOS) for adult and geriatric patients with mood disorders admitted to inpatient psychiatric beds. METHOD: Admission and discharge data from a large urban mental health centre, from 2005 to 2010 inclusive, were retrospectively analyzed. Using the Resident Assessment Instrument-Mental Health, an assessment that is used to collect demographic and clinical information within 72 hours of hospital admission, 199 geriatric mood disorder admissions were compared with 570 adult mood disorder admissions. Predictors of hospital LOS were determined using a series of general linear models. RESULTS: Living alone, number of recent psychiatric admissions, involuntary admission, and close or constant observation level predict longer hospital LOS in geriatric, but not in adult mood disorder, patients. Conversely, pain on admission predicts shorter hospital LOS in geriatric, but not among adult, mood disorder patients. Predictors of longer hospital LOS, irrespective of admission group (adult, compared with geriatric), include incapacity, negative symptoms, and increased dependence for instrumental activities of daily living. CONCLUSIONS: Addressing these predictive factors early on during admission and in the community may result in shorter hospital LOS and more optimal use of resources.

A randomized controlled trial of psychoeducation or cognitive-behavioral therapy in bipolar disorder: a Canadian Network for Mood and Anxiety treatments (CANMAT) study [CME].

OBJECTIVE: Bipolar disorder is insufficiently controlled by medication, so several adjunctive psychosocial interventions have been tested. Few studies have compared these psychosocial treatments, all of which are lengthy, expensive, and difficult to disseminate. We compared the relative effectiveness of a brief psychoeducation group intervention to a more comprehensive and longer individual cognitive-behavioral therapy intervention, measuring longitudinal outcome in mood burden in bipolar disorder. METHOD: This single-blind randomized controlled trial was conducted between June 2002 and September 2006. A total of 204 participants (ages 18-64 years) with DSM-IV bipolar disorder type I or II participated from 4 Canadian academic centers. Subjects were recruited via advertisements or physician referral when well or minimally symptomatic, with few exclusionary criteria to enhance generalizability. Participants were assigned to receive either 20 individual sessions of cognitive-behavioral therapy or 6 sessions of group psychoeducation. The primary outcome of symptom course and morbidity was assessed prospectively over 72 weeks using the Longitudinal Interval Follow-up Evaluation, which yields depression and mania symptom burden scores for each week. RESULTS: Both treatments had similar outcomes with respect to reduction of symptom burden and the likelihood of relapse. Eight percent of subjects dropped out prior to receiving psychoeducation, while 64% were treatment completers; rates were similar for cognitive-behavioral therapy (6% and 66%, respectively). Psychoeducation cost $180 per subject compared to cognitive-behavioral therapy at $1,200 per subject. CONCLUSIONS: Despite longer treatment duration and individualized treatment, cognitive-behavioral therapy did not show a significantly greater clinical benefit compared to group psychoeducation. Psychoeducation is less expensive to provide and requires less clinician training to deliver, suggesting its comparative attractiveness. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00188838.