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OBJECTIVE: Clinical investigators in Japan have long suggested that exposure to methamphetamine might cause a persistent schizophrenia-like psychosis. This possibility is discounted in the Western literature. To investigate the relationship between drug use and later schizophrenia, the authors conducted a large-scale cohort study of drug users initially free of persistent psychosis. METHOD: A population-based cohort study was conducted using data from California inpatient hospital discharge records from 1990 through 2000. Patients with methamphetamine-related conditions (N=42,412) and those with other drug use disorders (cannabis, cocaine, alcohol, and opioids) were propensity score-matched to individuals with primary appendicitis who served as a population proxy comparison group; the methamphetamine cohort was also matched to the other drug cohorts. Cox modeling was used to estimate differences between matched groups in the rates of subsequent admission with schizophrenia diagnoses. RESULTS: The methamphetamine cohort had a significantly higher risk of schizophrenia than the appendicitis group (hazard ratio=9.37) and the cocaine, opioid, and alcohol groups (hazard ratios ranging from 1.46 to 2.81), but not significantly different from that of the cannabis group. The risk of schizophrenia was higher in all drug cohorts than in the appendicitis group. CONCLUSIONS: Study limitations include difficulty in confirming schizophrenia diagnoses independent of drug intoxication and the possibility of undetected schizophrenia predating drug exposure. The study's findings suggest that individuals with methamphetamine-related disorders have a higher risk of schizophrenia than those with other drug use disorders, with the exception of cannabis use disorders. The elevated risk in methamphetamine users may be explained by shared etiological mechanisms involved in the development of schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: To describe the socio-demographic characteristics and clinical outcomes of patients who leave the emergency department (ED) without being seen by a physician.Methods: This 3-month prospective study was conducted at a downtown Toronto teaching hospital. Patients who left the ED without being seen (LWBS) were matched with controls based on registration time and triage level. Subjects and controls were interviewed by telephone within 1 week after leaving the ED.Results: During the study period, 386 (3.57%) of 10 808 ED patients left without being seen. One-third of these had no fixed address or no telephone, and only 92 (23.8%) consented to a telephone interview. They cited excessive wait time as the most common reason for leaving the ED (in 36.7% of cases). Despite leaving the ED without being seen, they were no more likely than those in the control group to seek follow-up medical attention (70% in both groups). Among those from both groups who did seek follow-up, the LWBS patients were more likely to do so the same day or the day after leaving the ED. The LWBS patients often lacked a regular physician (39.1% v. 21.7%; p = 0.01) and were more likely to attend an ED or urgent care clinic (34.8% v. 12.0%; p < 0.001). Controls were more likely to follow up with a family physician (37.0% v. 23.9%; p = 0.06). The LWBS and control groups did not differ in subjective health status at 48 hours after leaving the ED, nor in subsequent re-investigation in hospital.Conclusions: Patients who leave the ED without being seen have different socio-demographic features, methods of accessing the health care system, affiliations and expectations than the general ED population. They are often socially disenfranchised, with limited access to traditional primary care. These patients are generally low acuity, but they are at risk of important and avoidable adverse outcomes. [ABSTRACT FROM AUTHOR]

Objectives: To assess patient comprehension of emergency department discharge instructions and to describe other predictors of patient compliance with discharge instructions.Methods: Patients departing from the emergency department of an inner-city teaching hospital were invited to undergo a structured interview and reading test, and to participate in a follow-up telephone interview 2 weeks later. Two physicians, blinded to the other's data, scored patient comprehension of discharge information and compliance with discharge instructions. Inter-rater reliability was assessed using a kappa-weighted statistic, and correlations were assessed using Spearman's rank correlation coefficient and Fisher's exact test.Results: Of 106 patients approached, 88 (83%) were enrolled. The inter-rater reliability of physician rating scores was high (kappa = 0.66). Approximately 60% of subjects demonstrated reading ability at or below a Grade 7 level. Comprehension was positively associated with reading ability (r = 0.29, p = 0.01) and English as first language (r = 0.27, p = 0.01). Reading ability was positively associated with years of education (r = 0.43, p < 0.0001) and first language (r = 0.24, p = 0.03), and inversely associated with age (r = -0.21, p = 0.05). Non-English first language and need for translator were associated with poorer comprehension of discharge instructions but not related to compliance. Compliance with discharge instructions was correlated with comprehension (r = 0.31, p = 0.01) but not associated with age, language, education, years in anglophone country, reading ability, format of discharge instructions, follow-up modality or association with a family physician.Conclusions: Emergency department patients demonstrated poor reading skills. Comprehension was the only factor significantly related to compliance; therefore, future interventions to improve compliance with emergency department instructions will be most effective if they focus on improving comprehension. [ABSTRACT FROM AUTHOR]

Abstract Background The context of the current study was mandatory adoption of electronic clinical documentation within a large mental health care organization. Psychiatric electronic documentation has unique needs by the nature of dense narrative content. Our goal was to determine if speech recognition (SR) would ease the creation of electronic progress note (ePN) documents by physicians at our institution. Methods Subjects: Twelve physicians had access to SR software on their computers for a period of four weeks to create ePN. Measurements: We examined SR software in relation to its perceived usability, data entry time savings, impact on the quality of care and quality of documentation, and the impact on clinical and administrative workflow, as compared to existing methods for data entry. Data analysis: A series of Wilcoxon signed rank tests were used to compare pre- and post-SR measures. A qualitative study design was used. Results Six of twelve participants completing the study favoured the use of SR (five with SR alone plus one with SR via hand-held digital recorder) for creating electronic progress notes over their existing mode of data entry. There was no clear perceived benefit from SR in terms of data entry time savings, quality of care, quality of documentation, or impact on clinical and administrative workflow. Conclusions Although our findings are mixed, SR may be a technology with some promise for mental health documentation. Future investigations of this nature should use more participants, a broader range of document types, and compare front- and back-end SR methods.

The article reports on a study showing that haloperidol and olanzapine begin to reduce psychosis in people with schizophrenia spectrum disorders who are experiencing acute agitation within 24 hours of administration. The study revealed that the clinical effects of antipsychotics occur earlier than previously thought.

Objective: Treatment of schizophrenia (SCZ) was revolutionized with the development of the antipsychotic medications. Although imaging studies have linked antipsychotic D₂ receptor occupancy and clinical response in SCZ, heterogeneity between cohorts and methods has made it challenging to generalize findings across studies. The main objective of this meta-analysis was to analyze the relationship between in vivo estimation of typical and atypical antipsychotic D₂ receptor occupancy and treatment response in SCZ.Methods: Using the keywords "dopamine D₂ receptor occupancy," "schizophrenia," "PET/SPECT" and "antipsychotics," and further refining our search to journal articles with information on % striatal D₂ occupancy and % change in clinical symptoms as indexed by either the BPRS or the PANSS, our final analysis consisted of 16 imaging studies (20 cohorts; N=206).Results: The first step of the meta-analysis confirmed the positive relationship between antipsychotic medication and clinical improvement in SCZ (ES=1.36; 95% CI: 1.13-1.60). The second step of our analysis revealed that when D₂ occupancy was limited to less than 80% in order to control for the appearance of extrapyramidal symptoms, high D₂ occupancy was correlated with reduction in clinical scores (r=0.4, p<0.001) for medications other than clozapine or quetiapine.Conclusions: Our results suggest that D₂ occupancy is a contributing factor for the mechanism of antipsychotic effect in SCZ for some but not all antipsychotic medications. [ABSTRACT FROM AUTHOR]

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.

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., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

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 .

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.

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.)

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.

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., (© 2013 Elsevier B.V. and ECNP. All rights reserved.)

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., (© 2013 John Wiley & Sons Ltd.)

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.

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 β-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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

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.

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., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © American Academy of Addiction Psychiatry.)

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.

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.

Objective: While a significant body of research has demonstrated high comorbidity rates between depression and obesity, the vast majority of this work has considered depression as a unitary diagnosis. Given that increased appetite and weight gain are highly characteristic of the "atypical" subtype of depression, while classic depression is characterized by decreased appetite and weight loss, it would be important to examine whether increased obesity risk is consistent across the major vegetative subtypes of depression or is limited to the atypical subtype., Method: Using data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we identified 5,092 US adults with past or current major depression based on DSM-IV-TR criteria and 1,500 gender-matched controls. Each depressed subject was designated as having classic, atypical, or undifferentiated depression based on core vegetative symptoms. Logistic regression models examined rates of current obesity (defined as a current body mass index [kg/m2] > 30) across the 3 depressive subgroups and nondepressed controls, adjusting for demographic differences. To limit the possible effect of current depressive symptoms on observed obesity rates, secondary analyses were completed in individuals with past depression only., Results: Subjects with atypical depression had markedly elevated obesity rates compared to population controls and to other depressed subjects, with corresponding pairwise odds ratios consistently greater than 2.0 (P < .001). In contrast, obesity rates were not significantly different in subjects with classic depression and nondepressed controls. These results were manifest in individuals with either current or past depression and were independent of gender and age., Conclusions: While many individuals with classic depression will present with obesity due to the high prevalence of both disorders, only atypical depression is associated with an elevated risk of obesity relative to the population at large. Refining the target phenotype(s) for future work on depression and obesity might improve our understanding, prevention, and treatment of this complex clinical problem., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

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., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Objective: Early, effective treatment in first-episode schizophrenia is advocated, although evidence based on a systematic approach over multiple antipsychotic trials is lacking. Employing a naturalistic design, we examined response rates over 3 circumscribed antipsychotic trials., Method: Between June 2003 and December 2008, 244 individuals with first-episode schizophrenia or schizoaffective disorder according to DSM-IV criteria were treated at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, following an algorithm that moved them through 2 antipsychotic trials, followed by a trial with clozapine. For the first 2 trials, treatment consisted of risperidone followed by olanzapine, or vice versa; each trial consisted of 3 stages (low-, full-, or high-dose) lasting up to 4 weeks at each level and adjusted according to response/tolerability. Clinical response was defined as a Clinical Global Impressions-Improvement score of 2 (much improved) or 1 (very much improved) and/or a Brief Psychiatric Rating Scale Thought Disorder subscale score ≤ 6. Data were analyzed retrospectively, and publication of anonymized clinical data was approved by the Research Ethics Board of the Centre for Addiction and Mental Health in May 2003., Results: In trial 1, 74.5% of individuals responded, with rates significantly higher for olanzapine (82.1%, 115/140) versus risperidone (66.3%, 69/104; P = .005). With trial 2, response rate dropped dramatically to 16.6% but again was significantly higher for olanzapine (25.7%, 9/35) compared to risperidone (4.0%, 1/25; P = .04). Response rate climbed above 70% once more, specifically 75.0% (21/28), in those individuals who agreed to a third trial with clozapine., Conclusions: Results confirm a high response rate (75%) to initial antipsychotic treatment in first-episode schizophrenia. A considerably lower response rate (< 20%) occurs with a second antipsychotic trial. Results here were specific to olanzapine and risperidone, suggesting clinical differences (ie, olanzapine more effective than risperidone). A subsequent trial with clozapine is clearly warranted, although it remains unclear whether outcome would be further enhanced if it were used earlier in the treatment algorithm., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Background: Improvements are greatest in the earlier weeks of antipsychotic treatment of patients with non-resistant schizophrenia., Aims: To address the early time-line for improvement with antipsychotics in treatment-resistant schizophrenia., Method: Randomised double-blind trials of antipsychotic medication in adult patients with treatment-resistant schizophrenia were investigated (last search June 2010). A series of metaregression analyses were carried out to examine the effect of time on the average item scores in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) at three or more distinct time points within the first 6 weeks of treatment., Results: Study duration varied from 4 weeks to 1 year and the definitions of treatment resistance as well as of treatment response were not necessarily consistent across 19 identified studies, resulting in highly variable rates of response (0–76%).The mean standardised baseline item score in the PANSS or BPRS was 3.4 (s.e. = 0.06) in the five studies included in the meta-regression analysis, with the average baseline Clinical Global Impression – Severity score being 5.2 (marked illness). For the pooled population treated with a range of antipsychotics (n = 1019), significant reductions in the mean item scores occurred during the first 4 weeks; improvements observed in later weeks were smaller and non-significant. In contrast, weekly improvement with clozapine was significant throughout (n = 356)., Conclusions: Our findings provide preliminary evidence that the majority of improvement with antipsychotics may occur relatively early.More consistent improvements with clozapine may be associated with a gradual titration. To further elucidate response patterns, future studies are needed to provide data over regular intervals during earlier stages of treatment.

The atypical antipsychotics (AAPs) have been associated with increased risk of type-2 diabetes. Evidence suggests direct, drug-related effects independent of weight gain and although mechanisms underlying this phenomenon are unclear, it has been suggested that the heterogeneous receptor binding profile of the AAPs may influence receptors implicated in glucose metabolism. This study aimed to clarify weight gain-independent mechanisms of AAP-induced changes in insulin secretion by deconstructing their binding profile with representative antagonists. Healthy rats were pretreated with a single subcutaneous dose of darifenacin 6 mg/kg (n=10), a selective M(3) muscarinic antagonist; ketanserin 2mg/kg (n=10), a 5HT(2A) antagonist; raclopride 0.3mg/kg (n=11) a selective D(2)/D(3) antagonist; terfenadine 20mg/kg (n=9) a selective H(1) antagonist; or, vehicle (n=11). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic β-cells. Acute treatment with darifenacin and ketanserin significantly decreased insulin response to glucose challenge as compared to controls, which was confirmed in the darifenacin group by reduced C-peptide levels. Treatment with raclopride resulted in an increased insulin response and a strong tendency to increased C-peptide levels. H(1) blockade did not result in effects on insulin or C-peptide. Results suggest that the effects of antipsychotics on glucose dysregulation may be related to direct inhibitory effects of muscarinic (M(3)) and serotonergic (5HT(2)) antagonism on insulin secretion. Based on the expression of D(2)-like receptors in β-cells, which mediate inhibition of insulin secretion, we propose that prolonged D(2) blockade with antipsychotics may predispose to depletion of insulin stores and an eventual defect in pancreatic compensation., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Background: It remains unknown as to whether the antipsychotic dose needed for the acute-phase treatment of schizophrenia is also necessary for relapse prevention., Aim: To compare the efficacy between standard dose [(World Health Organization daily defined dose (DDD)] vs low dose (≥50% to <1 DDD) or very low dose (<50% DDD) for relapse prevention in schizophrenia., Data Source: Double-blind, randomized, controlled trials with a follow-up duration of ≥24 weeks, including ≥2 dosage groups of the same antipsychotic drug for relapse prevention in schizophrenia, were searched using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE (last search: August 2009)., Data Extraction: Data on overall treatment failure, hospitalization, relapse, and dropouts due to side effects were extracted and combined in a meta-analysis., Data Synthesis: Thirteen studies with 1395 subjects were included in this meta-analysis. Compared with the standard-dose treatment, the low-dose therapy did not show any statistically significant difference in overall treatment failure or hospitalization, while the standard dose showed a trend-level (P = .05) superiority in risk of relapse. The very low-dose group was inferior to the standard-dose group in all efficacy parameters. No significant difference was found in the rate of dropouts due to side effects between either standard dose vs low dose or very low dose., Conclusions: Although antipsychotic treatment with ≥50% to <1 DDD may be as effective as standard-dose therapy, there are insufficient clinical trial data to draw firm conclusions on standard- vs low-dose maintenance antipsychotic therapy for schizophrenia.

Background: Gamma (γ) oscillations (30-50 Hz) have been shown to be excessive in patients with schizophrenia (SCZ) during working memory (WM). WM is a cognitive process that involves the online maintenance and manipulation of information that is mediated largely by the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS) represents a non-invasive method to stimulate the cortex that has been shown to enhance cognition and γ oscillatory activity during WM., Methodology and Principal Findings: We examined the effect of 20 Hz rTMS over the DLPFC on γ oscillatory activity elicited during the N-back task in 24 patients with SCZ compared to 22 healthy subjects. Prior to rTMS, patients with SCZ elicited excessive γ oscillatory activity compared to healthy subjects across WM load. Active rTMS resulted in the reduction of frontal γ oscillatory activity in patients with SCZ, while potentiating activity in healthy subjects in the 3-back, the most difficult condition. Further, these effects on γ oscillatory activity were found to be specific to the frontal brain region and were absent in the parieto-occipital brain region., Conclusions and Significance: We suggest that this opposing effect of rTMS on γ oscillatory activity in patients with SCZ versus healthy subjects may be related to homeostatic plasticity leading to differential effects of rTMS on γ oscillatory activity depending on baseline differences. These findings provide important insights into the neurophysiological mechanisms underlying WM deficits in SCZ and demonstrated that rTMS can modulate γ oscillatory activity that may be a possible avenue for cognitive potentiation in this disorder.