Search

OBJECTIVE: Investigators have reported that weight gain attributed to clozapine is associated with its clinical response. However, weight gain is a nonspecific physiological variable that, in itself, does not explain the mechanism underlying this relation. Alternatively, other biological variables that are often associated with weight gain, such as serum lipids, may assist in explaining this observation. The primary objective of this study was to determine whether an increase in serum lipids is associated with improvement in schizophrenia symptoms during steady state treatment with clozapine. METHODS: The data for this study represent a subset of data from a randomized, double-blinded trial that evaluated subjects with schizophrenia who demonstrated a poor treatment response to clozapine. While continuing their clozapine therapy, subjects were randomly assigned to receive either risperidone 3 mg daily or placebo for 8 weeks. This course of treatment was followed by an optional (open-label) 18 weeks of augmentation with risperidone. In the present study, we included all subjects from the previously reported trial who had fasting lipid analyses and Positive and Negative Syndrome Scale (PANSS) scores from days 7 and 63 (n = 55). For the primary analyses, we used multiple regression to examine the association between serum lipid concentrations and PANSS scores, after controlling for weight. RESULTS: The analyses showed that the change in serum lipid concentration predicted change in symptoms over that of change in weight. Specifically, an increase in serum triglyceride concentration was associated with a decrease in the total PANSS score (p = 0.037). In addition, an increase in either serum total cholesterol concentration (p = 0.007), serum triglyceride concentration (p = 0.017) or their combined effect (p = 0.010) was associated with a decrease in PANSS negative subscale scores. CONCLUSION: Elevation of serum lipids is associated with an improvement in schizophrenia symptoms in subjects treated with clozapine. Although the mechanism is unclear, serum lipids may play a role in influencing clozapine's therapeutic activity. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a chronic debilitating disease that affects approximately 110,000 Canadians (0.55% lifetime prevalence). Risperidone long-acting injection (RLAI) is the first injectable, long-acting, atypical antipsychotic drug marketed in Canada.Objective: The aim of this study was to assess the clinical effectiveness and hospitalization rates of patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder treated with RLAI in a community mental health care setting.Methods: Data were collected between August 1, 2006 and September 30, 2006 via a retrospective chart review of outpatients diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder who received treatment from 1 of the 8 mental health teams within the Vancouver Community Mental Health Organization (VCMHO) in Vancouver, British Columbia, Canada. Collected data included: frequency and duration of institutional care, discharge and relapse rates, demographic variables, diagnosis history, RLAI medication history, and history of other medications. The overall severity of symptoms before and after RLAI treatment and the improvement in symptoms during treatment were evaluated using the Clinical Global Impression Scales for severity (CGI-S)(1 = not ill to 7 = extremely ill) and improvement (CGI-I)(1 = very much improved to 7 = very much worse).Results: Forty-four patients were identified as having received RLAI. The charts of 19 patients (10 men, 9 women; mean [SD] age at time of chart audit, 36.7 [11.7] years; mean [SD] age at primary diagnosis, 23.6 [7.4] years; race: white, 10 [52.6%]; Asian, 6 [31.6%]; American Indian, 1 [5.3%]; black, 1 [5.3%]; other, 1 [5.3%]) were included in the analysis. The majority of patients (78%) had been treated with another antipsychotic drug prior to treatment with RLAI: risperidone (77%), quetiapine (47%), zuclopenthixol (43%), olanzapine (43%), and loxapine (17%). Mean (SD) CGI-S Scale score declined significantly from 5.29 (1.3) before treatment initiation to 3.05 (1.0) posttreatment (P < 0.001). Mean (SD) CGI-I Scale score was 2.58 (0.71) (P < 0.001); 94% of patients had a CGI-I score

Antipsychotics are the only therapeutic class indicated in the symptomatic management of psychotic disorders. However, individuals diagnosed with schizophrenia or schizoaffective disorder may not always benefit from these first-line agents. This refractoriness to conventional treatment can be difficult to address in most clinical settings. Therefore, a referral to a tertiary-care program that is better able to deliver specialized care in excess of the needs of most individuals may be necessary. The average outcome following a period of treatment at these programs tends to be one of improvement. Nonetheless, accurate prognostication of individual-level responses may be useful in identifying those who are unlikely to improve despite receiving specialized care. Thus, the main objective of this study was to predict symptom severity around the time of discharge from the Refractory Psychosis Program in British Columbia, Canada using only clinicodemographic information and prescription drug data available at the time of admission. To this end, a different boosted beta regression model was trained to predict the total score on each of the five factors of the Positive and Negative Syndrome Scale (PANSS) using a data set composed of 320 hospital admissions. Internal validation of these prediction models was then accomplished by nested cross-validation. Insofar as it is possible to make comparisons of model performance across different outcomes, the correlation between predictions and observations tended to be higher for the negative and disorganized factors than the positive, excited, and depressed factors on internal validation. Past scores had the greatest effect on the prediction of future scores across all 5 factors. The results of this study serve as a proof of concept for the prediction of symptom severity using this specific approach., Competing Interests: RP reports personal fees from Janssen, Lundbeck and Otsuka. WH reports personal fees from Canadian Agency for Drugs and Technology in Health, AlphaSights, Guidepoint, Translational Life Sciences, Otsuka, Lundbeck, and Newron; grants from Canadian Institutes of Health Research, BC Mental Health and Addictions Services; and has been a consultant (non-paid) for In Silico. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Procyshyn, White, Gicas, Honer and Barr.)

Aim: Long acting injectable (LAI) antipsychotics are an alternative to oral antipsychotic (OAP) treatment and may be beneficial for patients in the early stages of schizophrenia. This study aims to provide a comprehensive review on the efficacy of first-generation and second-generation LAI antipsychotics in recent-onset, first-episode, and early psychosis patients., Methods: MEDLINE, EMBASE, PsycINFO, and Web of Science Core databases were used to search for studies that used LAIs in early psychosis patients. Studies published up to 06 Jun 2019 were included with no language restrictions applied. Inclusion criteria were a diagnosis of schizophrenia or related disorder, where patients were in their first episode or had a duration of illness ≤5 years., Results: 33 studies were included: 8 RCTs, 4 post-hoc analyses, 2 case reports, and 19 naturalistic studies. The majority of studies evaluated risperidone LAIs (N = 14) and paliperidone palmitate (N = 10), while the remainder investigated fluphenazine decanoate (N = 3), flupentixol decanoate (N = 2), and aripiprazole (N = 1). Two studies did not specify the LAI formulation used, and one cohort study compared the efficacy of multiple different LAI formulations., Conclusions: While the majority of data is based on naturalistic studies investigating risperidone LAIs or paliperidone palmitate, LAIs may be an effective treatment for early psychosis patients in terms of adherence, relapse reduction, and symptom improvements. There is still a need to conduct more high quality RCTs that investigate the efficacy of different LAI formulations in early psychosis patients., Competing Interests: WGH has received consulting fees or sat on paid advisory boards for the Canadian Agency for Drugs and Technology in Health, AlphaSights, In Silico (unpaid), Newron, Translational Life Sciences and Otsuka/Lundbeck. RMP has received consulting fees or sat on paid advisory boards for Janssen, Lundbeck and Otsuka; is on the speaker’s bureau for Janssen, Lundbeck and Otsuka. All other authors have no conflict of interest to declare.

The second-generation antipsychotic drugs are widely used in the field of psychiatry, for an expanding number of different conditions. While their clinical efficacy remains indispensable, many of the drugs can cause severe metabolic side-effects, resulting in an increased risk of developing cardiometabolic disorders. The physiological basis of these side-effects remains an ongoing area of investigation. In the present study, we examined the potential role of peripheral catecholamines in antipsychotic-induced glucose intolerance. Adult female rats were acutely treated with either the first-generation antipsychotic drug haloperidol (0.1, 0.5 or 1 mg/kg) or the second-generation drugs risperidone (0.25, 1.0 or 2.5 mg/kg), olanzapine (1.5, 7.5 or 15 mg/kg) or clozapine (2, 10 or 20 mg/kg) or vehicle. Fasting glucose levels were measured and then animals were subjected to the intraperitoneal glucose tolerance test. Levels of peripheral norepinephrine, epinephrine and dopamine were concurrently measured in the same animals 75, 105 and 135 min after drug treatment. All antipsychotics caused glucose intolerance, with strongest effects by clozapine > olanzapine > risperidone > haloperidol. Plasma catecholamines were also increased by drug treatment, with greatest effects for norepinephrine and epinephrine caused by clozapine > risperidone > olanzapine > haloperidol. Importantly, there were strong and statistically significant associations between norepinephrine/epinephrine levels and glucose intolerance for all drugs. These findings confirm that increases in peripheral catecholamines co-occur in animals that exhibit antipsychotic-induced glucose intolerance, and these effects are strongly associated with each other, providing further evidence for elevated catecholamines as a substrate for antipsychotic metabolic side-effects., Competing Interests: WH has received consulting fees or sat on paid advisory boards for: Guidepoint, In Silico Biosciences, Translational Life Sciences, AbbVie and Newron. RP has been a member of the following advisory boards in the past 3 years: Janssen, Lundbeck, and Otsuka; a member of the following speaker’s bureaus in the past 3 years: Janssen, Lundbeck, and Otsuka; and received grants from the Canadian Institutes of Health Research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Boyda, Pham, Huang, Ho, Procyshyn, Yuen, Honer and Barr.)

Competing Interests: R.M. Procyshyn has received consulting fees or sat on paid advisory boards for Janssen, Lundbeck and Otsuka and is on the speakers bureau for Eisai, Janssen, Lundbeck and Otsuka. No other competing interests were declared.

The Iowa Gambling Task (IGT) is a widely used measure of decision making, but its value in signifying behaviors associated with adverse, "real-world" consequences has not been consistently demonstrated in persons who are precariously housed or homeless. Studies evaluating the ecological validity of the IGT have primarily relied on traditional IGT scores. However, computational modeling derives underlying component processes of the IGT, which capture specific facets of decision making that may be more closely related to engagement in behaviors associated with negative consequences. This study employed the Prospect Valence Learning (PVL) model to decompose IGT performance into component processes in 294 precariously housed community residents with substance use disorders. Results revealed a predominant focus on gains and a lack of sensitivity to losses in these vulnerable community residents. Hypothesized associations were not detected between component processes and self-reported health-risk behaviors. These findings provide insight into the processes underlying decision making in a vulnerable substance-using population and highlight the challenge of linking specific decision making processes to "real-world" behaviors., Competing Interests: WH has received consulting fees or sat on Advisory Boards for the Translational Life Sciences (TLS), AlphaSights, GuidePoint, Newron, In silico, AbbVie, and Otsuka and holds shares in TLS and AbCellera. AB has received consulting fees or sat on Advisory Boards for the Bristol-Myers Squibb, Eli Lilly, and Roche. AR has received Advisory Board fees from the Hofmann-La Roche. GM has received consulting fees or sat on paid advisory boards for Apotex, AstraZeneca, BMS, Janssen, Lundbeck, Otsuka, Pfizer, and Sunovion and also received fees for lectures sponsored by the AstraZeneca, BMS, Janssen, Otsuka, and Eli Lilly, and has received grants from the Janssen Pharmaceuticals. RP has received speaking and Advisory Board fees from the Janssen, Lundbeck, and Otsuka. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Baitz, Jones, Campbell, Jones, Gicas, Giesbrecht, Loken Thornton, Barone, Wang, Panenka, Lang, Vila-Rodriguez, Leonova, Barr, Procyshyn, Buchanan, Rauscher, MacEwan, Honer and Thornton.)

Early intervention is essential for favorable long-term outcomes in schizophrenia. However, there is limited guidance in the scientific literature on how best to choose between dopamine D 2 receptor (D 2 R) partial agonists and D 2 R antagonists in early stages of schizophrenia. The aim of this meta-analysis was to directly compare D 2 R partial agonists with D 2 R antagonists for efficacy and tolerability, using randomized controlled trials (RCTs) that involved participants diagnosed with first-episode psychosis, schizophrenia, or related psychotic disorders with a duration of illness ≤5 years. Fourteen RCTs, involving 2494 patients, were included in the meta-analysis. Aripiprazole was the only identified D 2 R partial agonist, and was not significantly different from pooled D 2 R antagonists for overall symptom reduction or all-cause discontinuation. However, aripiprazole was more favorable than pooled D 2 R antagonists for depressive symptoms, prolactin levels, and triglyceride levels. Specifically, aripiprazole was more favorable than paliperidone for triglyceride levels and more favorable than risperidone and olanzapine, but less favorable than ziprasidone, for weight gain. In addition, aripiprazole was less favorable for akathisia compared with second-generation D 2 R antagonists, in particular olanzapine and quetiapine, and less favorable for discontinuation due to inefficacy than risperidone. Lastly, aripiprazole was more favorable than haloperidol for various efficacy and tolerability outcomes. In conclusion, aripiprazole's efficacy did not differ substantially from D 2 R antagonists in the early course of schizophrenia, whereas differential tolerability profiles were noted. More double-blind RCTs are required comparing the efficacy and tolerability of aripiprazole as well as other D 2 R partial agonists with D 2 R antagonists in early stages of schizophrenia.

The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation., Competing Interests: WP reports personal fees from Abbatis Bioceuticals, Medipure Pharmaceuticals and is owner of Translational Life Sciences. RP reports personal fees from Janssen, Lundbeck and Otsuka. WH reports personal fees from Canadian Agency for Drugs and Technology in Health, AlphaSights, Guidepoint, Translational Life Sciences, Otsuka, Lundbeck, and Newron, grants from Canadian Institutes of Health Research, BC Mental Health and Addictions Services, and has been a consultant (non-paid) for In Silico. AB has been a scientific advisor to Emerald Health Therapeutics, Cannevert Therapeutics, Global Cannabis Applications Corp, Medipure Pharmaceuticals, Vitality Biopharma and Oakum Cannabis Corp. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yuen, Kim, Procyshyn, Panenka, Honer and Barr.)

Background: The second generation antipsychotic drugs represent the most common form of pharmacotherapy for schizophrenia disorders. It is now well established that most of the second generation drugs cause metabolic side-effects. Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) are two commonly used antipsychotic drugs with moderate metabolic liability. However, there is a dearth of preclinical data that directly compares the metabolic effects of these two drugs, using sophisticated experimental procedures. The goal of the present study was to compare metabolic effects for each drug versus control animals., Methods: Adult female rats were acutely treated with either risperidone (0.1, 0.5, 1, 2, 6 mg/kg), paliperidone (0.1, 0.5, 1, 2, 6 mg/kg) or vehicle and subjected to the glucose tolerance test; plasma was collected to measure insulin levels to measure insulin resistance with HOMA-IR. Separate groups of rats were treated with either risperidone (1, 6 mg/kg), paliperidone (1, 6 mg/kg) or vehicle, and subjected to the hyperinsulinemic euglycemic clamp., Results: Fasting glucose levels were increased by all but the lowest dose of risperidone, but only with the highest dose of paliperidone. HOMA-IR increased for both drugs with all but the lowest dose, while the three highest doses decreased glucose tolerance for both drugs. Risperidone and paliperidone both exhibited dose-dependent decreases in the glucose infusion rate in the clamp, reflecting pronounced insulin resistance., Conclusions: In preclinical models, both risperidone and paliperidone exhibited notable metabolic side-effects that were dose-dependent. Differences between the two were modest, and most notable as effects on fasting glucose., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: WGH has received consulting fees or sat on paid advisory boards for Otsuka/Lundbeck, Newron, AlphaSights, Guidepoint, Translational Life Sciences and holds shares in Translational Life Sciences and Eli Lilly. He was additionally supported by the Jack Bell Chair in Schizophrenia. RMP has been a member of the following advisory boards in the past 3 years: Janssen, Lundbeck, and Otsuka; a member of the following speaker’s bureaus in the past 3 years: Janssen, Lundbeck, and Otsuka; and received grants from the Canadian Institutes of Health Research. All other authors declare that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Antipsychotic drugs represent the most effective treatment for chronic psychotic disorders. The newer second generation drugs offer the advantage of fewer neurological side-effects compared to prior drugs, but many cause serious metabolic side-effects. The underlying physiology of these side-effects is not well-understood, but evidence exists to indicate that the sympathetic nervous system may play an important role. In order to examine this possibility further, we treated separate groups of adult female rats acutely with either the first generation antipsychotic drug haloperidol (0.1 or 1 mg/kg) or the second generation drugs risperidone (0.25 or 2.5 mg/kg), clozapine (2 or 20 mg/kg), olanzapine (3 or 15 mg/kg) or vehicle by intraperitoneal injection. Blood samples were collected prior to drug and then 30, 60, 120, and 180 mins after treatment. Plasma samples were assayed by HPLC-ED for levels of norepinephrine, epinephrine, and dopamine. Results confirmed that all antipsychotics increased peripheral catecholamines, although this was drug and dose dependent. For norepinephrine, haloperidol caused the smallest maximum increase (+158%], followed by risperidone (+793%), olanzapine (+952%) and clozapine (+1,684%). A similar pattern was observed for increases in epinephrine levels by haloperidol (+143%], olanzapine (+529%), risperidone (+617%) then clozapine (+806%). Dopamine levels increased moderately with olanzapine [+174%], risperidone [+271%], and clozapine [+430%]. Interestingly, levels of the catecholamines did not correlate strongly with each other prior to treatment at baseline, but were increasingly correlated after treatment as time proceeded. The results demonstrate antipsychotics can potently regulate peripheral catecholamines, in a manner consistent with their metabolic liability., Competing Interests: WH has received consulting fees or sat on paid advisory boards for Otsuka/Lundbeck, Newron, AlphaSights, Guidepoint, Translational Life Sciences and holds shares in Translational Life Sciences and Eli Lilly. He was additionally supported by the Jack Bell Chair in Schizophrenia. RP has been a member of the following advisory boards in the past 3 years: Janssen, Lundbeck, and Otsuka; a member of the following speaker's bureaus in the past 3 years: Janssen, Lundbeck, and Otsuka; and received grants from the Canadian Institutes of Health Research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Boyda, Ho, Tse, Procyshyn, Yuen, Kim, Honer and Barr.)

Background: The "trimorbidity" of substance use disorder and mental and physical illness is associated with living in precarious housing or homelessness. The extent to which substance use increases risk of psychosis and both contribute to mortality needs investigation in longitudinal studies., Methods and Findings: A community-based sample of 437 adults (330 men, mean [SD] age 40.6 [11.2] years) living in Vancouver, Canada, completed baseline assessments between November 2008 and October 2015. Follow-up was monthly for a median 6.3 years (interquartile range 3.1-8.6). Use of tobacco, alcohol, cannabis, cocaine, methamphetamine, and opioids was assessed by interview and urine drug screen; severity of psychosis was also assessed. Mortality (up to November 15, 2018) was assessed from coroner's reports and hospital records. Using data from monthly visits (mean 9.8, SD 3.6) over the first year after study entry, mixed-effects logistic regression analysis examined relationships between risk factors and psychotic features. A past history of psychotic disorder was common (60.9%). Nonprescribed substance use included tobacco (89.0%), alcohol (77.5%), cocaine (73.2%), cannabis (72.8%), opioids (51.0%), and methamphetamine (46.5%). During the same year, 79.3% of participants reported psychotic features at least once. Greater risk was associated with number of days using methamphetamine (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.05-1.24, p = 0.001), alcohol (aOR 1.09, 95% CI 1.01-1.18, p = 0.04), and cannabis (aOR 1.08, 95% CI 1.02-1.14, p = 0.008), adjusted for demographic factors and history of past psychotic disorder. Greater exposure to concurrent month trauma was associated with increased odds of psychosis (adjusted model aOR 1.54, 95% CI 1.19-2.00, p = 0.001). There was no evidence for interactions or reverse associations between psychotic features and time-varying risk factors. During 2,481 total person years of observation, 79 participants died (18.1%). Causes of death were physical illness (40.5%), accidental overdose (35.4%), trauma (5.1%), suicide (1.3%), and unknown (17.7%). A multivariable Cox proportional hazard model indicated baseline alcohol dependence (adjusted hazard ratio [aHR] 1.83, 95% CI 1.09-3.07, p = 0.02), and evidence of hepatic fibrosis (aHR 1.81, 95% CI 1.08-3.03, p = 0.02) were risk factors for mortality. Among those under age 55 years, a history of a psychotic disorder was a risk factor for mortality (aHR 2.38, 95% CI 1.03-5.51, p = 0.04, adjusted for alcohol dependence at baseline, human immunodeficiency virus [HIV], and hepatic fibrosis). The primary study limitation concerns generalizability: conclusions from a community-based, diagnostically heterogeneous sample may not apply to specific diagnostic groups in a clinical setting. Because one-third of participants grew up in foster care or were adopted, useful family history information was not obtainable., Conclusions: In this study, we found methamphetamine, alcohol, and cannabis use were associated with higher risk for psychotic features, as were a past history of psychotic disorder, and experiencing traumatic events. We found that alcohol dependence, hepatic fibrosis, and, only among participants <55 years of age, history of a psychotic disorder were associated with greater risk for mortality. Modifiable risk factors in people living in precarious housing or homelessness can be a focus for interventions., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: WGH has received consulting fees or sat on paid advisory boards for In Silico, Otsuka/Lundbeck, Newron, AlphaSights, the Centre for Drug Research and Development, and the Canadian Agency for Drugs and Technology in Health. He was additionally supported by the Jack Bell Chair in Schizophrenia. FVR received research support from Canadian Institutes of Health Research (CIHR), Brain Canada, Michael Smith Foundation for Health Research, and Vancouver Coastal Health Research Institute; received in-kind equipment support for this investigator-initiated trial from MagVenture; and has been on an advisory board for Janssen. RMP has been a member of the following advisory boards in the past 3 years: Janssen, Lundbeck, and Otsuka; a member of the following speaker’s bureaus in the past 3 years: Janssen, Lundbeck, and Otsuka; and received grants from the Canadian Institutes of Health Research. GWM has received consulting fees or sat on paid advisory boards for: Apotex, AstraZeneca, BMS, Janssen, Lundbeck, Otsuka, Pfizer, and Sunovion. He also received fees for lectures sponsored by AstraZeneca, BMS, Janssen, Otsuka, and Eli Lilly, and has received grants from Janssen Pharmaceuticals. JSGM has received institutional grants from Gilead Sciences, J&J, Merck, ViiV Healthcare, and a Knowledge Translation Award from the Canadian Institutes of Health Research. JSGM has also served as an advisor to Government of Canada and the Government of British Columbia in the last year. AET has received grants from the Canadian Institutes of Health Research (CIHR) and the William and Ada Isabelle Steel Fund. This does not alter our adherence to PLOS Medicine policies on sharing data and materials. AAJ, KMG, SS, TSW, OL, GNS, TAS, ATV, TB, AR, DJL, VDL, WJP, and AMB declared that no competing interests exist.

Background: Homeless and precariously housed individuals experience a high burden of comorbid illnesses, and excess mortality. Cross-sectional studies report a high rate of cognitive impairment. Long-term trajectories have not been well investigated in this group., Aims: To longitudinally assess risks for premature and/or accelerated cognitive ageing, and the relationship with early mortality in homeless and precariously housed people., Method: This is a 9-year community-based study of 375 homeless and precariously housed individuals from Vancouver, Canada. Annual cognitive testing assessed verbal learning and memory, and inhibitory control. Linear mixed-effects models examined associations between clinical risk factors (traumatic brain injury, psychotic disorders, viral exposure, alcohol dependence) and cognitive change over 9 years. Cox regression models examined the association between cognition and mortality., Results: Traumatic brain injury and alcohol dependence were associated with decline in verbal memory. Inhibitory control declined, independent of risk factors and to a greater extent in those who died during the study. Better inhibitory control was associated with a 6.6% lower risk of mortality at study entry, with a 0.3% greater effect for each year of life. For each one-point increase in the Charlson Comorbidity Index score at study entry, the risk of mortality was 9.9% higher, and was consistent across age. Adjusting for comorbidities, inhibitory control remained a significant predictor of mortality., Conclusions: Findings raise the possibility of a premature onset, and accelerated trajectory, of cognitive ageing in this group of homeless and precariously housed people. Traumatic brain injury, alcohol dependence and cognition could be treatment priorities.

Background: Cannabis is commonly used for its medical properties. In particular, cannabis is purported to have beneficial effects on a wide range of neuropsychiatric conditions. Studies assessing mental health in cannabis dispensary users typically evaluate symptoms using self-report check lists, which provide limited information about symptom severity, and whether subjects meet criteria for a psychiatric diagnosis. There is, therefore, a need for studies which assess mental health in dispensary users with standardized and well validated scientific instruments, such as those used in clinical drug trials., Methods: One hundred medical cannabis users were recruited from a community dispensary. All subjects completed a structured clinical interview with the Mini-International Neuropsychiatric Interview (MINI). Subjects also completed the Perceived Stress Scale-10, PROMIS Fatigue Scale, PROMIS Sleep Disturbance Scale, Beck Depression Inventory, the Patient Health Questionnaire-15 and the Brief Pain Inventory. Details about cannabis use were also recorded., Results: Lifetime prevalence of mental illness in this cohort was high, and a large proportion of subjects endorsed psychological symptoms. The proportion of subjects who met criteria for classification of a current psychiatric disorder was low for mood disorders, but high for anxiety disorders and substance abuse/dependence. Cannabis use differed between the main psychiatric conditions., Conclusions: The present results indicate that rates of mental illness may be high in medical cannabis dispensary users. Use of structured clinical assessments combined with standardized symptom severity questionnaires provide a feasible way to provide a more rigorous and detailed evaluation of conditions and symptoms in this population.

Objective: Homeless and marginally housed youth are particularly vulnerable members of society, and are known to experience numerous health problems, including psychiatric illness, substance use, and viral infection. Despite the presence of these risk factors for cognitive compromise, there is limited research on the cognitive functioning of homeless and marginally housed youth. The present study examines the degree and pattern of cognitive impairment and associations with key risk factors in a sample of marginally housed young adults. Method: Participants ( N = 101) aged 20-29 years old were recruited from single-room occupancy hotels, and underwent cognitive, psychiatric, neurological, and serological assessments. Results: Forty percent of participants were identified as mildly cognitively impaired across multiple domains, and 16% were moderately-severely impaired. Deficits in memory and attention were most prevalent, while impairments in inhibitory control/processing speed and cognitive flexibility were also present but tended to be less severe. Developmental and historical factors (premorbid intellectual functioning, neurological soft signs, earlier exposure to and longer duration of homelessness or marginal housing), as well as current health risks (stimulant dependence and hepatitis C exposure), were associated with cognitive impairment. Conclusions: The strikingly high rate of cognitive impairment in marginally housed young adults represents a major public health concern and is likely to pose a significant barrier to treatment and rehabilitation. These results suggest that the pathway to cognitive impairment involves both developmental vulnerability and modifiable risk factors. This study highlights the need for early interventions that address cognitive impairment and risk factors in marginalized young people., (Copyright © 2019 Waclawik, Jones, Barbic, Gicas, O'Connor, Smith, Leonova, Mathias, Barr, Procyshyn, Lang, Woodward, MacEwan, Panenka, Yamamoto, Honer and Thornton.)

Competing Interests: R. Procyshyn has received consulting fees or sat on paid advisory boards for Janssen, Lundbeck and Otsuka; and is on the speaker’s bureau for Janssen, Lundbeck and Otsuka. P. Tibbo has received speaking fees and sat on paid advisory boards for Janssen, Lundbeck, Otsuka and Sunovion. D. Kim and L. Downing declare no competing interests.

Introduction: Cognition is impaired in homeless and vulnerably housed persons. Within this heterogeneous and multimorbid group, distinct profiles of cognitive dysfunction are evident. However, little is known about the underlying neurobiological substrates. Imaging structural covariance networks provides a novel investigative strategy to characterizing relationships between brain structure and function within these different cognitive subgroups., Method: Participants were 208 homeless and vulnerably housed persons. Cluster analysis was used to group individuals on the basis of similarities in cognitive functioning in the areas of attention, memory, and executive functioning. The principles of graph theory were applied to construct two brain networks for each cognitive group, using measures of cortical thickness and gyrification. Global and regional network properties were compared across networks for each of the three cognitive clusters., Results: Three cognitive groups were defined by: higher cognitive functioning across domains (Cluster 1); lower cognitive functioning with a decision-making strength (Cluster 3); and an intermediate group with a relative executive functioning weakness (Cluster 2). Between-group differences were observed for cortical thickness, but not gyrification networks. The lower functioning cognitive group exhibited higher segregation and reduced integration, higher centrality in select nodes, and less spatially compact modules compared with the two other groups., Conclusions: The cortical thickness network differences of Cluster 3 suggest that major disruptions in structural connectivity underlie cognitive dysfunction in a subgroup of people who have a high multimorbid illness burden and who are vulnerably housed or homeless. The origins, and possible plasticity of these structure-function relationships identified with network analysis warrant further study., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: WGH has received consulting fees or sat on paid advisory boards for In Silico, Otsuka/Lundbeck, Newron, AlphaSights, the Centre for Drug Research and Development, and the Canadian Agency for Drugs and Technology in Health. He was additionally supported by the Jack Bell Chair in Schizophrenia. FVR received research support from Canadian Institutes of Health Research (CIHR), Brain Canada, Michael Smith Foundation for Health Research, and Vancouver Coastal Health Research Institute; received in-kind equipment support for this investigator-initiated trial from MagVenture; and has been on an advisory board for Janssen. RMP has been a member of the following advisory boards in the past 3 years: Janssen, Lundbeck, and Otsuka; a member of the following speaker’s bureaus in the past 3 years: Janssen, Lundbeck, and Otsuka; and received grants from the Canadian Institutes of Health Research. GWM has received consulting fees or sat on paid advisory boards for: Apotex, AstraZeneca, BMS, Janssen, Lundbeck, Otsuka, Pfizer, and Sunovion. He also received fees for lectures sponsored by AstraZeneca, BMS, Janssen, Otsuka, and Eli Lilly, and has received grants from Janssen Pharmaceuticals. AET has received grants from the Canadian Institutes of Health Research (CIHR) and the William and Ada Isabelle Steel Fund. This does not alter our adherence to PLOS ONE policies on sharing data and materials. KMG, AAJ, WJP, CJG, DJL, OL, AMB, WS, AR, ATV, and TB declared that no competing interests exist.

Objective: We investigated white matter differences associated with distinct neurocognitive profiles derived from a large cohort of marginally housed persons with comorbid physical and mental illnesses. Our prior work identified three profile cluster groups: a high functioning group (Cluster 1), a low functioning group with relative strength in decision-making (Cluster 3), and an intermediary group with a relative decision-making weakness (Cluster 2). This study extends previous findings of cortical gray matter differences between these groups with evidence for putative neurodevelopmental abnormalities in the low cognitive functioning group (i.e., Cluster 3). We hypothesized that altered white matter diffusion would be associated with the lowest functioning neurocognitive profile and would be associated with previously observed gray matter differences., Method: Participants from a socially impoverished neighborhood in Vancouver, Canada underwent neurocognitive evaluation and neuroimaging. We performed Tract-Based Spatial Statistics using diffusion tensor imaging data from 184 participants to examine whole-brain differences in white matter microstructure between cluster analytically derived neurocognitive profiles, as well as unitary neurocognitive measures. Correlations between frontal gray and white matter were also examined., Results: Cluster 3 showed increased diffusion in predominately bilateral frontal and interhemisphere tracts (vs. Clusters 1 and 2), with relatively greater diffusion in the left hemisphere (vs. Cluster 1). Differences in radial diffusivity were more prominent compared with axial diffusivity. A weak association between regional frontal fractional anisotropy and previously defined abnormalities in gyrification was observed., Conclusions: In a socially marginalized sample, we established several patterns in the covariation of white matter diffusion and neurocognitive functioning. These patterns elucidate the neurobiological substrates and vulnerabilities that are apt to underlie functional impairments inherent to this complex and heterogeneous population., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Paliperidone palmitate is a second generation antipsychotic, approved for the treatment of schizophrenia in the form of the long-acting injectable (LAI) products INVEGA SUSTENNA® (once monthly injection) and INVEGA TRINZA® (once every 3 months injection). Paliperidone palmitate dissolves slowly after deep intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. The pharmacokinetic (PK) profile of the INVEGA SUSTENNA® formulation is biphasic, comprised of an initial relatively fast zero-order input, which allows rapid attainment of therapeutic concentrations without oral supplementation; and a subsequent maintained second-stage, first-order input, allowing for once monthly administration. Changes to the manufacturing processes can substantially alter the release characteristics of paliperidone palmitate LAI and consequently its PK profile. As an example, larger or smaller particle sizes of paliperidone palmitate can result in a delayed or accelerated release of paliperidone into the systemic circulation, respectively. Such changes are clinically relevant, as transient excursions above therapeutic plasma concentrations can be associated with an increased risk of adverse effects, including tachycardia, hypotension, QT prolongation, and extrapyramidal symptoms. Conversely, a delay in attaining therapeutic plasma concentrations of paliperidone on initiation of treatment, or a return to low plasma concentrations before the end of a dosing interval during repeated dosing, increases the risk of relapse. Given the integral relationship of the PK profile to the product's clinical effects, it is important to have bioequivalence standards that reflect the complexity of the paliperidone palmitate LAI PK profile if one is to consider therapeutic equivalence based on simple bioequivalence testing. Although both the EMA and U.S. FDA have product-specific guidelines to determine bioequivalence, their requirements differ substantially. In Canada, no LAI product-specific bioequivalence guidance exists for multiphasic medication delivery systems, and the recently revised Comparative Bioavailability Standards: Formulations Used for Systemic Effects guidance applies only to oral and non-injectable formulations. We recommend that new Canadian standards be developed for multiphasic and biphasic intramuscular / subcutaneous (IM/SC) products, including paliperidone palmitate LAI products, because, similar to modified-release oral dosage forms, a different PK profile in modified-release IM/SC products can result in clinically meaningful differences in safety, efficacy, and tolerability. To ensure bioequivalence for both newly initiated and switch patients, this paper proposes bioequivalence standards that could be adopted in Canada that include two studies, a multiple-dose cross-over study, and a single-dose study with partial AUC metrics.

Metabolic abnormalities are serious health problems in individuals with schizophrenia. Paradoxically, studies have noted an association where individuals who gained body weight or who have increased their serum lipids demonstrated a better antipsychotic response. As serum lipids serve as more specific physiological markers than body weight, the objective of this study was to review studies that examined the association between changes in serum lipids and changes in symptoms during antipsychotic treatment in individuals with schizophrenia. A Medline® literature search was performed. Fourteen studies were included and analyzed. Evidence suggests that increases in serum lipids may be associated with decreases in symptoms during antipsychotic treatment. This inverse association may be independent of confounding variables, such as weight gain, and may be most evident during treatment with clozapine. Also, according to recent randomized controlled trials, lipid-lowering agents do not appear to worsen symptoms although this needs to be further investigated in clozapine-treated patients. Future studies should investigate the association in question in a larger population and identify underlying mechanisms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Competing Interests: A. Barr has received grants from Bristol-Myers Squibb and the Canadian Institutes of Health Research. R. White has received consulting fees or sat on paid advisory boards for Janssen, Lundbeck and Otsuka and has received a grant from ThermoFisher/Affymetrix. W. Honer has received consulting fees or sat on paid advisory boards for the Canadian Agency for Drugs and Technology in Health, the Centre for Drug Research and Development, AlphaSights, In Silico (unpaid) and Otsuka/Lundbeck. R. Procyshyn has received consulting fees or sat on paid advisory boards for Janssen, Lundbeck and Otsuka; is on the speaker’s bureau for Janssen, Lundbeck and Otsuka; and has received grants from the Canadian Institutes of Health Research. D. Kim has no conflict of interest to declare.

Retrospective data were collected from 330 individuals who were treated at a tertiary care program for treatment-resistant psychosis between 1994 and 2010. The main objectives were to compare the use of antipsychotic monotherapy to polypharmacy and to characterize within-individual changes in treatment and symptomatology between admission and discharge. At admission, individuals who were prescribed only one antipsychotic were comparable to those who were prescribed at least two antipsychotics with regard to demographics and symptom severity. The use of psychotropic medications other than antipsychotics was also similar between the two groups. However, the magnitude of antipsychotic utilization was greater in individuals who were receiving antipsychotic polypharmacy. In addition, a greater proportion received excessive doses at admission. Similar findings were observed when the two antipsychotic prescribing practices were compared at discharge. Three important patterns were identified when investigating within-individual changes. First, fewer individuals were prescribed more than one antipsychotic at discharge. This was accompanied by a general decrease in the magnitude of antipsychotic utilization. Second, the number of individuals who were prescribed clozapine had increased by discharge. Most who were already prescribed clozapine at admission had their doses increased. Third, improvements in symptomatology were observed across all of the subscales included in the Positive and Negative Symptom Scale (PANSS); 57.9% of individuals experienced a relative reduction in total PANSS scores exceeding 20%. Based on these findings, it is possible to alleviate symptom severity while reducing antipsychotic utilization when patients are treated at a tertiary care program for treatment-resistant psychosis., Competing Interests: Dr. Honer has received consulting fees or sat on advisory boards for In Silico, Eli Lilly, Roche, Lundbeck, and Otsuka. Dr. Barr has received consulting fees or sat on advisory boards for Bristol-Myers Squibb, Eli Lilly, and Roche. Dr. Procyshyn has received speaking and advisory board fees from Janssen, Lundbeck, Otsuka, and Sunovion and was a member of speaker’s bureaus for AstraZeneca, Janssen, Lundbeck, and Otsuka. The other authors declare no potential competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The second generation antipsychotic drug risperidone is widely used in the field of child and adolescent psychiatry to treat conditions associated with disruptive behavior, aggression and irritability, such as autism spectrum disorders. While risperidone can provide symptomatic relief for many patients, there is considerable individual variability in the therapeutic response and side-effect profile of the medication. One well established biological factor that contributes to these individual differences is genetic variation in the cytochrome P450 enzyme 2D6. The 2D6 enzyme metabolizes risperidone and therefore affects drug levels and dosing. In the present review, we summarize the current literature on 2D6 variants and their effects on risperidone responses, specifically in children and adolescents. Relevant articles were identified through systematic review, and after irrelevant articles were discarded, ten studies were included in the review. Most prospective studies were well controlled, but often did not have a large enough sample size to make robust statements about rarer variants, including those categorized as ultra-rapid and poor metabolizers. Individual studies demonstrated a role for different genetic variants in risperidone drug efficacy, pharmacokinetics, hyperprolactinemia, weight gain, extrapyramidal symptoms and drug-drug interactions. Where studies overlapped in measurements, there was typically a consensus between results. These findings indicate that the value of 2D6 genotyping in the youth population treated with risperidone requires further study, in particular with the less common variants.

Background: Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and has minimal risk for extrapyramidal symptoms. Therapeutic benefits, however, are accompanied by a myriad of cardiometabolic side-effects. The specific reasons for clozapine's high propensity to cause adverse cardiometabolic events remain unknown, but it is believed that autonomic dysfunction may play a role in many of these. Objective: This systematic review summarizes the literature on autonomic dysfunction and related cardiovascular side effects associated with clozapine treatment. Method: A search of the EMBASE, MEDLINE, and EBM Cochrane databases was conducted using the search terms antipsychotic agents, antipsychotic drug * , antipsychotic * , schizophrenia, schizophren * , psychos * , psychotic * , mental ill * , mental disorder * , neuroleptic * , cardiovascular * , cardiovascular diseases, clozapine * , clozaril * , autonomic * , sympathetic * , catecholamine * , norepinephrine, noradrenaline, epinephrine, adrenaline. Results: The search yielded 37 studies that were reviewed, of which only 16 studies have used interventions to manage cardiovascular side effects. Side effects reported in the studies include myocarditis, orthostatic hypotension and tachycardia. These were attributed to sympathetic hyperactivity, decreased vagal contribution, blockade of cholinergic and adrenergic receptors, reduced heart rate variability and elevated catecholamines with clozapine use. Autonomic neuropathy was identified by monitoring blood pressure and heart rate changes in response to stimuli and by spectral analysis of heart rate variability. Metoprolol, lorazepam, atenolol, propranolol, amlodipine, vasopressin and norepinephrine infusion were used to treat tachycardia and fluctuations in blood pressure, yet results were limited to case reports. Conclusion: The results indicate there is a lack of clinical studies investigating autonomic dysfunction and a limited use of interventions to manage cardiovascular side effects associated with clozapine. As there is often no alternative treatment for refractory schizophrenia, the current review highlights the need for better designed studies, use of autonomic tests for prevention of cardiovascular disease and development of novel interventions for clozapine-induced side effects.

Objective: Young adults living in single room occupancy (SRO) hotels, a form of low-income housing, are known to have complex health and substance problems compared to their peers in the general population. The objective of this study is to comprehensively describe the mental, physical, and social health profile of young adults living in SROs., Methods: This study reports baseline data from young adults aged 18-29 years, as part of a prospective cohort study of adults living in SROs in Vancouver, British Columbia, Canada. Baseline and follow-up data were collected from 101 young adults (median follow-up period 1.9 years [IQR 1.0-3.1]). The comprehensive assessment included laboratory tests, neuroimaging, and clinician- and patient-reported measures of mental, physical, and social health and functioning., Results: Three youth died during the preliminary follow-up period, translating into a higher than average mortality rate (18.6, 95% CI 6.0, 57.2) compared to age- and sex-matched Canadians. High prevalence of interactions with the health, social, and justice systems was reported. Participants were living with median two co-occurring illnesses, including mental, neurological, and infectious diseases. Greater number of multimorbid illnesses was associated with poorer real-world functioning (ρ = - 0.373, p < 0.001). All participants reported lifetime alcohol and cannabis use, with pervasive use of stimulants and opioids., Conclusion: This study reports high mortality rates, multimorbid illnesses, poor functioning, poverty, and ongoing unmet mental health needs among young adults living in SROs. Frequent interactions with the health, social, and justice systems suggest important points of intervention to improve health and functional trajectories of this vulnerable population.

We characterized traumatic brain injury (TBI) and studied its associations with mental and physical health in a community cohort of homeless and vulnerably housed individuals. Detailed mental and physical health structured interviews, neuropsychological testing, and multimodal magnetic resonance imaging (MRI) were performed on 283 participants. Two TBI participant groups were defined for primary analyses: those with a self-reported history of TBI and those with MRI confirmation of TBI. By self-report, 174 participants (61.5%) reported a previous serious head or face injury (symptomatic or asymptomatic), with 100 (35.3%) experiencing symptoms consistent with TBI (any post-injury loss of consciousness, confusion, or memory loss). Persons self-reporting TBI had poorer current mental and physical health, more ongoing neurological symptoms, and a higher rate of mood disorders, compared to those with no TBI. The presence of a mood disorder, a TBI history, and an interaction between these factors contributed to lower mental health. There was evidence of TBI in 20 participants (6.9%) on clinical MRI sequences. These participants had globally lower cortical gray matter volumes and lower white matter fractional anisotropy (FA) values. Neurocognitive test scores positively correlated with both FA and cortical gray matter volumes in participants with MRI evidence of trauma. Previous TBI is associated with poorer mental and physical health in homeless and vulnerably housed individuals and interacts with mood disorders to exacerbate poor mental health. Focal traumatic lesions evident on MRI are associated with diffusely lower gray matter volumes and white matter integrity, which predict cognitive functioning.

Antipsychotic medications can effectively treat psychotic symptoms in individuals with schizophrenia. However, side effects including cardiovascular and extrapyramidal symptoms are often inevitable. Exercise has proven effective in ameliorating cardiometabolic abnormalities in individuals with schizophrenia. In addition, exercise has consistently been an effective intervention for improving the symptoms associated with schizophrenia. We report here two cases in which individuals with schizoaffective disorder treated with a long-acting injectable antipsychotic medication displayed worsening of extrapyramidal symptoms over the course of a 12-week exercise program. This can be attributed to an increase in blood flow to the depot site during exercise, accelerating the rate of absorption and bioavailability of the antipsychotic medication and subsequently increasing dopamine D 2 blockade. Clinicians need to be vigilant when patients receiving long-acting injectable antipsychotic medications engage in exercise.

Objective: The Hotel Study was initiated in Vancouver's Downtown East Side (DTES) neighborhood to investigate multimorbidity in homeless or marginally housed people. We evaluated the clinical effectiveness of existing, illness-specific treatment strategies and assessed the effectiveness of health care delivery for multimorbid illnesses., Method: For context, we mapped the housing locations of patients presenting for 552,062 visits to the catchment hospital emergency department (2005-2013). Aggregate data on 22,519 apprehensions of mentally ill people were provided by the Vancouver Police Department (2009-2015). The primary strategy was a longitudinal cohort study of 375 people living in the DTES (2008-2015). We analysed mortality and evaluated the clinical and health service delivery effectiveness for infection with human immunodeficiency virus or hepatitis C virus, opioid dependence, and psychosis., Results: Mapping confirmed the association between poverty and greater number of emergency visits related to substance use and mental illness. The annual change in police apprehensions did not differ between the DTES and other policing districts. During 1581 person-years of cohort observation, the standardized mortality ratio was 8.43 (95% confidence interval, 6.19 to 11.50). Physician visits were common (84.3% of participants over 6 months). Clinical treatment effectiveness was highest for HIV/AIDS, intermediate for opioid dependence, and lowest for psychosis. Health service delivery mechanisms provided examples of poor access, poor treatment adherence, and little effect on multimorbid illnesses., Conclusions: Clinical effectiveness was variable, and illness-specific service delivery appeared to have little effect on multimorbidity. New models of care may need to be implemented.

Chronic prescription of antipsychotics seems to lose its therapeutic benefits in the prevention of recurring psychotic symptoms. In many instances, the occurrence of relapse from initial remission is followed by an increase in dose of the prescribed antipsychotic. The current understanding of why this occurs is still in its infancy, but a controversial idea that has regained attention recently is the notion of iatrogenic dopamine supersensitivity. Studies on cell cultures and animal models have shown that long-term antipsychotic use is linked to both an upregulation of dopamine D&lt;sub&gt;2&lt;/sub&gt;-receptors in the striatum and the emergence of enhanced receptor affinity to endogenous dopamine. These findings have been hypothesized to contribute to the phenomenon known as dopamine supersensitivity psychosis (DSP), which has been clinically typified as the foundation of rebound psychosis, drug tolerance, and tardive dyskinesia. The focus of this review is the update of evidence behind the classification of antipsychotic induced DSP and an investigation of its relationship to treatment resistance. Since antipsychotics are the foundation of illness management, a greater understanding of DSP and its prevention may greatly affect patient outcomes.

Background: Psychostimulant drug use is commonly associated with drug-related infection, including the human immunodeficiency virus (HIV). Both psychostimulant use and HIV infection are known to damage brain white matter and impair cognition. To date, no study has examined white matter integrity using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) in chronic psychostimulant users with comorbid HIV infection, and determined the relationship of white matter integrity to cognitive function., Methods: Twenty-one subjects (mean age 37.5 ± 9.0 years) with a history of heavy psychostimulant use and HIV infection (8.7 ± 4.3 years) and 22 matched controls were scanned on a 3T MRI. Fractional anisotropy (FA) values were calculated with DTI software. Four regions of interest were manually segmented, including the genu of the corpus callosum, left and right anterior limbs of the internal capsule, and the anterior commissure. Subjects also completed a neurocognitive battery and questionnaires about physical and mental health., Results: The psychostimulant using, HIV positive group displayed decreased white matter integrity, with significantly lower FA values for all white matter tracts (p < 0.05). This group also exhibited decreased cognitive performance on tasks that assessed cognitive set-shifting, fine motor speed and verbal memory. FA values for the white matter tracts correlated with cognitive performance on many of the neurocognitive tests., Conclusions: White matter integrity was thus impaired in subjects with psychostimulant use and comorbid HIV infection, which predicted worsened cognitive performance on a range of tests. Further study on this medical comorbidity is required.

Brain derived neurotrophic factor (BDNF) is a molecular trophic factor that plays a key role in neuronal survival and plasticity. Single nucleotide polymorphisms (SNPs) of the BDNF gene have been associated with specific phenotypic traits in a large number of neuropsychiatric disorders and the response to psychotherapeutic medications in patient populations. Nevertheless, due to study differences and occasionally contrasting findings, substantial further research is required to understand in better detail the association between specific BDNF SNPs and these psychiatric disorders. While considerable progress has been made recently in developing advanced genotyping platforms of SNPs, many high-throughput probe- or array-based detection methods currently available are limited by high costs, slow processing times or access to advanced instrumentation. The polymerase chain reaction (PCR)-based, tetra-primer amplification refractory mutation system (T-ARMS) method is a potential alternative technique for detecting SNP genotypes efficiently, quickly, easily, and cheaply. As a tool in psychopathology research, T-ARMS was shown to be capable of detecting five common SNPs in the BDNF gene (rs6265, rs988748, rs11030104, 11757G/C and rs7103411), which are all SNPs with previously demonstrated clinical relevance to schizophrenia and depression. The present technique therefore represents a suitable protocol for many research laboratories to study the genetic correlates of BDNF in psychiatric disorders. Copyright Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

Objectives: Socially disadvantaged people experience greater risk for illnesses that may contribute to premature death. This study aimed to evaluate the impact of treatable illnesses on mortality among adults living in precarious housing., Design: A prospective cohort based in a community sample., Setting: A socially disadvantaged neighbourhood in Vancouver, Canada., Participants: Adults (N=371) living in single room occupancy hotels or recruited from the Downtown Community Court and followed for median 3.8 years., Main Outcome Measures: Participants were assessed for physical and mental illnesses for which treatment is currently available. We compared cohort mortality rates with 2009 Canadian rates. Left-truncated Cox proportional hazards modelling with age as the time scale was used to assess risk factors for earlier mortality., Results: During 1269 person-years of observation, 31/371 (8%) of participants died. Compared with age-matched and sex-matched Canadians, the standardised mortality ratio was 8.29 (95% CI 5.83 to 11.79). Compared with those that had cleared the virus, active hepatitis C infection was a significant predictor for hepatic fibrosis adjusting for alcohol dependence and age (OR=2.96, CI 1.37 to 7.08). Among participants <55 years of age, psychosis (HR=8.12, CI 1.55 to 42.47) and hepatic fibrosis (HR=13.01, CI 3.56 to 47.57) were associated with earlier mortality. Treatment rates for these illnesses were low (psychosis: 32%, hepatitis C virus: 0%) compared with other common disorders (HIV: 57%, opioid dependence: 61%) in this population., Conclusions: Hepatic fibrosis and psychosis are associated with increased mortality in people living in marginal conditions. Timely diagnosis and intervention could reduce the high mortality in marginalised inner city populations., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Groups of nonrefractory patients with schizophrenia, taking antipsychotics other than clozapine, show distinct trajectories of treatment response over time. Whether similar patterns of response occur with clozapine-treated patients remains uncertain., Method: We used a cluster analysis approach for longitudinal data (k-means longitudinal) to analyze individual patient data from 2 pivotal studies of clozapine, compared with chlorpromazine. Trajectories and symptom severity were examined in a younger, less chronic, mixed-sample (study 16, n=100) and in treatment-refractory (study 30, n=257) patients., Results: Early-good and delayed-partial trajectory groups were observed, with the early-good trajectory group comprised of 73/100 (73.0%) from the mixed patient study, and 147/257 (57.2%) refractory patients. In the mixed patient sample, the distribution of clozapine and chlorpromazine treatments did not differ between the early-good and delayed-partial trajectory groups; in refractory patients proportionately more clozapine treatment was present in the early-good (87/147, 59.2%), compared with the delayed-partial (35/110, 31.8%), trajectory group. In the early-good trajectory group, improvement in mean symptom severity was 63% in mixed-study patients. Clozapine resistance appeared to be present in 10/50 (20.0%) mixed-study patients, and in 35/122 (28.9%) refractory patients., Conclusions: Early-good and delayed-partial response trajectories are seen in clozapine studies. The advantage of clozapine over chlorpromazine is seen most clearly in previous refractory patients, within the early-good trajectory group. Good and partial or poor responders to clozapine may merit further investigation.

Over the past two decades, there has been a notable rise in the use of antipsychotic drugs, as they are used to treat an increasing number of neuropsychiatric disorders. This rise has been led predominantly by greater use of the second generation antipsychotic (SGA) drugs, which have a low incidence of neurological side-effects. However, many SGAs cause metabolic dysregulation, including glucose intolerance and insulin resistance, thus increasing the risk of cardiometabolic disorders. The metabolic effects of the novel SGA lurasidone, which was approved by the Food and Drug Administration in 2010, remain largely unknown. As rodent models accurately predict the metabolic effects of SGAs in humans, the aim of the present study was to use sophisticated animal models of glucose tolerance and insulin resistance to measure the metabolic effects of lurasidone. In parallel, we compared the SGA olanzapine, which has established metabolic effects. Adult female rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c.) or olanzapine (10.0 mg/kg, s.c.) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c.) or olanzapine (1.5 and 15 mg/kg, s.c.) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC). Compared to vehicle treated animals, lurasidone caused mild glucose intolerance in the GTT with a single dose, but there was no effect on insulin resistance in the GTT, measured by HOMA-IR. The HIEC also confirmed no effect of lurasidone on insulin resistance. In contrast, olanzapine demonstrated dose-dependent and potent glucose intolerance, and insulin resistance in both tests. Thus, in preclinical models, lurasidone demonstrates mild metabolic liability compared to existing SGAs such as olanzapine. However, confirmation of these effects in humans with equivalent tests should be confirmed.

Second generation antipsychotic (SGA) drugs are effective treatments for psychosis. Common side-effects of SGAs include metabolic dysregulation and risk of cardiometabolic disorders. Metabolic side-effects, including glucose intolerance, can be accurately modelled in rodents. The benefits of interventions used for treating metabolic side-effects of SGAs are mostly unknown. In a 9 wk longitudinal study, female rats were given daily olanzapine (10 mg/kg s.c.) or vehicle. Animals were either sedentary or allowed 1 or 3 h daily access to a running wheel, with total wheel revolutions electronically quantified to reflect exercise intensity. Glucose tolerance tests were performed once weekly to measure glycemic control. Drug levels were measured at week 4. At week 9, abdominal fat and skeletal muscle levels of Glucose Transporter 4 (GLUT4) were measured. Exercise intensity progressively increased over time in all groups given access to running wheels; however, rats treated with olanzapine consistently exercised less than those given the vehicle. Olanzapine caused acute and persistent glucose intolerance throughout the study, which was markedly, though incompletely, ameliorated by exercise. Exercise did not affect glycemic regulation in vehicle-treated rats. Olanzapine-treated rats showed greater central adiposity. Levels of GLUT4 in skeletal muscle were higher in both groups of exercising than in sedentary rats, and GLUT4 values were negatively correlated with glucose intolerance. Routine exercise reduced olanzapine-induced glucose intolerance and increased skeletal muscle levels of GLUT 4, the insulin-responsive transporter that mediates glucose uptake into cells. The current animal model is suitable for evaluating physiological pathways involved with glucose intolerance.

Background: The Independent Scientific Committee on Drugs (ISCD) assigned quantitative scores for harm to 20 drugs. We hypothesized that a personalized, ISCD-based Composite Harm Score (CHS) would be associated with poor health outcomes in polysubstance users., Methods: A prospective community sample (n=293) of adults living in marginal housing was assessed for substance use. The CHS was calculated based on the ISCD index, and the personal substance use characteristics over four weeks. Regression models estimated the association between CHS and physical, psychological, and social health outcomes., Results: Polysubstance use was pervasive (95.8%), as was multimorbid illness (median 3, possible range 0-12). The median CHS was 2845 (interquartile range 1865-3977). Adjusting for age and sex, every 1000-unit CHS increase was associated with greater mortality (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.07-2.01, p = 0.02), and persistent hepatitis C infection (OR 1.29, 95% CI 1.02-1.67, p = 0.04). The likelihood of substance-induced psychosis increased 1.39-fold (95% CI 1.13-1.67, p = 0.001). The amount spent on drugs increased 1.51-fold (1.40-1.62, p < 0.001) and the odds of having committed a crime increased 1.74-fold (1.46-2.10, p < 0.001). Multimorbid illness increased 1.43-fold (95% CI 1.26-1.63, p < 0.001)., Conclusions: Greater CHS predicts poorer physical, psychological, and social health, and may be a useful quantitative, personalized measure of risk for drug-related harm.

Background: Antipsychotic drugs can be used to help treat a wide variety of psychiatric disorders. However, specific antipsychotic drugs for any particular patient may need to be changed for a number of different reasons, including a lack of therapeutic efficacy and / or intolerance to medication side-effects. Drug switching may occur through a limited number of established patterns. The nature of these changes is not well characterized in youth, despite their frequent occurrence., Methods: A retrospective analysis of antipsychotic drug switches was conducted on patients who had been admitted as inpatients to a tertiary care child and adolescent psychiatric institute. PharmaNet (a large, central administrative database) records of all medications prescribed in the 52 weeks prior to admission, and then between admission and discharge, were analyzed for switching patterns. Additional data regarding diagnoses were obtained from medical chart review., Results: Patients represented a diagnostically heterogeneous population, and almost all antipsychotic drugs were administered off-label. In the one year prior to and during admission to the hospital, a total of 31 out of 139 patients switched antipsychotic drugs. The frequency of switching increased closer to the time of admission, and the proportional rate of switching was even higher during hospital stay. The most common switch was from risperidone to quetiapine. Our analysis identified three main patterns of drug switching, all occurring with similar frequency: titrated drug switches, abrupt drug switches and concurrent drug administration., Conclusions: The present study indicates that antipsychotic drug switching in youth may be relatively common, particularly in the year prior to hospitalization. No specific manner of drug switching predominates. This study also demonstrates the feasibility of using large administrative databases to characterise switching patterns in youth.

Background: The second generation antipsychotic (SGA) drugs are widely used in psychiatry due to their clinical efficacy and low incidence of neurological side-effects. However, many drugs in this class cause deleterious metabolic side-effects. Animal models accurately predict metabolic side-effects for SGAs with known clinical metabolic liability. We therefore used preclinical models to evaluate the metabolic side-effects of glucose intolerance and insulin resistance with the novel SGAs asenapine and iloperidone for the first time. Olanzapine was used as a comparator., Methods: Adults female rats were treated with asenapine (0.01, 0.05, 0.1, 0.5, 1.0 mg/kg), iloperidone (0.03, 0.5, 1.0, 5.0, 10.0 mg/kg) or olanzapine (0.1, 0.5, 1.5, 5.0, 10.0 mg/kg) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with asenapine (0.1 and 1.0 mg/kg), iloperidone (1.0 and 10 mg/kg) or olanzapine (1.5 and 15 mg/kg) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC)., Results: Asenapine showed no metabolic effects at any dose in either test. Iloperidone caused large and significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with both doses in the HIEC. Olanzapine caused significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with the higher dose in the HIEC., Conclusions: In preclinical models, asenapine shows negligible metabolic liability. By contrast, iloperidone exhibits substantial metabolic liability, comparable to olanzapine. These results emphasize the need for appropriate metabolic testing in patients treated with novel SGAs where current clinical data do not exist.

Background: The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance. These symptoms have been accurately modelled in rodents., Methods: We compared the effects of 3 distinct classes of antidiabetic drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapineinduced metabolic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assessment of insulin resistance equation., Results: Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels., Limitations: We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by antidiabetic treatments., Conclusion: The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metabolism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs primarily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose dysregulation caused by olanzapine and how it can be reversed.