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Fidel Vila-Rodriguez,1 Donna J Lang,2 Heather Baitz,3 Kristina Gicas,3 Allen E Thorton,3 Thomas S Ehmann,1 Geoff N Smith,1 Alasdair M Barr,4 Ivan J Torres,1 Lili C Kopala,1 G William MacEwan,1 Daniel J Müller,5 James L Kennedy,5 William G Honer11Department of Psychiatry, 2Division of Neuroradiology, Department of Radiology, The University of British Columbia, Vancouver, 3Department of Psychology, Simon Fraser University, Burnaby, 4Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, BC, 5Department of Psychiatry, Centre for Mental Health and Addictions, University of Toronto, Toronto, ON, CanadaBackground: Verbal memory impairment is a core feature in schizophrenia even at early stages of the disease, but its etiopathogenesis is not fully understood. The APOE-ε4 is the main genetic risk factor for late-onset Alzheimer’s disease. Our primary goal was to ascertain whether APOE-ε4 status had a pleiotropic effect in early stages of the illness.Participants and methods: A total of 86 first-episode psychosis (FEP) outpatients and 39 healthy volunteers were recruited. Demographic and clinical data, APOE genotyping, and a neuropsychological test battery including the California Verbal Learning Test – second edition (CVLT-II) were administered and assessed at study entry and at 1-year follow-up. Data were analyzed using mixed-model repeated measures, where the dependent variable was verbal memory indexed by California Verbal Learning Test (CVLT) Trials 1–5 total recall score.Results: FEP-APOE-ε4 carriers and FEP-APOE-ε4 noncarriers had similar symptom severity, clinical outcomes, premorbid and current intelligence quotient, and exposure to antipsychotics. There was a main effect of group on CVLT 1–5 (FEP =43.30 vs control =58.25; F[1, 119.7]=42.97; P

Objective: The Global Assessment of Functioning scale (GAF) is included as axis V in the DSM-IV multiaxial diagnostic system. The GAF is simple to administer and routinely used in treatment planning and as a measure of program performance. The GAF assesses both symptom severity and functional impairment, but the resultant rating provides no information about the contribution of each of these domains. This study aimed to improve the clinical utility of the GAF by creating subscales.Methods: The authors divided the scale into its two principal domains: descriptors of social and occupational functioning (SOFAS) and descriptors of symptoms (GAF minus SOFAS descriptors). These and other measures of symptoms and functioning were used to assess 407 patients while acutely psychotic and again after treatment.Results: Symptom scores were of greater severity than functional impairment scores in most cases. Because of this, the GAF score tended to reflect symptom severity rather than functional impairment. The symptom rating was more strongly correlated with measures of positive symptoms, and the functional rating had higher associations with negative symptoms and functional impairment. Both scales were good indicators of clinical change.Conclusions: Findings indicate that GAF ratings for patients with psychosis tend to reflect symptom severity rather than functional impairment. Splitting the GAF into two parts resulted in greater discrimination for this patient group yet retained ease of administration. [ABSTRACT FROM AUTHOR]

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]

Genetic counseling is an important clinical service that is routinely offered to families affected by genetic disorders or by complex disorders for which genetic testing is available. It is not yet routinely offered to individuals with serious mental illnesses and their families, but recent findings that beliefs about the cause of mental illness can affect an individual's adaptation to the illness suggest that genetic counseling may be a useful intervention for this population. In a genetic counseling session the counselor discusses genetic and environmental contributors to disease pathogenesis; helps individuals explore conceptions, fears, and adaptive strategies; and provides nondirective support for decision making. Expected outcomes may include reductions in fear, stigma, and guilt associated with a psychiatric diagnosis; improvements in adherence to prescribed medications; declines in risk behaviors; and reductions in misconceptions about the illness. The authors endorse a multidisciplinary approach in which a psychiatrist and genetic counselor collaborate to provide comprehensive psychiatric genetic counseling. [ABSTRACT FROM AUTHOR]

The psychostimulant methamphetamine (MA) is a highly addictive drug that has surged in popularity over the last decade in North America. A burgeoning number of clandestine drug laboratories has led to dramatic increases in MA production, which have resulted in significant public health, legal and environmental problems. Current evidence indicates that exposure to MA is neurotoxic, and neuroimaging studies confirm that long-term use in humans may lead to extensive neural damage. These physiological changes are commonly associated with persistent forms of cognitive impairment, including deficits in attention, memory and executive function. In the present review, we provide a comprehensive description of the factors relating to MA use and the major health-related consequences, with an emphasis on MA-induced psychosis. It is hoped that increased knowledge of MA abuse will provide the basis for future treatment strategies. [ABSTRACT FROM AUTHOR]

Examines the hippocampal connectivity of presynaptic proteins SNAP-25 and synaptophysin from schizophrenic cases. Reduction in hippocampal SNAP-25 immunoreactivity in schizophrenia; Disconnection of a subset of hippocampal circuitry; Increased synaptophysin immunoreactivity in the granule cell layer of dentate gyrus.

Background: Severe psychomotor agitation and aggression often require immediate pharmacological intervention, but clear evidence-based recommendations for choosing among the multiple options are lacking. To address this gap, we plan a systematic review and individual-participant-data network meta-analysis to investigate their comparative effectiveness in real-world emergency settings with increased precision., Methods: We will include randomized controlled trials investigating intramuscular or intravenous pharmacological interventions, as monotherapy or in combination, in adults with severe psychomotor agitation irrespective of the underlying diagnosis and requiring rapid tranquilization in general or psychiatric emergency settings. We will exclude studies before 2002, those focusing on specific reasons for agitation and placebo-controlled trials to avoid concerns related to the transitivity assumption and potential selection biases. We will search for eligible studies in BIOSIS, CENTRAL, CINAHL Plus, Embase, LILACS, MEDLINE via Ovid, PubMed, ProQuest, PsycINFO, ClinicalTrials.gov, and WHO-ICTRP. Individual-participant data will be requested from the study authors and harmonized into a uniform format, and aggregated data will also be extracted from the studies. At least two independent reviewers will conduct the study selection, data extraction, risk-of-bias assessment using RoB 2, and applicability evaluation using the RITES tool. The primary outcome will be the number of patients achieving adequate sedation within 30 min after treatment, with secondary outcomes including the need for additional interventions and adverse events, using odds ratios as the effect size. If enough individual-participant data will be collected, we will synthesize them in a network meta-regression model within a Bayesian framework, incorporating study- and participant-level characteristics to explore potential sources of heterogeneity. In cases where individual-participant data are unavailable, potential data availability bias will be explored, and models allowing for the inclusion of studies reporting only aggregated data will be considered. We will assess the confidence in the evidence using the Confidence in Network Meta-Analysis (CINeMA) approach., Discussion: This individual-participant-data network meta-analysis aims to provide a fine-tuned synthesis of the evidence on the comparative effectiveness of pharmacological interventions for severe psychomotor agitation in real-world emergency settings. The findings from this study can greatly be provided clearer evidence-based guidance on the most effective treatments., Systematic Review Registration: PROSPERO CRD42023402365., (© 2024. The Author(s).)

Objective: To examine the relationship between schizophrenia, antipsychotic medication adherence and driver responsibility for motor vehicle crash., Design: Retrospective observational cohort study using 20 years of population-based administrative health and driving data., Setting: British Columbia, Canada., Participants: Licensed drivers who were involved in a police-attended motor vehicle crash in British Columbia over a 17-year study interval (2000-16)., Exposures: Incident schizophrenia was identified using hospitalisation and physician services data. Antipsychotic adherence was estimated using prescription fill data to calculate the 'medication possession ratio' (MPR) in the 30 days prior to crash., Primary Outcome Measures: We deemed drivers 'responsible' or 'non-responsible' for their crash by applying a validated scoring tool to police-reported crash data. We used logistic regression to evaluate the association between crash responsibility and exposures of interest., Results: Our cohort included 808 432 drivers involved in a police-attended crash and for whom crash responsibility could be established. In total, 1689 of the 2551 drivers with schizophrenia and 432 430 of the 805 881 drivers without schizophrenia were deemed responsible for their crash, corresponding to a significant association between schizophrenia and crash responsibility (66.2% vs 53.7%; adjusted OR (aOR), 1.67; 95% CI, 1.53 to 1.82; p<0.001). The magnitude of this association was modest relative to established crash risk factors (eg, learner license, age ≥65 years, impairment at time of crash). Among the 1833 drivers with schizophrenia, near-optimal antipsychotic adherence (MPR ≥0.8) in the 30 days prior to crash was not associated with lower crash responsibility (aOR, 1.04; 95% CI, 0.83 to 1.30; p=0.55)., Conclusions: Crash-involved drivers with schizophrenia are more likely to be responsible for their crash, but the magnitude of risk is similar to socially acceptable risk factors such as older age or possession of a learner license. Contemporary driving restrictions for individuals with schizophrenia appear to adequately mitigate road risks, suggesting more stringent driving restrictions are not warranted., Competing Interests: Competing interests: WH is a consultant to Translational Life Sciences, AbbVie, Newron, and Otsuka., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu 2 R and mGlu 3 R) in brains of schizophrenia patients may explain the limited efficacy of mGlu 2/3 R ligands in clinical trials. Studies evaluating mGlu 2/3 R levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected. Toxicological analyses identified cases who were (AP+) or were not (AP-) receiving antipsychotic treatment near the time of death. Protein and mRNA levels of mGlu 2 R and mGlu 3 R, as well as GRM2 and GRM3 promoter-attached histone posttranslational modifications, were quantified. Experimental animal models were used to compare with data obtained in human tissues. Compared to matched controls, schizophrenia cortical samples had lower mGlu 2 R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu 3 R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D 2 and serotonin 5HT 2A receptors correlated with higher density of mGlu 3 R, but not mGlu 2 R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu 2 R, but not mGlu 3 R regulation observed in schizophrenia brains. mGlu 2 R and mGlu 3 R mRNA levels, and the epigenetic control mechanisms did not parallel the alterations at the protein level, and in some groups correlated inversely. Insufficient cortical availability of mGlu 2 R and mGlu 3 R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu 3 R, but not mGlu 2 R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu 3 R expression are activated to counterbalance mGluR loss of function is described., (© 2024. The Author(s).)

This systematic review aimed to review neuroimaging studies comparing clozapine-resistant schizophrenia patients with clozapine-responding patients, and with first-line antipsychotic responding (FLR) patients. A total of 19 studies including 6 longitudinal studies were identified. Imaging techniques comprised computerized tomography (CT, n = 3), structural magnetic resonance imaging (MRI, n = 7), magnetic resonance spectroscopy (MRS, n = 5), functional MRI (n = 1), single-photon emission computerized tomography (SPECT, n = 3) and diffusion tensor imaging (DTI, n = 1). The most consistent finding was hypo-frontality in the clozapine-resistant group compared with the clozapine-responding group with possible differences in frontal-striatal-basal ganglia circuitry as well as the GABA level between the two treatment-resistant groups. Additional statistically significant findings were reported when comparing clozapine-resistant patients with the FLR group, including lower cortical thickness and brain volume of multiple brain regions as well as lower Glx/Cr level in the dorsolateral prefrontal cortex. Both treatment-resistant groups were found to have extensive differences in neurobiological features in comparison with the FLR group. Overall results suggested treatment-resistant schizophrenia is likely to be a neurobiological distinct type of the illness. Clozapine-resistant and clozapine-responding schizophrenia are likely to have both shared and distinct neurobiological features. However, conclusions from existing studies are limited, and future multi-center collaborative studies are required with a consensus clinical definition of patient samples, multimodal imaging tools, and longitudinal study designs., (© 2023. The Author(s).)

Background and Hypothesis: There is limited evidence to guide the approaches to clozapine treatment. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for the optimization of clozapine monotherapy., Study Design: We conducted an online Delphi survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group comprising experts from twenty-nine countries. The threshold criterion for a consensus recommendation was ≥ 75% agreement ("agree" and "strongly agree" responses) on a question. Agreement of ≥ 50% but < 75% in a second or third Delphi round was deemed to provide guidance., Study Results: Forty-nine (first round), 32 (second round), and 48 (third round) of the 91 current TRRIP members participated. Expert recommendations at ≥ 75% comprised second-line treatment with clozapine in cases of persistent positive symptoms with co-occurring extrapyramidal symptoms, tardive dyskinesia, or suicidality/aggression. There was considerable disagreement on myocarditis screening parameters. The management of somatic and neuropsychiatric adverse drug reactions warrants further research for more evidence-based recommendations. Rechallenge with clozapine was recommended for eosinophilia, sinus tachycardia and fever and guidance (agreement ≥ 50%) was reached for pneumonia and thrombocytopenia., Conclusions: Given the limited evidence available, this consensus-based series of recommendations and guidance statements supports clinical decision-making to optimize clozapine monotherapy and provides guidance for future research in treatment-resistant schizophrenia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.)

Introduction Street soccer makes the sport accessible to people affected by homelessness or precarious housing. There is overwhelming evidence that exercise improves physical and mental health. In addition, sport facilitates positive peer pressure that leads to beneficial life changes. Method To examine participants' accounts of the effects of street soccer in a sample of socially disadvantaged players from Western Canada, we collected 73 cross-sectional self-reports of life changes via a questionnaire. The questionnaire included questions on social, mental, and physical health, including substance use. This allowed the calculation of a modified composite harm score. Results Participants reported improved physical (46% of participants) and mental (43% of participants) health, reduced cigarette (50% of smokers), alcohol (45% of users), cannabis (42% of users), and other non-prescribed drug use, increased number of friends (88% of participants), improved housing (60% of participants), increased income (19% of participants), increased community medical supports (40% of participants), and decreased conflicts with police (47% of those with prior recent conflict). Perceived reductions in substance use were supported by significant changes in composite harm score. Conclusion Street soccer appears to promote improved physical, mental, and social health among people affected by homelessness or precarious housing, with reduction in substance use likely to be a key factor. This work builds upon past qualitative research showing the benefits of street soccer and supports future research which may help elucidate the mechanisms by which street soccer has beneficial effects., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Bates et al.)

Objectives: Non-adherence to antipsychotics is the greatest obstacle to treating schizophrenia. We assessed the economic and clinical impacts of adherence to antipsychotics among people living with HIV/AIDS (PLWH) and schizophrenia in British Columbia, Canada., Design and Setting: A population-based cohort study in British Columbia, Canada., Methods: Eligible PLWH were enrolled in the Seek and Treat for Optimal Prevention HIV/AIDS population-based cohort during 2001-2016, diagnosed with schizophrenia, on antipsychotics for ≥1 day, and followed for ≥1 year from schizophrenia diagnosis date or 1 January 2001, whichever occurred last., Primary and Secondary Outcome Measures: A two-part model assessed the marginal effect of adherence on healthcare costs (in 2016 Canadian dollar), while logistic regression examined the effect on virological failure, and generalised linear mixed models examined the effect on hospital readmissions within 30 days and length of hospital stay., Results: Among 726 PLWH with schizophrenia, ≥80% adherence to antipsychotics increased from 25% (50/198) in 2001 to 41% (225/554) in 2016. In most years, we observed no difference in adherence to antipsychotics among those who used only injectables, only non-injectables, and a combination of both, or among those who have ever consumed typical/first-generation antipsychotics and who consumed only atypical/second-generation antipsychotics. Overall healthcare costs were higher in the non-adherent group ($C2185), driven by the average annual hospitalisation costs ($C5517), particularly among women ($C8806) and people who ever injected drugs (PWID) ($C5985). Non-adherent individuals also experienced higher hospital readmissions (adjusted odds ratio (aOR) 1.48, 95% CI 1.23 to 1.77), and longer hospital stays (adjusted mean ratio 1.23, 95% CI 1.13 to 1.35) in comparison to adherent individuals. We found no difference in virological failure by adherence groups, except when we stratified by gender where the aOR for women was 2.48 (95% CI 1.06 to 5.82)., Conclusions: Our results showed that implementing strategies and interventions to increase antipsychotic adherence, particularly among women and PWID, will be critical in addressing this public health challenge., Competing Interests: Competing interests: JSGM: Institutional grants have been provided by Gilead, Merck and ViiV Healthcare. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Homeless or precariously housed individuals live with poor health and experience premature mortality compared with the general population, yet little is known about age-related brain changes among these individuals. We evaluated whether MRI measures of brain structure are differentially associated with age and selected risk factors among individuals who are homeless or precariously housed compared with a general population sample., Methods: We compared T1-weighted and diffusion tensor imaging measures of brain macrostructure and white matter microstructure in a well-characterised sample of 312 precariously housed participants with a publicly available dataset of 382 participants recruited from the general population. We used piecewise and multiple linear regression to examine differential associations between MRI measures and between the samples, and to explore associations with risk factors in the precariously housed sample., Results: Compared with the general population sample, older age in the precariously housed sample was associated with more whole-brain atrophy (β=-0.20, p=0.0029), lower whole-brain fractional anisotropy (β=-0.32, p<0.0001) and higher whole-brain mean diffusivity (β=0.69, p<0.0001). Several MRI measures had non-linear associations with age, with further adverse changes after age 35-40 in the precariously housed sample. History of traumatic brain injury, stimulant dependence and heroin dependence was associated with more atrophy or alterations in white matter diffusivity in the precariously housed sample., Conclusions: Older age is associated with adverse MRI measures of brain structure among homeless and precariously housed individuals compared with the general population. Education, improvements in care provision and policy may help to reduce the health disparities experienced by these individuals., Competing Interests: Competing interests: TF is supported by a Sauder Family/Heart and Stroke Professorship of Stroke Research, the Heart and Stroke Foundation of Canada and the Michael Smith Foundation for Health Research. FV-R receives research support from CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute and Weston Brain Institute for investigator-initiated research, philanthropic support from the Seedlings Foundation, in-kind equipment support for this investigator-initiated trial from MagVenture, and has received honoraria for participation in an advisory board for Janssen. WH has received consulting fees from Translational Life Sciences, Guidepoint and AbbVie for work unrelated to the Hotel Study. All other authors have no disclosures., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This article reports on an American Society of Pharmacology and Therapeutics, Division of Drug Metabolism and Disposition symposium held at Experimental Biology on April 2, 2022, in Philadelphia. As of July 2022, over 500 million people have been infected with SARS-CoV-2 (the virus causing COVID-19) and over 12 billion vaccine doses have been administered. Clinically significant interactions between viral infections and hepatic drug metabolism were first recognized over 40 years ago during a cluster of pediatric theophylline toxicity cases attributed to reduced hepatic drug metabolism amid an influenza B outbreak. Today, a substantive body of research supports that the activated innate immune response generally decreases hepatic cytochrome P450 activity. The interactions extend to drug transporters and other organs and have the potential to impact drug absorption, distribution, metabolism, and excretion (ADME). Based on this knowledge, altered ADME is predicted with SARS-CoV-2 infection or vaccination. The report begins with a clinical case exploring the possibility of SARS-CoV-2 vaccination increasing clozapine levels. This is followed by discussions of how SARS-CoV-2 infection or vaccines alter the metabolism and disposition of complex drugs, such as nanoparticles and biologics and small molecule therapies. The review concludes with a discussion of the effects of viral infections on placental amino acid transport and their potential to impact fetal development. The session improved our understanding of the impact of emerging viral infections and vaccine technologies on drug metabolism and disposition, which will help mitigate drug toxicity and improve drug and vaccine safety and effectiveness. SIGNIFICANCE STATEMENT: Altered pharmacokinetics of small molecule and complex molecule drugs and fetal brain distribution of amino acids following SARS-CoV-2 infection or immunization are possible. The proposed mechanisms involve decreased liver cytochrome P450 metabolism of small molecules, enhanced innate immune system metabolism of complex molecules, and altered placental and fetal blood-brain barrier amino acid transport, respectively. Future research is needed to understand the effects of these interactions on adverse drug responses, drug and vaccine safety, and effectiveness and fetal neurodevelopment., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: We aimed to characterize mortality among people with HIV (PWH) and psychotic disorders (PWH/psychosis+) vs. PWH alone (PWH/psychosis-)., Method: A population-based analysis of mortality in PWH (age ≥19) in British Columbia (BC) from April 1996 to March 2017 was conducted using data from the Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) study. Deaths were identified from the Vital Statistics Data (classified as HIV vs. non-HIV causes). Mortality trends across all fiscal years were examined. Cox models assessed the hazard of psychotic disorders on mortality; possible differences between schizophrenia and nonschizophrenia types of psychotic disorders were also evaluated., Results: Among 13 410 PWH included in the analysis, 1572 (11.7%) met the case definition for at least one psychotic disorder. Over the study period, 3274 deaths (PWH/psychosis-: n  = 2785, PWH/psychosis+: n  = 489) occurred. A decline over time in all-cause mortality and HIV-related mortality was observed in both PWH/psychosis+ and PWH/psychosis- ( P value <0.0001). A decline in non-HIV mortality was observed among PWH/psychosis- ( P value = 0.003), but not PWH/psychosis+ ( P value = 0.3). Nonschizophrenia psychotic disorders were associated with increased risk of mortality; adjusted hazard ratios with (95% confidence intervals): all-cause 1.75 (1.46-2.09), HIV-related 2.08 (1.60-2.69), non-HIV-related 1.45 (1.11-1.90). Similar associations between schizophrenia and mortality were not observed., Conclusion: People with co-occurring HIV and nonschizophrenia psychotic disorders experienced a significantly higher risk of mortality vs. PWH without any psychotic disorder. Implementing care according to syndemic models considering interactions between HIV and particularly episodic psychotic disorders could help manage mortality risk more effectively among PWH/psychosis+., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Treatment-refractory psychosis (TRP) is a significant clinical challenge. While clozapine is frequently effective, alternate or augmentation strategies are often necessary. Evidence supports effectiveness of electroconvulsive therapy (ECT), but questions remain about optimal treatment parameters and impacts of concomitant pharmacotherapy., Objective: /Hypothesis: To analyze the impact of clozapine, anticonvulsant medication, mood state, and ECT electrode placement on outcomes in TRP. We hypothesized that ECT would lead to greater reduction in positive symptoms, particularly in patients receiving clozapine., Methods: Retrospective study in a tertiary TRP program. The Positive and Negative Syndrome Scale (PANSS) was used for clinical outcomes, with positive subscore as primary outcome. Clinical and ECT data were analyzed using a linear modelling approach, controlling for relevant covariates., Results: A total of 309 patients were included. ECT plus clozapine associated with greater improvement in positive, general, and total symptoms than ECT alone. ECT associated with greater improvement in negative symptoms in depressed patients. Bifrontal placement was mostly equivalent to bitemporal, with greater reduction of positive symptoms in patients receiving clozapine, and associated with lower electrical dose in patients on anticonvulsants. Clozapine increased seizure duration, while anticonvulsants decreased it. Anticonvulsant use in ECT patients associated with equivalent to slightly improved symptom reduction., Conclusions: ECT's benefit in TRP may be greatest in patients receiving clozapine. ECT can improve negative symptoms in depressed TRP patients. Bifrontal placement is effective in TRP. Clozapine and anticonvulsants have opposite effects on seizure duration, but anticonvulsants may not adversely affect clinical outcomes of ECT for TRP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Ainsworth receives research support from the University of British Columbia Clinician Investigator Program. Dr. White receives honoraria from HLS Therapeutics, is on an advisory panel with HLS Therapeutics, and receives consulting fees from the Canadian Agency for Drugs and Technologies in Health. Dr. Honer has received consulting fees or sat on paid advisory boards for In Silico Biosciences, Translational Life Sciences, and AbbVie. Dr. Vila-Rodriguez receives research support from CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute, and Weston Brain Institute for investigator-initiated research; philanthropic support from Seedlings Foundation; and in-kind equipment support from MagVenture. He has received honoraria for participation in an advisory board for Allergan. Ms. Avina-Galindo, Mr. Zhan, and Ms. Gregory have no disclosures., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Psychosis is a well established complication of non-prescription drug use. We sought to measure the 1-year mortality of emergency department patients with substance-induced psychosis (SIP)., Methods: This study was a multi-centre, retrospective electronic medical records review of patients presenting to the ED with substance-induced psychosis (SIP). We interrogated the hospital ED database from Jan 1, 2018 and Jan 1, 2019 to identify consecutive patients. All patients were followed for one year from index visit, and classified as alive/dead at that time. Patients were included in the study if they met the following criteria: 1) ED discharge diagnosis of psychosis NOS and a positive urine drugs of abuse screen (UDAS) or the patient verbally endorsed drug use, or 2) Mental disorder due to drug use and "disorganized thought", "bizarre behavior" or "delusional behavior" documented in the chart and one or more of the following criteria: a) arrival with police, b) mental health certification, c) physical restraints, d) chemical restraints. We excluded patients who were not British Columbia residents, since we were unable to ascertain if they were alive or dead at 1 year from their index ED visit. Primary statistical analysis was logistic regression for risk of death in 1 year, based on plausible risk factors, selected a priori., Results: We identified 813 presentations for SIP (620 unique patients). The median age of the entire cohort was 35 years (IQR 28-44), and 69.5% (n = 565) were male. Thirty five patients (4.3%; 95% CI 3.2-5.9) had died one year after their initial presentation to the ED for SIP. Separate multivariable logistic regression analyses, controlling for age, demonstrated schizophrenia (OR 4.2, 95% CI 1.8-11.1) significantly associated with increased 1-year mortality., Conclusions: In our study of patients presenting to the ED with SIP, the 1-year mortality was 4.3%. Controlling for age, schizophrenia was a notable risk factor for increased 1-year mortality., Competing Interests: The authors have declared that no competing interests exist.

Background: There are currently relatively few effective pharmacological treatments for obesity, and existing ones may be associated with limiting side-effects. In the search for novel anti-obesity agents, drugs that modify central serotonergic systems have historically proven to be effective in promoting weight loss. Psilocin, which is rapidly metabolized from psilocybin, is an agonist at multiple serotonin receptors. In the present study we assessed the effects of psilocybin and a positive control (metformin) on changes in body weight in a rat model of obesity., Methods: Five groups of adult male rats were pre-conditioned with a cafeteria diet until obese (>600 g) and then treated with either psilocybin (0.1, 1, or 5 mg/kg, i.p.), metformin (300 mg/kg, p.o.) or vehicle control. Treatments were for 27 consecutive weekdays, and body weights and high calorie food intake were recorded daily. Fasting glucose levels were recorded after 11 days of treatment. At the end of treatment rats completed a glucose tolerance test, and multiple fat pads were dissected out to assess adiposity., Results: The medium dose psilocybin group had to be terminated from the study prematurely. Both the low and high dose psilocybin groups caused a significant decrease in changes in body weight compared to controls. The metformin group produced a greater decrease in change in body weight than either psilocybin groups or controls. Both high dose psilocybin and metformin decreased consumption of the high calorie diet, and exhibited decreased central adiposity., Conclusion: Psilocybin demonstrated modest but significant effects on weight gain. Further study is recommended., Competing Interests: WH has received consulting fees or sat on paid advisory boards for the Canadian Agency for Drugs and Technology in Health, AlphaSights, Guiepoint, in silico, Translational Life Sciences, Otsuka, Lundbeck, and Newron. WP was the founder and CEO of Translational Life Sciences, an early stage science company focused on psychedelic-based therapeutics. AB served as a consultant to Translational Life Sciences. 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 Huang, Pham, Panenka, 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.

Objective: Traumatic brain injury (TBI) is increasingly recognized as a common and impactful health determinant in homeless and precariously housed populations. We sought to describe the history of TBI in a precariously housed sample and evaluate how TBI was associated with the initial loss and lifetime duration of homelessness and precarious housing., Method: We characterized the prevalence, mechanisms, and sex difference of lifetime TBI in a precariously housed sample. We also examined the impact of TBI severity and timing on becoming and staying homeless or precariously housed; 285 precariously housed participants completed the Brain Injury Screening Questionnaire in addition to other health assessments., Results: A history of TBI was reported in 82.1% of the sample, with 64.6% reporting > 1 TBI, and 21.4% reporting a moderate or severe TBI. Assault was the most common mechanism of injury overall, and females reported significantly more traumatic brain injuries due to physical abuse than males (adjusted OR = 1.26, 95% CI = 1.14 to 1.39, P < 0.0001). The first moderate or severe TBI was significantly closer to the first experience of homelessness ( b = 2.79, P = 0.003) and precarious housing ( b = 2.69, P < 0.0001) than was the first mild TBI. In participants who received their first TBI prior to becoming homeless or precariously housed, traumatic brain injuries more proximal to the initial loss of stable housing were associated with a longer lifetime duration of homelessness (RR = 1.04, 95% CI = 1.02 to 1.06, P < 0.0001) and precarious housing (RR = 1.03, 95% CI = 1.01 to 1.04, P < 0.0001)., Conclusions: These findings demonstrate the high prevalence of TBI in this vulnerable population, and that aspects of TBI severity and timing are associated with the loss and lifetime duration of stable housing.

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.)

Background: Homeless and precarious housed persons are particularly prone to traumatic brain injuries (TBIs), but existent incidence rates are hampered by poor case acquisition. We rigorously documented TBIs in precariously housed persons transitioning in and out of homelessness., Methods: Between December 2016 and May 2018, 326 precariously housed participants enrolled in a longitudinal study in Vancouver, Canada were assessed monthly for TBI occurrences after education on sequelae. Over one participant-year, 2433 TBI screenings were acquired for 326 person-years and variables associated with odds of incident TBI were evaluated., Findings: One hundred participants acquired 175 TBIs, yielding an observed incidence proportion of 30·7% and event proportion of 53·7%. Of the injured, 61% reported one TBI and 39% reported multiple injuries. Acute intoxication was present for more than half of the TBI events assessed. Additionally, 9·7% of TBI events occurred in the context of a drug overdose. Common injury mechanisms were falls (45·1%), assaults (25·1%), and hitting one's head on an object (13·1%). In this community-based but non-randomly recruited sample, exploratory analyses identified factors associated with odds of an incident TBI over one year of follow-up, including: schizophrenia disorders (odds ratio (OR) = 0·43, 95% confidence interval (CI) 0·19, 0·94), role functioning (OR = 0·69, 95% CI 0·52, 0·91), opioid dependence (OR = 2·17, 95% CI 1·27, 3·72) and those reporting past TBIs (OR = 1·99, 95% CI 1·13, 3·52)., Interpretation: Given the ubiquity of TBIs revealed in this precariously housed sample, we identify an underappreciated and urgent healthcare priority. Several factors modified the odds of incident TBI, which can facilitate investigations into targeted prevention efforts., Funding: Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, William and Ada Isabelle Steel Research Fund, Simon Fraser University Vice-President Research Undergraduate Student Research Award and Simon Fraser University Psychology Department Research Grant., Competing Interests: WJP: Grant funding from the Canadian Institutes of Health Research, Brain Injury Canada and ACRM Task Force LX: Grant funding from Simon Fraser University Undergraduate Student Research Award. XJH: Grant funding from the Canadian Natural Science and Engineering Discovery Grant Program and Simon Fraser University Undergraduate Student Research Award. WGH: Grant funding from the Canadian Institutes of Health Research AET: Grant funding from the Canadian Institutes of Health Research; Simon Fraser University William and Ada Isabelle Steel Research Fund and Simon Fraser University Psychology Department Research Grant. All other authors report no conflicts., (© 2022 The Author(s).)

Physical activity relates to reduced dementia risk, but the cellular and molecular mechanisms are unknown. We translated animal and in vitro studies demonstrating a causal link between physical activity and microglial homeostasis into humans. Decedents from Rush Memory and Aging Project completed actigraphy monitoring (average daily activity) and cognitive evaluation in life, and neuropathological examination at autopsy. Brain tissue was analyzed for microglial activation via immunohistochemistry (anti-human HLA-DP-DQ-DR) and morphology (% Stage I, II, or III), and synaptic protein levels (SNAP-25, synaptophysin, complexin-I, VAMP, syntaxin, synaptotagmin-1). Proportion of morphologically activated microglia (PAM) was estimated in ventromedial caudate, posterior putamen, inferior temporal (IT), and middle frontal gyrus. The 167 decedents averaged 90 years at death, two-thirds were nondemented, and 60% evidenced pathologic Alzheimer's disease (AD). Adjusting for age, sex, education, and motor performances, greater physical activity associated with lower PAM in the ventromedial caudate and IT. Relationships between physical activity and PAM in the ventromedial caudate or IT were particularly prominent in adults evidencing microinfarcts or AD pathology, respectively. Mediational analyses indicated that PAM IT mediated ∼30% of the relationships between (1) physical activity and synaptic protein in IT, and (2) physical activity and global cognition, in separate models. However, the size of the mediation depended on AD pathology ranging from >40% in adults with high AD burden, but <10% in adults with low AD burden. Lower microglial activation may be a pathway linking physical activity to age-related brain health in humans. Physical activity may promote AD-related synaptic and cognitive resilience through reduction of pro-inflammatory microglial states. SIGNIFICANCE STATEMENT Physical activity relates to better cognitive aging and reduced risk of neurodegenerative disease, yet the cellular and molecular pathways linking behavior-to-brain in humans are unknown. Animal studies indicate that increasing physical activity leads to decreased microglial activation and corresponding increases in synaptogenesis and neurogenesis. We objectively monitored physical activity (accelerometer-based actigraphy) and cognitive performances in life, and quantified microglial activation and synaptic markers in brain tissue at death in older adults. These are the first data supporting microglial activation as a physiological pathway by which physical activity relates to brain heath in humans. Although more interventional work is needed, we suggest that physical activity may be a modifiable behavior leveraged to reduce pro-inflammatory microglial states in humans., (Copyright © 2022 the authors.)

A recent increase in the literature regarding the evidence base for clozapine has made it increasingly difficult for clinicians to judge "best evidence" for clozapine use. As such, we aimed at elucidating the state-of-the-art for clozapine with regard to efficacy, effectiveness, tolerability, and management of clozapine and clozapine-related adverse events in neuropsychiatric disorders. We conducted a systematic PRISMA-conforming quantitative meta-review of available meta-analytic evidence regarding clozapine use. Primary outcome effect sizes were extracted and transformed into relative risk ratios (RR) and standardized mean differences (SMD). The methodological quality of meta-analyses was assessed using the AMSTAR-2 checklist. Of the 112 meta-analyses included in our review, 61 (54.5%) had an overall high methodological quality according to AMSTAR-2. Clozapine appears to have superior effects on positive, negative, and overall symptoms and relapse rates in schizophrenia (treatment-resistant and non-treatment-resistant subpopulations) compared to first-generation antipsychotics (FGAs) and to pooled FGAs/second-generation antipsychotics (SGAs) in treatment-resistant schizophrenia (TRS). Despite an unfavorable metabolic and hematological adverse-event profile compared to other antipsychotics, hospitalization, mortality and all-cause discontinuation (ACD) rates of clozapine surprisingly show a pattern of superiority. Our meta-review outlines the superior overall efficacy of clozapine compared to FGAs and most other SGAs in schizophrenia and suggests beneficial efficacy outcomes in bipolar disorder and Parkinson's disease psychosis (PDP). More clinical studies and subsequent meta-analyses are needed beyond the application of clozapine in schizophrenia-spectrum disorders and future studies should be directed into multidimensional clozapine side-effect management to foster evidence and to inform future guidelines., (© 2021. The Author(s).)

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.

Studies on the long-term development and early predictors of treatment-resistant schizophrenia (TRS) and clozapine-resistant TRS (CR-TRS) in patients with first-episode schizophrenia-spectrum disorders (FES) are limited and have not considered the impact of early intervention services (EIS). This study aimed to explore the development of TRS and CR-TRS among patients with FES over 12 years of follow-up. Of the 1234 patients with FES, 15% developed TRS. A total of 450 patients with schizophrenia or schizoaffective disorder were included in a nested case-control study (157 TRS and 293 non-TRS). Younger age of onset, poorer premorbid social adjustment during adulthood, longer duration of first episode, a greater number of relapses, and a higher antipsychotic dose in the first 24 months were associated with earlier TRS. CR-TRS patients, constituting 25% of TRS patients, had a poorer premorbid social adjustment in late adolescence and longer delay before clozapine initiation compared with non-CR-TRS. CR-TRS had poorer clinical and functional outcomes at 12-year follow-up. However, TRS patients on clozapine had a lower mortality rate compared with non-TRS patients. EIS did not have a significant impact on the development of TRS, but patients in the EIS group had a shorter delay of clozapine initiation. Results suggested that neurodevelopmental factors, early clinical characteristics, and requirement for higher antipsychotic dose may be associated with TRS development, highlighting multiple pathways leading to this form of illness. Specific interventions including relapse prevention and early initiation of clozapine during the early course of illness may reduce the rate of TRS and improve patient outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: D. Thompson is an unpaid reviewer for the Canadian Council on Continuing Education in Pharmacy program on clozapine, which received funding from HLS Therapeutics. She also received payment for presenting at a drug-induced movement disorder workshop and the University of British Columbia Continuing Pharmacy Education Conference and received an honorarium from the Canadian Pharmaceutical Association for reviewing chapters on psychiatric and substance use topics for the Compendium of Pharmaceutical Choices. She is an unpaid member of the British Columbia Schizophrenia Society Medical Advisory Board. R.F. White has received honoraria from HLS Therapeutics. W.G. Honer has received consulting fees or sat on paid advisory boards for Translational Life Sciences, AbbVie and Guidepoint. C. Delorme reports no competing interests.

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.

Background: Evidence for the management of inadequate clinical response to clozapine in treatment-resistant schizophrenia is sparse. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for treatment strategies for clozapine-refractory patients with schizophrenia., Methods: We conducted an online survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group. An agreement threshold of ≥75% (responses "agree" + "strongly agree") was set to define a first-round consensus. Questions achieving agreement or disagreement proportions of >50% in the first round, were re-presented to develop second-round final consensus recommendations., Results: Forty-four (first round) and 49 (second round) of 63 TRRIP members participated. Expert recommendations at ≥75% agreement included raising clozapine plasma levels to ≥350 ng/ml for refractory positive, negative, and mixed symptoms. Where plasma level-guided dose escalation was ineffective for persistent positive symptoms, waiting for a delayed response was recommended. For clozapine-refractory positive symptoms, combination with a second antipsychotic (amisulpride and oral aripiprazole) and augmentation with ECT achieved consensus. For negative symptoms, waiting for a delayed response was recommended, and as an intervention for clozapine-refractory negative symptoms, clozapine augmentation with an antidepressant reached consensus. For clozapine-refractory suicidality, augmentation with antidepressants or mood-stabilizers, and ECT met consensus criteria. For clozapine-refractory aggression, augmentation with a mood-stabilizer or antipsychotic medication achieved consensus. Generally, cognitive-behavioral therapy and psychosocial interventions reached consensus., Conclusions: Given the limited evidence from randomized trials of treatment strategies for clozapine-resistant schizophrenia (CRS), this consensus-based series of recommendations provides a framework for decision making to manage this challenging clinical situation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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 and Purpose: We aim to describe the burden, characteristics, and cognitive associations of cerebral small vessel disease in a Canadian sample living with multimorbidity in precarious housing., Methods: Participants received T1, T2-fluid-attenuated inversion recovery, and susceptibility-weighted imaging 3T magnetic resonance imaging sequences and comprehensive clinical, laboratory, and cognitive assessments. Cerebral small vessel disease burden was characterized using a modified Small Vessel Disease (mSVD) score. One point each was given for moderate-severe white matter hyperintensities, ≥1 cerebral microbleeds, and ≥1 lacune. Multivariable regression explored associations between mSVD score, risk factors, and cognitive performance., Results: Median age of the 228 participants (77% male) was 44.7 years (range, 23.3-63.2). In n=188 participants with consistent good quality magnetic resonance imaging sequences, mSVD scores were 0 (n=127, 68%), 1 (n=50, 27%), and 2 (n=11, 6%). Overall, one-third had an mSVD ≥1 n=61 (32%); this proportion was unchanged when adding participants with missing sequences n=72/228 (32%). The most prevalent feature was white matter hyperintensities 53/218 (24%) then cerebral microbleed 16/191 (8%) and lacunes 16/228 (7%). Older age (odds ratio, 1.10 [95% CI, 1.05-1.15], P <0.001), higher diastolic blood pressure (odds ratio, 1.05 [95% CI, 1.01-1.09], P =0.008), and a history of injection drug use (odds ratio, 3.13 [95% CI, 1.07-9.16], P =0.037) had significant independent associations with a mSVD score of ≥1 in multivariable analysis. mSVD ≥1 was associated with lower performance on tests of verbal memory, sustained attention, and decision-making, contributing 4% to 5% of the variance in each cognitive domain., Conclusions: The 32% prevalence of cerebral small vessel disease in this young, socially marginalized cohort was higher than expected for age and was associated with poorer cognitive performance.

Concurrent disorder refers to a diverse set of combinations of substance use disorders and mental disorders simultaneously in need of treatment. Concurrent disorders are underdiagnosed, undertreated, and more complex to manage, practicing the best recommendations can support better outcomes. The purpose of this work is to systematically assess the quality of the current concurrent disorders' clinical recommendation management guidelines. Literature searches were performed by two independent authors in electronic databases, web, and gray literature. The inclusion criteria were English language clinical management guidelines for adult concurrent disorders between 2000 and 2020. The initial search resulted in 8841 hits. A total of 24 guidelines were identified and assessed with the standardized guidelines assessment tool: AGREE II (Appraisal of Guidelines for Research and Evaluation). Most guidelines had acceptable standards, however, only the NICE guidelines had all detailed information on all AGREE II Domains. Guidelines generally supported combinations of treatments for individual disorders with a very small evidence base for concurrent disorders, and they provided little recommendation for further structuring of the field, such as level of complexity or staging, or evaluating different models of treatment integration.

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.

Objective : The amygdala is a brain region comprised of a group of functionally distinct nuclei that play a central role in social behavior. In homeless and precariously housed individuals, high rates of multimorbidity, and structural aspects of the environment may dysregulate social functioning. This study examined the neurobiological substrates of social connection in homeless and precariously housed persons by examining associations between amygdala nuclei volumes and social network size. Methods : Sixty participants (mean age 43.6 years; 73.3% male) were enrolled from an ongoing study of homeless and precariously housed adults in Vancouver, Canada. Social network size was assessed using the Arizona Social Support Interview Schedule. Amygdala nuclei volumes were extracted from anatomic T1-weighted MRI data. The central and basolateral amygdala nuclei were selected as they are implicated in anxiety-related and social behaviors. The hippocampus was included as a control brain region. Multivariable regression analysis investigated the relationship between amygdala nuclei volumes and social network size. Results : After controlling for age, sex, and total brain volume, individuals with the larger amygdala and central nucleus volumes had a larger network size. This association was not observed for the basolateral amygdala complex, though subsequent analysis found the basal and accessory basal nuclei of the basolateral amygdala were significantly associated with social network size. No association was found for the lateral amygdala nucleus or hippocampus. Conclusions : These findings suggest that select amygdala nuclei may be differentially involved in the social connections of persons with multimorbid illness and social marginalization., (Copyright © 2020 Jones, Thornton, Jones, Knerich, Lang, Woodward, Panenka, Su, Barr, Buchanan, Honer and Gicas.)

Competing Interests: W. Honer has received consulting fees or sat on paid advisory boards for the Canadian Agency for Drugs and Technology in Health, AlphaSights, Guidepoint, In Silico, Translational Life Sciences, Otsuka, Lundbeck and Newron. S. Clark has recieved an investigator-initated grant, participated in an advisory and an educational board and recieved speakers fees from Lundbeck-Otsuka Australia and received an investigator-initiated grant from Janssen-Cilag Australia. He has received speakers fees from Servier Australia. C. Correll has been a consultant and/or advisor to or has received honoraria from Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda and Teva. He has provided expert testimony for Janssen and Otsuka. He served on a data safety monitoring board for Lundbeck, Rovi, Supernus and Teva. He has received grant support from the Berlin Institute of health, Janssen, the National Institute of Mental Health, Patient Centered Outcomes Research Institute, Takeda and the Thrasher Foundation. He has received royalties from UpToDate and is a stock option holder of LB Pharma. A. Hasan has been on the advisory boards and has received speaker fees from Janssen, Lundbeck and Otsuka. O. Howes reports receiving speaker fees, participating on advisory boards, and/or receiving investigator-initiated funding from manufacturers of antipsychotics, including clozapine. J. Kane declares consulting fees/honoraria from Acadia, Alkermes, Allergan, Eli Lilly, Forum, Genentech, Dainippon Sumitomo, H. Lundbeck, Intracellular Therapies, Janssen Pharmaceutical, Jazz Pharma, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Roche, Sunovion, Takeda and Teva, as well as grant support from Otsuka, Lundbeck and Janssen. He is also a shareholder in Vanguard Research Group and LB Pharmaceuticals, Inc. D. Kelly has served as a consultant for Lundbeck, HLS Therapeutics and Alkermes, and is a joint holder of a patent for analytical microdevices for mental health treatment monitoring (US9581536B2). J. MacCabe has received research grants from, and acted as an unpaid consultant to Lundbeck and Saladax Biomedical. D. Taylor has received research funding from Janssen and Sunovion and lecture payments form Janssen, Lundbeck, Otsuka and Recordati. O. Freudenreich has received a grant from Avanir for a clinical trial involving patients taking clozapine and royalties from UpToDate for the entry on clozapine. No other authors declared competing interests.