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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]

Ventricular cerebrospinal fluid (vCSF) obtained at autopsy from 230 participants in the Religious Orders Study was analyzed for alpha tocopherol (αT, vitamin E) and gamma tocopherol (γT) in relation to brain tissue neuropathological diagnoses (NIA-Reagan criteria); neuritic plaque density and neurofibrillary tangle state (Braak stage); and cognitive function proximate to death. Neither vCSF αT nor γT was related to the pathological diagnosis of Alzheimer's disease, but vCSF αT concentration was inversely related to neuritic plaque density (β = -0.21, SE = 0.105, p = 0.04) in regression models adjusted for age, gender, education, and APOE-4. Ventricular CSF αT concentration was positively associated with perceptual speed (β = 0.27, SE = 0.116, p = 0.02) whereas the γT/αT ratio was negatively associated with episodic memory (β = -0.037, SE = 0.017, p = 0.04). Only vCSF αT, but not γT, was correlated with postmortem interval (PMI). Adjustment for PMI had no effect on significance of associations between αT and perceptual speed or γT/αT and episodic memory, but after this adjustment the αT concentration was no longer significantly associated with neuritic plaques. These data suggest that vCSF αT, but not γT, is weakly associated with less Alzheimer's disease neuropathology, specifically neuritic plaques, and correlates with better performance on tests of perceptual speed. [ABSTRACT FROM AUTHOR]

Medication errors are among the most common medical errors and cause significant morbidity and in some cases mortality. The objective of this article is to review the literature on medication errors in psychiatry. We completed a comprehensive search of both peer- and non-peer-reviewed articles that investigated medication errors in psychiatry. Our primary focus was to examine patient-, provider- and system-related factors that contributed to medication errors. Due to differences in research design and denominators used to determine error rates, the reported prevalence rates of medication errors in psychiatry vary widely. Patient-related factors identified as contributing to medication errors included non-adherence to medication, failure of patients to inform their various care providers about the medications they are taking and symptoms of psychiatric illnesses. Provider-related factors identified as contributing to medication errors were also identified and included clinical practices associated with prescribing, transcription, dispensing, administration and monitoring. Finally, the healthcare system also has a major role to play in reducing medication errors by ensuring seamless continuity of care, mandating medication reconciliation programmes, ensuring adequate clinical pharmacy services and supporting a nonpunitive medication error reporting system. Although the literature raises awareness of these specific contributing factors, there is still a great need for more systematic evaluations of the problem including root cause analysis. Medication errors in psychiatry have been studied almost exclusively in the inpatient setting and thus little is known about the incidence and significance in outpatient and community settings. [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.

Objective: The authors performed a longitudinal study of the effects on thalamic volume of switching from typical to atypical antipsychotic medications.Method: Magnetic resonance imaging scans were acquired from 10 subjects with chronic schizophrenia taking typical antipsychotics and 20 healthy volunteers. Subjects with schizophrenia were switched to olanzapine; both groups were rescanned.Results: At baseline, thalamic volumes in subjects with chronic schizophrenia were 5.8% greater than those of healthy volunteers. At follow-up, there was no significant difference between groups. Additional analysis revealed a significant positive correlation between baseline thalamic volume and dosage of typical antipsychotic medication. Higher dosages at baseline were correlated with larger reductions in volume after the switch to olanzapine.Conclusions: Antipsychotic medication effects may be a factor in the wide range of thalamic volume differences reported between subjects with schizophrenia and healthy volunteers. [ABSTRACT FROM AUTHOR]

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.)

The contribution of anticholinergic burden to cognitive function in patients with treatment resistant schizophrenia (TRS) is uncertain. This case-control study aims to comprehensively examine the association between treatment resistance and cognitive functions and the contribution of anticholinergic burden in patients with schizophrenia. Anticholinergic burden of all patients was calculated using the Anticholinergic Cognitive Burden scale. Exploratory Factor Analysis of 11 cognitive assessments identified four cognitive domains: verbal memory, attention and general cognitive functions, visual memory and processing speed, and executive function. Two structural equation models (SEM) examined the relationship of TRS and these cognitive functions with, and without considering anticholinergic burden. A total of 288 participants were included (TRS N=111, non-TRS N=177). Patients with TRS performed poorer than the non-TRS group only in the executive function domain. Anticholinergic burden contributed significantly to the attention and general cognitive functions, visual memory and processing speed, and executive function. The impact of TRS on executive function was no longer significant after adding anticholinergic burden to the SEM. Results suggested that anticholinergic burden contributes to a wide range of cognitive function impairment in patients with schizophrenia and is likely to be part of the apparent differences of cognitive function between TRS and non-TRS., Competing Interests: Declaration of competing interest No relevant conflicts of interest were reported by any of the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Housing insecurity is associated with co-occurring depression and pain interfering with daily activities. Network analysis of depressive symptoms along with associated risk or protective exposures may identify potential targets for intervention in patients with co-occurring bodily pain. In a community-based sample of adults (n = 408) living in precarious housing or homelessness in Vancouver, Canada, depressive symptoms were measured by the Beck Depression Inventory; bodily pain and impact were assessed with the 36-item Short Form Health Survey. Network and bootstrap permutation analyses were used to compare depressive symptoms endorsed by Low versus Moderate-to-Severe (Mod + Pain) groups. Multilayer networks estimated the effects of risk and protective factors. The overall sample was comprised of 78% men, mean age 40.7 years, with 53% opioid use disorder and 14% major depressive disorder. The Mod + Pain group was characterized by multiple types of pain, more persistent pain, more severe depressive symptoms and a higher rate of suicidal ideation. Global network connectivity did not differ between the two pain groups. Suicidal ideation was a network hub only in the Mod + Pain group, with high centrality and a direct association with exposure to lifetime trauma. Antidepressant medications had limited impact on suicidal ideation. Guilt and increased feelings of failure represented symptoms from two other communities of network nodes, and completed the shortest pathway from trauma exposure through suicidal ideation, to the non-prescribed opioid exposure node. Interventions targeting these risk factors and symptoms could affect the progression of depression among precariously housed patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: To examine cognitive intraindividual variability (IIV) dispersion as a predictor of everyday functioning and mortality in persons who are homeless or precariously housed., Method: Participants were 407 community-dwelling adults, followed for up to 13 years. Neurocognition was assessed at baseline and IIV dispersion was derived using a battery of standardized tests. Functional outcomes (social, physical) were obtained at baseline and last follow-up. Mortality was confirmed with Coroner's reports and hospital records ( N   = 103 deaths). Linear regressions were used to predict current social and physical functioning from IIV dispersion. Repeated measures Analysis of Covariance were used to predict long-term change in functioning. Cox regression models examined the relation between IIV dispersion and mortality. Covariates included global cognition (i.e. mean-level performance), age, education, and physical comorbidities., Results: Higher IIV dispersion predicted poorer current physical functioning ( B = -0.46 p = .010), while higher global cognition predicted better current ( B   = 0.21, p = .015) and change in social functioning over a period of up to 13 years ( F   = 4.23, p = .040). Global cognition, but not IIV dispersion, predicted mortality in individuals under 55 years old (HR = 0.50, p = .013)., Conclusions: Our findings suggest that indices of neurocognitive functioning (i.e. IIV dispersion and global cognition) may be differentially related to discrete dimensions of functional outcomes in an at-risk population. IIV dispersion may be a complimentary marker of emergent physical health dysfunction in precariously housed adults and may be best used in conjunction with traditional neuropsychological indices.

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).)

Objective: SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function SETD1A variants have been associated with numerous neurodevelopmental phenotypes, including intellectual disability and schizophrenia. While the association between rare coding variants in SETD1A and schizophrenia has achieved genome-wide significance by rare variant burden testing, only a few studies have described the psychiatric phenomenology of such individuals in detail. This systematic review and case report aims to characterize the neurodevelopmental and psychiatric phenotypes of SETD1A variant-associated schizophrenia., Methods: A PubMed search was completed in July 2022 and updated in May 2023. Only studies that reported individuals with a SETD1A variant as well as a primary psychotic disorder were ultimately included. Additionally, another two previously unpublished cases of SETD1A variant-associated psychosis from our own sequencing cohort are described., Results: The search yielded 32 articles. While 15 articles met inclusion criteria, only five provided case descriptions. In total, phenotypic information was available for 11 individuals, in addition to our own two unpublished cases. Our findings suggest that although individuals with SETD1A variant-associated schizophrenia may share a number of common features, phenotypic variability nonetheless exists. Moreover, although such individuals may exhibit numerous other neurodevelopmental features suggestive of the syndrome, their psychiatric presentations appear to be similar to those of general schizophrenia populations., Conclusions: Loss-of-function SETD1A variants may underlie the development of psychosis in a small percentage of individuals with schizophrenia. Identifying such individuals may become increasingly important, given the potential for advances in precision medicine treatment approaches., Competing Interests: Declaration of Competing Interest IT has served as consultant for Boehringer Ingelheim in the past 3 years. SY has served on advisory boards of Amgen, AstraZeneca, Bayer, Incyte, and Roche., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Studies have reported positive associations between drug-induced movement disorders (DIMDs) and symptoms of psychosis in patients with schizophrenia. However, it is not clear which subtypes of symptoms are related to each other, and whether one symptom precedes another. The current report assessed both concurrent and temporal associations between DIMDs and symptoms of psychosis in a community-based sample of homeless individuals., Methods: Participants were recruited in Vancouver, Canada. Severity of DIMDs and psychosis was rated annually, allowing for the analysis of concurrent associations between DIMDs and Positive and Negative Syndrome Scale (PANSS) five factors. A brief version of the PANSS was rated monthly using five psychotic symptoms, allowing for the analysis of their temporal associations with DIMDs. Mixed-effects linear and logistic regression models were used to assess the associations., Results: 401 participants were included, mean age of 40.7 years (SD = 11.2) and 77.4% male. DIMDs and symptoms of psychosis were differentially associated with each other, in which the presence of parkinsonism was associated with greater negative symptoms, dyskinesia with disorganized symptoms, and akathisia with excited symptoms. The presence of DIMDs of any type was not associated with depressive symptoms. Regarding temporal associations, preceding delusions and unusual thought content were associated with parkinsonism, whereas dyskinesia was associated with subsequent conceptual disorganization., Conclusions: The current study found significant associations between DIMDs and symptoms of psychosis in individuals living in precarious housing or homelessness. Moreover, there were temporal associations between parkinsonism and psychotic symptoms (delusions or unusual thought content), and the presence of dyskinesia was temporally associated with higher odds of clinically relevant conceptual disorganization., Competing Interests: Declaration of competing interest DDK, AAJ, KMG, PWJ, AMP, LHNL, RMC, WJP, OL, DJL, AET and AMB have no competing interests. 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. WGH has received consulting fees or sat on paid advisory boards for: In Silico (unpaid), Translational Life Sciences, and AbbVie., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder., Methods: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation., Findings: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented., Interpretation: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores., Funding: German Research Foundation (grant number: 428509362)., Competing Interests: Declaration of interests RAM has received speaker or consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and co-directs a company that designs digital resources to support treatment of mental illness. JMK has been a consultant or advisor for, or has received honoraria from, Alkermes, Allergan, LB Pharmaceuticals, H Lundbeck, Intracellular Therapies, Janssen Pharmaceuticals, Johnson & Johnson, Merck, Minerva, Neurocrine, Newron, Otsuka, Pierre Fabre, Reviva, Roche, Sumitomo Dainippon, Sunovion, Takeda, Teva, and UpToDate, and is a shareholder in LB Pharmaceuticals and Vanguard Research Group. CA has been a consultant to, or has received honoraria or grants from, Acadia, Abbot, Ambrosetti, AMGEN, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Forum, Gedeon Richter, Janssen Cilag, Lundbeck, Merck, Otsuka, Pfizer, Roche, Servier, Shire, Schering Plough, Sunovion, and Takeda. WWF has received consulting fees from Boehringer Ingelheim, Angelini, Richter, and Recordati, and grant support from Lundbeck and Otsuka. PF received paid speakership from Otsuka, Recordati, Richter, Rovi, and Janssen, and is a member of advisory boards of Richter, Rovi, and Janssen. AH has received paid speakerships from AbbVie, Janssen, Otsuka, Rercordati, and Lundbeck. He was member of Rovi, Recordati, Otsuka, Lundbeck, and Janssen advisory boards. SRM has received consulting fees from Boehringer-Ingelheim, H. Lundbeck, Otsuka, Takeda, Teva, Roche, Genentech, Targacept, Forum, AbbVie, Allergan, and Neurocrine. He has received research support from Boehringer-Ingelheim, Takeda, and Neurocrine. NS has been a consultant or advisor to, or has received honoraria, from Alkermes, Lundbeck, Otsuka, Otsuka Canada, and Teva. WGH has received consulting fees or sat on paid advisory boards for In Silico Biosciences, Translational Life Sciences, Newron, Otsuka, and AbbVie. RWB is a data and safety monitoring board member for Merck, Newron, and Roche; on the advisory board for Acadia, Boehringer Ingelheim, Karuna, Neurocrine, and Roche; and consultant for Boehringer Ingelheim. MD is an employee of Minerva Neurosciences. MW He has received advisory board, speaker's, or consultant fees from, and owns stock, with Acadia, Dexcel, Janssen, Lundbeck, Minerva, Pfizer, Roche, and Teva. OH was a part-time employee of H. Lundbeck, and has received investigator-initiated research funding from, or participated in, advisory or speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche, and Viatris/Mylan. Neither he nor his family have holdings/a financial stake in any pharmaceutical company. He has a patent for the use of dopaminergic imaging. CUC has been a consultant or advisor to, or has received honoraria from, AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Cardio Diagnostics, Compass, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a data safety monitoring board for Lundbeck, Relmada, Reviva, Rovi, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantics. In the past 3 years, SL has received honoraria as a consultant, adviser, or lecturer from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharpp and Dome, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitsubishi. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Homeless and precariously housed persons exhibit significant memory impairment, but the component processes underlying memory dysfunction have not been explored. We examined the serial position profile (i.e., primacy and recency effects) of verbal memory and its neuroanatomical correlates to identify the nature of memory difficulties in a large cohort of homeless and precariously housed adults. Method: The sample included 227 community-dwelling homeless and precariously housed adults. Serial position scores (primacy, middle, recency) were computed using the Hopkins Verbal Learning Test-Revised. Paired sample t-tests were used to compare percent recall from each word list region. Age-adjusted correlations assessed associations between serial position scores and other cognitive domains (attention, processing speed, executive functioning). Regression analyses were conducted to examine regional brain volumes of interest (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex [DLPFC]) and their differential associations with serial position scores. Results: The serial position profile was characterized by a diminished recency effect in relation to the primacy effect. Serial position scores positively correlated with sustained attention and cognitive control. Larger hippocampal volume was associated with better primacy item recall. DLPFC volume was not associated with serial position recall after adjustment for false discovery rate. There were no associations between regional brain volumes and recency item recall. Conclusion: Our results suggest that commonly reported memory difficulties in homeless and precariously housed adults are likely secondary to a core deficit in executive control due to compromised frontal lobe functioning. These findings have implications for cognitive rehabilitation in this complex and vulnerable group.

The objective of this study was to evaluate an association of selective serotonin reuptake inhibitor (SSRI) use with late life cognitive decline and further investigate the association with brain pathology. Using the data are from two harmonized clinical-pathologic cohort studies with annual cognitive testing we found that SSRI use was associated with significantly faster global cognitive decline and this association was present in those with and without pre-existing cognitive impairment at the time of SSRI initiation. In separate analyses of persons who died during the study and underwent neuropathologic examination, SSRI use was related to higher level of paired helical filament tau tangles and faster rate of global cognitive decline. However, when SSRI use and tangles were included in the same model, the association of SSRI use with rate of global cognitive decline was reduced by more than 50% and no longer statistically significant. SSRI use was associated with higher postmortem level of tau tangles, possibly because SSRI are being used to treat neurobehavioral symptoms associated with dementia, and this relationship appears to partly account for the association of SSRI use with more rapid cognitive decline., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Clozapine is the only medication found to be effective for patients with treatment resistant schizophrenia-spectrum disorders (TRS) and its prescription patterns may impact on their outcomes. The study aims to explore the impact of clozapine dosing frequency, dose level and presence of pharmacological augmentation on the clinical, social and cognitive outcomes in patients with TRS. Patients with TRS and on clozapine were interviewed. Daily defined dose (DDD) and anticholinergic burden were calculated. Patients were categorized in three ways: the single daily dose (SDD) and multiple daily dose (MDD), ≤300 mg/day (LD) and >300 mg/day (HD) of clozapine, and clozapine monotherapy (MT) and augmentation therapy (AT). The impact of these clozapine prescription patterns and their interaction on patient outcomes were examined with ANOVA. Of 124 patients on clozapine, 98 patients (79%) had SDD, 59 patients (47.6%) received LD, and 58 patients (46.8%) had MT. Patients in the LD group had significantly better cognitive functions. Though no significant effect of clozapine dosing frequency on outcomes, among patients on LD, those on MDD had better processing speed, short-term and visual memory. Patients with MT had better motivation. Among patients on HD, those with MT had better motivation and vocational functioning. These results provide guidance to the clozapine prescription in a naturalistic setting to achieve optimizing outcomes for patients with TRS in social and cognitive functions. Further longitudinal studies are needed to verify the results., Competing Interests: Conflict of interest No relevant conflicts of interests reported by all authors., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Introduction: Serial position effects in verbal memory are associated with in vivo fluid biomarkers and neuropathological outcomes in Alzheimer's disease (AD). To extend the biomarker literature, associations between serial position scores and postmortem levels of brain phosphorylated tau (p-tau) were examined, in the context of Braak stage of neurofibrillary tangle progression., Method: Participants were 1091 community-dwelling adults (M age  = 80.2, 68.9% female) from the Rush University Religious Orders Study and Memory and Aging Project who were non-demented at enrollment and followed for a mean of 9.2 years until death. The CERAD Word List Memory test administered at baseline and within 1 year of death was used to calculate serial position (primacy, recency) and total recall scores. Proteomic analyses quantified p-tau 217 and 202 from dorsolateral prefrontal cortex samples. Linear regressions assessed associations between cognitive scores and p-tau with Braak stage as a moderator., Results: Cognitive status proximal to death indicated 34.7% were unimpaired, 26.2% met criteria for MCI, and 39.0% for dementia. Better baseline primacy recall, but not recency recall, was associated with lower p-tau 217 levels across Braak stages. Delayed recall showed a similar pattern as primacy. There was no main effect of immediate recall, but an interaction with Braak stages indicated a negative association with p-tau 217 level only in Braak V-VI. Within 1 year of death, there were no main effects for cognitive scores; however, recency, immediate and delayed recall scores interacted with Braak stage showing better recall was associated with lower p-tau 217 only in Braak V-VI. No associations were observed with p-tau 202., Conclusions: Primacy recall measured in non-demented adults may be sensitive to emergent tau phosphorylation that occurs in the earliest stages of AD. Serial position scores may complement the routinely used delayed recall score and p-tau biomarkers to detect preclinical AD.

Background: Preliminary evidence suggest clozapine is associated with more favorable impact on concurrent substance use disorder related outcomes in patients with concurrent schizophrenia spectrum disorders (SSD). At the same time, there is a dearth of evidence with regards to clozapine outcomes in the context of concurrent methamphetamine or amphetamine use disorder (MAUD)., Aims: To examine whether clozapine use decreases rate of methamphetamine or amphetamine (MA) relapses and increases the likelihood of maintaining abstinence from any MA use., Methods: A descriptive-analytic retrospective cohort study was conducted on individuals with SSD-MAUD in an inpatient provincial treatment and rehabilitation center for concurrent disorders. Antipsychotic exposure was categorized as "on clozapine" or "on other antipsychotic(s)." Data were collected using electronic health records. Logistic regression was used to examine association of clozapine treatment with likelihood of complete abstinence from MA use for the duration of antipsychotic exposure. Negative binomial regression was used to examine association of clozapine treatment with rate of MA relapses for the duration of antipsychotic exposure., Results: The majority of the 87 included patients were male. Ethnicity was diverse, with the largest groups self-identifying as Indigenous and European. Clozapine use was both associated with increased likelihood of maintaining abstinence from MA use (adjusted odds ratio (aOR) = 3.05, 95% confidence intervals (CI) = 1.15-8.1, p  = 0.025), and decreased rate of MA relapses (aRR = 0.45, 95% CI = 0.25-0.82, p  = 0.009) for the duration of antipsychotic exposure. Co-prescription of psychostimulants was associated with increased rate of MA relapses (aRR = 2.43, 95% CI = 1.16-5.10, p  = 0.019)., Conclusion(s): In this study, clozapine use compared with other antipsychotics in SSD was associated with improved outcomes related to severe concurrent MAUD. Co-prescription of psychostimulant medications was associated with a poor outcome., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RR, LF, HM, NM, and SP have none to declare; MD reports receiving personal fees from Eisai Ltd, Otsuka, Winterlight Labs, and the Ontario Brain Institute; CAB is founder and CEO of Sequence2Script Inc.; WGH is a consultant to AbbVie, and Translational Life Sciences; and CGS is a consultant to Clearmind Medicine.

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).)

Objective: Many individuals living in precarious housing or homelessness have multimorbid illnesses, including substance use, psychiatric, and neurological disorders. Movement disorders (MDs) associated substance use are amongst the poorly studied subtopics of drug-induced MDs. The aim of the present study was, therefore, to determine the proportion affected and severity of different signs of MDs, as well as their associations with substance use in a community-based sample of precariously housed and homeless individuals., Methods: Participants were recruited from an impoverished urban neighborhood and were assessed for substance dependence and self-reported substance use (alcohol, cannabis, cocaine, methamphetamine, nicotine, and opioids), as well as for the severity of signs of MDs (akathisia, dyskinesia, dystonia, and parkinsonism). Adjusted regression models were used to estimate the associations of the severity of signs with the frequency of substance use over the past 4 weeks and with the baseline diagnosis of substance dependence., Results: The proportion of the sample with clinically relevant signs of MDs in any of the four categories was 18.6% (n = 401), and these participants demonstrated lower levels of functioning than those without signs. Of the different types of substance use, only methamphetamine (its frequency of use and dependence) was significantly associated with greater severity of overall signs of MDs. Frequency of methamphetamine use significantly interacted with age and sex, whereby older female participants exhibited the greatest overall severity with increased methamphetamine use. Of the different signs of MDs, methamphetamine use frequency was positively associated with the severity of trunk/limb dyskinesia and hypokinetic parkinsonism. Relative to no use, concurrent use of antipsychotics demonstrated lower severity of trunk/limb dyskinesia and greater severity of hypokinetic parkinsonism with methamphetamine use, and greater severity of dystonia with cocaine use., Conclusions: Our study found a high proportion of MDs in a relatively young sample, and their severity was consistently associated with methamphetamine use, moderated by participant demographics and antipsychotic use. These disabling sequelae represent an important and understudied neurological condition that may affect quality of life and will require further study., Competing Interests: Declaration of Competing Interest DD Kim: reports no disclosures relevant to the manuscript. RM 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. LHN Lee: reports no disclosures relevant to the manuscript. WJ Panenka: grant funding from the Canadian Institutes of Health Research, Brain Injury Canada, and ACRM Task Force. JL Stubbs: reports no disclosures relevant to the manuscript. AA Jones: reports no disclosures relevant to the manuscript. LL Cho: reports no disclosures relevant to the manuscript. O Leonova: reports no disclosures relevant to the manuscript. KM Gicas: reports no disclosures relevant to the manuscript. AE Thornton: grant funding from the Canadian Institutes of Health Research, the Simon Fraser University William and Ada Isabelle Steel Research Fund, and the Simon Fraser University Psychology Department Research Grant. DJ Lang: reports no disclosures relevant to the manuscript. GW MacEwan: reports no disclosures relevant to the manuscript. WG 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 (TLS), Otsuka, Lundbeck, and Newron; and holds shares in TLS and Eli Lilly. AM Barr: reports no disclosures relevant to the manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Psychotic symptoms are increasingly recognized as a distinguishing clinical feature in patients with dementia due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Within this group, carriers of the C9orf72 repeat expansion are particularly prone to develop delusions and hallucinations., Methods: The present retrospective study sought to provide novel details about the relationship between FTLD-TDP pathology and the presence of psychotic symptoms during life., Results: We found that FTLD-TDP subtype B was more frequent in patients with psychotic symptoms than in those without. This relationship was present even when corrected for the presence of C9orf72 mutation, suggesting that pathophysiological processes leading to the development of subtype B pathology may increase the risk of psychotic symptoms. Within the group of FTLD-TDP cases with subtype B pathology, psychotic symptoms tended to be associated with a greater burden of TDP-43 pathology in the white matter and a lower burden in lower motor neurons. When present, pathological involvement of motor neurons was more likely to be asymptomatic in patients with psychosis., Conclusions: This work suggests that psychotic symptoms in patients with FTLD-TDP tend to be associated with subtype B pathology. This relationship is not completely explained by the effects of the C9orf72 mutation and raises the possibility of a direct link between psychotic symptoms and this particular pattern of TDP-43 pathology., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

The approach to analysis of and interpretation of findings from the Beck Depression Inventory (BDI), a self-report questionnaire, depends on sample characteristics. To extend work using conventional BDI scoring, the BDI's suitability in assessing symptom severity in a homeless and precariously housed sample was examined using Rasch analysis. Participants (n=478) recruited from an impoverished neighbourhood in Vancouver, Canada, completed the BDI. Rasch analysis using the partial credit model was done, and the structural validity, unidimensionality, and reliability of the BDI were studied. A receiver operating characteristic curve determined a Rasch cut-off score consistent with clinical depression, and Rasch scores were correlated with raw scores. Good fit to the Rasch model was observed after rescoring all items and removing Item 19 (Weight Loss), and unidimensionality and reliability were satisfactory. Item 9 (Suicidal Wishes) represented the most severe symptom. Rasch-based scores detected clinical depression with moderate sensitivity and specificity, and were positively correlated with conventional scores. The BDI in a community-based sample of homeless and precariously housed adults satisfied Rasch model expectations in a 20-item format, and is suitable for assessing symptom severity. Future research on depression in similar samples may reveal more information on using specific symptoms to determine clinical significance., Competing Interests: Declaration of Competing Interest LLC, AAJ, CG, KMG, OL, TB, AET, DJL, GWM, WJP, and AMB have no competing interests. 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. FVR 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. FVR has also received in-kind equipment support for this investigator-initiated trial from MagVenture and honoraria for participation in advisory board for Janssen. WGH has received consulting fees or sat on paid advisory boards for: In Silico (unpaid), Translational Life Sciences, and AbbVie., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.)

Objective: Serial position scores on verbal memory tests are sensitive to early Alzheimer's disease (AD)-related neuropathological changes that occur in the entorhinal cortex and hippocampus. The current study examines longitudinal change in serial position scores as markers of subtle cognitive decline in older adults who may be in preclinical or at-risk states for AD., Methods: This study uses longitudinal data from the Religious Orders Study and the Rush Memory and Aging Project. Participants ( n = 141) were included if they did not have dementia at enrollment, completed follow-up assessments, and died and were classified as Braak stage I or II. Memory tests were used to calculate serial position (primacy, recency), total recall, and episodic memory composite scores. A neuropathological evaluation quantified AD, vascular, and Lewy body pathologies. Mixed effects models were used to examine change in memory scores. Neuropathologies and covariates (age, sex, education, APOE e4) were examined as moderators., Results: Primacy scores declined ( β = -.032, p < .001), whereas recency scores increased ( β = .021, p = .012). No change was observed in standard memory measures. Greater neurofibrillary tangle density and atherosclerosis explained 10.4% of the variance in primacy decline. Neuropathologies were not associated with recency change., Conclusions: In older adults with hippocampal neuropathologies, primacy score decline may be a sensitive marker of early AD-related changes. Tangle density and atherosclerosis had additive effects on decline. Recency improvement may reflect a compensatory mechanism. Monitoring for changes in serial position scores may be a useful in vivo method of tracking incipient AD.

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: Contrasting the well-described effects of early intervention (EI) services for youth-onset psychosis, the potential benefits of the intervention for adult-onset psychosis are uncertain. This paper aims to examine the effectiveness of EI on functioning and symptomatic improvement in adult-onset psychosis, and the optimal duration of the intervention., Methods: 360 psychosis patients aged 26-55 years were randomized to receive either standard care (SC, n = 120), or case management for two (2-year EI, n = 120) or 4 years (4-year EI, n = 120) in a 4-year rater-masked, parallel-group, superiority, randomized controlled trial of treatment effectiveness (Clinicaltrials.gov: NCT00919620). Primary (i.e. social and occupational functioning) and secondary outcomes (i.e. positive and negative symptoms, and quality of life) were assessed at baseline, 6-month, and yearly for 4 years., Results: Compared with SC, patients with 4-year EI had better Role Functioning Scale (RFS) immediate [interaction estimate = 0.008, 95% confidence interval (CI) = 0.001-0.014, p = 0.02] and extended social network (interaction estimate = 0.011, 95% CI = 0.004-0.018, p = 0.003) scores. Specifically, these improvements were observed in the first 2 years. Compared with the 2-year EI group, the 4-year EI group had better RFS total ( p = 0.01), immediate ( p = 0.01), and extended social network ( p = 0.05) scores at the fourth year. Meanwhile, the 4-year ( p = 0.02) and 2-year EI ( p = 0.004) group had less severe symptoms than the SC group at the first year., Conclusions: Specialized EI treatment for psychosis patients aged 26-55 should be provided for at least the initial 2 years of illness. Further treatment up to 4 years confers little benefits in this age range over the course of the study.

Background: Antipsychotic medications are the mainstay of treatment for schizophrenia and are associated with a reduction in psychiatric hospitalization and overall mortality. Some evidence suggest that antipsychotic medications might have a varying effect on the improvement of comorbid substance use disorders (SUDs), with clozapine showing more favorable outcomes., Aim: We systematically reviewed all available evidence on effects of clozapine on the improvement of SUDs other than nicotine., Methods: Electronic searches of MEDLINE, Embase, PsycINFO, and CINHAL were conducted up to March 1, 2022. Studies of any methodological design involving two concepts: (1) clozapine and (2) SUD terms (excluding nicotine) were included. For SUD outcomes with three or more comparative studies with available raw data meta-analysis was performed. SUD outcomes not meeting criteria for meta-analysis were described qualitatively. Risk of bias was examined using "Downs and Black," and "Q-Coh" instruments., Results: The majority of individuals in the included 31 studies were male and of European ancestry. Abstinence was the most common outcome. Most of the studies were of low-to-moderate quality, and none of the studies met all the quality criteria. Pooled findings from four observational studies in samples of patients with predominantly comorbid alcohol use disorder showed that clozapine treatment is associated with significantly higher odds of remaining abstinent. In addition clozapine was associated with decreased odds of psychiatric hospitalization in all but one observational study., Conclusions: Our systematic review and meta-analysis builds upon previous reviews, and it suggests the association of clozapine treatment with significantly higher odds of remaining abstinent from substance use and decreased likelihood of psychiatric hospitalization, compared with continuing treatment with other antipsychotic medications. Still, the validity of this association needs greater exploration and providing recommendations for the utility of clozapine in individuals without treatment-resistant psychosis and comorbid SUDs would be premature.

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.)