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Reduced hippocampal volume in schizophrenia is a well-replicated finding. New imaging techniques allow delineation of hippocampal subfield volumes. Studies including predominantly chronic patients demonstrate differences between subfields in sensitivity to illness, and in associations with clinical features. We carried out a cross-sectional and longitudinal study of first episode, sub-chronic, and chronic patients, using an imaging strategy that allows for the assessment of multiple hippocampal subfields. Hippocampal subfield volumes were measured in 34 patients with schizophrenia (19 first episode, 6 sub-chronic, 9 chronic) and 15 healthy comparison participants. A subset of 10 first episode and 12 healthy participants were rescanned after six months. Total left hippocampal volume was smaller in sub-chronic (p = 0.04, effect size 1.12) and chronic (p = 0.009, effect size 1.42) patients compared with healthy volunteers. The CA2-3 subfield volume of chronic patients was significantly decreased (p = 0.009, effect size 1.42) compared to healthy volunteers. The CA4-DG volume was significantly reduced in all three patient groups compared to healthy group (all p < 0.005). The two affected subfield volumes were inversely correlated with severity of negative symptoms (p < 0.05). There was a small, but statistically significant decline in left CA4-DG volume over the first six months of illness (p = 0.01). Imaging strategies defining the subfields of the hippocampus may be informative in linking symptoms and structural abnormalities, and in understanding more about progression during the early phases of illness in schizophrenia.

Cognition is impaired in homeless and vulnerably housed persons. Within this heterogeneous and multimorbid group, distinct profiles of cognitive dysfunction are evident. However, little is known about the underlying neurobiological substrates. Imaging structural covariance networks provides a novel investigative strategy to characterizing relationships between brain structure and function within these different cognitive subgroups. Participants were 208 homeless and vulnerably housed persons. Cluster analysis was used to group individuals on the basis of similarities in cognitive functioning in the areas of attention, memory, and executive functioning. The principles of graph theory were applied to construct two brain networks for each cognitive group, using measures of cortical thickness and gyrification. Global and regional network properties were compared across networks for each of the three cognitive clusters. Three cognitive groups were defined by: higher cognitive functioning across domains (Cluster 1); lower cognitive functioning with a decision-making strength (Cluster 3); and an intermediate group with a relative executive functioning weakness (Cluster 2). Between-group differences were observed for cortical thickness, but not gyrification networks. The lower functioning cognitive group exhibited higher segregation and reduced integration, higher centrality in select nodes, and less spatially compact modules compared with the two other groups. The cortical thickness network differences of Cluster 3 suggest that major disruptions in structural connectivity underlie cognitive dysfunction in a subgroup of people who have a high multimorbid illness burden and who are vulnerably housed or homeless. The origins, and possible plasticity of these structure-function relationships identified with network analysis warrant further study.

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

Objective: The amygdala is a brain region comprised of a group of functionally distinct nuclei that play a central role in social behaviour. 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 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.

Second-generation antipsychotic medications are used to treat schizophrenia and a range of other psychotic disorders, although adverse effects, including cardiovascular and metabolic abnormalities and extrapyramidal symptoms, are often inevitable. Studies have shown that exercise, as an adjunct therapy, can be effective in reducing the core symptoms of schizophrenia as well as ameliorating intrinsic and antipsychotic-induced cardiometabolic abnormalities. However, it is noteworthy that exercise may need to be implemented with caution in some individuals receiving certain antipsychotic treatment regimens. We report here two cases of exercise-associated worsening of extrapyramidal symptoms in two individuals with schizoaffective disorder treated with a long-acting injectable antipsychotic medication over the course of a 12-week exercise program. This worsening of extrapyramidal symptoms can be attributed to an increase in blood flow to the site of injection during exercise, accelerating the rate of absorption and bioavailability of the antipsychotic medication and subsequently increasing dopamine D2 receptor blockade. When monitoring drug therapy for patients receiving long-acting injectable antipsychotic medications, pharmacists and other healthcare professionals need to consider exercise as a contributing factor for the emergence of extrapyramidal symptoms.

BackgroundHomeless 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.MethodsWe 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.ResultsCompared 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.ConclusionsOlder 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.

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

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. 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. 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.

Background: In addition to the hallmark cognitive and functional impairments mounting evidence indicates that schizophrenia is also associated with an increased risk for the development of secondary complications, in particular cardio-metabolic disease. This is thought to be the result of various factors including physical inactivity and the metabolic side effects of psychotropic medications. Therefore, non-pharmacological approaches to improving brain health, physical health, and overall well-being have been promoted increasingly. Methods: We report on the health-related physical fitness (body composition, blood pressure, heart rate, and aerobic fitness) and lipid profile of persons living with schizophrenia and effective means to address the challenges of exercise training in this population. Results: There was a markedly increased risk for cardio-metabolic disease in 13 persons living with schizophrenia (Age = 31 ± 7 years) including low aerobic fitness (76% ± 34% of predicted), reduced HDL (60% of cohort), elevated resting heart rate (80% of cohort), hypertension (40% of cohort), overweight and obesity (69% of cohort), and abdominal obesity (54% of cohort). Individualized exercise prescription (3 times/week) was well tolerated, with no incidence of adverse exercise-related events. The exercise adherence rate was 81% ± 21% (Range 48%–100%), and 69% of the participants were able to complete the entire exercise training program. Exercise training resulted in clinically important changes in physical activity, aerobic fitness, exercise tolerance, blood pressure, and body composition. Conclusion: Persons living with schizophrenia appear to be at an increased risk for cardio-metabolic disease. An individualized exercise program has shown early promise for the treatment of schizophrenia and the various cognitive, functional, and physiological impairments that ultimately affect health and well-being.

People living in precarious housing or homelessness have higher than expected rates of psychotic disorders, persistent psychotic symptoms, and premature mortality. Psychotic symptoms can be modeled as a complex dynamic system, allowing assessment of roles for risk factors in symptom development, persistence, and contribution to premature mortality. The severity of delusions, conceptual disorganization, hallucinations, suspiciousness, and unusual thought content was rated monthly over 5 years in a community sample of precariously housed/homeless adults ( = 375) in Vancouver, Canada. Multilevel vector auto-regression analysis was used to construct temporal, contemporaneous, and between-person symptom networks. Network measures were compared between participants with ( = 219) or without ( = 156) history of psychotic disorder using bootstrap and permutation analyses. Relationships between network connectivity and risk factors including homelessness, trauma, and substance dependence were estimated by multiple linear regression. The contribution of network measures to premature mortality was estimated by Cox proportional hazard models. Delusions and unusual thought content were central symptoms in the multilevel network. Each psychotic symptom was positively reinforcing over time, an effect most pronounced in participants with a history of psychotic disorder. Global connectivity was similar between those with and without such a history. Greater connectivity between symptoms was associated with methamphetamine dependence and past trauma exposure. Auto-regressive connectivity was associated with premature mortality in participants under age 55. Past and current experiences contribute to the severity and dynamic relationships between psychotic symptoms. Interrupting the self-perpetuating severity of psychotic symptoms in a vulnerable group of people could contribute to reducing premature mortality.