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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. [ABSTRACT FROM AUTHOR]

Introduction: Relationships between subjective cognitive functioning (SCF), objective cognitive functioning (OCF), and depressive symptoms are poorly understood in treatment-resistant psychosis (TRP). This study (a) compares SCF in TRP using positively and negatively worded scales, (b) assess these scales' accuracy, and (c) explores the association between these scales and depressive symptoms. We hypothesised that both SCF scales would be highly correlated, minimally associated with OCF, and similarly associated with depressive symptoms. Methods: Archival clinical data from 52 TRP inpatients was utilised. OCF composite scores were derived from a broad neuropsychological battery. SCF was assessed using the norm-referenced PROMIS 2.0 Cognitive Abilities (positively worded) and Concerns (negatively worded) subscales. A depressive symptom score was derived from the Positive and Negative Syndrome Scale. Results: SCF ratings were higher in patients than OCF. There was a small but significant correlation between PROMIS subscales (r =.30). Neither PROMIS subscale was associated with OCF (r = −.11, r =.01). Depressive symptoms were correlated with the positively (r = −.29) but not negatively worded scale (r = −.13). Conclusion: Individuals with TRP inaccurately rate their cognitive functioning and tend to overestimate their ability. Positively and negatively worded SCF scales associate variably with depressive symptoms, indicating they may not be used interchangeably in TRP. [ABSTRACT FROM AUTHOR]

Background: 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. Method: 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 (n = 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 (n = 219) or without (n = 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Rationale: How striatal dopamine synthesis capacity (DSC) contributes to the pathogenesis of negative symptoms in first-episode schizophrenia (SZ) and delusional disorder (DD) has seldom been explored. As negative symptoms during active psychotic episodes can be complicated by secondary influences, such as positive symptoms, longitudinal investigations may help to clarify the relationship between striatal DSC and negative symptoms and differentiate between primary and secondary negative symptoms. Objective: A longitudinal study was conducted to examine whether baseline striatal DSC would be related to negative symptoms at 3 months in first-episode SZ and DD patients. Methods: Twenty-three first-episode age- and gender-matched patients (11 DD and 12 SZ) were consecutively recruited through an early intervention service for psychosis in Hong Kong. Among them, 19 (82.6%) patients (9 DD and 10 SZ) were followed up at 3 months. All patients received an 18F-DOPA PET/MR scan at baseline. Results: Baseline striatal DSC (Kocc;30–60) was inversely associated with negative symptoms at 3 months in first-episode SZ patients (rs = − 0.80, p = 0.010). This association remained in SZ patients even when controlling for baseline negative, positive, and depressive symptoms, as well as cumulative antipsychotic dosage (β = − 0.69, p = 0.012). Such associations were not observed in first-episode DD patients. Meanwhile, the severity of negative symptoms at 3 months was associated with more positive symptoms in DD patients (rs = 0.74, p = 0.010) and not in SZ patients. Conclusions: These findings highlight the role of striatal DSC in negative symptoms upon resolution of active psychotic episodes among first-episode SZ patients. Baseline striatal dopamine activity may inform future symptom expression with important treatment implications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: In persons with severe psychiatric disorders, distinct neurocognitive profiles hold differential associations to positive, negative and disorganized symptom dimensions of psychosis. These patterns portend specific functional outcomes, treatment efficacy, and prognoses. Similar associations have not been established in multimorbid samples in which persons present with a complex array of psychiatric symptoms. The objective of this study was to (1) establish neurocognitive profiles in a multimorbid, marginalized sample and (2) investigate their pattern(s) of association with psychiatric symptom dimensions and psychosocial outcomes. Participants and Methods: Participants (n =370; M age = 45 years; 74% male) were precariously housed, substance-using adults with multimorbidity, recruited from Single-Room Occupancy hotels and a community court within the Downtown Eastside of Vancouver, BC, Canada. Data were collected as part of a longitudinal examination consisting of annual, bi-annual, and monthly neurocognitive, psychosocial, and psychiatric assessments. Neurocognitive scores were combined into five cognitive domains (Attentional Control [AC]; Processing Speed [PS]; Fluid Reasoning [Problem Solving and Reversal Learning; Gf]; Encoding and Retrieval [ER]; and Decision Making [DM]) and submitted to a latent profile analysis. The resulting profiles capturing neurocognition were validated on sociodemographic and clinical variables. Finally, the profiles were compared across previously validated, population-distinct factors derived from the Positive and Negative Syndrome Scale (PANSS), as well as on measures of psychosocial functioning. Results: An optimal goodness-of-fit was reached for a three-profile model (BLRT=127.86, p =.01). Profile 1 (n =207, 55.9%) showed stronger neurocognition (all p <.05), with a within-profile strength in Gf (p <.001). With the exception of ER, Profile 2 (n =109, 29.5%) exhibited inferior neurocognition across all indicators compared to Profile 1 (all p <.05); yet showed a relative, within-profile strength in Gf (p <.01). Profile 3 (n =54, 14.6%) generally displayed comparable impairments to Profile 2. Additionally, their performance on Gf was remarkably low compared to Profiles 1 and 2 (p <.001). Psychiatrically, compared to Profile 1, Profile 2 exhibited more positive/disorganized symptoms and general psychopathology, as well as higher total PANSS (all p <.05), whereas Profile 3 showed the poorest insight/awareness (p <.01). Profiles 2 and 3 had lower levels of adaptive functioning and work productivity compared to Profile 1 (all p <.01). Conclusions: Three neurocognitive profiles were detected in a sample of precariously housed adults with multimorbidity: one profile of comparatively higher neurocognitive capacity, with less symptoms of psychosis and better psychosocial functioning; a second profile of comparatively poorer neurocognition and psychosocial functioning, with more symptoms of psychosis; and a third profile with a severe deficit in fluid reasoning and poor insight and awareness. Given their poor insight, the third profile may be comprised of particularly vulnerable persons at greater risk of unmet healthcare needs. Interventions to improve these individuals' understanding of their personal health risks might facilitate their capacity to access services. Conversely, individuals from Profile 2 may benefit from outreach programs focusing on medication access and adherence to address their symptoms of psychosis. In sum, our findings suggest that the confluence of neurocognition and psychiatric symptoms may implicate unique treatment approaches and outcomes in precariously-housed persons with multimorbid conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Prior research has suggested that treatment-resistant psychosis (TRP) may be a categorically distinct subtype from treatment-responsive psychotic disorders. However, relatively few studies have investigated the cognitive profile of individuals with TRP. Moreover, no prior studies have investigated the effectiveness of using the NIH Toolbox Cognition Battery (NTCB) for assessing cognition among psychiatric inpatients despite its promising efficiency and practicality in such settings. The current study aimed to investigate the validity of the NTCB and the associated cognitive profile of inpatients with TRP. Methods: Participants (N = 38) were administered the NTCB and a neuropsychological test battery. The Positive and Negative Syndrome Scale and the Routine Assessment of Patient Progress measured psychosis symptomatology and daily functioning, respectively. Results: Results showed deficits relative to normative values in fluid cognitive abilities using the NTCB, as predicted. There was strong convergent validity and adequate divergent validity between the NTCB subtests and corresponding neuropsychological measures, though no NTCB subtest correlated with performance on the Wisconsin Card Sorting Task. NTCB performance correlated with positive and disorganized symptoms of psychosis as well as daily functioning. Conclusions: Taken together, the NTCB appears to be a relatively strong tool for cognitive screening among psychiatric inpatients and may be used to identify which patients might benefit from further neuropsychological evaluation. [ABSTRACT FROM AUTHOR]

Rationale: Schizophrenia and stimulant-induced psychosis (SIP) represent two different forms of psychotic disorder, with different etiologies. While many of the symptoms of psychosis are common to both disorders, there have been few direct comparisons between these conditions, especially when controlling for stimulant use in individuals with schizophrenia. Objectives: We directly compared both psychotic disorders with a comprehensive battery of clinical, neurocognitive and neuroanatomical measures. This included one group with SIP (and concurrent stimulant dependence) and two groups with schizophrenia (either with or without concurrent stimulant dependence). Methods: Ninety-six participants were recruited from a marginalized urban population, which included 39 with SIP (and concurrent stimulant dependence), 18 with schizophrenia (without stimulant dependence), and 39 with schizophrenia (with concurrent stimulant dependence). All subjects had extensive clinical and neurocognitive evaluations, complemented with structural MRI including diffusion tensor imaging (DTI) sequences to determine regional brain volumes and white matter connectivity. Results: Both positive and negative symptoms were greater in the SZ-dependent group than the other two. Neurocognitive function was broadly similar. The structural brain imaging revealed lateralized changes to the left parietal/temporal lobe, in which regional volumes were smaller in the SZ-dependent than the SZ-non-dependent group. DTI analysis indicated extensive decreases in fractional anisotropy, with parallel increases in radial diffusivity, in the SIP group compared to the SZ-dependent group. Conclusions: These findings reveal both similarities and differences between SIP and schizophrenia. Furthermore, schizophrenia with concurrent stimulant dependence may be associated with a different clinical and neuroanatomical profile as compared to schizophrenia alone. [ABSTRACT FROM AUTHOR]

Background: Although relapse in psychosis is common, a small proportion of patients will not relapse in the long term. We examined the proportion and predictors of patients who never relapsed in the 10 years following complete resolution of positive symptoms from their first psychotic episode. Method: Patients who previously enrolled in a 12-month randomized controlled trial on medication discontinuation and relapse following first-episode psychosis (FEP) were followed up after 10 years. Relapse of positive symptoms was operationalized as a change from a Clinical Global Impression scale positive score of <3 for at least 3 consecutive months to a score of ⩾3 (mild or more severe). Baseline predictors included basic demographics, premorbid functioning, symptoms, functioning, and neurocognitive functioning. Results: Out of 178 first-episode patients, 37 (21%) never relapsed during the 10-year period. Univariate predictors (p ⩽ 0.1) of patients who never relapsed included a duration of untreated psychosis (DUP) ⩽30 days, diagnosed with non-schizophrenia spectrum disorders, having less severe negative symptoms, and performing better in logical memory immediate recall and verbal fluency tests. A multivariate logistic regression analysis further suggested that the absence of any relapsing episodes was significantly related to better short-term verbal memory, shorter DUP, and non-schizophrenia spectrum disorders. Conclusions: Treatment delay and neurocognitive function are potentially modifiable predictors of good long-term prognosis in FEP. These predictors are informative as they can be incorporated into an optimum risk prediction model in the future, which would help with clinical decision making regarding maintenance treatment in FEP. [ABSTRACT FROM AUTHOR]

Retrospective data were collected from 330 individuals who were treated at a tertiary care program for treatment-resistant psychosis between 1994 and 2010. The main objectives were to compare the use of antipsychotic monotherapy to polypharmacy and to characterize within-individual changes in treatment and symptomatology between admission and discharge. At admission, individuals who were prescribed only one antipsychotic were comparable to those who were prescribed at least two antipsychotics with regard to demographics and symptom severity. The use of psychotropic medications other than antipsychotics was also similar between the two groups. However, the magnitude of antipsychotic utilization was greater in individuals who were receiving antipsychotic polypharmacy. In addition, a greater proportion received excessive doses at admission. Similar findings were observed when the two antipsychotic prescribing practices were compared at discharge. Three important patterns were identified when investigating within-individual changes. First, fewer individuals were prescribed more than one antipsychotic at discharge. This was accompanied by a general decrease in the magnitude of antipsychotic utilization. Second, the number of individuals who were prescribed clozapine had increased by discharge. Most who were already prescribed clozapine at admission had their doses increased. Third, improvements in symptomatology were observed across all of the subscales included in the Positive and Negative Symptom Scale (PANSS); 57.9% of individuals experienced a relative reduction in total PANSS scores exceeding 20%. Based on these findings, it is possible to alleviate symptom severity while reducing antipsychotic utilization when patients are treated at a tertiary care program for treatment-resistant psychosis. [ABSTRACT FROM AUTHOR]

Objectives: The neurobiological underpinnings of bipolar I disorder are not yet understood. Previous structural neuroimaging studies of bipolar disorder have produced rather conflicting results. We hypothesise that clinical sub-phenotypes of bipolar I disorder defined by their psychotic symptoms, especially those with mood-incongruent psychotic features, may have more extensive structural brain abnormalities. Methods: We investigated structural brain alterations in patients with first-episode mania (n = 55) with mood-congruent (n = 16) and mood-incongruent (n = 32) psychotic features, as well as those without psychotic symptoms (n = 7), relative to healthy subjects (n = 56). Results: Total intracranial volume was significantly reduced in patients with mood-incongruent psychosis compared to healthy subjects while cerebrospinal fluid (CSF) volume was significantly increased. Patients with mood-congruent psychosis showed significant reduction in total white matter volume and significant CSF volume increase. Patients with psychosis had significant volume reduction in anterior cingulate and medial prefrontal cortices. Relative to mood-congruent psychotic features, mood-incongruent psychotic features were associated with volume reduction in the left middle temporal gyrus, right inferior parietal gyrus, right fusiform gyrus, left middle orbitofrontal gyrus and cerebellum. Conclusions: While preliminary, our findings suggest that the presence and type of psychosis in first-episode mania may be phenotypic markers of underlying biological variants of bipolar disorder. [ABSTRACT FROM AUTHOR]

Background: 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-e4 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-e4 carriers and FEP-APOE-e4 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<0.001) as well as an APOE-ε4 by group by time (F[4, 116.2]=2.73, P=0.033) interaction with only FEP-APOE-ε4 carriers showing improved verbal memory at follow-up. Conclusion: Our study is the first to report improvement in verbal memory in persons afflicted by FEP who are APOE-ε4 carriers and replicates the prominent verbal memory deficits present in FEP. Our work provides further evidence pointing to an antagonistic pleiotropic effect of APOE-ε4 in neuropsychiatric disorders. Our results merit further research into antagonistic pleiotropic effects in schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: The objective of this article is to identify best practices in the diagnosis and assessment of patients with schizophrenia spectrum and other psychotic disorders. The diagnosis and assessment may occur in a range of situations from the emergency room to the outpatient clinic and at different stages of the disorder. The focus may be on acute exacerbations of illness, residual symptoms, levels of function, or changes in the response to treatment.Methods: A systematic search was conducted for guidelines published in the last 5 years for schizophrenia and schizophrenia spectrum disorders. The guidelines were rated by at least 2 raters, and recommendations adopted on the diagnosis and assessment were primarily drawn from the American Psychiatric Association practice guidelines for the psychiatric evaluation of adults and the National Institute for Health and Care Excellence guideline on psychosis and schizophrenia in adults. A number of de novo recommendations were also developed.Results: Eleven recommendations were identified that cover a range of assessment situations from diagnosis to the involvement of families in assessments.Conclusions: An accurate assessment establishes the baseline for treatment planning based on clinical decision making for both pharmacotherapy and psychosocial treatments. [ABSTRACT FROM AUTHOR]

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

With sufficient drug exposure, some individuals develop transient psychotic symptoms referred to as 'substance-induced psychosis' (SIP), which closely resemble the symptoms observed in schizophrenia spectrum disorders. The comparability in psychotic presentation between SIP and the schizophrenias suggests that similar underlying neural deficits may contribute to the emergence of psychosis across these disorders. Only a small number of studies have investigated structural alterations in SIP, and all have been limited to volumetric imaging methods, with none controlling for the effects of chronic drug exposure. To investigate white matter abnormalities associated with SIP, diffusion tensor imaging was employed in a group of individuals with cocaine-associated psychosis (CAP; n = 24) and a cocaine-dependent non-psychotic (CDN) group (n = 43). Tract-based spatial statistics was used to investigate group differences in white matter diffusion parameters. The CAP group showed significantly lower fractional anisotropy values than the CDN group (p < 0.05) in voxels within white matter tracts of fronto-temporal, fronto-thalamic and interhemispheric pathways. The greatest differences in white matter integrity were present in the corpus callosum, corona radiata, bilateral superior longitudinal fasciculi and bilateral inferior longitudinal fasciculi. Additionally, the CAP group had voxels of significantly higher radial diffusivity in a subset of the previously mentioned pathways. These results are the first description of white matter integrity abnormalities in a SIP sample and indicate that differences in these pathways may be a shared factor in the expression of different forms of psychosis. [ABSTRACT FROM AUTHOR]

This follow-up study of a randomized clinical trial examines a cohort of patients who had participated in the trial 10 years ago to establish what factors were associated with successful discontinuation of antipsychotic medication regimens. [ABSTRACT FROM AUTHOR]

Approximately half of psychostimulant users experience psychotic symptoms, which include both positive and negative symptoms. Prior reports have exclusively used positive symptoms to characterize psychostimulant associated psychosis. Symptoms vary dramatically in severity, though most investigations categorize psychosis as a dichotomous occurrence. To explore the association between different substances of abuse and the severity of psychotic symptoms, we investigated 171 individuals meeting DSM-IV-TR criteria for psychostimulant (cocaine or methamphetamine) dependence in an observational cross-sectional study. Participants were predominantly male (72.5%), recruited from a socially disadvantaged neighborhood in Vancouver, Canada, with a mean age of 45.5(±8.8) years. Of the total sample, 85% were dependent on cocaine, and 28.1% were dependent on methamphetamine. Participants had a median total PANSS score of 63, ranging from 37 to 111. Demographic information, current substance use and early substance exposure were used to predict positive and negative psychotic symptom severity in linear regression models. Increased severity of positive psychotic symptoms was significantly related to greater methamphetamine and marijuana use in the past 28 days, and methadone-abstinence. Negative symptom severity was related to increased opioid use in the past 28 days. There was no overlap between predictors of positive and negative symptom severity. [ABSTRACT FROM AUTHOR]

Rates of psychopathology are elevated in marginalized and unstably housed persons, underscoring the need for applicable clinical measures for these populations. The Positive and Negative Syndrome Scale (PANSS) is a clinical instrument principally developed for use in schizophrenia to identify the presence and severity of psychopathology symptoms. The current study investigates whether a reliable and valid PANSS factor structure emerges in a marginally housed, heterogeneous sample recruited from the Downtown Eastside of Vancouver where substance use disorders and psychiatric illness are pervasive. Participants (n = 270) underwent structured clinical assessments including the PANSS and then were randomly assigned to either exploratory (EFA) or confirmatory factor analytic (CFA) subsamples. EFA pointed to a novel three factor PANSS. This solution was supported by CFA. All retained items (28 out of 30) load significantly upon hypothesized factors and model goodness of fit analyses are in the acceptable to good range. Each of the three first-order factor constructs, labeled Psychosis/Disorganized, Negative Symptoms/Hostility, and Insight/Awareness, contributed significantly to measurement of a higher-order psychopathology construct. Further, the latent structure of this 3-factor solution appears temporally consistent over one-year. This PANSS factor structure appears valid and reliable for use in persons with multimorbidity, including substance use disorders. The structure is somewhat distinct from existing solutions likely due to the unique characteristics of this marginally housed sample. [ABSTRACT FROM AUTHOR]

Objective To examine the treatment delay associated with community and inpatient pathways into care for persons experiencing a first episode of psychosis. Methods A total of 104 clients entering a specialized early psychosis intervention ( EPI) program and their family members were assessed for help-seeking behaviours, psychiatric symptoms, level of functioning and duration of untreated psychosis (DUP). Results DUP (median = 30.5 weeks) was associated with younger age of onset, poorer engagement with the EPI program and more severe symptoms. Almost one-third of clients had four or more contacts before receiving antipsychotic medication or entering the EPI program and one in five received interventions not specifically indicated for psychosis. Referrals directly involving family members accounted for about 81% of hospital-initiated treatment (39% of all referrals) and 46% of community-initiated treatment (61% of all referrals). Community entry was associated with longer DUP, more time-seeking treatment, younger age of onset, younger age at referral, greater likelihood of receiving other medication or counselling before receiving antipsychotic medication, schizophrenia, less severe symptoms and less substance use in the previous year. Those with schizophrenia showed no differences across pathway type for time-seeking treatment, being provided interventions not specifically indicated for psychosis after onset or rates of substance use. Conclusions Treatment delay and the provision of interventions not specifically indicated for psychosis may be increased in first-episode populations who are younger and have less severe symptoms. Improving literacy about early psychosis in both professionals and families merits greater attention. [ABSTRACT FROM AUTHOR]

Contemporary analyses demonstrate an early response to antipsychotic treatment in non-refractory schizophrenia. The profile of response to clozapine is unknown. We used meta-analytic and statistical procedures to examine the response profile to clozapine. We identified 19 unique, randomized, double-blind controlled clinical trials with suitable time course data, representing 1745 subjects. Individual subject data were available for 419 subjects, obtained from two industry-sponsored trials. Symptom severity scores from the BPRS or the PANSS were entered into regression analyses to estimate linear and quadratic coefficients of the rate of change of symptom severity over 4 weeks. Both linear and quadratic regression coefficients for clozapine, and for comparator antipsychotics differed significantly from zero (p ≤ 0.001), indicating early response profiles. Compared with other antipsychotic arms, for clozapine the treatment response was greater (d = −0.578, p = 0.021), and the linear coefficient was steeper (d = −0.502, p = 0.042); the quadratic coefficients indicating attenuation did not differ. Analyses of 6-week data and individual subject data from non-refractory and refractory trials were consistent with the primary findings. Somewhat surprisingly, clozapine shows an early response profile, similar in pattern but somewhat larger in magnitude than other antipsychotic drugs. [ABSTRACT FROM AUTHOR]

Antipsychotic medications can contribute to neurocognitive and motor impairments, but specific links to individualized pharmacological treatment regimens are unclear. In 68 participants with stabilized first-episode psychosis (FEP), we investigated the links between neuropsychological functions and an established anticholinergic potency index and a new D2 antagonist potency index developed in our lab. Each participant's psychiatric medication regimen was converted into estimated receptor antagonist loads based upon specific medication dosage(s) and reported in vitro brain muscarinic cholinergic and D2 receptor antagonism. In addition to the global neuropsychological impairments of FEP participants, the findings supported the hypothesized links between receptor antagonist loads and specific deficits. Higher anticholinergic load was associated with poorer delayed verbal memory but was not related to motor functioning. In contrast, higher D2 load was associated with poorer motor functioning but not verbal memory. These selective antagonist load associations explained 19% of the variance in motor functioning and 17% of the variance in delayed verbal memory. Evidently, some of the neuropsychological impairments found in persons with FEP are selectively related to the specific pharmacodynamics and the dosing of their medication regimens. Moreover, these effects can be readily estimated from practical and inexpensive indices. (JINS, 2012, 18, 1–11) [ABSTRACT FROM PUBLISHER]

Aim: Although phase-specific early intervention for first-episode psychosis has been implemented in many different parts of the world, limited medium-term outcome data are available in non-Western populations with relatively low mental health resources. The study aimed to determine the effectiveness of phase-specific early intervention in first-episode psychosis. Method: In this cohort study, we compared the 3-year outcome of 700 first-episode psychosis patients who received phase-specific early intervention with that of 700 patients matched for age, sex and diagnosis who received standard psychiatric care prior to early intervention. Using a structured data acquisition procedure, we determined functional outcome, symptom levels, relapse, recovery, suicidal behaviour and service utilization from clinical records. Results: Patients in the early intervention group had longer full-time employment or study ( P < 0.001), fewer days of hospitalization ( P < 0.001), less severe positive symptoms ( P = 0.006), less severe negative symptoms ( P = 0.001), fewer suicides ( P = 0.009) and fewer disengagements ( P = 0.002) than the historical control group. Additionally, more patients in the early intervention group experienced a period of recovery ( P = 0.001), but the two groups had similar rates of relapse ( P = 0.08) and durations of untreated psychosis ( P = 0.72). Conclusions: The 3-year outcome in phase-specific early intervention compared favourably with that of standard psychiatric care, particularly with respect to functional outcome and reduction in hospitalizations, suicides and disengagements. However, intervention did not appear to reduce the rate of relapse. [ABSTRACT FROM AUTHOR]

Abnormalities of amount and function of presynaptic terminals may have an important role in the mechanism of illness in schizophrenia. The SNARE proteins (SNAP-25, syntaxin, and VAMP) are enriched in presynaptic terminals, where they interact to form a functional complex to facilitate vesicle fusion. SNARE protein amounts are altered in the cortical regions in schizophrenia, but studies of protein–protein interactions are limited. We extended these investigations to the striatal regions (such as the nucleus accumbens, ventromedial caudate (VMC), and dorsal caudate) relevant to disease symptoms. In addition to measuring SNARE protein levels, we studied SNARE protein–protein interactions using a novel ELISA method. The possible effect of antipsychotic treatment was investigated in parallel in the striatum of rodents that were administered haloperidol and clozapine. In schizophrenia samples, compared with controls, SNAP-25 was 32% lower (P=0.015) and syntaxin was 26% lower (P=0.006) in the VMC. In contrast, in the same region, SNARE protein–protein interactions were higher in schizophrenia (P=0.008). Confocal microscopy of schizophrenia and control VMC showed qualitatively similar SNARE protein immunostaining. Haloperidol treatment of rats increased levels of SNAP-25 (mean 24%, P=0.003), syntaxin (mean 18%, P=0.010), and VAMP (mean 16%, P=0.001), whereas clozapine increased only the VAMP level (mean 13%, P=0.004). Neither drug altered SNARE protein–protein interactions. These results indicate abnormalities of amount and interactions of proteins directly related to presynaptic function in the VMC in schizophrenia. SNARE proteins and their interactions may be a novel target for the development of therapeutics. [ABSTRACT FROM AUTHOR]

Aim: There has been increasing interest in the concept of applying genetic counselling to psychiatric disorders, but despite its relevance to psychiatric illness, and interest from the target group, there have been no empiric investigations of psychiatric genetic counselling. In a population of unaffected parents of individuals with first episode as well as more chronic psychotic disorders, we aimed to investigate whether psychiatric genetic counselling: is perceived to be useful, could increase understanding of the causes of psychiatric illness and decrease concern about other relatives becoming affected. Methods: Subjects ( n = 13) participated in a genetic counselling session. The session was a clinical intervention similar to what would be carried out as part of a referral for any disease with a hereditary component, but specific for psychosis. Questionnaires were used to assess (pre-counselling): motivations for attending, concern about other relatives developing psychiatric illness, and (post-counselling) whether the intervention: (i) improved understanding of mental illness; (ii) modified concern about other relatives becoming affected; and (iii) was perceived to be useful. Results: Desire for knowledge motivated participation. Immediately after the session, and 1 month later >92% and 100% of participants, respectively, felt that the session was useful. Genetic counselling reduced concern about other relatives becoming affected as risks were lower than participants had expected. All participants felt that their understanding of the causes of psychiatric illness had improved through genetic counselling. Conclusion: Psychiatric genetic counselling may benefit parents of individuals with psychiatric illnesses. Avenues for future research are highlighted. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Recently, in a post-mortem and a subsequent structural MR study, a significantly increased gyrification index (GI) was demonstrated in the frontal lobe in individuals with schizophrenia. To examine whether frontal lobe hypergyria is region-specific and whether this might be a suitable endophenotype in the search for the genetic basis of schizophrenia, the frontal as well as parieto-occipital GI were determined in MRI scans of families affected with schizophrenia. Method: In the MRI scans of 48 subjects suffering from schizophrenia, in 82 of their first-degree relatives and in 41 control subjects, the GI was determined in three sections anterior to the genu of the corpus callosum and three sections posterior to the splenium, thus allowing for a selective determination of this measure in the frontal as well as the parietal lobe. Outer and inner contours constituting the GI was determined in each section by manual tracing. Statistical analysis was performed using MANOVA with factors diagnostic group and intervening factors from preliminary analyses. Results: The frontal, but not parieto-occipital GI was significantly higher in schizophrenic patients as well as unaffected relatives compared with control subjects (right: 7%, F =13.24, df=3, 155, p <0.0005, left: 6%, F =8.92, df=3, 155, p <0.0005). There was no overall difference between affected and unaffected family members. On the left side however, there was a significant interaction between diagnostic group and genetic loading (F =4.68, df=2, 101, p =0.01): significantly higher GI was found in affected compared with unaffected family members only in uniaffected and not multiaffected families. Conclusions: These results support our primary finding of hypergyria in the frontal lobe in schizophrenic patients. Compared to the parietal lobe, hypergyria seems to affect the frontal lobe selectively and serves as a suitable neurodevelopmental, possibly even an endophenotypic marker. [Copyright &y& Elsevier]

Schizophrenia is one of the most severe and disabling psychiatric disorders. Antipsychotic drugs offer considerable benefits in controlling symptoms and preventing relapse. The strategy for the present review of clinical trials was to ask ‘What are the features of schizophrenia and the existing treatments of the illness that have implications for future clinical trials’? Six key facts were identified.First, schizophrenia is genetically ‘complex’. Trials may benefit from designs including genetically related illnesses, by focussing on cross-cutting aspects of the phenotype such as psychosis or cognitive dysfunction, and by collecting information on possible moderators and mediators of treatment response.Second, schizophrenia affects multiple neurotransmitter systems. Mutiple signalling pathways may need to be considered, with different time courses of response. Outcome measures from clinical trials could be collected at more frequent intervals, particularly in the early phase of response.Third, the clinical features used to define the illness are a mix of symptoms and social-occupational dysfunction, yet treatment response is often defined only by changes in symptoms. Multiple measures of functioning need to be collected at baseline and at the endpoint of trials. Consensus definitions for response, remission, relapse, recovery and recurrence need to be developed.Fourth, schizophrenia is often highly disabling. Linking treatment response in clinical trials to measures of quality-adjusted life-years will allow comparison with other medical illnesses using common metrics.Fifth, the general health and care of individuals with schizophrenia is often poor. ‘Complex’ interventions, which include, but are not limited to, antipsychotic medications, need to be designed and tested for the problems facing these patients.Finally, large gaps exist between clinical trials, practice guidelines and patterns of practice. Trials need to be designed to investigate widely used approaches such as antipsychotic polypharmacy, where actual practice diverges from evidence-based guidelines. [ABSTRACT FROM AUTHOR]

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Movement disorders in first-episode psychosis are increasingly recognized; however, the prevalence and clinical correlates are uncertain. We compared antipsychotic exposed (≤ 12 weeks) with non-exposed first-episode patients, and report prevalence as well as clinical and demographic variables associated with extrapyramidal dysfunction. Data are baseline assessments from a multicentre, international drug trial of first-episode psychosis (n = 535). Analysis intruded the Extrapyramidal Symptom Rating Scale, Premorbid Adjustment Scare, and the Positive and Negative Syndrome Scale. Of non-exposed patients, 28.1% (n = 47/167) had at least one mild sign of extrapyramidal dysfunction, as did 46.3% (n = 169/365) of previously exposed patients. Hypokinetic Parkinsonism was the most prevalent disorder. The severity of movement disorders and negative symptoms were correlated; however, the effect sizes were small. Logistic regression analysis indicated that the salient risk factors for all patients were: previous antipsychotic exposure [odds ratio (OR) = 2.4; 95% confidence interval (CI) 1.6-3.6] and poor premorbid functioning (OR = 1.8; 95% CI 1.2-2.6). For the non-exposed group (n = 167), the significant risk factors were: having severe mental illness in the family (OR = 2.9; 95% CI 1.2-7.2) and poor premorbid functioning (OR = 2.3; 95% CI 1.0-5.3). For the previously exposed group (n = 368), the significant variables were: poor premorbid functioning (OR = 1.8; 95% CI 1.2-2.8) and shorter duration of untreated psychosis (OR = 0.78; 95% CI 0.64-0.94). Although antipsychotic exposure was associated with extrapyramidal signs, the results indicate that many first-episode patients with no exposure to antipsychotics also had extrapyramidal dysfunction. In this group, family history and poor premorbid functioning appear to be associated with increased risk for movement disorders. [ABSTRACT FROM AUTHOR]

Background Converging neuroimaging and postmortem evidence indicates synaptic terminals are abnormal in schizophrenia. A putative molecular mechanism implicates abnormalities of proteins involved in the presynaptic secretory machinery, including the modulator proteins complexin I and complexin II. Objectives To determine the amount and distribution of complexin proteins in the hippocampus of subjects with schizophrenia, in parallel with markers for excitatory and inhibitory nerve terminals. The functional implications were also investigated. Design We used immunocytochemistry to study complexin I and complexin II proteins in hippocampus, as well as the vesicular transporters for γ-aminobutyric acid (GABA) and for glutamate. Immunocytochemical findings were correlated with cognitive function assessed through medical record review. To further explore the implications of the human findings, we studied rats exposed to haloperidol, amphetamine, and ketamine as well as rats trained in memory tasks. Subjects We studied hippocampal sections from 12 subjects with schizophrenia and 12 subjects with no known neuropsychiatric disorder. Results The absolute values and ratio of the hippocampal presynaptic proteins complexin II—complexin I were lower in subjects with schizophrenia. Disturbances in the complexin proteins in subjects with schizophrenia were greater than those observed for vesicular γ-aminobutyric acid or vesicular glutamate transporters. The lower complexin II–complexin I ratio in several hippocampal subfields in subjects with schizophrenia was inversely correlated with the severity of antemortem cognitive impairment. In contrast, the hippocampal complexin II–complexin I ratio was higher in rats trained in a memory task compared with untrained rats. Treatment of rats with antipsychotic drugs or with the psychotomimetic drugs amphetamine or ketamine did not alter the complexin II–complexin I ratio. Conclusions The pathology of hippocampal complexin proteins might play an important role in schizophrenia, especially concerning cognitive disturbances. [ABSTRACT FROM AUTHOR]

A cohort of 168 psychotic patients underwent computerised tomography (CT) during their first admission. Cortical atrophy was present in 40% of patients. The frequency of atrophy increased with age, but did not differ between patients with schizophrenia, schizoaffective disorder, bipolar disorder or psychotic depression. Other CT findings of note were present in 6.6% of patients, and included four infarctions, three arachnoid cysts, and one each of venous angioma, colloid cyst, cavum vergae and post-traumatic changes. The frequency of CT findings other than atrophy was increased in the psychotic depression group. The findings support the proposal of the onset of psychosis being an indication for CT. [ABSTRACT FROM AUTHOR]

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]

The article discusses the mechanisms and treatment of clozapine-induced obsessive-compulsive symptoms (OCS). The clinical challenge of determining the origin of OCS in individuals with schizophrenia is discussed. It is noted that neuroimaging studies implicate hyperdopaminergic activity in the pathophysiology of obsessive-compulsive disorder. It is also mentioned that add-on selective serotonin reuptake inhibitors can be effective in treating clozapine-induced OCS.

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine" by T. K. Rajji, B. H. Mulsant and S. Davies in the June 2015 issue.

The article discusses a study which investigated the effect of discontinuation of maintenance treatment with quetiapine on relapse in patient with first episode psychosis who have completed at least one year of maintenance therapy. The randomised controlled trial included 178 patients enrolled in a territory-wide early psychosis service in Hong Kong, China. It was found that discontinuation of maintenance treatment increased risk of relapse in the following year.

Abstract: Atypical antipsychotic medications generally maintain or increase gray matter amount and functioning. First-episode psychosis patients have lower gray matter volume in the middle frontal gyrus, as well as worse performance on spatial working memory tasks compared to controls. This study investigated the effects of short-term four- and eight-week atypical treatment on middle frontal thickness and spatial working memory in first-episode psychosis patients. Nineteen drug-naïve first-episode psychosis patients treated with risperidone or quetiapine and 26 controls completed structural magnetic resonance imaging, a spatial working memory task, and clinical assessment at three intervals (baseline, four weeks, and eight weeks; all patients and 23 controls completed all three assessments). Caudal and rostral middle frontal thicknesses were measured using the automated program Freesurfer. Positive, negative, and general symptoms of the Positive and Negative Syndrome Scale (PANSS) decreased significantly in patients, with most of the change occurring in the first four weeks of treatment. Patients demonstrated an increase in rostral middle frontal thickness over eight weeks of treatment compared to controls. There was a medium effect size relationship between reduction in negative symptoms at four and eight weeks, and a change in rostral middle frontal thickness over eight weeks. No changes were found in spatial working memory ability. Short-term atypical treatment with risperidone or quetiapine can increase prefrontal cortical thickness in psychosis. These findings are notable given the role of the rostral middle frontal region in cognition and the relationship between better cognitive functioning and better functional outcome in psychosis. [Copyright &y& Elsevier]

Abstract: There is some evidence for prefrontal (PF) lobe changes in schizophrenia while the parieto-occipital (PO) region seems to be unaffected. This magnetic resonance imaging (MRI) study was performed to examine shape differences as part of the spectrum of structural abnormalities in schizophrenia. The measurements were done on families affected with schizophrenia to identify the influence of genetic and environmental factors on these changes. The sample under study consisted of 164 subjects including 45 family members (FM) suffering from schizophrenia, 27 FM with other psychiatric disorders and 51 FM without psychiatric disorders based on ICD-10 criteria. In addition, 41 nonpsychiatric control subjects were included in the study. On defined planes at the corpus callosum boundary of the PF and the PO, brain width, height and length were measured on coronal slices. Ratios of these linear measurements were also calculated based on the idea that a plane can be approximated by a circle if the concerning ratio comes close to 1. It was hypothesized that these relative brain shape parameters, especially the PF ratio width/height, would show differences between schizophrenic patients and control subjects. For all members from families with schizophrenia compared with control subjects, there were significant differences in the PF, but not in the PO region. PF height was increased. PF ratios of width/height and height/(2×length) were closer to 1 in affected families than in control subjects. The results can be interpreted as an indication for PF brain shape changes in subjects with a disposition for schizophrenia. On coronal and sagittal planes situated at the corpus callosum, their PF could be approximated by a circle better than in control subjects. As the frontal lobe takes shape late in brain development, underlying genetic mechanisms may be dysregulated in schizophrenic patients and subjects at risk to develop the disorder. [Copyright &y& Elsevier]

Objective: Individuals with early psychosis may have prefrontal-limbic cortical deficits, which are associated with symptom severity and cognitive impairment. This study investigated the impact of an exercise intervention on fronto-temporal cortical plasticity in female participants with early psychosis.Methods: In a cohort of 51 female participants with early psychosis from Hong Kong, we investigated the effects of a 12-week, moderate intensity aerobic or Hatha yoga exercise trial (yoga (N = 21), aerobic (N = 18) or waitlist group (N = 12)) on cortical grey matter. Clinical assessments and structural MRI were completed pre- and post- a 12-week exercise intervention.Results: Increases in cortical volume and thickness were observed in the medial temporal cortical regions, primarily in fusiform cortical thickness (F(2, 48) = 4.221, p = 0.020, η2 = 0.150) and volume (F(2, 48) = 3.521, p = 0.037, η2 = 0.128) for participants with early psychosis in the aerobic arm, but not in the yoga and waitlist arms. Increased fusiform cortical thickness (ß = 0.402, p = 0.003) was associated with increased hippocampal volume for all psychosis participants. For the aerobic group only, increases in the entorhinal and fusiform temporal gyri were associated with reduced symptom severity.Conclusions: These findings suggest exercise-induced neuroplasticity in medial temporal cortical regions occurs with aerobic exercise. These changes may be associated with improvements in psychosis symptom severity. People with early psychosis may benefit from exercise interventions, particularly aerobic exercise, as an adjunct treatment to address clinical, physical health, and neuroanatomic concerns. NIH National Library of Medicine ClinicalTrials.gov Registration #: NCT01207219https://clinicaltrials.gov/ct2/show/NCT01207219. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the ‘rTMS for the Treatment of Negative Symptoms in Schizophrenia’ (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. In an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS. [ABSTRACT FROM AUTHOR]

Abstract: Second generation antipsychotic drugs are routinely used as treatment for psychotic disorders. Many of these compounds, including olanzapine, cause metabolic side-effects such as impaired glucose tolerance and insulin resistance. Individual antidiabetic drugs can help control elevated glucose levels in patients treated with antipsychotics, but the effects of combining antidiabetics, which routinely occurs with Type 2 diabetes mellitus patients, have never been studied. Presently, we compared the effects of the three different antidiabetics metformin (500mg/kg, p.o.), rosiglitazone (30mg/kg, p.o.) and glyburide (10mg/kg, p.o.) on metabolic dysregulation in adult female rats treated acutely with olanzapine. In addition, dual combinations of each of these antidiabetics were compared head-to-head against each other and the individual drugs. The animals received two daily treatments with antidiabetics and were then treated acutely with olanzapine (10mg/kg, i.p.). Fasting glucose and insulin levels were measured, followed by a 2h glucose tolerance test. Olanzapine caused a large and highly significant glucose intolerance compared to vehicle treated rats. Rosiglitazone decreased glucose levels non-significantly, while both metformin and glyburide significantly decreased glucose levels compared to olanzapine-only treated animals. For antidiabetic dual-drug combinations, the rosiglitazone–metformin group showed an unexpected increase in glucose levels compared to all of the single antidiabetic drugs. However, both the metformin–glyburide and rosiglitazone–glyburide groups showed significantly greater reductions in glucose levels following olanzapine than with single drug treatment alone for metformin or rosiglitazone, bringing glucose levels down to values equivalent to vehicle-only treated animals. These findings indicate that further study of antidiabetic dual-drug combinations in patients treated with antipsychotic drugs is warranted. [Copyright &y& Elsevier]

Abstract: Objective: Relapse is common among patients with psychotic disorders. Identification of relapse predictors is important for decision regarding maintenance medication. Naturalistic studies often identify medication non-adherence as a dominant predictor. There are relatively few studies for predictors where adherence is already known. It is this situation i.e., discontinuation of medication that predictors will be most useful. We identify predictors for relapse in situations of (i) discontinuation and (ii) continuation of maintenance medication. Method: Analysis of relapse predictors is based on a randomized controlled study (n =178) comparing relapse rates between patients who discontinued or continued medication for at least 1year following first-episode psychosis. Demographic, clinical and neurocognitive variables were assessed at baseline as predictors of relapse within 1year. Results: Risk of relapse was 79% in the discontinuation group and 41% in the maintenance group. Predictors in the discontinuation group were diagnosis of schizophrenia, poorer semantic fluency performance, and higher blink rate. Predictors in the continuation group were disinhibition soft signs and more general psychopathology symptoms. Conclusion: Different predictors of relapse were identified for first episode psychosis patients who discontinued and continued maintenance medication. Neurocognitive dysfunctions are important predictors for both groups. While signs of frontal dysfunction and dopamine hyperactivity predict relapse in the discontinuation group, sign of cognitive disinhibition predicts relapse in the continuation group. [Copyright &y& Elsevier]

Abstract: Introduction: Small hippocampi and impaired memory are common in patients with psychosis and brain-derived neurotrophic factor (BDNF) plays a critical role in hippocampal neuroplasticity and memory. A common BDNF allele (Val66Met) has been the focus of numerous studies but results from the few BDNF-imaging studies are complex and contradictory. The objective of this study was to determine the association between Val66Met and hippocampal volume in patients with first episode psychosis. Secondary analyses explored age-related associations and the relationship between Val66Met and memory. Method: Hippocampal volume and BDNF genotyping were obtained for 58 patients with first-episode psychosis and 39 healthy volunteers. Patients were recruited from an early psychosis program serving a catchment-area population. Results: Hippocampal volume was significantly smaller in patients than controls (F1,92 =4.03, p<0.05) and there was a significant group-by-allele interaction (F1,92 =3.99, p<0.05). Hippocampal volume was significantly smaller in patients than controls who were Val-homozygotes but no group differences were found for Met carriers. Findings were not affected by diagnosis, antipsychotic medication, or age, and there was no change in hippocampal volume during a one-year follow-up. Val-homozygous patients had worse immediate and delayed memory than their Met counterparts. Conclusions: Results suggest the effects of the BDNF Val66Met allele may be different in patients with psychosis than in healthy adults. Hippocampal volume in patient and control Met allele carriers was very similar suggesting that illness-related factors have minimal influence in this group. In contrast, Val homozygosity was related to smaller hippocampi and poorer memory functioning only in patients with psychosis. [Copyright &y& Elsevier]

Abstract: Introduction: Cigarette smoking is common in psychotic disorders and may be initiated in an attempt to control features of illness. However, genetic, obstetric and early life conditions are risks for starting to smoke in the general population but their role in psychotic patients is unclear. Method: Smoking history and the putative predictors of starting to smoke were assessed in a community-wide sample of 115 first episode psychosis patients. The proportion that initiated smoking was compared with that from population surveys and the impact of risk factors was assessed within the patient sample. Results: Most patients began smoking before illness onset and the proportion who initiated smoking was significantly high by the onset of a functional decline. Gestational tobacco exposure was a risk for smoking and was also associated with low birthweight, poor academic achievement, and obesity. Low familial socioeconomic position but not familial psychiatric problems also predicted smoking initiation. Discussion: In most cases, smoking preceded illness onset and was not a response to early features of illness. General population predictors of starting to smoke were also associated with smoking initiation in psychotic patients. Of these risks, exposure to tobacco during gestation is noteworthy in that it affects brain development and is associated with cognitive, behavioral, psychiatric and general health problems. In addition, nicotine interacts with other substances of abuse. The initiation of smoking before illness onset and the association with developmental problems raises the question of whether cigarette smoking influences some aspects of illness in patients with psychosis. [Copyright &y& Elsevier]

Abstract: Using an automatized gray level index (GLI) method, we recently found cytoarchitectonic abnormalities in schizophrenia in Brodmann area 10 (BA10) [Vogeley, K., Tepest, R., Schneider-Axmann, T., Hutte, H., Zilles, K., Honer, W.G., Falkai, P., 2003. Automated image analysis of disturbed cytoarchitecture in Brodmann area 10 in schizophrenia, Schizophrenia Research 62, 133–140]. As another potential key region involved in the pathophysiology of schizophrenia, we have now investigated BA9 in the same sample consisting of 20 schizophrenic cases and 20 controls. The GLI value represents the area-percentage covered by perikarya in measuring fields of microscopic images. BA9 was analyzed with respect to the factors diagnosis and gender for six different compartments approximately corresponding to the neocortical layers. The main result in BA9 was a significant interaction of diagnosis and gender for GLI in layers IV and V on the left side. Subsequent analyses separately performed concerning gender revealed a significant GLI increase in layer V on the left side in male patients compared with controls. However, after an adjustment of error probabilities for multiple testing, differences did not reach significance. No GLI difference was observed in the sample between diagnostic groups for females and between the diagnostic groups in general. Comparisons with our BA10 results suggest that cytoarchitectural changes relevant to schizophrenia appear different in various Brodmann areas. Since increases in GLI were found only in selected layers (V and VI) of BA9, these findings do not support a generalized neuropil reduction across all cortical layers. [Copyright &y& Elsevier]