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Neuroprotective and other functional proteins of mitochondria were quantified in extracts of plasma neural-derived exosomes from ten first-episode psychosis (FP) patients and ten matched psychiatrically normal controls (ctls). Astrocyte-derived extracellular vesicles (ADEVs) and neuron-derived extracellular vesicles (NDEVs) were immunoabsorbed separately from physically precipitated plasma total EVs. Extracted mitochondrial ATP synthase was specifically immunofixed to plastic wells for quantification of catalytic activity based on conversion of NADH to NAD(+). Other extracted mitochondrial functional proteins were quantified by ELISAs. All protein levels were normalized with EV content of the CD81 exosome marker. FP patient ADEV level but not NDEV level of mitochondrial ATP synthase activity was significantly lower than that of ctls. FP patient ADEV and NDEV levels of the functionally critical mitochondrial proteins mitofusin 2 and cyclophilin D, but not of transcription factor A of mitochondria, and of the mitochondrial short open-reading frame neuroprotective and metabolic regulatory peptides humanin and MOTS-c were significantly lower than those of ctls. In contrast, FP patient NDEV, but not ADEV, level of the mitochondrial-tethering protein syntaphilin, but not of myosin VI, was significantly higher than that of ctls. The distinctively different neural levels of some mitochondrial proteins in FP patients than ctls now should be correlated with diverse clinical characteristics. Drugs that increase depressed levels of proteins and mimetics of deficient short open-reading frame peptides may be of therapeutic value in early phases of schizophrenia.

The current study sought to expand on prior reports of the validity and reliability of the CAINS (CAINS) by examining its performance across diverse non-academic clinical settings as employed by raters not affiliated with the scale's developers and across a longer test-retest follow-up period. The properties of the CAINS were examined within the Management of Schizophrenia in Clinical Practice (MOSAIC) schizophrenia registry. A total of 501 participants with a schizophrenia spectrum diagnosis who were receiving usual care were recruited across 15 national Patient Assessment Centers and evaluated with the CAINS, other negative symptom measures, and assessments of functioning, quality of life and cognition. Temporal stability of negative symptoms was assessed across a 3-month follow-up. Results replicated the two-factor structure of the CAINS reflecting Motivation and Pleasure and expression symptoms. The CAINS scales exhibited high internal consistency and temporal stability. Convergent validity was supported by significant correlations between the CAINS subscales with other negative symptom measures. Additionally, the CAINS was significantly correlated with functioning and quality of life. Discriminant validity was demonstrated by small to moderate associations between the CAINS and positive symptoms, depression, and cognition (and these associations were comparable to those found with other negative symptom scales). Findings suggest that the CAINS is a reliable and valid tool for measuring negative symptoms in schizophrenia across diverse clinical samples and settings.

Background We have limited knowledge about the effects of antipsychotic exposure on the development of gestational diabetes mellitus (GDM). Aim of this study is to perform a systematic review and meta-analysis to assess GDM risk associated with antipsychotic exposure in pregnancy. Methods Systematic literature search was performed using PubMed, Science Direct, Scopus, and Web of Science databases up to August 22, 2018. No restrictions to language or date were applied. Randomized, controlled trials, case-control, or cohort studies reporting GDM risk in antipsychotic-exposed, healthy controls or antipsychotic-ceased patients were included in the meta-analysis. The primary outcomes were study defined GDM, including number of events, odds ratios, and/or risk ratios (RR) with confidence intervals (CI). Results Ten studies were included in the meta-analysis. The total number of subjects was 6213 for the antipsychotic-exposed group, 6836 for antipsychotic-ceased control group, and 1 677 087 for the healthy control group. Compared with the healthy controls, the unadjusted cumulative RR for GDM associated with antipsychotic use was 1.63 (95% CI = 1.20-2.22). Adjusted risk for GDM was significantly higher in antipsychotic exposure group than in healthy controls (RR = 1.30, 95% CI = 1.023-1.660). The adjusted RR for GDM was similar between the antipsychotic-exposed group and the antipsychotic-ceased group (RR = 0.78, 95% CI = 0.281-2.164). No significant association was found between study quality, smoking, alcohol use, gestational age, and cumulative GDM risk. Discussion Our results indicate an increased risk of GDM with antipsychotic exposure in pregnant women, who may benefit from close pregnancy monitoring, early testing for GDM, targeting modifiable risk factors, and lifestyle modifications.

Emerging research highlights the potential cognitive benefits of physical exercise (PE) programs for schizophrenia (SCZ). The few recent efficacy studies that examined augmenting cognitive training (CT) with PE suggest superior effects of the combination. The next step is to consider strategies to enhance adherence in real-world settings if this type of combined treatment is going to be effective. We present the first community effectiveness data for PE and CT that included a motivationally-enhancing, self-determined approach to exercise, in lieu of participant payment. Eighty-five outpatients with schizophrenia attending an intensive outpatient program were randomized to 18 h of either (A) self-determined PE regimen with choice from a menu of different activities; (B) tablet-based neurofeedback CT focused on processing speed (PS) and working memory (WM), or (C) a time-matched combination of PE and CT. Assessments were conducted at baseline, post, and follow-up (2 mo). All groups improved in WM from baseline to post, with greatest gains in the PE only group. At follow-up, cognitive gains originally observed in the PE-only group disappeared, while the PE + CT group evidenced improvements in WM and psychotic symptoms. Notably, attrition for PE was only 7%. Our data shows that combining PE and CT leads to lasting effects that are superior to those of either intervention alone. The low PE drop-out rate suggests a self-determined approach to the exercise regimen was tolerable, and may be an important component of future community implementation efforts. Keywords: Schizophrenia, Motivation, Physical exercise, Cognitive training

Background The Management of Schizophrenia in Clinical Practice (MOSAIC), a disease-based registry of schizophrenia, was initiated in December 2012 to address important gaps in our understanding of the impact and burden of schizophrenia and to provide insight into the current status of schizophrenia care in the US. Recruitment began in December 2012 with ongoing assessment continuing through May 2014. Methods Participants were recruited from a network of 15 centralized Patient Assessment Centers supporting proximal care sites. Broad entry criteria included patients diagnosed with schizophrenia, schizophreniform or schizoaffective disorder, presenting within the normal course of care, in usual treatment settings, aged ≥ 18 years and able to read and speak English. Results By May 2014, 550 participants (65.8% male, 59.8% White, 64.4% single, mean age 42.9 years), were enrolled. The majority had a diagnosis of schizophrenia (62.0%). Mean illness duration at entry was 15.0 years. Common comorbidities at entry were high lipid levels (26.9%), hypertension (23.1%) and type II diabetes (13%). Participants were categorized by baseline overall Clinical Global Impression—Schizophrenia Severity Score as minimally (9.1%), mildly (25.3%), moderately (39.9%), markedly (22.3%) and severely (3.4%) ill. Most commonly used second generation antipsychotics at entry were risperidone (17.8%), clozapine (16.5%), olanzapine (14.0%), aripiprazole (13.6%) and quetiapine (5.6%). Conclusions No large-scale patient registry has been conducted in the US to longitudinally follow patients with schizophrenia and describe symptom attributes, support network, care access and disease burden. These data provide important epidemiological, clinical and outcome insights into the burden of schizophrenia in the US.

Patients with schizophrenia have high rates of obesity and cardiovascular morbidity, which are strongly associated with obstructive sleep apnea (OSA). The prevalence and risk factors for OSA are not well studied in patients with schizophrenia.The purpose of this study was to evaluate the frequency of OSA symptoms in a sample of outpatients with schizophrenia.This cross-sectional study was a secondary analysis of data generated from an insomnia study that evaluated 175 outpatients with schizophrenia or schizoaffective disorder in a single, large urban community mental health center. Results of scales evaluating insomnia were used to complete the STOP questionnaire, which is a screening tool for OSA validated in surgical populations. Appropriate statistical analysis was done to compare participants across groups.Patients were classified into high risk for OSA (STOP ≥ 2) (57.7%), and low risk for OSA (STOP score2) (42.3%). We also identified patients with a known diagnosis of OSA (14.9%). Patients with diagnosed OSA had significantly higher STOP scores (mean 2.7 vs. 1.6 [t = 6.3; p0.001]). Only 23.8% of patients in the high-risk group were diagnosed with OSA. Body mass index was significantly higher in the diagnosed group (F[2,169] = 25; p0.001) as was diabetes (χ2 [2, N = 175] = 35, p0.001).A large number of outpatients with severe mental illness are at high risk for OSA. The STOP questionnaire is easy to use and appears to have a very high clinical utility to detect OSA. Based on our findings, further studies are warranted to validate the tool in patients with severe mental illness.

Aim To compare the prevalence of diabetes in patients with schizophrenia treated at a community mental health center with controls in the same metropolitan area and to examine the effect of antipsychotic exposure on diabetes prevalence in schizophrenia patients. Methods The study was a comprehensive chart review of psychiatric notes of patients with schizophrenia and schizoaffective disorder treated at a psychosis program in a community mental health center. Data collected included psychiatric diagnoses, diabetes mellitus diagnosis, medications, allergies, primary care status, height, weight, body mass index (BMI), substance use and mental status exam. Local population data was downloaded from the Centers for Disease Control Behavioral Risk Factor Surveillance System. Statistical methods used were χ2 test, Student's t test, general linear model procedure and binary logistic regression analysis. Results The study sample included 326 patients with schizophrenia and 1899 subjects in the population control group. Demographic data showed control group was on average 7.6 years older (P = 0.000), more Caucasians (78.7% vs 38.3%, P = 0.000), and lower percentage of males (40.7% vs 58.3%, P = 0.000). Patients with schizophrenia had a higher average BMI than the subjects in the population control (32.11, SD = 7.72 vs 27.62, SD = 5.93, P = 0.000). Patients with schizophrenia had a significantly higher percentage of obesity (58.5% vs 27%, P = 0.000) than the population group. The patients with schizophrenia also had a much higher rate of diabetes compared to population control (23.9% vs 12.2%, P = 0.000). After controlling for age sex, and race, having schizophrenia was still associated with increased risk for both obesity (OR = 3.25, P = 0.000) and diabetes (OR = 2.42, P = 0.000). The increased risk for diabetes remained even after controlling for obesity (OR = 1.82, P = 0.001). There was no difference in the distribution of antipsychotic dosage, second generation antipsychotic use or multiple antipsychotic use within different BMI categories or with diabetes status in the schizophrenia group. Conclusion This study demonstrates the high prevalence of obesity and diabetes in schizophrenia patients and indicates that antipsychotics may not be the only contributor to this risk.

Patients with schizophrenia experience higher rates of obesity as well as related morbidity and mortality than the general population does. Women with schizophrenia are at particular risk for antipsychotic-associated weight gain, obesity, and related medical disorders such as diabetes and cardiovascular disease. Given preclinical studies revealing the role of the endogenous opioid systems in human appetite and the potential of antipsychotic medications to interfere with this system, we hypothesized that opioid antagonists may be beneficial in arresting antipsychotic-associated weight gain and promoting further weight loss in women with schizophrenia. In the present study, 24 overweight women with a diagnosis of schizophrenia or schizoaffective disorder were randomized to placebo or naltrexone (NTX) 25 mg/d for 8 weeks. The primary outcome measure was a change in body weight from baseline. The patients in the NTX group had significant weight loss (-3.40 kg) compared with weight gain (+1.37 kg) in the patients in the placebo group. Mainly, nondiabetic subjects lost weight in the NTX arm. These data support the need to further investigate the role of D2 blockade in reducing food reward-based overeating. A larger study addressing the weaknesses of this pilot study is currently underway.

Background: Prolonged duration of untreated psychosis (DUP) is associated with poor outcomes. The TIPS study halved DUP with an early detection (ED) campaign; however, conventional statistical analyses, focused on mean estimates, failed to reveal the effects of ED across the full DUP distribution, restricting inferences about ED's effectiveness. Utilizing a novel quantile regression based analysis, we examined the differential impact of ED across DUP. Secondary analysis explored possible predictors of DUP, and moderators of the effect of the campaign.Methods: The TIPS ED campaign was conducted in two health care sectors in Norway, with two equivalent health care sectors serving as controls. Quantile regression analysis was performed to analyze ED campaign's effect.Results: 281 patients with first episode psychosis were recruited, including 141 from the ED area. ED had no effect on the first quartile (Q1) of DUP, whereas a significant reduction in Q2 (11 weeks), and Q3 (41 weeks) of DUP was observed. The effect of ED was significantly stronger on reducing Q3 than Q1 or Q2, suggesting that the campaign was more effective in longerDUP samples. Male gender and single status predicted longerDUP inQ3: by 38 and 27 weeks, respectively. Single status, but not gender, emerged as a significant moderator of ED campaign effect.Conclusions: Quantile regression provided in depth information about the non-uniformity, and moderators, of TIPS's ED effort across the full distribution of DUP, demonstrating the value of this analytic approach to re-examine prior, and plan analyses for future, early detection efforts. (C) 2019 Published by Elsevier B.V.

Objective Better understanding of the temporal development of cardiovascular risk will permit more targeted prevention of premature cardiovascular mortality in schizophrenia. Methods The sample for this analysis was drawn from referrals (between 2006 and '11) to an early psychosis clinic based in a U.S. urban community mental health center. 76 individuals with schizophrenia who were young (mean 22.4 years, SD 4.8), early course (median duration of illness 31 weeks) and with minimal prior antipsychotic exposure (median 2 weeks) were compared to age-, gender-, and race-matched peers drawn from the National Health and Nutrition Survey (2007–'08). Measures of cardiovascular risk at baseline, 6 months, and 1 year are reported. Results While indistinguishable from peers at entry, patients suffered pervasive adverse trajectories of cardiovascular risk factors over the subsequent year. 16 of 44 initial non-smokers became nicotine dependent and none of 32 entering smokers quit. 17 patients transitioned to overweight (BMI 25–29.9, n = 3) or obese (BMI > 30, n = 14) categories, while only 24 of 38 (63%) sustained normal weight over one year. Similar adverse trends in blood pressure, lipids, and fasting glucose led to an increase in prevalence of metabolic syndrome (1.31% to 5.26%). 10-year cardiovascular risk estimates showed a small and significant increase although remaining in the low risk ( Conclusions The early emergence of obesity and smoking in younger schizophrenia samples provides a rational focus for primary prevention of premature cardiovascular mortality. The first year of treatment constitutes the beginning of a critical period for such preventive efforts.

Introduction A substantial number of patients with treatment-resistant schizophrenia respond only partially to clozapine. Therefore, it has been common practice to use augmentation strategies to maximize clozapine's effect. But the efficacy of this strategy remains poorly established. We have conducted a randomized double-blind placebo controlled clinical trial in patients with schizophrenia currently receiving clozapine with partial response, and tested the efficacy of pimozide augmentation on positive and negative symptoms and also on neurocognitive measures. Methods Thirty-two outpatients enrolled in the clinical trial and 28 completed. Patients with adequate blood levels of clozapine were randomized to pimozide vs placebo and participated in the trial for 12 weeks receiving monthly assessments for Brief Psychiatric Rating Scale (BPRS) and Schedule for Assessment of Negative Symptoms (SANS), and weekly assessments for electrocardiogram (EKG), and side effects. Neurocognitive tests measuring verbal fluency, working memory, motor and attention/executive function were obtained at study entry and end of the trial. Results We found no significant effect of pimozide on BPRS total, psychosis and depression subscale items, SANS scores or QTc interval. Neurocognitive measures did not show significant improvement either. Discussion In this well controlled clinical trial of patients with treatment-resistant schizophrenia currently receiving clozapine, pimozide augmentation was not an effective strategy to maximize the benefit for better control of positive and negative symptoms or improving neurocognitive function.

The aim of this study was to evaluate the clinical utility of measuring waist circumference (WC) in obese individuals with severe psychiatric disabilities. Reliability of the measure and researchers' comfort were assessed. Thirty outpatients with a diagnosis of schizophrenia or schizoaffective disorder were recruited from an urban community mental health center and WC was measured using two methods by three different raters. Inter- and intra-rater reliability was calculated. Raters reported on their comfort with obtaining WC. There was good inter-rater reliability and an acceptable rate of error independent of measurement location. Overall, raters were not comfortable with the WC measurement process for multiple reasons and reported difficulty with the measurement process. Our findings suggest that non-medical staff can reliably and validly measure WC within a typical outpatient mental health treatment setting, but discomfort with the procedure and difficulty with the measurement process may interfere with this practice as part of usual care.

Background Individuals with schizophrenia have a life expectancy that is 20 years less than the general population, along with high rates of obesity and cardiovascular disease (CVD) mortality. Objective This study assessed the 10-year general CVD risk and vascular ages of 106 obese schizophrenia spectrum patients and 197 demographically matched obese controls without severe mental illness (SMI) from the National Health and Nutrition Examination Survey (NHANES). Methods Vascular age and general CVD risk were calculated using the Framingham global CVD calculator, which incorporates age, sex, total and HDL cholesterol levels, systolic blood pressure, smoking status, and diabetes or hypertension treatment. Results Obese schizophrenia spectrum patients had a mean vascular age that was 14.1 years older than their mean actual age, whereas obese NHANES participants had only a 6.7-year difference. The probability of experiencing a CVD event within the next 10 years was 10.7% for obese patients and 8.5% for obese NHANES participants. Conclusion These findings suggest that schizophrenia spectrum patients experience increased metabolic risk independent of weight. Primary care clinicians can utilize general CVD risk and vascular age scores to communicate metabolic risk more easily and to help make treatment decisions.

Objectives In this proof-of-concept trial, we examined the feasibility and preliminary efficacy of Understanding Social Situations (USS), a new social-cognitive intervention that targets higher level social-cognitive skills using methods common to neurocognitive remediation, including drill and practice and hierarchically structured training, which may compensate for the negative effects of cognitive impairment on learning. Method Thirty-eight individuals with schizophrenia spectrum disorders completed the same baseline assessment of cognitive and social-cognitive functioning twice over a 1-month period to minimize later practice effects, then received 7-10 sessions of USS training, and then completed the same assessment again at posttreatment. Results USS training was well tolerated and received high treatment satisfaction ratings. Large improvements on the USS Skills Test, which contained items similar to but not identical to training stimuli, suggest that we were effective in teaching specific training content. Content gains generalized to improvements on some of the social-cognitive tasks, including select measures of attributional bias and theory of mind. Importantly, baseline neurocognition did not impact the amount of learning during USS (as indexed by the USS Skills Test) or the amount of improvement on social-cognitive measures. Conclusions and implications for practice USS shows promise as a treatment for higher level social-cognitive skills. Given the lack of relationship between baseline cognition and treatment effects, it may be particularly appropriate for individuals with lower range cognitive function. (PsycINFO Database Record

Obesity is a serious medical problem that disproportionately affects people with severe mental illness. Behavioral strategies aimed at lifestyle modification have proven effective for weight loss in general population but have not been studied adequately among persons with schizophrenia. We have conducted a randomized controlled pilot trial of an established weight loss program, modified for this specific population, and supplemented with a novel food replacement program, as well as practical, community based teaching of shopping and preparing healthy food. The program not only arrested weight gain, and produced meaningful weight loss, but also weight loss continued 6 months after the intervention is completed. Cognitive impairment had no bearing to the extent a participant benefited from the program. As a conclusion, well designed simple behavioral programs can produce lasting weight loss for patients with schizophrenia and comorbid obesity, improve metabolic indices, and possibly decrease significant medical risks associated with obesity.

Diabetes is common and seen in one in five patients with schizophrenia. It is more prevalent than in the general population and contributes to the increased morbidity and shortened lifespan seen in this population. However, screening and treatment for diabetes and other metabolic conditions remain poor for these patients. Multiple factors including genetic risk, neurobiologic mechanisms, psychotropic medications, and environmental factors contribute to the increased prevalence of diabetes. Primary care physicians should be aware of adverse effects of psychotropic medications that can cause or exacerbate diabetes and its complications. Management of diabetes requires physicians to tailor treatment recommendations to address special needs of this population. In addition to behavioral interventions, medications such as metformin have shown promise in attenuating weight loss and preventing hyperglycemia in those patients being treated with antipsychotic medications. Targeted diabetes prevention and treatment is critical in patients with schizophrenia and evidence-based interventions should be considered early in the course of treatment. This paper reviews the prevalence, etiology, and treatment of diabetes in schizophrenia and outlines office based interventions for physicians treating this vulnerable population.

An association between deficit schizophrenia and summer birth has previously been reported. Confirmation of a separate risk factor for this group of patients is potentially important, but the number of subjects with deficit schizophrenia in previous reports has been small. This analysis used data from an epidemiological study of incident cases of psychosis to test the hypothesis that deficit schizophrenia is associated with summer birth.Data were drawn from records for the first year of clinical contact for all new patients coming into treatment for psychosis in the region of Dumfries and Galloway, Scotland, from 1979 to 1998. Patients with schizophrenia were classified as having deficit (N=65) or nondeficit (N=277) schizophrenia. Time of birth in the deficit and nondeficit groups was compared, and time of birth in the deficit group was compared with that for all births in Dumfries and Galloway during the study period.The deficit schizophrenia group had an excess of summer births, compared to both the nondeficit schizophrenia group and all births in Dumfries and Galloway. The difference between the deficit and nondeficit schizophrenia groups remained significant after accounting for demographic characteristics and symptoms of disorganization and hallucinations plus delusions. A measure of negative symptoms (as opposed to deficit schizophrenia) was a weaker predictor of summer birth.This study confirmed an association between deficit schizophrenia and summer birth in the nontropical regions of the Northern Hemisphere. The existence of a risk factor for deficit but not nondeficit schizophrenia is also consistent with other evidence that the pathophysiology of deficit schizophrenia differs from that for other types of the disorder.

Background: Emerging research highlights the potential cognitive benefits of physical fitness programs for schizophrenia. Physical exercise (PE) is a safe, nonstigmatizing, and side effect-free intervention that has the potential to mitigate neurocognitive dysfunction in psychosis. To date, only two recent studies have explored the possibility of combining PE and cognitive training therapy (CT). While both studies found a signal showing that combining PE and CT may improve cognition more than CT alone, the conclusions were limited by lack of randomization, no examination of biological factors, no study arm with PE only, low power due to small sample size (N < 22), or significant attrition during the physical exercise intervention (i.e., only 75% completed the PE regimen). Methods: In our randomized pilot with 82 outpatients, we examined the individual and synergistic effects of PE and/or CT using treatments designed to improve motivation for treatment and retain patients for the entire PE (and CT) intervention. This 3-arm study employed a self-determined PE regimen intended to improve motivation for exercising and neurofeedback-aided CT that monitored a biophysiologic gauge of motivation to maximize cognitive gains. Participants were allocated to 18 hours of either: (A) PE regimen where patients chose from a menu of activities for 12 weeks with each activity designed so participants would reach volitional exhaustion—a commonly accepted physiological gauge of strenuous exercise—at least twice per week; (B) tablet-based neurofeedback CT focused on processing speed and working memory, or (C) a combination of PE and CT, matched for total duration and treatment time. Assessments of cognition and symptoms were conducted at baseline, post (3 months), and follow-up (5 montha). Results: At post, all three groups showed significant improvements in working memory, with the PE group surpassing the other two in working memory and processing speed improvements. However, at 2-month follow-up, gains in the PE only group disappeared, and it was the PE+CT group that showed significant improvements in both cognition and negative symptoms. Notably, attrition for all three groups was only 4%–7% and even those with low baseline motivation attended as many sessions as those with high motivation while both saw improvements in cognition and negative symptoms. Conclusion: This pilot is the first study to show that combining PE and CT leads to lasting effects that are superior to those of either intervention alone. Moreover, our approach to PE and CT was well tolerated, and the low dropout rate may have further maximized the benefits of both types of interventions.

Early intervention services for psychotic disorders optimally interlock strategies to deliver: (i) Early Detection (ED) to shorten the time between onset of psychotic symptoms and effective treatment (i.e. Duration of Untreated Psychosis, DUP); and (ii) comprehensive intervention during the subsequent 2 to 5 years. In the latter category, are teams (‘First-episode Services’ or FES) that integrate several empirically supported treatments and adapt their delivery to younger patients and caregivers. There is an urgent need to hasten access to established FES in the U.S. Despite improved outcomes for those in treatment, these FES routinely engage patients a year or more after psychosis onset. The Scandinavian TIPS study was able to effectively reduce DUP in a defined geographic catchment. The guiding questions for this study are: can a U.S. adaptation of the TIPS approach to ED substantially reduce DUP and improve outcomes beyond existing FES? The primary aim is to determine whether ED can reduce DUP in the US, as compared to usual detection. ED will be implemented by one FES (STEP) based in southern Connecticut, and usual detection efforts will continue at a comparable FES (PREPR) serving the greater Boston metropolitan area. The secondary aim is to determine whether DUP reduction can improve presentation, engagement and early outcomes in FES care. A quasi-experimental design will compare the impact of ED on DUP at STEP compared to PREPR over 3 successive campaign years. The campaign will deploy 3 components that seek to transform pathways to care in 8 towns surrounding STEP. Social marketing approaches will inform a public education campaign to enable rapid and effective help-seeking behavior. Professional outreach and detailing to a wide variety of care providers, including those in the healthcare, educational and judicial sectors, will facilitate rapid redirection of appropriate patients to STEP. Finally, performance improvement measures within STEP will hasten engagement upon referral. STEP-ED will test an ED campaign adapted to heterogeneous U.S. pathways to care while also improving our understanding of these pathways and their impact on early outcomes. ClinicalTrials.gov: NCT02069925 . Registered 20 February 2014.

Background Insomnia is frequent in schizophrenia and may contribute to cognitive impairment as well as overuse of weight inducing sedative antipsychotics. We investigated the effects of eszopiclone on sleep and cognition for patients with schizophrenia-related insomnia in a double-blind placebo controlled study, followed by a two-week, single-blind placebo phase. Methods Thirty-nine clinically stable outpatients with schizophrenia or schizoaffective disorder and insomnia were randomized to either 3 mg eszopiclone ( n = 20) or placebo ( n = 19). Primary outcome measure was change in Insomnia Severity Index (ISI) over 8 weeks. Secondary outcome measure was change in MATRICS Consensus Cognitive Battery (MATRICS). Sleep diaries, psychiatric symptoms, and quality of life were also monitored. Results ISI significantly improved more in eszopiclone (mean = − 10.7, 95% CI = − 13.2; − 8.2) than in placebo (mean = − 6.9, 95% CI = − 9.5; − 4.3) with a between-group difference of − 3.8 (95% CI = − 7.5; − 0.2). MATRICS score change did not differ between groups. On further analysis there was a significant improvement in the working memory test, letter–number span component of MATRICS (mean = 9.8 ± 9.2, z = − 2.00, p = 0.045) only for subjects with schizophrenia on eszopiclone. There were improvements in sleep diary items in both groups with no between-group differences. Psychiatric symptoms remained stable. Discontinuation rates were similar. Sleep remained improved during single-blind placebo phase after eszopiclone was stopped, but the working memory improvement in patients with schizophrenia was not durable. Conclusions Eszopiclone stands as a safe and effective alternative for the treatment of insomnia in patients with schizophrenia. Its effects on cognition require further study.

Background Obesity is a growing health problem leading to high rates of mortality and morbidity in patients with severe mental illness (SMI). The increased rate of obesity is largely attributed to antipsychotic use. The effect of antipsychotic medications on H1 and 5HT2 receptors has been associated with weight gain, but there is also a substantial amount of evidence showing that D2 receptor blockade may be responsible for weight gain by interacting with the dopamine-opioid system. Unfortunately, current available medications for weight loss have limited efficacy in this population. Naltrexone, an opioid receptor antagonist, may be a promising agent to reduce antipsychotic induced weight gain by decreasing food cravings. We aim to investigate the safety and efficacy of two doses of naltrexone (25 mg & 50 mg) versus placebo for weight and health risk reduction in overweight and obese individuals (BMI ≥ 28) with SMI, who gained weight while being treated with antipsychotics. Methods and design One hundred and forty four patients will be recruited throughout the greater New Haven area. The participants will be randomized to naltrexone 25 mg/day, naltrexone 50 mg/day, or placebo in a 1:1:1 ratio. Participants will be on the study medication for 52 weeks, and assessed weekly for the first 4 weeks and bi-weekly thereafter. The primary outcome measurements are weight reduction and percentage achieving clinically significant weight loss (5% of total body weight). Waist circumference, body mass index, serum lipid profile, fasting glucose, and glycosylated hemoglobin are the secondary outcome measures. The effect of naltrexone on other outcome measurements such as schizophrenia symptoms, depression, dietary consumption, quality of life, cognitive functioning, physical activity, metabolism/inflammation markers, serum leptin, ghrelin, peptide YY, adinopectin, high sensitivity CRP, interleukin 6, interleukin-1B, interleukin-18, and tumor necrosis factor alpha (TNF-α) will be evaluated. The data will be analyzed by applying linear mixed effect models. Discussion This is the first large scale study investigating the safety and efficacy of naltrexone in antipsychotic induced weight gain; and hopefully, this may lead to a novel pharmacological option for management of this major health problem. Trial registration This trial is registered in http://www.clinicaltrials.gov as NCT01866098

A possible mechanism of antipsychotic-induced weight gain is activation of hypothalamic monophosphate-dependent kinase (AMPK) mediated by histamine 1 receptors. Alpha-lipoic acid (ALA), a potent antioxidant, counteracts this effect and may be helpful in reducing weight for patients taking antipsychotics. The objective of this open-label study was to assess the efficacy of ALA (1,200 mg) on twelve non-diabetic schizophrenia patients over ten weeks. Participants lost significant weight during the intervention (-2.2 kg±2.5 kg). ALA was well tolerated and was particularly effective for individuals taking strongly antihistaminic antipsychotics (-2.9 kg±2.6 kg vs. -0.5 kg±1.0 kg). Clinical Trial Registration: NCT01355952.

Objective: Weight gain is common for individuals with serious mental illness (SMI) receiving antipsychotic drug therapy. Contingency management (CM) is a behavioral intervention that rewards positive performance and has demonstrated effectiveness in reducing drug use in SMI populations. This study evaluated the feasibility of using CM to promote weight loss in individuals with SMI over 8 weeks. Method: 30 individuals (BMI ≥ 28 kg/m2) were randomized to one of three conditions: i) The combination of a standardized lifestyle modification (LM) program for individuals with SMI and payment for group attendance (CMattendance), ii) The combination of LM and payment for weight loss (CMweight), and iii) waitlist control (CON). After the waitlist period, those participants joined a LM group and received payment for behavioral change (CMbehavior). Results: Subjects in the CMattendance and in the CMweight group lost a mean of 1.16 kg and 1.23 kg, respectively, while subjects in the CON gained a mean of 0.68 kg. Subjects receiving CMbehavior, lost a mean of 2.54 kg, which was a significant weight loss compared to the control period. Conclusion: LM supplemented with CM may facilitate weight loss in patients taking antipsychotic medications; financial reimbursement for behavioral change may be particularly effective in this population.

The prevalence of Night Eating Syndrome (NES) in the general population is estimated to be 1.5%, however, the rates among individuals with schizophrenia and schizoaffective disorder are not yet established. This study sought to examine the frequency and correlates of NES-related behaviors in a sample of obese patients with schizophrenia. One-hundred outpatients diagnosed with schizophrenia or schizoaffective disorders completed the self-report Night Eating Questionnaire (NEQ) and were then interviewed as a follow-up for the specific assessment of NES. Based on a diagnostic interview, 12% of this sample met full criteria for NES, with an additional 10% meeting partial criteria for NES. Based on the NEQ alone, 8% met full criteria with an additional 8% meeting partial criteria. Night eating behaviors were associated with increased insomnia and depression. Our findings suggest that screening for NES among patients with serious mental illness may efficiently identify a subgroup with additional clinical needs.

Obesity has been associated with significant stigma and weight-related self-bias in community and clinical studies, but these issues have not been studied among individuals with schizophrenia. A consecutive series of 70 obese individuals with schizophrenia or schizoaffective disorder underwent assessment for perceptions of weight-based stigmatization, self-directed weight bias, negative affect, medication compliance, and quality of life. The levels of weight-based stigmatization and self-bias were compared with levels reported for nonpsychiatric overweight/obese samples. Weight measures were unrelated to stigma, self-bias, affect, and quality of life. Weight-based stigmatization was lower than published levels for nonpsychiatric samples, whereas levels of weight-based self-bias did not differ. After controlling for negative affect, weight-based self-bias predicted an additional 11% of the variance in the quality of life measure. Individuals with schizophrenia and schizoaffective disorder reported weight-based self-bias to the same extent as nonpsychiatric samples despite reporting less weight stigma. Weight-based self-bias was associated with poorer quality of life after controlling for negative affect.

Background Sleep difficulties are common in schizophrenia, however these complaints are often overshadowed by more prominent clinical concerns. The point prevalence of insomnia in this population is not well documented. Poor sleep is associated with lower quality of life, impaired cognition, and weight gain. Objectives The objectives of this study are to evaluate the prevalence of insomnia in schizophrenia and to explore the relationship of sleep to cognition, quality of life, and clinical variables. Method 175 outpatients with schizophrenia or schizoaffective disorder were assessed for insomnia. Participants were evaluated for sleep difficulties, sleep patterns, body mass index, and psychiatric symptoms. Participants were also administered a brief cognitive assessment of processing speed. Results 44% of the sample currently met the criteria for clinical insomnia. An additional 4% were successfully treated with medications. Insomnia was associated with depression and was an independent predictor of lower quality of life. Insomnia was also associated with high rates of night eating and patients with severe insomnia were significantly more obese. The type of antipsychotic did not account for the difference in body mass index. No difference between group means in cognition was detected, although those with severe insomnia did perform least well. Conclusion Clinical insomnia in outpatients with schizophrenia is highly prevalent and has a negative impact on quality of life and psychiatric symptoms. This study offers additional support to the association between poor sleep and higher weight, as well as indicating a potential link to night eating in this population. Assessment for sleep difficulties should be a routine part of clinical care.

Objective Studies in first episode psychosis samples about status of cardiovascular risk factors have shown discordant results. We aimed to determine the 10-year risk of developing coronary heart disease in a sample of first episode psychosis patients referred to an early intervention clinic and compared the same with age, gender, and race matched controls from the U.S. National Health and Nutrition Examination Survey (NHANES). Method We conducted a cross-sectional analysis of baseline data of 56 subjects enrolled in first episode psychosis clinic from April 2006 to January 2010. This sample was compared with age, gender, and race matched 145 individuals drawn from NHANES 2005–2006 database. Sociodemographic and clinical variables were collected. Physical examination including laboratory evaluation was used to screen for common medical illnesses. The 10-year risk of developing coronary heart disease was calculated by using a tool developed by the National Cholesterol Education Program (NCEP-ATP III). Results There were elevated rates of smoking (46%) and hypertension (11%) albeit statistically significant differences from the control could not be demonstrated for these measures or weight, body mass index, or total or HDL cholesterol, fasting plasma glucose, status of diabetes and impaired fasting plasma glucose, HbA1C level. The 10-year median (range) risk of developing coronary heart disease in patients and controls was 1 (0–5)% and 0 (0–9)% respectively. The difference was not statistically significant. Conclusions First episode psychosis patients do not present with significantly higher cardiovascular risk than age and race-matched controls despite clinically significant prevalence of individual risk factors. This sample presents an opportunity for early intervention for the primary prevention of cardiovascular morbidity and mortality.

A pilot study was conducted to examine if donepezil could enhance cognitive function in patients with schizophrenia. Fifteen subjects who were on stable olanzapine treatment were entered into a 6-week open-labeled trial of donepezil. Subjects received baseline and end-of-study P50 and neuropsychological assessments. Donepezil treatment resulted in significant improvement in manual dexterity. There were moderate improvements in verbal recall memory and visual memory and processing speed, with smaller changes in P50 and verbal recognition memory. There was no effect on an attention measure. There were no changes in either positive or negative symptoms. These results suggest that cholinergic tone modulation may enhance selective behavioral functions in patients with schizophrenia, but further study is required to delineate the full extent of the potential benefit of this approach.

Patients with deficit schizophrenia differ from other people with schizophrenia relative to course of illness, treatment response, and neurobiological correlates. An association between deficit schizophrenia and summer birth, in contrast to the winter birth risk factor associated with schizophrenia as a whole, has also been reported. We attempted to replicate the association between summer birth and deficit schizophrenia by using data from a prevalence survey in Nithsdale in southwest Scotland, in which all patients with schizophrenia in Nithsdale were identified and 87% were interviewed directly. Deficit schizophrenia was associated with summer birth, defined as birth in June/July/August (p < .02), June/July (p < .02), or July/August (p < .03). The association with summer birth is consistent with other evidence that patients with deficit schizophrenia have a pathophysiology that differs in some ways from that of other patients with schizophrenia.

Previous studies have suggested that deficit schizophrenia is a stable subtype of schizophrenia, and that patients with the deficit schizophrenia have different course of illness from other people with schizophrenia. We tested the ability of the deficit/nondeficit categorization to predict clinical features at five years' followup in a group of chronically ill outpatients. Outpatients categorized into deficit (N = 46) and nondeficit (N = 174) schizophrenia were assessed at an average of five years after the categorization was made. Raters making the followup assessments were blind to the initial categorization. At followup, the deficit patients had poorer quality of life, poorer social and occupational function, and more severe negative symptoms. Despite these differences, deficit patients were less distressed (as measured by depressive mood, anxiety, and guilt), and they did not have more severe hallucinations, delusions, thought disorder. These differences could not be attributed to demographic differences. The group differences in quality of life and level of psychosocial function remained significant after accounting for the severity of baseline negative symptoms. These findings confirm that patients with the deficit schizophrenia have a set of relatively stable clinical features that are associated with poor outcome.

In some reports, summer birth has been associated with deficit schizophrenia. Deficit schizophrenia and nondeficit schizophrenia also differ in several other ways.To conduct a combined analysis of the published and unpublished data sets from the northern hemisphere that relate deficit and nondeficit schizophrenia to month of birth.Studies of season of birth in which it was possible to make a deficit/nondeficit categorization.Published studies with samples of convenience and all known population-based studies with the deficit/nondeficit categorization were included. The studies came from 6 countries.Three published studies of samples of convenience, 2 population-based prevalence studies, and 5 population-based studies that approximated incident samples were included. Month of birth was compared for deficit and nondeficit schizophrenia, using meta-analytic fixed-effects models.A group x month goodness-of-fit chi2 showed a significant difference between deficit and nondeficit subjects in season of birth (P.001) in the studies that approximated incidence. This difference was largely due to an increase in deficit schizophrenia births in June and July (odds ratio, 1.9; 95% confidence interval, 1.3-2.9). Similar results were found in the prevalence studies. A similar pattern was found in 2 of the 3 samples of convenience, but when combined, these 3 samples did not show a significant deficit/nondeficit difference.Deficit schizophrenia has a season of birth pattern that differs from that of nondeficit schizophrenia. This analysis supports the notion of a separate disease within schizophrenia.

Background Impairments in working memory have been proposed to underlie a broad range of cognitive deficits seen in schizophrenia. Visual working memory impairments are frequently reported in schizophrenia. Investigations of visual working memory generally assume intact visual information processing, despite evidence of visual perceptual impairments in schizophrenia. In this study, we evaluated the integrity of the perceptual system for object and spatial visual information and the relevant working memory system, after adjusting for individual perceptual performance differences. Methods Thirty patients with schizophrenia and 20 healthy control subjects underwent testing using a task of perceptual discrimination of spatial and object visual stimuli. For testing visual working memory, a delay was introduced to the perceptual discrimination task. A thresholding procedure was used so that each subject adequately perceived the information during the working memory test. Results Subjects with schizophrenia exhibited impaired performance relative to controls for object and spatial visual perceptual discrimination. The extent of impairment was greater for the object than for the spatial test. After controlling for perceptual impairments, the subjects with schizophrenia exhibited impaired performance relative to controls for the spatial working memory test but not the object working memory test. Conclusions Findings implicate dysfunction of posterior brain areas that mediate visual perceptual processing and the prefrontal areas involved in the active maintenance of information during delay intervals. However, the systems that govern object and spatial visual perception and working memory appear to be affected differentially by schizophrenia.