Inspire self report scale (ISRS): A feasibility study of a Novel self report scale for people with schizophrenia spectrum disorders.

Clinician-rated symptom scales are the current standard for outcome measures in Schizophrenia Spectrum Disorders (SSD) research. There has been growing interest in the development of self-report measures for people with SSD to support measurement-based care and inclusive research. We developed the Inspire Self Report Scale (ISRS), which measures the current magnitude of well-being, mood symptoms, psychosis, negative symptoms and cognition using 10 questions on a Likert or Visual analogue scale (VAS). The main aim of this report was to investigate the correlation and concordance between patient self-report and clinician ratings on the ISRS during a clinical encounter. When ratings were discordant, we sought to identify whether the participant's or psychiatrist's rating was more accurate. The results indicated a moderately strong statistically significant correlation between participant and clinician ratings. There was a moderate concordance between participant and clinician ratings on the ISRS. When the results were discordant, the participant ratings were assessed to be more accurate than the clinician rating over 70% of the time. The ISRS has distinct utility compared to existing scales due to the measurement of present symptom severity, capturing multiple clinical domains, and time efficiency and ease of use. Thus, it may be useful in clinical and research settings.

Reductions in synaptic marker SV2A in early-course Schizophrenia.

Excess synaptic pruning during neurodevelopment has emerged as one of the leading hypotheses on the causal mechanism for schizophrenia. It proposes that excess synaptic elimination occurs during development before the formal onset of illness. Accordingly, synaptic deficits may be observable at all stages of illnesses, including in the early phases. The availability of [11C]UCB-J, the first-in-human in vivo synaptic marker, represents an opportunity for testing this hypothesis with a relatively high level of precision. The first two published [11C]UCB-J schizophrenia studies have documented significant, widespread reductions in binding in chronic patients. The present study tested the hypothesis that reductions are present in early-course patients. 18 subjects completed [11C]UCB-J PET scans, (nine with schizophrenia, average duration of illness of 3.36 years, and nine demographically-matched healthy individuals). We compared binding levels, quantified as non-displaceable specific binding (BPND), in a set of a priori-specified brain regions of interest (ROIs). Eight ROIs (left and right hippocampus, right superior temporal and Heschl's gyrus, left and right putamen, and right caudal and rostral middle frontal gyrus) showed large reductions meeting Bonferroni corrected significant levels, p < 0.0036. Exploratory, atlas-wide analyses confirmed widespread reductions in schizophrenia. We also observed significant positive correlations between binding levels and cognitive performance and a negative correlation with the severity of delusions. These results largely replicate findings from chronic patients, indicating that extensive [11C]UCB-J binding deficits are reliable and reproducible. Moreover, these results add to the growing evidence that excess synaptic pruning is a major disease mechanism for schizophrenia.

Cognition and Exercise: GENERAL OVERVIEW AND IMPLICATIONS FOR CARDIAC REHABILITATION.

Performance of endurance exercise is associated with a broad range of cognitive benefits, with notable improvements shown across a wide variety of populations including healthy populations as well as those with impaired cognition. By examining the effects of exercise in general populations, as well in populations where cognitive deficits are pronounced, and critical to self-care, we can learn more about using exercise to ameliorate cognitive issues and apply that knowledge to other patient populations, such as those eligible for cardiac rehabilitation (CR). Cognitive challenges are a concern within CR, as management of a chronic disease is cognitively taxing, and, as expected, deficits in cognition predict worse outcomes, including lower attendance at CR. Some subsets of patients within CR may be particularly at high risk for cognitive challenges including those with heart failure with low ejection fraction, recent coronary bypass surgery, multiple chronic conditions, and patients of lower socioeconomic status. Attendance at CR is associated with cognitive gains, likely through the progressive exercise component, with larger amounts of exercise over longer periods having greater benefits. Programs should identify at-risk patients, who could gain the most from completing CR, and provide additional support to keep those patients engaged. While engaged in CR, patients should be encouraged to exercise, at least at moderate intensity, and transitioned to a long-term exercise regimen. Overall, CR programs are well-positioned to support these patients and make significant contributions to their long-term well-being.

Increased activation product of complement 4 protein in plasma of individuals with schizophrenia.

Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood-brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean = 654 ± 16 ng/mL, 557 ± 94 respectively, p = 0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.

Roles of inflammation in intrinsic pathophysiology and antipsychotic drug-induced metabolic disturbances of schizophrenia.

Schizophrenia is a debilitating psychiatric illness that remains poorly understood. While the bulk of symptomatology has classically been associated with disrupted brain functioning, accumulating evidence demonstrates that schizophrenia is characterized by systemic inflammation and disturbances in metabolism. Indeed, metabolic disease is a major determinant of the high mortality rate associated with schizophrenia. Antipsychotic drugs (APDs) have revolutionized management of psychosis, making it possible to rapidly control psychotic symptoms. This has ultimately reduced relapse rates of psychotic episodes and improved overall quality of life for people with schizophrenia. However, long-term APD use has also been associated with significant metabolic disturbances including weight gain, dysglycemia, and worsening of the underlying cardiometabolic disease intrinsic to schizophrenia. While the mechanisms for these intrinsic and medication-induced metabolic effects remain unclear, inflammation appears to play a key role. Here, we review the evidence for roles of inflammatory mechanisms in the disease features of schizophrenia and how these mechanisms interact with APD treatment. We also discuss the effects of common inflammatory mediators on metabolic disease. Then, we review the evidence of intrinsic and APD-mediated effects on systemic inflammation in schizophrenia. Finally, we speculate about possible treatment strategies. Developing an improved understanding of inflammatory processes in schizophrenia may therefore introduce new, more effective options for treating not only schizophrenia but also primary metabolic disorders.

Suicide Reduction in Schizophrenia via Exercise (SUnRISE): study protocol for a multi-site, single-blind, randomized clinical trial of aerobic exercise for suicide risk reduction in individuals with schizophrenia.

BACKGROUND: Suicide risk among individuals with schizophrenia (SZ) is intractably high, with over 40% of individuals attempting to take their own lives during their lifetime and an estimated 5-10% completing suicide. At present, available pharmacological and psychotherapeutic treatments offer limited risk reduction benefits, and thus, there remains an urgent need to explore novel interventions that will ameliorate this risk. Aerobic exercise (AE) has been shown to improve a number of predictors of suicide risk (e.g., depressed mood, sleeping difficulties). As individuals with SZ display a highly sedentary lifestyle, AE may reduce suicide risk. METHODS: Employing a multi-site, single-blind, randomized clinical trial design, we will examine the impact of AE on risk for suicide and related variables in individuals with SZ. Participants will be randomized to one of two 12-week exercise interventions: AE or a stretching and toning (ST) control intervention. Primary outcome measures will include suicide risk (Columbia Suicide Severity Rating Scale, C-SSRS) and aerobic fitness (VO2max), along with additional measures of suicide risk, mood, emotion regulation, sleep, cognition, and physical activity, with assessments completed at baseline and after 6 and 12 weeks of interventions. DISCUSSION: It is hypothesized that AE will reduce suicide risk among individuals with SZ. This study may offer support for a more efficacious treatment method for this population in addition to the pre-existing pharmacological and psychotherapeutic treatment regimens. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03270098 . Registered on September 1, 2017.

Improving Cognition via Exercise (ICE): Study Protocol for a Multi-Site, Parallel-Group, Single-Blind, Randomized Clinical Trial Examining the Efficacy of Aerobic Exercise to Improve Neurocognition, Daily Functioning, and Biomarkers of Cognitive Change in Individuals with Schizophrenia.

Individuals with schizophrenia (SZ) display cognitive deficits that have been identified as major determinants of poor functioning and disability, representing a serious public health concern and an important target for interventions. At present, available treatments offer only minimal to moderate benefits to ameliorate cognitive deficits. Thus, there remains an urgent need to identify novel interventions to improve cognition in people with SZ. Emerging evidence from animal and basic human research suggests aerobic exercise training (AE) has beneficial effects on cognition. Preliminary findings suggest that AE is efficacious in improving cognitive functioning in SZ, however the extant studies have been limited by small samples, a dearth of information on biologically-relevant covariates, and limited information on impact on daily functioning. Additionally, while AE-related cognitive benefits have been linked to Brain-Derived Neurotrophic Factor (BDNF) upregulation, this putative mechanism needs confirmation. The present report describes a study protocol designed to address these limitations-we review and summarize the current literature on treatment of cognitive deficits in SZ, state the rationale for employing AE to target these deficits, and describe the current protocol-a multi-site, single-blind, randomized clinical trial aiming to recruit 200 community-dwelling individuals with SZ. Participants are randomized to one of two 12-week interventions: AE using active-play video games (i.e., Xbox Kinect) and traditional cardiovascular exercise equipment or a stretching-and-toning (ST) control intervention. Participants undergo assessments of aerobic fitness, cognition, and daily functioning, as well as BDNF and other biomarkers of cognitive change, at baseline and after 6-and 12-weeks.

Impact of age of onset of psychosis and engagement in higher education on duration of untreated psychosis.

BACKGROUND: The average age of onset of psychosis coincides with the age of college enrollment. Little is known about the impact of educational engagement on DUP in a college-aged population. AIMS: To determine DUP, and the impact of educational engagement, for college-aged participants of the RAISE study (n = 404). METHOD: We conducted secondary data analyses on the publicly available RAISE dataset. Subsamples were analyzed to determine the impact of age and educational engagement on DUP. RESULTS: DUP was significantly shorter (p < 0.02) for participants who were college-aged (18-22 years, n = 44) and engaged in post-secondary education (median = 12 weeks, mean = 29 weeks) compared with participants who were college-aged and not engaged in higher education (n = 92, median = 29 weeks, mean = 44 weeks). CONCLUSIONS: Educational engagement appears to be associated with a shorter DUP. This may be partially explained by the presence of on-site wellness centers in college settings. However, even among young people who engaged in post-secondary education DUP was still at, or beyond, the upper limit of WHO recommendations in this group. Future research exploring how colleges could improve their capacity to detect and refer at risk students for treatment at an earlier stage is recommended.

Clozapine Titration for People in Early Psychosis: A Chart Review and Treatment Guideline.

PURPOSE/BACKGROUND: The use of clozapine, particularly in young people, is often limited by early treatment-emergent adverse effects including drowsiness and lethargy. Concerns about adverse effects, medication adherence, and the need for blood monitoring often impede the use of clozapine in this population, leading to repeated trials of less effective medications. Current clozapine dosing recommendations are based on people further in the course of their illness and thus reflect different responsiveness and sensitivities to antipsychotic medication. As such, there is a need for evidence-based guidelines for titration and dosing of clozapine among people in early psychosis. METHODS/PROCEDURES: We performed a chart review of 14 people treated with clozapine within our early psychosis team. Data regarding dose titration, response, time to discontinuation, symptom severity, weight gain, and other adverse effects were gathered at clozapine initiation, 3 months, and last available visit on clozapine. FINDINGS/RESULTS: People treated with slow titration within their first year of psychosis onset achieved sustained response at very low maintenance doses (mean dose = 81 mg/d, mean duration of treatment = 200 weeks) compared with slow titration with longer duration of illness (mean dose = 350 mg/d, mean duration of treatment = 68 weeks) or standard dose titration in early psychosis (mean dose = 112 mg/d, mean duration of treatment = 38 weeks). The most common adverse effects in all groups were weight gain and sedation, with the groups requiring higher mean doses reporting a broader range of adverse effects. There was no apparent difference in the clinical global impression for severity or improvement between the slow titration and standard titration groups in people with early psychosis. These observations are synthesized into a proposed treatment guideline for use of clozapine among people in early psychosis. IMPLICATIONS/CONCLUSIONS: We describe development of a slow titration approach to initiating clozapine among people in early psychosis. This approach resulted in clinical response at remarkably low maintenance doses of clozapine among people within their first year of illness, but not in those with longer duration of symptoms. Slow titration also led to good tolerability and acceptance of clozapine treatment for some patients.

Pathophysiology of drug induced weight and metabolic effects: findings from an RCT in healthy volunteers treated with olanzapine, iloperidone, or placebo.

Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions. We hypothesized that antipsychotics induce weight gain primarily through increased caloric intake, which causes secondary dyslipidemia and insulin resistance. Subjects were phenotyped pre- and post-treatment for body weight, adiposity by dual energy X-ray absorptiometry, energy expenditure by indirect calorimetry, food intake, oral glucose tolerance, plasma lipids, glucose, insulin, and other hormones. We found significantly increased food intake and body weight but no change in energy expenditure in olanzapine-treated subjects, with associated trends towards lipid abnormalities and insulin resistance the extent of which were presumably limited by the duration of treatment. Iloperidone treatment led to modest non-significant and placebo no weightgain, lipid increases and alterations in insulin metabolism. We conclude that second generation antipsychotic drugs, as represented by olanzapine, produce their weight and metabolic effects, predominantly, by increasing food intake which leads to weight gain that in turn induces metabolic consequences, but also through other direct effects on lipid and glucose metabolism independant of food intake and weight gain.

Genetic Correlation Profile of Schizophrenia Mirrors Epidemiological Results and Suggests Link Between Polygenic and Rare Variant (22q11.2) Cases of Schizophrenia.

New methods in genetics research, such as linkage disequilibrium score regression (LDSR), quantify overlap in the common genetic variants that influence diverse phenotypes. It is becoming clear that genetic effects often cut across traditional diagnostic boundaries. Here, we introduce genetic correlation analysis (using LDSR) to a nongeneticist audience and report transdisciplinary discoveries about schizophrenia. This analytical study design used publically available genome wide association study (GWAS) data from approximately 1.5 million individuals. Genetic correlations between schizophrenia and 172 medical, psychiatric, personality, and metabolomic phenotypes were calculated using LDSR, as implemented in LDHub in order to identify known and new genetic correlations. Consistent with previous research, the strongest genetic correlation was with bipolar disorder. Positive genetic correlations were also found between schizophrenia and all other psychiatric phenotypes tested, the personality traits of neuroticism and openness to experience, and cigarette smoking. Novel results were found with medical phenotypes: schizophrenia was negatively genetically correlated with serum citrate, positively correlated with inflammatory bowel disease, and negatively correlated with BMI, hip, and waist circumference. The serum citrate finding provides a potential link between rare cases of schizophrenia (strongly influenced by 22q11.2 deletions) and more typical cases of schizophrenia (with polygenic influences). Overall, these genetic correlation findings match epidemiological findings, suggesting that common variant genetic effects are part of the scaffolding underlying phenotypic comorbidity. The "genetic correlation profile" is a succinct report of shared genetic effects, is easily updated with new information (eg, from future GWAS), and should become part of basic disease knowledge about schizophrenia.

The Impact of Hypomania on Aerobic Capacity and Cardiopulmonary Functioning-A Case Report.

Background: Hypomanic episodes are characterized by increased goal-directed behavior and psychomotor agitation. While the affective, cognitive, and behavioral manifestations of such episodes are well-documented, their physiological influence on aerobic capacity and cardiopulmonary functioning are unknown. Methods: We describe a case report of an individual with schizophrenia who experienced a hypomanic episode while serving as a control participant (wait list) in a single-blind, randomized clinical trial examining the impact of aerobic exercise (AE) on neurocognition in people schizophrenia. As part of the trial, participants completed two scheduled clinical assessments and cardiopulmonary exercise tests (VO2max) at baseline and 12 weeks later at end of study. All participants received standard psychiatric care during the trial. Following a baseline assessment in which he displayed no evidence of mood lability, the subject returned on Week-12 for his scheduled follow-up assessment displaying symptoms of hypomania. He was able to complete the follow-up assessment, as well as third assessment 2 weeks later (Week-14) when his hypomanic symptoms ebbed. Results: While not engaging in AE, the subject's aerobic capacity, as indexed by VO2max, increased by 33% from baseline to Week-12. In comparison, participants engaged in the aerobic exercise training increased their aerobic capacity on average by 18%. In contrast, participants in the control group displayed a small decline (-0.5%) in their VO2max scores. Moreover, the subject's aerobic capacity increased even further by Week-14 (49% increase from baseline), despite the ebbing of his hypomania symptoms at that time. These changes were accompanied by increases in markers of aerobic fitness including peak heart rate, respiratory exchange rate, peak minute ventilation, watts, and peak systolic blood pressure. Resting systolic and diastolic blood pressure, and peak diastolic blood pressure remained unchanged. Conclusions: Our findings suggest that hypomania produce substantial increase in aerobic capacity and that such elevations may remain sustained following the ebbing of hypomanic symptoms. Such elevations may be attributed to increased mobility and goal-directed behavior associated with hypomania, as individuals in hypomanic states may ambulate more frequently, for longer duration, and/or at higher intensity. Our results provide a first and unique view into the impact of hypomania on aerobic capacity and cardiopulmonary functioning.

Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia.

For decades, there have been observations demonstrating significant metabolic disturbances in people with schizophrenia including clinically relevant weight gain, hypertension, and disturbances in glucose and lipid homeostasis. Many of these findings pre-date the use of antipsychotic drugs (APDs) which on their own are also strongly associated with metabolic side effects. The combination of APD-induced metabolic changes and common adverse environmental factors associated with schizophrenia have made it difficult to determine the specific contributions of each to the overall metabolic picture. Data from drug-naïve patients, both from the pre-APD era and more recently, suggest that there may be an intrinsic metabolic risk associated with schizophrenia. Nevertheless, these findings remain controversial due to significant clinical variability in both psychiatric and metabolic symptoms throughout patients' disease courses. Here, we provide an extensive review of classic and more recent literature describing the metabolic phenotype associated with schizophrenia. We also suggest potential mechanistic links between signaling pathways associated with schizophrenia and metabolic dysfunction. We propose that, beyond its symptomatology in the central nervous system, schizophrenia is also characterized by pathophysiology in other organ systems directly related to metabolic control.

Should Antipsychotic Medications for Schizophrenia Be Given for a Lifetime?: A Naturalistic, Long-Term Follow-Up Study.

BACKGROUND: Schizophrenia remains a major health problem despite antipsychotic medications that, for most patients, can decrease acute symptoms, decrease relapses, and contribute to partial and sometimes strong positive response in patients with chronic symptoms. What has not been clear-because a double-blind, randomized, placebo-controlled trial is not feasible or ethical-is how many years after the initial episode, or onset of antipsychotic treatment, should medication be continued to achieve the best global outcome. We designed a small, clinical study to retrospectively perform a detailed follow-up to examine antipsychotic medication because it relates to both global outcome and life satisfaction. METHODS: This is a naturalistic study of 35 patients with chronic schizophrenia examining antipsychotic medication adherence from 8 to 50 years (average, 21 y) after onset of antipsychotic treatment. The sample was derived from all patients treated for many years in 1 physician's academic clinic. Most were treated by community physicians before referral to the academic clinic. Information was gathered on (1) medication adherence, (2) long-term global outcomes (based on both the patient ratings and a blind clinician's assessment [blind to medication data] on both the Global Outcome Scale and the Global Assessment of Functioning Scale), and (3) a patient-rated Satisfaction With Life Scale. Spearman rank order correlations were used to relate medication adherence to global outcomes and life satisfaction, as were linear regression models adjusted for demographic and clinical characteristics. RESULTS: A total of 35 patients (mean age, 45 y; mean years of possible medication since onset of treatment, 21 y) were assessed. Medication adherence was a statistically significant predictor of better long-term global outcomes and life satisfaction, both in Spearman rank order correlations and in covariate-adjusted linear regressions (all P values <0.01). Poor medication adherence was associated with poor outcomes, often disastrous, with low life satisfaction. Other variables such as presence of substance use disorders or family support did not explain the difference between those who adhered and those who did not. CONCLUSIONS: In this naturalistic study, patients who adhered to antipsychotic medication had better long-term global outcomes than those who had poor adherence. Study limitations include the potential for residual confounding. This sample provides data consistent with the recommendation, in the absence of clinically important unwanted drug effects like tardive dyskinesia or large weight gain, for continuous, long-term antipsychotic treatment for chronic schizophrenia.