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Background: Several etiologies can underlie the development of late-onset psychosis, defined by first psychotic episode after age 40 years. Late-onset psychosis is distressing to patients and caregivers, often difficult to diagnose and treat effectively, and associated with increased morbidity and mortality. Methods: The literature was reviewed with searches in Pubmed, MEDLINE, and the Cochrane library. Search terms included “psychosis,” “delusions,” hallucinations,” “late onset,” “secondary psychoses,” “schizophrenia,” bipolar disorder,” “psychotic depression,” “delirium,” “dementia,” “Alzheimer’s,” “Lewy body,” “Parkinson’s, “vascular dementia,” and “frontotemporal dementia.” This overview covers the epidemiology, clinical features, neurobiology, and therapeutics of late-onset psychoses. Results: Late-onset schizophrenia, delusional disorder, and psychotic depression have unique clinical characteristics. The presentation of late-onset psychosis requires investigation for underlying etiologies of “secondary” psychosis, which include neurodegenerative, metabolic, infectious, inflammatory, nutritional, endocrine, and medication toxicity. In delirium, psychosis is common but controlled evidence is lacking to support psychotropic medication use. Delusions and hallucinations are common in Alzheimer’s disease, and hallucinations are common in Parkinson’s disease and Lewy body dementia. Psychosis in dementia is associated with increased agitation and a poor prognosis. Although commonly used, no medications are currently approved for treating psychosis in dementia patients in the USA and nonpharmacological interventions need consideration. Conclusion: The plethora of possible causes of late-onset psychosis requires accurate diagnosis, estimation of prognosis, and cautious clinical management because older adults have greater susceptibility to the adverse effects of psychotropic medications, particularly antipsychotics. Research is warranted on developing and testing efficacious and safe treatments for late-onset psychotic disorders.

Variation in prescription of psychotropic medications to patients with schizophrenia spectrum disorders may underlie health inequities. Using a national U.S. Medicaid sample, the authors examined prescription patterns of psychotropic medications commonly used for managing schizophrenia.Data from the 2011-2012 Medicaid Analytic eXtract were examined for demographic predictors of and variation across states in psychotropic medication prescription among adult patients diagnosed as having schizophrenia spectrum disorders (N=357,914). Percentages of patients in each state who filled prescriptions of at least 15 days of any antipsychotic, clozapine, antidepressant, benzodiazepine, mood stabilizer, or long-acting injectable (LAI) antipsychotic medication were determined after adjustment for demographic and clinical covariates. Multivariate regressions of clinical and demographic factors predicting prescription patterns were conducted.Prescribing patterns for all types of psychotropic medications varied across states. Clozapine and LAI prescriptions showed the most dramatic differences across states and among patients with different demographic characteristics. Across states, adjusted proportions of prescriptions ranged from 4% to 22% for LAIs and from 1% to 11% for clozapine. Non-Hispanic Blacks and people of other race-ethnicities were more likely than non-Hispanic Whites to fill prescriptions for LAIs, and non-Hispanic Whites were more likely than individuals from other racial-ethnic groups to fill prescriptions for clozapine and all other medications.Considerable variation in prescribing patterns of LAIs and clozapine by race-ethnicity and across states suggests uneven quality of care for individuals with schizophrenia spectrum disorders in the United States. A better understanding of what causes this variation could inform policy makers to improve treatment for this vulnerable population.

Background COVID-19 has profoundly affected the work of mental health professionals with many transitioning to telehealth to comply with public health measures. This large international study examined the impact of the pandemic on mental health clinicians’ telehealth use. Methods This survey study was conducted with mental health professionals, primarily psychiatrists and psychologists, registered with WHO's Global Clinical Practice Network (GCPN). 1206 clinicians from 100 countries completed the telehealth section of the online survey in one of six languages between June 4 and July 7, 2020. Participants were asked about their use, training (i.e., aspects of telehealth addressed), perceptions, and concerns. Outcomes Since the pandemic onset, 1092 (90.5%) clinicians reported to have started or increased their telehealth services. Telephone and videoconferencing were the most common modalities. 592 (49.1%) participants indicated that they had not received any training. Clinicians with no training or training that only addressed a single aspect of telehealth practice were more likely to perceive their services as somewhat ineffective than those with training that addressed two or more aspects. Most clinicians indicated positive perceptions of effectiveness and patient satisfaction. Quality of care compared to in-person services and technical issues were the most common concerns. Findings varied by WHO region, country income level, and profession. Interpretation Findings suggest a global practice change with providers perceiving telehealth as a viable option for mental health care. Increasing local training opportunities and efforts to address clinical and technological concerns is important for meeting ongoing demands.

BACKGROUND Mobile health (mHealth) technologies have been used extensively in psychosis research. In contrast, their integration into clinical care has been sparse, despite substantial increase in the availability of smartphone-based apps targeting mental health care. One potential reason is that few of these apps have been developed with input from stakeholders (e.g., clinicians), the primary users of data from such applications, making their integration into routine clinical care challenging. OBJECTIVE This qualitative study sought clinicians’ input to inform the adaptation of FREEDoM, an app-based mHealth intervention designed to enhance treatment of patients with first-episode psychosis (FEP). METHODS The FREEDoM app was developed to enhance the quality, quantity, and timeliness of clinical and functional data available to clinicians and patients in order to enhance their therapeutic relationship and increase shared decision-making. Following the app’s initial development, semi-structured qualitative interviews were conducted with 11 FEP treatment providers at three sites to elicit input on the app. We then conducted summary template and matrix analysis to systematically categorize suggested adaptations using dimension of the Framework for Reporting Adaptations and Modifications to Evidence-based interventions (FRAME) and documented the rationale for adopting/rejecting suggestions. RESULTS The clinicians provided 31 suggestions (18 adopted, 13 rejected). Suggestions to add/refine content were most common (e.g., adding questions within the app). Adaptations to context were most often related to plans for implementing the intervention, how reported data were displayed to clinicians, and with whom reports were shared. Reasons for suggestions primarily included factors related to clients’ health narratives/priorities (e.g., symptom’s functional impact vs. their frequency/severity), providers’ clinical judgment (e.g., need for clinically relevant information), and organizations’ mission/culture. Reasons for rejecting suggestions included need for resources beyond intervention scope, concerns regarding dilution of the intervention core components, and increasing patient burden. CONCLUSIONS This study describes the development of the FREEDoM app, an innovative stakeholder-informed intervention designed to enhance treatment for individuals with FEP. Our study illustrates a pragmatic application of the FRAME and provides methods and tools for rapid analysis to track adaptations and related decision-making processes, potentially contributing to its acceptance and use in clinical care. CLINICALTRIAL Trial registration: ClinicalTrials.gov #NCT04248517, registered Jan. 30, 2020 https://clinicaltrials.gov/ct2/show/NCT04248517?term=using+mhealth&draw=2&rank=4

Adults with schizophrenia have increased risk of suicide with highest risk among younger adults. We investigated whether means of suicide among these adults were different from the general population.This retrospective longitudinal analysis used the National Death Index to characterize means of suicide among 4 cohorts of Medicare patients with schizophrenia (2007-2016) by age: 18 to 34, 35 to 44, 45 to 54, and aged 55+ years. Means of suicide were categorized by age at death and sex. Adjusted hazard ratios were calculated for common means. Mortality rates per 100,000 person-years were estimated by age group stratified by sex, and standardized to the general population by age, sex, and race-ethnicity using standardized mortality ratios.668,836 adults were included with 2218 suicide decedents: 1444 men and 774 women. The most common means of suicide was poisoning (36.8 %), with a significant sex difference by means: 55.9 % of women died by poisoning, 13.8 % by firearms, 11.0 % by hanging and 9.4 % by jumping, while among men suicide by poisoning (26.6 %), firearms (25.5 %), and hanging (24.2 %) were similar, followed by jumping (12.0 %). Suicide by poisoning among the schizophrenia cohort was 10 times that of the general population, while suicide by firearm was twice that of the general population.Means of suicide differed for patients with schizophrenia compared to the general population: poisoning was the most common means among men and women with schizophrenia, while firearms accounted for over half of all suicides in the general U.S.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

This pilot study examined violence risk assessment among a sample of young adults receiving treatment for early psychosis. In this study, thirty participants were assessed for violence risk at baseline. Participants completed follow-up assessments at 3, 6, 9 and 12 months to ascertain prevalence of violent behavior. Individuals were on average 24.1 years old (SD = 3.3 years) and predominantly male (n = 24, 80%). In this sample, six people (20%) reported engaging in violence during the study period. Individuals who engaged in violence had higher levels of negative urgency (t(28) = 2.21, p = 0.035) This study sought to establish the feasibility, acceptability, and clinical utility of violence risk assessment for clients in treatment for early psychosis. Overall, this study found that most individuals with early psychosis in this study (who are in treatment) were not at risk of violence. Findings suggest that violent behavior among young adults with early psychosis is associated with increased negative urgency. Supplementary Information The online version contains supplementary material available at 10.1007/s10597-021-00922-6.

Objective Cognitive impairment in schizophrenia is a core feature of the disorder. Computerized cognitive training has shown promise in pilot studies. A 26-week randomized blinded placebo-controlled trial was conducted to investigate the effect of a novel computerized cognitive training program on cognitive and functional capacity outcomes. Method The study followed MATRICS guidelines for the evaluation of interventions designed to improve cognitive function in schizophrenia. Participants (N = 150) were randomized to experimental (computerized cognitive training in a game-like format) or active control (computer games) groups. Training was conducted in-clinic, with an intended training schedule of 5 days per week, 1 h per day, for 26 weeks. Co-primary outcome measures were the MATRICS Consensus Cognitive Battery (MCCB) composite score and the UCSD Performance-Based Skills Assessment (UPSA-2) total score, secondary outcome measures included the Cognitive Assessment Interview (CAI) and the Short-Form-12 Mental Composite Score (SF-12 MCS). Target engagement was assessed with task-learning based assessment. Results At baseline, the groups were well matched. No significant effect of the experimental treatment was seen on the primary or secondary outcome measures compared to the active control. Review of the task learning/target engagement data suggested inadequate target engagement. Conclusions Results do not support a cognitive or functional capacity benefit from this implementation of a computerized cognitive training program in people with schizophrenia. In future trials, careful consideration is merited of the assessment of task learning/target engagement, the effects of making the cognitive training game-like on motivation, and the implicit effects of trial requirements on participant selection.

Importance Although adults with schizophrenia have an increased risk of suicide, sample size limitations of previous research have hindered characterizations of suicide risk across the life span. Objective To describe suicide mortality rates and correlates among adults with schizophrenia across the life span and standardized mortality ratios (SMRs) for suicide compared with the general US population. Design, Setting, and Participants Five national retrospective longitudinal cohorts of patients with schizophrenia in the Medicare program from January 1, 2007, to December 31, 2016, were identified by age: 18 to 34, 35 to 44, 45 to 54, 55 to 64, and 65 years or older. Death record information was obtained from the National Death Index. The total cohort included 668 836 Medicare patients with schizophrenia, 2 997 308 years of follow-up, and 2218 suicide deaths. Data were analyzed from September 30, 2020, to March 10, 2021. Main Outcomes and Measures For each age group, suicide mortality rates per 100 000 person-years and adjusted hazard ratios (aHRs) with 95% CIs of suicide were determined. Suicide SMRs were estimated for the total cohort and by sex and age cohorts standardized to the general US population by age, sex, and race/ethnicity. Results The study population of adults 18 years and older included 668 836 Medicare recipients with schizophrenia (52.5% men, 47.5% women). The total suicide rate per 100 000 person-years was 74.00, which is 4.5 times higher than that for the general US population (SMR, 4.54; 95% CI, 4.35-4.73) and included a rate of 88.96 for men and 56.33 for women, which are 3.4 (SMR, 3.39; 95% CI, 3.22-3.57) and 8.2 (SMR, 8.16; 95% CI, 7.60-8.75) times higher, respectively, than the rates for the general US population. Suicide rates were significantly higher for men (aHR, 1.44; 95% CI, 1.29-1.61) and those with depressive (aHR, 1.32; 95% CI, 1.17-1.50), anxiety (aHR, 1.15; 95% CI, 1.02-1.30), drug use (aHR, 1.55; 95% CI, 1.36-1.76), and sleep disorders (aHR, 1.22; 95% CI, 1.07-1.39), suicidal ideation (aHR, 1.41; 95% CI, 1.22-1.63), and suicide attempts or self-injury (aHR, 2.48; 95% CI, 2.06-2.98). The adjusted hazards of suicide were lower for Hispanic patients (aHR, 0.66; 95% CI, 0.54-0.80) or Black patients (aHR, 0.29; 95% CI, 0.24-0.35) than White patients. The suicide rate declined with age, from 141.95 (SMR, 10.19; 95% CI, 9.29-11.18) for patients aged 18 to 34 years to 24.01 (SMR, 1.53; 95% CI, 1.32-1.77) for patients 65 years or older. The corresponding declines per 100 000 person-years were from 153.80 (18-34 years of age) to 34.17 (65 years or older) for men and from 115.70 (18-34 years of age) to 18.66 (65 years or older) for women. In the group aged 18 to 34 years, the adjusted hazards of suicide risk were significantly increased for patients with suicide attempt or self-injury (aHR, 2.57; 95% CI, 18.20-2.04) and with comorbid drug use disorders (aHR, 1.48; 95% CI, 1.17-1.88), but not with comorbid depressive disorders (aHR, 0.99; 95% CI, 0.38-1.26) during the year before the start of follow-up. Conclusions and Relevance In this cohort study of adult Medicare patients with schizophrenia, suicide risk was elevated, with the highest absolute and relative risk among young adults. These patterns support suicide prevention efforts with a focus on young adults with schizophrenia, especially those with suicidal symptoms and substance use.

Importance People with schizophrenia are at high risk of receiving a diagnosis of dementia. Understanding the magnitude and timing of this increased risk has important implications for practice and policy. Objective To estimate the age-specific incidence and prevalence of dementia diagnoses among older US adults with schizophrenia and in a comparison group without serious mental illness (SMI). Design, setting, and participants This retrospective cohort study used a 50% random national sample of Medicare beneficiaries 66 years or older with fee-for-service plans and Part D prescription drug coverage from January 1, 2007, to December 31, 2017. The cohort with schizophrenia included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and at least 2 outpatient claims or at least 1 inpatient claim for schizophrenia during the qualifying years. The comparison group included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and without a diagnosis of schizophrenia, bipolar disorder, or recurrent major depressive disorder during the qualifying year. Data were analyzed from January 1 to July 31, 2020. Main outcomes and measures Dementia was defined using the Centers for Medicare & Medicaid Services Chronic Conditions Warehouse diagnosis codes for Alzheimer disease and related disorders or senile dementia. Incident diagnoses were defined by at least 12 consecutive eligible months without a qualifying code before meeting dementia criteria. Results The study population of 8 011 773 adults 66 years or older (63.4% women; mean [SD] age, 74.0 [8.2] years) included 74 170 individuals with a diagnosis of schizophrenia (56.6% women) and 7 937 603 without an SMI diagnosis (63.5% women) who contributed 336 814 and 55 499 543 person-years of follow-up, respectively. At 66 years of age, the prevalence of diagnosed dementia was 27.9% (17 640 of 63 287) among individuals with schizophrenia compared with 1.3% (31 295 of 2 389 512) in the group without SMI. By 80 years of age, the prevalence of dementia diagnoses was 70.2% (2011 of 2866) in the group with schizophrenia and 11.3% (242 094 of 2 134 602) in the group without SMI. The annual incidence of dementia diagnoses per 1000 person-years at 66 years of age was 52.5 (95% CI, 50.1-54.9) among individuals with schizophrenia and 4.5 (95% CI, 4.4-4.6) among individuals without SMI and increased to 216.2 (95% CI, 179.9-252.6) and 32.3 (95% CI, 32.0-32.6), respectively, by 80 years of age. Conclusions and relevance In this cohort study, compared with older adults without SMI, those with schizophrenia had increased risk of receiving a diagnosis of dementia across a wide age range, possibly because of cognitive and functional deterioration related to schizophrenia or factors contributing to other types of dementia. High rates of dementia among adults with schizophrenia have implications for the course of illness, treatment, and service use.

BACKGROUND: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.METHODS: The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.RESULTS: Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.CONCLUSIONS: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.

BackgroundSuicide 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.MethodsEmploying 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.DiscussionIt 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 registrationClinicaltrials.gov,NCT03270098. Registered on September 1, 2017.

Aim Although the absolute risk of violence is small for individuals with mental illnesses, a specific subgroup of individuals who appear to be at increased risk for violence includes young people experiencing emerging or early psychosis. Prior research has identified risk factors for violence in this population, though no prior studies using a formal risk assessment tool have been identified. This study used the Historical Clinical Risk Management-20, version 3 (HCR-20) to identify risk of future violence among a sample of young adults with early psychosis and relevant predictors of risk unique to this population. Methods The HCR-20 was administered to a sample of young adults with early psychosis (N = 53) enrolled at one OnTrackNY site, part of a statewide program providing early intervention services to young adults presenting with a first episode of non-affective psychosis. A Confirmatory Factor Analysis (CFA) was conducted to explore the relative importance of the HCR-20 items for this population. Results The average age of participants was 21.9 years (SD 3.6 years) and most were male (69.8%, n = 37). Most patients were assessed to be at low risk for future violence based on the Case Prioritization summary risk rating (67.9%, n = 36). The CFA identified 4 items that were not of relative predictive value in identifying the risk of violence in this sample: history of substance use (item H5), history of major mental disorder (item H6), living situation (item R2), and personal support (item R3). Conclusion This study presents a formal approach to assessing violence risk in a population at elevated risk of violence, demonstrates the feasibility of using a standardized risk assessment tool in early intervention services, and identifies factors of particular importance associated with predicting violence in this population. Future research should implement violence risk assessment with a structured tool such as the HCR-20 and assess its accuracy in predicting future violent behavior in this setting.

Objective To determine if a single baseline adherence assessment (Brief Adherence Rating Scale [BARS]) could identify patients who are likely to respond to long-acting injectable (LAI) antipsychotic treatment. Method The current secondary analysis included a sub-sample of adult outpatients (N = 176) with schizophrenia or schizoaffective disorder who participated in the “A Comparison of Long-Acting Injectable Medications for Schizophrenia (ACLAIMS)” trial and had a baseline BARS assessment and a baseline and month 3 Positive and Negative Syndrome Scale (PANSS) rating. The main outcome was LAI treatment response, defined as a ≥ 20% decrease (baseline to month 3) on the PANSS total score. Receiver Operating Characteristic (ROC) and Area Under the Curve (AUC) analysis was conducted to determine the optimal cutpoint of baseline BARS adherence in discriminating LAI treatment response at month 3. A logistic mixed model estimated the odds of response to LAI treatment at month 3 from the optimal baseline BARS cutpoint. Results The ROC analysis determined that the single baseline BARS rating (cutoff ≤66%), indicating low adherence, best discriminated patients likely to respond to LAI treatment (AUC = 0.603, SE = 0.046, 95% binomial exact CI = 0.527 to 0.676, p = 0.025), with 38% sensitivity and 85% specificity. The logistic mixed model analysis revealed that patients with ≤66% BARS adherence had 3.464 times the predicted odds (95% CI = 1.604 to 7.480, p = 0.001) of responding to LAI treatment than those who were >66% BARS adherent. Conclusion A single baseline BARS assessment discriminated response to LAI treatment suggesting it is a reasonable tool to identify candidates for LAI antipsychotic treatment.

International audience; Fewer than half of new drugs have data on their comparative benefits and harms against existing treatment options at the time of regulatory approval in Europe and the USA. Even when active-comparator trials exist, they might not produce meaningful data to inform decisions in clinical practice and health policy. The uncertainty associated with the paucity of well designed active-comparator trials has been compounded by legal and regulatory changes in Europe and the USA that have created a complex mix of expedited programmes aimed at facilitating faster access to new drugs. Comparative evidence generation is even sparser for medical devices. Some have argued that the current process for regulatory approval needs to generate more evidence that is useful for patients, clinicians, and payers in health-care systems. We propose a set of five key principles relevant to the European Medicines Agency, European medical device regulatory agencies, US Food and Drug Administration, as well as payers, that we believe will provide the necessary incentives for pharmaceutical and device companies to generate comparative data on drugs and devices and assure timely availability of evidence that is useful for decision making. First, labelling should routinely inform patients and clinicians whether comparative data exist on new products. Second, regulators should be more selective in their use of programmes that facilitate drug and device approvals on the basis of incomplete benefit and harm data. Third, regulators should encourage the conduct of randomised trials with active comparators. Fourth, regulators should use prospectively designed network meta-analyses based on existing and future randomised trials. Last, payers should use their policy levers and negotiating power to incentivise the generation of comparative evidence on new and existing drugs and devices, for example, by explicitly considering proven added benefit in pricing and payment decisions.

ImportanceRandomized controlled trials have demonstrated increased all-cause mortality in elderly patients with dementia treated with newer antipsychotics. It is unknown whether this risk generalizes to non-elderly adults using newer antipsychotics as augmentation treatment for depression.ObjectiveThis study examined all-cause mortality risk of newer antipsychotic augmentation for adult depression.DesignPopulation-based new-user/active comparator cohort study.SettingNational healthcare claims data from the US Medicaid program from 2001-2010 linked to the National Death Index.ParticipantsNon-elderly adults (25-64 years) diagnosed with depression who after ≥3 months of antidepressant monotherapy initiated either augmentation with a newer antipsychotic or with a second antidepressant. Patients with alternative indications for antipsychotic medications, such as schizophrenia, psychotic depression, or bipolar disorder, were excluded.ExposureAugmentation treatment for depression with a newer antipsychotic or with a second antidepressant.Main outcomeAll-cause mortality during study follow-up ascertained from the National Death Index.ResultsThe analytic cohort included 39,582 patients (female = 78.5%, mean age = 44.5 years) who initiated augmentation with a newer antipsychotic (n = 22,410; 40% = quetiapine, 21% = risperidone, 17% = aripiprazole, 16% = olanzapine) or with a second antidepressant (n = 17,172). The median chlorpromazine equivalent starting dose for all newer antipsychotics was 68mg/d, increasing to 100 mg/d during follow-up. Altogether, 153 patients died during 13,328 person-years of follow-up (newer antipsychotic augmentation: n = 105, follow-up = 7,601 person-years, mortality rate = 138.1/10,000 person-years; antidepressant augmentation: n = 48, follow-up = 5,727 person-years, mortality rate = 83.8/10,000 person-years). An adjusted hazard ratio of 1.45 (95% confidence interval, 1.02 to 2.06) indicated increased all-cause mortality risk for newer antipsychotic augmentation compared to antidepressant augmentation (risk difference = 37.7 (95%CI, 1.7 to 88.8) per 10,000 person-years). Results were robust across several sensitivity analyses.ConclusionAugmentation with newer antipsychotics in non-elderly patients with depression was associated with increased mortality risk compared with adding a second antidepressant. Though these findings require replication and cannot prove causality, physicians managing adults with depression should be aware of this potential for increased mortality associated with newer antipsychotic augmentation.

Accounts of killings of civilians by police in the United States (U.S.) have attracted considerable public attention. In this study, using all civilian deaths (N = 1099) in the U.S. in 2015, compiled independently by The Washington Post and The Guardian newspapers, we identified characteristics of each interaction between the police and the deceased, such as whether the decedent was armed. We expanded the database to include systemic factors possibly related to these deaths, and examined death rates by demographics, presence of mental illness, and state-level predictors. Twenty-three percent (251 of 1099) of individuals killed during interactions with police in 2015 displayed signs of a mental illness. Race (African-American [RR = 2.57] compared to non-Hispanic Whites [95% CI 2.08–3.18]) and presence of mental illness (RR = 7.16 compared to no mental illness, 95% CI 6.21–8.25) were strongly associated with such fatalities. Individuals with mental illness were more likely to be armed with a knife (OR = 3.1, 95% CI 2.1–4.6), and were more likely to have been killed at home (OR = 2.8, 95% CI 1.9–4.0). The death rates for persons with evidence of mental illness during interactions with police are high. Our finding that many persons with mental illness were killed at home and were not brandishing a firearm suggests that more effective de-escalation methods might reduce the incidence of fatal outcomes.

Objective To characterize the role of antipsychotic medications in the community treatment of adult depression. Methods We identified adults (aged 18-64 years) with new episodes of depression treatment (ICD-9-CM 296.2, 296.3, 300.4, or 311) in US national Medicaid data (2001-2010). Patients with alternative ICD-9-CM antipsychotic indications, such as schizophrenia or bipolar disorder, were excluded. Each patient was followed for at least 1 year to characterize antipsychotic and antidepressant treatment and emerging alternative antipsychotic indications. For patients without alternative indications through day 45 following start of antipsychotic treatment, antipsychotics were considered to be intended for treatment of depression. Among this group, we determined whether antipsychotic initiation was preceded by minimally adequate treatment with antidepressants, defined as active antidepressant treatment for ≥ 31 days prior to and including the day of antipsychotic initiation. Results Within 1 year following onset, 14.0% of patients started an antipsychotic medication. A total of 41.3% of antipsychotic initiators developed an antipsychotic indication other than depression through day 45 following antipsychotic initiation, most often bipolar disorder or depression with psychotic features. The remaining 58.7% of antipsychotic initiators presumably started antipsychotics for nonpsychotic depression. Of these, 71.3% did not have minimally adequate antidepressant treatment prior to starting the antipsychotic medication. Conclusion Antipsychotic medications are used in approximately 1 in 7 patients with a new episode of depression. For 1 in 12 patients, the antipsychotic was considered to be intended for nonpsychotic depression. Almost three-quarters of these patients did not receive minimally adequate treatment with antidepressants prior to antipsychotic initiation. This pattern suggests potentially inappropriate and premature initiation of a drug class with substantial adverse effects and medical risks.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination. Refereed/Peer-reviewed

IMPORTANCE: Recent meta-analyses of randomized clinical trials (RCTs) comparing clozapine with nonclozapine second-generation antipsychotics (NC-SGAs) in schizophrenia have challenged clozapine’s superiority in treatment-resistant patients. However, patients in RCTs are not necessarily generalizable to those in clinical practice. OBJECTIVE: To conduct a systematic review and meta-analysis to compare various outcomes of clozapine vs oral NC-SGAs in cohort studies. DATA SOURCES: Systematic literature search in PubMed, PsycINFO, and CINAHL without language restriction from database inception until December 17, 2018. STUDY SELECTION: Nonrandomized cohort studies reporting effectiveness and/or safety outcomes comparing clozapine with NC-SGAs in schizophrenia or schizoaffective disorder. DATA EXTRACTION AND SYNTHESIS: Independent investigators assessed studies and extracted data. Using a random-effects model, the study calculated risk ratio (RR) unadjusted for covariates and follow-up duration, number needed to treat/number needed to harm (NNT/NNH) for dichotomous data, and standardized mean difference (SMD) or mean difference (MD) for continuous data. MAIN OUTCOMES AND MEASURES: Coprimary outcomes were hospitalization and all-cause discontinuation. Secondary outcomes included all effectiveness and safety outcomes reported in at least 3 analyzable studies. RESULTS: Of 8446 hits, 68 articles from 63 individual cohort studies (n = 109 341) (60.3% male; mean [SD] age of 38.8 [6.5] years, illness duration of 11.0 [5.1] years, and study duration of 19.1 [23.3] months) were meta-analyzed. Compared with NC-SGAs, despite greater illness severity (17 studies [n = 38 766]; Hedges g, 0.222; 95% CI, 0.013-0.430; P = .04), clozapine was significantly associated with lower hospitalization risk (19 studies [n = 49 453]; RR, 0.817; 95% CI, 0.725-0.920; P = .001; NNT, 18; 95% CI, 12-40) and all-cause discontinuation (16 studies [n = 56 368]; RR, 0.732; 95% CI, 0.639-0.838; P

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.

The authors examined the use of different classes of psychotropic medication in outpatient treatment of schizophrenia and schizoaffective disorder.Data from the United States Medicaid program were used to examine psychotropic medication use in a cohort of patients who had a diagnosis of schizophrenia or schizoaffective disorder in the calendar year 2010.The cohort of Medicaid recipients who filled one or more prescriptions for a psychotropic medication in 2010 included 116,249 patients classified as having schizophrenia and 84,537 classified as having schizoaffective disorder. During 2010, 86.1% of patients with schizoaffective disorder and 70.1% with schizophrenia were treated with two or more different classes of psychotropic.Psychotropic medications other than antipsychotics were commonly prescribed for individuals with a diagnosis of schizophrenia or schizoaffective disorder. Their widespread use and uncertainty about their net benefits signal a need for research on their efficacy, safety, and appropriate use in these conditions.

OBJECTIVE: To investigate subgroup responses to long-acting injectable (LAI) haloperidol decanoate (HD) and paliperidone palmitate (PP) in a randomized controlled trial that found no difference between the treatments on the primary outcome of efficacy failure. METHOD: A Comparison of Long-Acting Injectable Medications for Schizophrenia (ACLAIMS) enrolled 311 participants from March 2011 to July 2013 meeting DSM-VI-TR criteria for diagnoses of schizophrenia or schizoaffective disorder at risk of relapse due to medication non-adherence or substance abuse. Participants were randomly assigned to double-blinded treatment with HD or PP and followed for up to 2 years. A committee blinded to treatment assignment adjudicated efficacy failure based on meeting at least one of these criteria: psychiatric hospitalization, crisis stabilization, increased outpatient visits, could not discontinue oral antipsychotic, discontinued assigned LAI due to inadequate therapeutic benefit, or prolonged need for adjunctive oral antipsychotic medication. Survival analyses examined modification of treatment effects on efficacy failure by age, gender, race, substance abuse, baseline symptom severity, and baseline adherence. Mixed effect linear models and analysis of covariance examined this modification on safety outcomes. RESULTS: An interaction between age and treatment (p=0.009) revealed younger participants assigned HD had longer time to efficacy failure than those assigned PP. Interactions were not significant between treatment group and gender, race, substance use disorder, baseline symptom severity, or baseline adherence. An interaction of treatment and age on akathisia (p=0.047) found an advantage for PP that was larger among younger persons. An advantage for HD on serum prolactin levels was larger among younger women (p=0.033). CONCLUSION: Among younger persons, HD was associated with lower rates of efficacy failure than PP. Age effects on adverse effects were mixed. Age-related heterogeneity of antipsychotic treatment effects warrants further investigation and consideration in clinical practice. CLINICAL TRIALS REGISTRATION: A Comparison of Long-acting Injectable Medications for Schizophrenia (ACLAIMS) https://clinicaltrials.gov/ct2/show/NCT01136772?term=ACLAIMS&rank=1, NCT01136772

The personal and societal costs of schizophrenia spectrum disorders are immense. Affected individuals may experience positive, negative and mood symptoms; medical and substance use comorbidities; and cognitive impairment that significantly impair social and occupational functioning. Globally, schizophrenia is a leading cause of years lost to disability, with a particularly large burden among adolescents and young adults.1 Treatment of schizophrenia spectrum disorders aims at improved functioning and recovery across the lifespan, but symptom reduction and relapse prevention are important interim goals. Although antipsychotic medications reduce psychotic symptoms and greatly decrease the risk of relapse, their effectiveness in real-world practice is decreased by non-adherence.2 A meta-analysis of studies that used trained personnel to measure antipsychotic medication adherence found that not ‘regularly taking medications as prescribed’ is prevalent in an average of 41% of participants across 10 studies.3 Despite this high prevalence, providers are often unaware of this issue and generally overestimate medication adherence in their patients.4 Long-acting injectable (LAI) formulations of antipsychotic medications were developed to improve adherence. The first LAIs, fluphenazine enanthate and decanoate, were introduced in 1966 in the context of large-scale deinstitutionalisation of patients with serious mental illnesses and the consequent need for effective community-based treatment. Numerous LAI antipsychotics have been developed and marketed in the meantime. Table 1 lists the LAI antipsychotic medications currently available in the USA and the UK.5 ,6 View this table: Table 1 Long-acting antipsychotic injectable medications available in the USA and the UK5 ,6 LAIs reduce the frequency at which a patient has to decide whether to take medication. Rather than deciding to take a medication once or twice daily, the patient must only decide to have an injection administered once or twice monthly. Pharmacokinetically, LAIs provide a more stable steady-state concentration of medication in the blood compared with daily oral …

This Open Forum describes research methods to ensure high-quality health services research using electronic health records (EHRs) as a data source. The authors describe unique characteristics of EHRs that could introduce data inaccuracies into research, and they outline a framework for methods to evaluate the validity of EHR-derived data, including the development of data extraction rules and ways to validate those rules. The authors argue that the use of such methods will help ensure the validity of research using EHRs as a data source.

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R-2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. Refereed/Peer-reviewed

J. Lönnqvist on työryhmän Psychiat Genomics Consortium jäsen. Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on similar to 150,000 individuals give a higher accuracy than LDSC estimates based on similar to 400,000 individuals (from combinedmeta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser.

Publisher's version (útgefin grein), Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is −0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health., This research is supported by the Australian National Health and Medical Research Council (1080157, 1087889, 1103418, 1127440), and the Australian Research Council (DP160102126, FT160100229). This research has been conducted using the UK Biobank Resource. UK Biobank (http://www.ukbiobank.ac.uk) Research Ethics Committee (REC) approval number is 11/NW/0382. Our reference number approved by UK Biobank is 14575.

Sequential multiple assignment randomized trials (SMARTs) are increasingly being used to inform clinical and intervention science. In a SMART, each patient is repeatedly randomized over time. Each randomization occurs at a critical decision point in the treatment course. These critical decision points often correspond to milestones in the disease process or other changes in a patient’s health status. Thus, the timing and number of randomizations may vary across patients and depend on evolving patient-specific information. This presents unique challenges when analyzing data from a SMART in the presence of missing data. This paper presents the first comprehensive discussion of missing data issues typical of SMART studies: we describe five specific challenges, and propose a flexible imputation strategy to facilitate valid statistical estimation and inference using incomplete data from a SMART. To illustrate these contributions, we consider data from the Clinical Antipsychotic Trial of Intervention and Effectiveness (CATIE), one of the most well-known SMARTs to date.

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

Antipsychotic medications are largely ineffective for approximately 30% of patients with schizophrenia that is considered "treatment resistant." Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia, but it is rarely used. This nationwide study examined predictors of clozapine use to help identify ways to optimize its use.A retrospective study using U.S. Medicaid claims data from 45 states was conducted among 326,119 individuals with a schizophrenia spectrum disorder (ICD-9-CM code 295.X) who initiated one or more antipsychotic treatment episodes between January 2002 and December 2005. Multivariable logistic regression models were used to calculate odds ratios of baseline patient and county factors associated with clozapine initiation.Among 629,809 unique antipsychotic treatment episodes, 79,934 showed service use patterns consistent with treatment resistance. Clozapine accounted for 2.5% of starts of antipsychotic medication among patients in the overall sample and for 5.5% of starts among patients with treatment resistance. Clozapine initiation was significantly associated with male sex, younger age, white race, more frequent outpatient service use for schizophrenia, and greater prior-year hospital use for mental health. Treatment resistance and living in a county with historically high rates of clozapine use were among the strongest predictors of clozapine use.The clozapine initiation rate was low compared with the expected proportion of patients who warrant a clozapine trial and was strongly affected by local treatment practices. Efforts to address irregular access to clozapine are needed to improve recovery opportunities for people with schizophrenia in the United States.

Importance People with schizophrenia are commonly treated with psychotropic medications in addition to antipsychotics, but there is little evidence about the comparative effectiveness of these adjunctive treatment strategies. Objective To study the comparative real-world effectiveness of adjunctive psychotropic treatments for patients with schizophrenia. Design, Setting, and Participants This comparative effectiveness study used US national Medicaid data from January 1, 2001, to December 31, 2010, to examine the outcomes of initiating treatment with an antidepressant, a benzodiazepine, a mood stabilizer, or another antipsychotic among adult outpatients (aged 18-64 years) diagnosed with schizophrenia who were stably treated with a single antipsychotic. Data analysis was performed from January 1, 2017, to June 30, 2018. Multinomial logistic regression models were used to estimate propensity scores to balance covariates across the 4 medication groups. Weighted Cox proportional hazards regression models were used to compare treatment outcomes during 365 days on an intention-to-treat basis. Main Outcomes and Measures Risk of hospitalization for a mental disorder (primary), emergency department (ED) visits for a mental disorder, and all-cause mortality. Results The study cohort included 81 921 adult outpatients diagnosed with schizophrenia (mean [SD] age, 40.7 [12.4] years; 37 515 women [45.8%]) who were stably treated with a single antipsychotic and then initiated use of an antidepressant (n = 31 117), a benzodiazepine (n = 11 941), a mood stabilizer (n = 12 849), or another antipsychotic (n = 26 014) (reference treatment). Compared with initiating use of another antipsychotic, initiating use of an antidepressant was associated with a lower risk (hazard ratio [HR], 0.84; 95% CI, 0.80-0.88) of psychiatric hospitalization, whereas initiating use of a benzodiazepine was associated with a higher risk (HR, 1.08; 95% CI, 1.02-1.15); the risk associated with initiating use of a mood stabilizer (HR, 0.98; 95% CI, 0.94-1.03) was not significantly different from initiating use of another antipsychotic. A similar pattern of associations was observed in psychiatric ED visits for initiating use of an antidepressant (HR, 0.92; 95% CI, 0.88-0.96), a benzodiazepine (HR, 1.12; 95% CI, 1.07-1.19), and a mood stabilizer (HR, 0.99; 95% CI, 0.94-1.04). Initiating use of a mood stabilizer was associated with an increased risk of mortality (HR, 1.31; 95% CI, 1.04-1.66). Conclusions and Relevance In the treatment of schizophrenia, initiating adjunctive treatment with an antidepressant was associated with reduced risk of psychiatric hospitalization and ED visits compared with initiating use of alternative psychotropic medications. Associations of benzodiazepines and mood stabilizers with poorer outcomes warrant clinical caution and further investigation.

Early treatment for individuals experiencing schizophrenia has received increasing attention because of its potential to alter the course of illness and improve outcomes (1). A critical component of optimal early treatment includes appropriate use of medications. Because of differential responses to medications in first-episode and multiepisode schizophrenia, prominent guidelines suggest different treatment practices for these patient groups (2, 3). For example, the 2010 Schizophrenia Patient Outcomes Research Team (PORT) underlines the importance of using low dosages of medication and specifies thatolanzapineandclozapineshouldnotbefirst-linetreatments because of their risks of adverse effects (3). Becausemedication experiences for individuals at the beginning of treatment may have a lasting impact on their attitudes toward medication and courseof illness, this is acritical timetooptimizeprescribing.To theextent thatadhering to theguidelines leads tobetterefficacy, tolerability, and positive interactions with mental health professionals, this could have a significant impact in first-episode patients. TheRecoveryAfteranInitialSchizophreniaEpisodeproject’s Early Treatment Program (RAISE-ETP) study is a nationwide comparative effectiveness trial that enrolled404 individualswith a schizophrenia spectrum diagnosis at 34 community sites throughout thecountry. Studyparticipantshadreceived less than 6monthsof antipsychotic treatmentat enrollment.Therelatively large sample and geographic breadth of the study provided the first opportunity to characterize typical community treatment of early-phase schizophrenia patients in the United States. In this issue, Robinson et al. (4) report on prescription practices observed in first-episode schizophrenia in the RAISE-ETP study. The investigators obtained detailed information regarding each participant’s prescribed medications at study entry and determined whether the medication treatment was consistent with practice guidelines. The investigators also examined participantand system-level factors associated with medication patterns that did not conform to practice guidelines and therefore could “benefit from changes.” Theinvestigators foundevidenceofpotentiallyproblematic prescribing for 159 individuals (39.4%of thesample).Themost common issues were use of an antidepressant along with an antipsychotic without a clear indication; prescription of olanzapine; and use of more than one antipsychotic. A small subgroup also had psychotropic medications prescribed without antipsychotics. While the article focuses on potential prescribing problems, it isfirstworthnoting that theprescribing formore than 60% of the sample appeared to follow existing guidelines. Given that guidelines are notmeant to dictate prescribing for an individual patient, the appropriate benchmark for conformant practice is not clear. In a study of quality of schizophrenia care, Young et al. (5) found that for 34 of 84 patients receiving poor-quality care, patient factors such as poor adherence and substanceusecontributedto theproblematicprescribing.Some nonconformant prescribing may in fact be appropriate for particular patients given their history of treatment response, their symptoms, and their preferences. It isalso important to note that prescribing that conforms to guidelines is not necessarily optimal. Guideline-conformant treatment suggests but is not synonymous with highquality care. Notwithstanding the limitations of prescribing guidelines, this studyunderlinesseveral concerns inprescribing psychotropic medications in individuals experiencing a first episode of psychosis. With respect to antipsychotic prescribing, use of combinations of antipsychotics is not supported by evidence and may be associated with more adverse effects (3, 6). This is particularly important in the careof individualswith first-episode psychosis, who are extraordinarily vulnerable to medication side effects (3). The increased complexity of dosage schedules involving polypharmacy, the increased likelihood of adverse effects, and the lack of evidence for effectiveness all argue strongly against polypharmacy in this population. If two individual antipsychotics do not provide adequate benefit, evidence strongly supports and guidelines recommend using clozapine rather than combinations of antipsychotics (2, 3). Clinicians who rarely treat first-episode patients may not be awareof the extent of problemswith olanzapine use in this population.ThePORTrecommends against usingolanzapine

This study examined the clinical significance of switching from olanzapine, quetiapine, or risperidone to aripiprazole by examining changes in predicted risk of cardiovascular disease (CVD) according to the Framingham Risk Score (FRS) and metabolic syndrome status. FRS estimates 10-year risk of "hard" coronary heart disease (CHD) outcomes (myocardial infarction and coronary death) while metabolic syndrome is associated with increased risk of CVD, stroke, and diabetes mellitus.Changes in FRS and metabolic syndrome status were compared between patients with BMI ≥ 27 and non-HDL-C ≥ 130 mg/dL randomly assigned to stay on stable current treatment (olanzapine, quetiapine, or risperidone) or switch to treatment with aripiprazole with 24 weeks of follow-up. All study participants were enrolled in a behavioral program that promoted healthy diet and exercise.The pre-specified analyses included 89 switchers and 98 stayers who had post-baseline measurements needed to assess changes. Least squares mean estimates of 10-year CHD risk decreased more for the switch (from 7.0% to 5.2%) than the stay group (from 7.4% to 6.4%) (p = 0.0429). The odds ratio for having metabolic syndrome (stay vs. switch) at the last observation was 1.748 (95% CI 0.919, 3.324, p = 0.0885).Switching from olanzapine, quetiapine, or risperidone to aripiprazole was associated with larger reductions in predicted 10-year risk of CHD than the behavioral program alone. The advantage of switching on metabolic syndrome was not statistically significant. The benefits of switching must be balanced against its risks, which in this study included more discontinuations of the study treatment but no significant increase in symptoms or hospitalizations.

Combining psychotropic medications is common for people diagnosed with schizophrenia facing a variety of clinical circumstances. This review provides an update on evidence regarding the effectiveness of polypharmacy approaches.Epidemiology studies have demonstrated that polypharmacy is extremely common, but evidence regarding all polypharmacy approaches for schizophrenia from randomized controlled trials remains scarce. Combinations of antipsychotic medicines are unsupported by evidence. Antidepressants are commonly used to treat depressive symptoms; this logical role for antidepressants has little support from randomized controlled trials (RCTs) but may be associated with lower suicide and all-cause mortality. Insufficient evidence supports the use of benzodiazepines for schizophrenia; possible risks of benzodiazepines, including increased mortality rates revealed in observational studies, warrant caution and further study.The lack of evidence regarding common treatment strategies exacerbates the tremendous challenge of providing optimal pharmacotherapy for individuals with schizophrenia. Comparative effectiveness research, using observational methods when appropriate and RCTs when possible, is needed to inform clinical practice, use resources wisely and improve outcomes.

Schizophrenia is characterized by extensive neurocognitive deficits, which are linked to greater disability, poorer functional outcome, and have been suggested to impact daily functioning more than clinical symptoms. Aerobic exercise (AE) has emerged as a potential intervention. This review examines the impact of AE on brain structure and function along with neurocognitive performance in individuals with schizophrenia. Preliminary evidence indicates that AE can increase hippocampal volume and cortical thickness, in addition to exerting a neuroprotective effect against hippocampal volume decrease and cortical thinning. There is also evidence that AE is able to significantly increase serum brain-derived neurotrophic factor (BDNF) levels, which are implicated in neurogenesis, neuroplasticity, and cognitive improvement. Finally, evidence suggests that AE plays a significant role in improving overall cognition, including improvements in processing speed, working memory, and visual learning. The authors discuss the implications of the findings and provide recommendations for future research and areas of inquiry.

Randomized controlled trials for antipsychotic drugs have a variety of design features suited to diverse purposes. Efficacy (or explanatory) trials seek to establish if a drug can reduce psychotic symptoms under ideal circumstances. To isolate drug effects, researchers enroll carefully selected patients. Specialized research personnel use rating scales of symptoms that are sensitive to drug effects as the study primary outcomes. Large simple trials (LSTs) are conducted at typical treatment settings with usual clinical personnel and enroll large numbers of participants so small but clinically important differences between treatment options can be detected. LSTs focus narrowly on clearly defined, patient-oriented outcomes. To some extent, practical trials can be conceptualized as hybrids of efficacy and large simple trials. Practical trials provide independent evidence to inform decision makers about the everyday effectiveness of clinically relevant alternative interventions. Practical trial researchers include a heterogeneous population of patients and collect data on a broad range of meaningful health outcomes at many types of practice settings intended to represent usual treatment. The designers of practical trials make trade-offs between internal validity, external validity, the breadth of issues addressed, and the ability to detect small differences. The different objectives of trials should be considered in the interpretation of the complete body of randomized evidence on antipsychotic drugs.

This study assessed the relative cost-effectiveness of haloperidol decanoate (HD), a first-generation long-acting injectable (LAI) antipsychotic, and paliperidone palmitate (PP), a second-generation LAI antipsychotic.A double-blind, randomized 18-month clinical trial conducted at 22 clinical research sites in the United States compared the cost-effectiveness of HD and PP among 311 adults with schizophrenia or schizoaffective disorder who had been clinically assessed as likely to benefit from an LAI antipsychotic. Patients were randomly assigned to monthly intramuscular injections of HD (25-200 mg) or PP (39-234 mg) for up to 24 months. Quality-adjusted life years (QALYs) were measured by a schizophrenia-specific algorithm based on the Positive and Negative Syndrome Scale and side-effect assessments; total health care costs were assessed from the perspective of the health system.Mixed-model analysis showed that PP was associated with .0297 greater QALYs over 18 months (p=.03) and with $2,100 more in average costs per quarter for inpatient and outpatient services and medication compared with HD (p.001). Bootstrap analysis with 5,000 replications showed an incremental cost-effectiveness ratio for PP of $508,241 per QALY (95% confidence interval=$122,390-$1,582,711). Net health benefits analysis showed a .98 probability of greater cost-effectiveness for HD compared with PP at an estimated value of $150,000 per QALY and a .50 probability of greater cost-effectiveness at $500,000 per QALY.HD was more cost-effective than PP, suggesting that PP's slightly greater benefits did not justify its markedly higher costs, which are likely to fall once the medication's patent expires.

Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e −15 ), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e −6 ). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e −11 ) and neurobehavioral phenotypes in mouse (OR = 1.18, P=7.3e −5 ). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).

Objective This multisite randomized trial addressed risks and benefits of staying on long-acting injectable haloperidol or fluphenazine versus switching to long-acting injectable risperidone microspheres.

It has been over 10 years since the initiation of the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and 5 years since the first publication of its primary results (1). In this period, the initial report has been cited in the literature over 1,600 times (2) while more than 80 articles from the study’s extensive database (Table 1), as well as a book serving as an archive of the study’s results and implications (3), have been published. In the meantime, several more randomized trials comparing the effectiveness of antipsychotics have been completed (4–6), meta-analyses that bear on the findings of the CATIE study have been performed (7, 8), and commentaries on CATIE’s findings and critiques of its methodology have been published (9–11). All of these help us to view the CATIE study in a broader context and enable us to determine what we really learned from it. When the CATIE study was designed in 1999– 2000, the prevailing opinion of researchers and clinicians alike was that the newer (second-generation) antipsychotic drugs were vastly superior to the older (first-generation) antipsychotic drugs in efficacy and safety. This largely reflected the results of studies sponsored by the manufacturers of the new drugs (12, 13), marketing messages of pharmaceutical companies and the hopes of many who wanted better treatments. Indeed, the hypothesis and expectation of the CATIE study investigators was that the firstgeneration antipsychotic perphenazine would be inferior to the newer agents. Consequently, the finding that perphenazine was similar in effectiveness to most other medications had a profound effect that extended beyond the scientific and psychiatric communities to the lay public and various stakeholder groups. Somewhat sensational news reports decried the preferential use and greater cost of the newer medications and the marketing practices that led to them. For example, the September 21, 2005, editorial page of The New York Times opined, “A government-financed study has provided the strongest evidence yet that the system for approving and promoting drugs is badly out of whack. The study compared five drugs used to treat schizophrenia and found that most of the newest, most heavily prescribed drugs were no better than an older drug that is far cheaper. The nation is wasting billions of dollars on heavily marketed drugs that have never proved themselves in head-to-head competition against cheaper competitors” (14). But what did we really learn from the CATIE study? In this commentary, we summarize its major implications and their relevance to clinical practice. We will also address some of the study’s most relevant critiques.