Medications Associated with Lower Mortality in a SARS-CoV-2 Positive Cohort of 26,508 Veterans.

BACKGROUND: Many severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positive patients take commonly prescribed medications with properties which may affect mortality. OBJECTIVE: Assess if common medications postulated to affect clinical outcomes are associated with mortality in SARS-CoV-2 positive patients in the Veterans Health Administration (VHA). DESIGN: Observational national cohort analysis. PARTICIPANTS: Consecutive 26,508 SARS-CoV-2 positive Veterans (7% of 399,290 tested from March 1 to September 10, 2020) constitute the study cohort. MAIN MEASURES: The primary outcome was 30-day mortality from the first positive SARS-CoV-2 test date. In patients receiving medications or drug pairs within 2 weeks post-SARS-CoV-2 positive test, 30-day mortality was estimated as relative risk (RR) on the log-binomial scale or using multinomial models with and without adjusting for covariates. KEY RESULTS: The 26,508 SARS-CoV-2 positive patients were predominantly male (89%) and White (59%), and 82% were overweight/obese. Medications associated with decreased 30-day mortality risk included the following: metformin (aRR, 0.33; 95% CI, 0.25-0.43), colchicine, angiotensin-converting-enzyme inhibitors (ACEi), angiotensin II receptor blockers, statins, vitamin D, antihistamines, alpha-blockers, anti-androgens, and nonsteroidal anti-inflammatory drugs (aRR, 0.69; 95% CI, 0.61-0.78). The effect of co-prescribed medications on 30-day mortality risk revealed the lowest risk for combined statins and metformin (aRR, 0.21; 95% CI, 0.15-0.31), followed by ACEi and statins (aRR, 0.25; 95% CI, 0.18-0.35), ACEi and metformin (aRR, 0.26; 95% CI, 0.17-0.40), antihistamines and NSAIDs (aRR, 0.41; 95% CI, 0.32-0.52), and in men, combined alpha-blockers and anti-androgens (aRR, 0.51; 95% CI, 0.42-0.64). CONCLUSIONS: In this large national cohort, treatment of SARS-CoV-2 positive patients with individual or co-prescribed metformin and statins, ACEi and statins (or metformin) and other medications was associated with a markedly decreased 30-day mortality and can likely be continued safely. Clinical trials may assess their therapeutic benefit.

"Pigmented Extramammary Paget Disease"-A Potential Mimicker of Malignant Melanoma and a Pitfall in Diagnosis: A Case Report and Review of the Literature.

Extramammary Paget disease (EMPD) is a rare intraepithelial carcinoma and an uncommon variant of Paget disease affecting areas of the apocrine-rich skin of the perineum, vulva, and less commonly, axilla. Women in their sixth to eighth decades are commonly affected. It is exceedingly rare for EMPD to present on the face, chest, abdomen, or other nonapocrine sites and even more unusual for EMPD to present as a pigmented lesion. The relationship between Paget cells in pigmented extramammary Paget disease (PEMPD) and reactive proliferation and colonization by melanocytes has been poorly explored. The relevance of this rare entity resides in its potential to be misdiagnosed clinically and histopathologically as malignant melanoma in situ. Therefore, application of a panel of immunostains and careful analysis and interpretation of these findings are essential to arrive at the correct diagnosis. We report a new case of PEMPD on a nonapocrine site. The specimen was examined by routine microscopy including hematoxylin and eosin stain as well as immunostains. Histologic examination revealed characteristic features of PEMPD confirmed with immunohistochemical stains.

Eosinophilic Dermatosis of Myeloproliferative Disease in a Young Adult With Diffuse Large B-Cell Lymphoma.

Exaggerated insect bite reactions present as exuberant papular and vesiculobullous lesions in patients with hematologic malignant neoplasms. The most commonly reported hematological malignancy with exaggerated insect bite reactions is chronic lymphocytic leukemia. Other reported reactions have been seen in patients with mantle cell lymphoma. Clinical presentation may vary with many patients unaware of a previous insect bite. Therefore, the terms "exaggerated bite-like reaction" and "eosinophilic dermatosis of myeloproliferative disease" have been proposed. The lesions may wax and wane or persist for many years, and they seem to be unrelated to the underlying hematologic disorder course or therapy. In some circumstances, the lesions may actually precede the diagnosis of the hematological malignancy. In this study, we describe a case of "eosinophilic eruption of myeloproliferative disease" associated with diffuse large B-cell lymphoma in a young adult. To the best of our knowledge, this is the first case reported in association with diffuse large B-cell lymphoma.

Longitudinal Patterns of Multimorbidity in Gulf War Era Veterans With and Without Gulf War Illness.

Objectives: To examine whether severe Gulf War illness (SGWI) case status was associated with longitudinal multimorbidity patterns. Methods: Participants were users of the Veteran Health Administration Health Care System drawn from the Gulf War Era Cohort and Biorepository (n = 840). Longitudinal measures of multimorbidity were constructed using (1) electronic health records (Charlson Comorbidity Index; Elixhauser; and Veterans Affairs Frailty Index) from 10/1/1999 to 6/30/2023 and (2) self-reported medical conditions (Deficit Accumulation Index) since the war until the survey date. Accelerated failure time models examined SGWI case status as a predictor of time until threshold level of multimorbidity was reached, adjusted for age and sociodemographic and military characteristics. Results: Models, adjusted for covariates, revealed that (1) relative to the SWGI- group, the SGWI+ group was associated with an accelerated time for reaching each threshold and (2) the relationship between SGWI and each threshold was not moderated by age. Discussion: Findings suggest that veterans with SGWI experienced accelerated aging.

Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial.

The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6Mage [2.9] years; 21 women; placebo group: 39; 18.3Mage [2.7]; 22 women); and 42 healthy controls (19.2Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; ηp2 = 0.062; verbal learning: p = 0.015; ηp2 = 0.072 both medium effects; delayed recall: p = 0.001; ηp2 = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ; ACTRN12607000608460).

Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study.

BACKGROUND: Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia. METHODS: We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides. FINDINGS: Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01]). INTERPRETATION: Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia. FUNDING: National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.

Sleep disturbances and the At Risk Mental State: A systematic review and meta-analysis.

AIMS: To synthesise and investigate how sleep disturbances relate to psychotic symptoms, functioning and Quality of Life (QoL) in At Risk Mental State (ARMS) youth. METHOD: A comprehensive search of six databases (MEDLINE, PsycINFO, Embase, CINAHL, Web of Science and CENTRAL) was conducted. Eligible studies provided data on sleep disturbances or disorders in ARMS patients. RESULTS: Sixteen studies met the inclusion criteria (n = 1962 ARMS patients) including 7 cross-sectional studies, 2 RCT's and 7 cohort studies. Narrative synthesis revealed that self-reported sleep (e.g., general disturbances, fragmented night time sleep and nightmares) was poorer among ARMS patients compared to healthy controls. In the limited studies (n = 4) including objective measurements of sleep disturbances, ARMS patients experienced higher levels of movement during sleep, more daytime naps and increased sleep latency compared to controls. Furthermore, sleep disturbances were associated with attenuated psychotic symptoms and functional outcomes cross-sectionally and longitudinally. Only one study investigated the relationship between sleep and QoL. The exploratory meta-analysis revealed a significant difference in self-reported sleep disturbances measured by the PSQI (mean difference in score: 3.30 (95% CI 1.87, 4.74), p < 0.00001) and SIPS (mean difference in score: 1.58 (95% CI 0.80, 2.35), p < 0.00001) of ARMS patients compared to control groups. CONCLUSIONS: ARMS individuals report impaired sleep quality and reduced sleep quantity compared to healthy controls. However, further research is needed to explore the longitudinal relationship between sleep disruptions and QoL in early psychosis. Significant variations in how sleep is measured across studies highlight a need to assess disturbances to sleep using robust and consistent approaches in this patient group.

The Interaction of Vitamin D and Corticosteroids: A Mortality Analysis of 26,508 Veterans Who Tested Positive for SARS-CoV-2.

This data-based cohort consisted of 26,508 (7%) United States veterans out of the 399,290 who tested positive for SARS-CoV-2 from 1 March to 10 September 2020. We aimed to assess the interaction of post-index vitamin D (Vit D) and corticosteroid (CRT) use on 30-day mortality among hospitalized and non-hospitalized patients with coronavirus disease 2019 (COVID-19). Combination Vit D and CRT drug use was assessed according to four multinomial pairs (-|+, -|-, +|+, +|-). Respective categorical effects were computed on a log-binomial scale as adjusted relative risk (aRR). Approximately 6% of veterans who tested positive for SARS-CoV-2 died within 30 days of their index date. Among hospitalized patients, a significantly decreased aRR was observed for the use of Vit D in the absence of CRTs relative to patients who received CRTs but not Vit D (aRR = 0.30; multiplicity corrected, p = 0.0004). Among patients receiving systemically administered CRTs (e.g., dexamethasone), the use of Vit D was associated with fewer deaths in hospitalized patients (aRR = 0.51) compared with non-hospitalized patients (aRR = 2.5) (P-for-Interaction = 0.0071). Evaluating the effect of modification of these compounds in the context of hospitalization may aid in the management of COVID-19 and provide a better understanding of the pathophysiological mechanisms underlying this and future infectious disease outbreaks.

COVID-19-Associated Mortality in US Veterans with and without SARS-CoV-2 Infection.

BACKGROUND: We performed an observational Veterans Health Administration cohort analysis to assess how risk factors affect 30-day mortality in SARS-CoV-2-infected subjects relative to those uninfected. While the risk factors for coronavirus disease 2019 (COVID-19) have been extensively studied, these have been seldom compared with uninfected referents. METHODS: We analyzed 341,166 White/Black male veterans tested for SARS-CoV-2 from March 1 to September 10, 2020. The relative risk of 30-day mortality was computed for age, race, ethnicity, BMI, smoking status, and alcohol use disorder in infected and uninfected subjects separately. The difference in relative risk was then evaluated between infected and uninfected subjects. All the analyses were performed considering clinical confounders. RESULTS: In this cohort, 7% were SARS-CoV-2-positive. Age >60 and overweight/obesity were associated with a dose-related increased mortality risk among infected patients relative to those uninfected. In contrast, relative to never smoking, current smoking was associated with a decreased mortality among infected and an increased mortality in uninfected, yielding a reduced mortality risk among infected relative to uninfected. Alcohol use disorder was also associated with decreased mortality risk in infected relative to the uninfected. CONCLUSIONS: Age, BMI, smoking, and alcohol use disorder affect 30-day mortality in SARS-CoV-2-infected subjects differently from uninfected referents. Advanced age and overweight/obesity were associated with increased mortality risk among infected men, while current smoking and alcohol use disorder were associated with lower mortality risk among infected men, when compared with those uninfected.

Granular Cell Tumor Imaging Using Optical Coherence Tomography.

BACKGROUND: Granular cell tumor (GCT) is a relatively uncommon tumor that may affect the skin. The tumor can develop anywhere on the body, although it is predominately seen in oral cavities and in the head and neck regions. Here, we present the results of optical coherence tomography (OCT) imaging of a large GCT located on the abdomen of a patient. We also present an analytical method to differentiate between healthy tissue and GCT tissues. MATERIALS AND METHODS: A multibeam, Fourier domain, swept source OCT was used for imaging. The OCT had a central wavelength of 1305 ± 15 nm and lateral and axial resolutions of 7.5 and 10 µm, respectively. Qualitative and quantitative analyses of the tumor and healthy skin are reported. RESULTS: Abrupt changes in architectures of the dermal and epidermal layers in the GCT lesion were observed. These architectural changes were not observed in healthy skin. DISCUSSION: To quantitatively differentiate healthy skin from tumor regions, an optical attenuation coefficient analysis based on single-scattering formulation was performed. The methodology introduced here could have the capability to delineate boundaries of a tumor prior to surgical excision.

The importance of constructive feedback: Implications of top-down regulation in the development of neural circuits.

Neural circuits in sensory pathways develop through a general strategy of overproduction of synapses followed by activity-driven pruning to fine-tune connectivity for optimal function. The early visual pathway, consisting of the retina → visual thalamus → primary visual cortex, has served for decades as a powerful model system for probing the mechanisms and logic of this process. In addition to these feedforward projections, the early visual pathway also includes a substantial feedback component in the form of corticothalamic projections from the deepest layer of primary visual cortex. The role of this feedback in visual processing has been studied extensively in mature animals, yet historically, its role in development has received comparatively little attention. Recent technological advances allowing for selective manipulation of neural activity in development led to the uncovering of a role for feedback in guiding the refinement of the forward projection from retina to visual thalamus. Here we discuss the implications of feedback exerting influence on the development of sensory pathways. We propose several possible advantages to constructing neural circuits with top-down regulation, and discuss the potential significance of this finding for certain neurologic disorders.

Cortical Feedback Regulates Feedforward Retinogeniculate Refinement.

According to the prevailing view of neural development, sensory pathways develop sequentially in a feedforward manner, whereby each local microcircuit refines and stabilizes before directing the wiring of its downstream target. In the visual system, retinal circuits are thought to mature first and direct refinement in the thalamus, after which cortical circuits refine with experience-dependent plasticity. In contrast, we now show that feedback from cortex to thalamus critically regulates refinement of the retinogeniculate projection during a discrete window in development, beginning at postnatal day 20 in mice. Disrupting cortical activity during this window, pharmacologically or chemogenetically, increases the number of retinal ganglion cells innervating each thalamic relay neuron. These results suggest that primary sensory structures develop through the concurrent and interdependent remodeling of subcortical and cortical circuits in response to sensory experience, rather than through a simple feedforward process. Our findings also highlight an unexpected function for the corticothalamic projection.

A longitudinal investigation of childhood communication ability and adolescent psychotic experiences in a community sample.

BACKGROUND: Some childhood speech and language impairments precede psychosis but it is not clear whether they also precede adolescent psychotic experiences and whether this association is specific to psychotic experiences. METHODS: Pragmatic language and expressive speech and language (parent-assessed using the Children's Communication Checklist) at age 9 and psychotic experiences and depression at ages 12 and 18 were investigated in 7659 participants from the Avon Longitudinal Study of Parents and Children. Associations were investigated using multivariate modelling. RESULTS: Poorer pragmatic language at 9years was associated with psychotic experiences at both ages (12years OR 1.22, 95% CI 1.11, 1.34; 18years OR 1.25, 95% CI 1.10, 1.41) but only with depression at 18years (OR 1.10, 95% CI 1.00, 1.22). Poorer expressive speech and language ability was not associated with psychotic experiences or depression at either age. There was evidence that pragmatic language was specifically associated with psychotic experiences at age 12 but no evidence that the strength of any of the associations changed over time. CONCLUSIONS: Deficits in pragmatic language precede early and late adolescent psychotic experiences and early adolescent depression. Interventions aimed at helping children improve pragmatic language skills may reduce the incidence of adolescent psychopathology and associated psychological disorder and dysfunction later in life.

Sexual trauma increases the risk of developing psychosis in an ultra high-risk "prodromal" population.

Studies indicate a high prevalence of childhood trauma in patient cohorts with established psychotic disorder and in those at risk of developing psychosis. A causal link between childhood trauma and development of psychosis has been proposed. We aimed to examine the association between experience of childhood trauma and the development of a psychotic disorder in a large "Ultra High Risk" (UHR) for psychosis cohort. The data were collected as part of a longitudinal cohort study of all UHR patients recruited to research studies at the Personal Assessment and Clinical Evaluation clinic between 1993 and 2006. Baseline data were collected at recruitment to these studies. The participants completed a comprehensive follow-up assessment battery (mean time to follow-up 7.5 years, range 2.4-14.9 years), which included the Childhood Trauma Questionnaire (CTQ), a self-report questionnaire that assesses experience of childhood trauma. The outcome of interest was transition to a psychotic disorder during the follow-up period. Data were available on 233 individuals. Total CTQ trauma score was not associated with transition to psychosis. Of the individual trauma types, only sexual abuse was associated with transition to psychosis (P = .02). The association remained when adjusting for potential confounding factors. Those with high sexual abuse scores were estimated to have a transition risk 2-4 times that of those with low scores. The findings suggest that sexual trauma may be an important contributing factor in development of psychosis for some individuals.

Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: twelve-month outcome.

OBJECTIVE: The ultra-high risk clinical phenotype is associated with substantial distress and functional impairment and confers a greatly enhanced risk for transition to full-threshold psychosis. A range of interventions aimed at relieving current symptoms and functional impairment and reducing the risk of transition to psychosis has shown promising results, but the optimal type and sequence of intervention remain to be established. The aim of this study was to determine which intervention was most effective at preventing transition to psychosis: cognitive therapy plus low-dose risperidone, cognitive therapy plus placebo, or supportive therapy plus placebo. METHOD: A double-blind, randomized, placebo-controlled 12-month trial of low-dose risperidone, cognitive therapy, or supportive therapy was conducted in a cohort of 115 clients of the Personal Assessment and Crisis Evaluation Clinic, a specialized service for young people at ultra-high risk of psychosis located in Melbourne, Australia. Recruitment commenced in August 2000 and ended in May 2006. The primary outcome measure was transition to full-threshold psychosis, defined a priori as frank psychotic symptoms occurring at least daily for 1 week or more and assessed using the Comprehensive Assessment of At-Risk Mental States. Secondary outcome measures were psychiatric symptoms, psychosocial functioning, and quality of life. RESULTS: The estimated 12-month transition rates were as follows: cognitive therapy + risperidone, 10.7%; cognitive therapy + placebo, 9.6%; and supportive therapy + placebo, 21.8%. While there were no statistically significant differences between the 3 groups in transition rates (log-rank test P = .60), all 3 groups improved substantially during the trial, particularly in terms of negative symptoms and overall functioning. CONCLUSIONS: The lower than expected, essentially equivalent transition rates in all 3 groups fail to provide support for the first-line use of antipsychotic medications in patients at ultra-high risk of psychosis, and an initial approach with supportive therapy is likely to be effective and carries fewer risks.

The 3rd Schizophrenia International Research Society Conference, 14-18 April 2012, Florence, Italy: summaries of oral sessions.

The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012 and this year had as its emphasis, "The Globalization of Research". Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.

Social cognition deficits and the 'ultra high risk' for psychosis population: a review of literature.

AIM: A number of risk factors for developing a psychotic disorder have been investigated in the 'ultra high risk' (UHR) population, including neurocognitive abilities, social functioning and, more recently, social cognition. We aimed to review the literature on social cognition in the UHR population. METHODS: Literature was restricted to English articles and identified using Pubmed, Medline, PsychINFO and CINAHLplus, as well as the reference lists of published studies and reviews. Search terms included social cognition, theory of mind, emotion recognition, attributional style, social knowledge, social perception, 'at risk mental state', psychosis prodrome 'clinical high risk' and 'ultra high risk'. Inclusion criteria were an outcome measure of a social cognition task and an UHR population defined by a structured validated instrument. RESULTS: Seven original research articles met the inclusion criteria, one of which was a conference abstract. One of the two studies that assessed theory of mind, two of the four studies that assessed emotion recognition and both the two studies that assessed social perception/knowledge found significant deficits in UHR patients. The single study that assessed attributional bias also reported differences in UHR patients compared with healthy controls. CONCLUSIONS: There is limited published literature on social cognitive performance in the UHR population. Despite this, deficits in certain social cognitive abilities do appear to be present, but further research with more reliable cross-cultural measures is needed. The characterization of social cognitive deficits in the UHR populations may aid in the identification of potential markers for development of a subsequent psychotic disorder, as well as targets for early intervention.

Randomized controlled trial of interventions for young people at ultra high risk for psychosis: 6-month analysis.

OBJECTIVE: Cognitive therapy and/or low-dose antipsychotic administered during the prodromal phase of schizophrenia may prevent or delay the onset of full-blown illness. However, it is unclear which of these treatments are most effective, how long treatment should be given, and whether effects will be sustained over a prolonged period. METHOD: In order to examine these issues, we conducted a randomized controlled trial of cognitive therapy + risperidone; cognitive therapy + placebo; and supportive therapy + placebo in young people at ultra high risk for developing a psychotic disorder (that is, putatively prodromal). The main outcome was transition to psychotic disorder, with level of symptoms and functioning the secondary outcomes. This article reports the interim 6-month follow-up results. The study was conducted from August 2000 to May 2007. RESULTS: Of a possible 464 eligible ultra high risk individuals, 115 were recruited to the randomized controlled trial (cognitive therapy + risperidone, n = 43; cognitive therapy + placebo, n = 44; and supportive therapy + placebo, n = 28). An additional 78 individuals agreed to follow-up assessments but not to randomization ("monitoring group," n = 78). At 6 months, 8 of the 115 participants (7.0%) and 4 of the monitoring group (5.1%) had developed psychotic disorder. There were no significant differences between the 3 randomized groups (log rank test, P = .92) or between all 4 groups (log rank test, P = .93). There was also no difference between the 4 groups in secondary measures, with all groups showing a reduction in symptoms and increased functioning. CONCLUSIONS: Rates of transition to psychosis were lower than expected, particularly in the control supportive therapy + placebo group. This may have accounted for the negative finding, as the sample was therefore underpowered to find any difference between groups. Alternatively, it may be that all treatments were equally effective or equally ineffective at 6 months. TRIAL REGISTRATION: http://www.anzctr.org.au Identifier: ACTRN012605000247673.