Showing papers in "Archives of General Psychiatry in 2012"

Predicting Psychosis: Meta-analysis of Transition Outcomes in Individuals at High Clinical Risk

Abstract: Context A substantial proportion of people at clinical high risk of psychosis will develop a psychotic disorder over time. However, the risk of transition to psychosis varies between centers, and some recent work suggests that the risk of transition may be declining. Objective To quantitatively examine the literature to date reporting the transition risk to psychosis in subjects at clinical high risk. Data Sources The electronic databases were searched until January 2011. All studies reporting transition risks in patients at clinical high risk were retrieved. Study Selection Twenty-seven studies met the inclusion criteria, comprising a total of 2502 patients. Data Extraction Transition risks, as well as demographic, clinical, and methodologic variables, were extracted from each publication or obtained directly from its authors. Data Synthesis There was a consistent transition risk, independent of the psychometric instruments used, of 18% after 6 months of follow-up, 22% after 1 year, 29% after 2 years, and 36% after 3 years. Significant moderators accounting for heterogeneity across studies and influencing the transition risks were the age of participants, publication year, treatments received, and diagnostic criteria used. There was no publication bias, and a sensitivity analysis confirmed the robustness of the core findings. Conclusions The state of clinical high risk is associated with a very high risk of developing psychosis within the first 3 years of clinical presentation, and the risk progressively increases across this period. The transition risk varies with the age of the patient, the nature of the treatment provided, and the way the syndrome and transition to psychosis are defined.

Prevalence, Persistence, and Sociodemographic Correlates of DSM-IV Disorders in the National Comorbidity Survey Replication Adolescent Supplement

Abstract: Context:Communityepidemiologicaldataontheprevalence and correlates of adolescent mental disorders are needed for policy planning purposes. Only limited data of this sort are available. Objective: To present estimates of 12-month and 30day prevalence, persistence (12-month prevalence among lifetime cases and 30-day prevalence among 12-month cases),andsociodemographiccorrelatesofcommonlyoccurring DSM-IV disorders among adolescents in the NationalComorbiditySurveyReplicationAdolescentSupplement.

The nature of dopamine dysfunction in schizophrenia and what this means for treatment

Abstract: Context Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D 2 receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia. Objective To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies. Data Sources The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011. Study Selection A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function. Data Extraction Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables. Data Synthesis There was a highly significant elevation (P 2/3 receptor availability (Cohen d = 0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used. Conclusions The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D 2/3 receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.

Testing Standard and Modular Designs for Psychotherapy Treating Depression, Anxiety, and Conduct Problems in Youth: A Randomized Effectiveness Trial

Abstract: Context Decades of randomized controlled trials have produced separate evidence-based treatments for depression, anxiety, and conduct problems in youth, but these treatments are not often used in clinical practice, and they produce mixed results in trials with the comorbid, complex youths seen in practice. An integrative, modular redesign may help. Objective Standard/separate and modular/integrated arrangements of evidence-based treatments for depression, anxiety, and conduct problems in youth were compared with usual care treatment, with the modular design permitting a multidisorder focus and a flexible application of treatment procedures. Design Randomized effectiveness trial. Setting Ten outpatient clinical service organizations in Massachusetts and Hawaii. Participants A total of 84 community clinicians were randomly assigned to 1 of 3 conditions for the treatment of 174 clinically referred youths who were 7 to 13 years of age (70% of these youths were boys, and 45% were white). The study was conducted during the period from January 12, 2005 to May 8, 2009. Interventions Standard manual treatment (59 youths [34% of the sample]; cognitive behavioral therapy for depression, cognitive behavioral therapy for anxiety, and behavioral parent training for conduct problems), modular treatment (62 youths [36%]; integrating the procedures of the 3 separate treatments), and usual care (53 youths [30%]). Main Outcome Measures Outcomes were assessed using weekly youth and parent assessments. These assessments relied on a standardized Brief Problem Checklist and a patient-generated Top Problems Assessment (ie, the severity ratings on the problems that the youths and parents had identified as most important). We also conducted a standardized diagnostic assessment before and after treatment. Results Mixed effects regression analyses showed that modular treatment produced significantly steeper trajectories of improvement than usual care and standard treatment on multiple Brief Problem Checklist and Top Problems Assessment measures. Youths receiving modular treatment also had significantly fewer diagnoses than youths receiving usual care after treatment. In contrast, outcomes of standard manual treatment did not differ significantly from outcomes of usual care. Conclusions The modular approach outperformed usual care and standard evidence-based treatments on multiple clinical outcome measures. The modular approach may be a promising way to build on the strengths of evidence-based treatments, improving their utility and effectiveness with referred youths in clinical practice settings. Trial Registration clinicaltrials.gov Identifier: NCT01178554

Childhood Adversities and First Onset of Psychiatric Disorders in a National Sample of US Adolescents

Abstract: Context Although childhood adversities (CAs) are known to be highly co-occurring, most research examines their associations with psychiatric disorders one at a time. However, recent evidence from adult studies suggests that the associations of multiple CAs with psychiatric disorders are nonadditive, arguing for the importance of multivariate analysis of multiple CAs. To our knowledge, no attempt has been made to perform a similar kind of analysis among children or adolescents. Objective To examine the multivariate associations of 12 CAs with first onset of psychiatric disorders in a national sample of US adolescents. Design A US national survey of adolescents (age range, 13-17 years) assessing DSM-IV anxiety, mood, behavior, and substance use disorders and CAs. The CAs include parental loss (death, divorce, and other separations), maltreatment (neglect and physical, sexual, and emotional abuse), and parental maladjustment (violence, criminality, substance abuse, and psychopathology), as well as economic adversity. Setting Dual-frame household-school samples. Participants In total, 6483 adolescent-parent pairs. Main Outcome Measures Lifetime DSM-IV disorders assessed using the World Health Organization Composite International Diagnostic Interview. Results Overall, exposure to at least 1 CA was reported by 58.3% of adolescents, among whom 59.7% reported multiple CAs. The CAs reflecting maladaptive family functioning were more strongly associated than other CAs with the onset of psychiatric disorders. The best-fitting model included terms for the type and number of CAs and distinguished between maladaptive family functioning and other CAs. The CAs predicted behavior disorders most strongly and fear disorders least strongly. The joint associations of multiple CAs were subadditive. The population-attributable risk proportions across DSM-IV disorder classes ranged from 15.7% for fear disorders to 40.7% for behavior disorders. The CAs were associated with 28.2% of all onsets of psychiatric disorders. Conclusions Childhood adversities are common, highly co-occurring, and strongly associated with the onset of psychiatric disorders among US adolescents. The subadditive multivariate associations of CAs with the onset of psychiatric disorders have implications for targeting interventions to reduce exposure to CAs and to mitigate the harmful effects of CAs to improve population mental health.

Cognitive Functioning in Prodromal Psychosis: A Meta-analysis

Abstract: Context A substantial proportion of people at clinical high risk (HR) of psychosis will develop a psychotic disorder over time. Cognitive deficits may predate the onset of psychosis and may be useful as markers of increased vulnerability to illness. Objective To quantitatively examine the cognitive functioning in subjects at HR in the literature to date. Data Sources Electronic databases were searched until January 2011. All studies reporting cognitive performance in HR subjects were retrieved. Study Selection Nineteen studies met the inclusion criteria, comprising a total of 1188 HR subjects and 1029 controls. Data Extraction Neurocognitive functioning and social cognition as well as demographic, clinical, and methodological variables were extracted from each publication or obtained directly from its authors. Data Synthesis Subjects at HR were impaired relative to controls on tests of general intelligence, executive function, verbal and visual memory, verbal fluency, attention and working memory, and social cognition. Processing speed domain was also affected, although the difference was not statistically significant. Later transition to psychosis was associated with even more marked deficits in the verbal fluency and memory domains. The studies included reported relatively homogeneous findings. There was no publication bias and a sensitivity analysis confirmed the robustness of the core results. Conclusions The HR state for psychosis is associated with significant and widespread impairments in neurocognitive functioning and social cognition. Subsequent transition to psychosis is particularly associated with deficits in verbal fluency and memory functioning.

Cerebrospinal Fluid Levels of β-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia.

Abstract: Context Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease. Objectives To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD. Design A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years). Setting Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. MAIN OUTCOME MEASURE Conversion to AD dementia. Results During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P Conclusions Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.

Clinical and Functional Outcome of Childhood Attention-Deficit/Hyperactivity Disorder 33 Years Later

Abstract: Context Prospective studies of childhood attention-deficit/hyperactivity disorder (ADHD) have not extended beyond early adulthood. Objective To examine whether children diagnosed as having ADHD at a mean age of 8 years (probands) have worse educational, occupational, economic, social, and marital outcomes and higher rates of ongoing ADHD, antisocial personality disorder (ASPD), substance use disorders (SUDs), adult-onset psychiatric disorders, psychiatric hospitalizations, and incarcerations than non-ADHD comparison participants at a mean age of 41 years. Design Prospective, 33-year follow-up study, with masked clinical assessments. Setting Research clinic. Participants A total of 135 white men with ADHD in childhood, free of conduct disorder, and 136 men without childhood ADHD (65.2% and 76.4% of original cohort, respectively). Main Outcome Measures Occupational, economic, and educational attainment; marital history; occupational and social functioning; ongoing and lifetime psychiatric disorders; psychiatric hospitalizations; and incarcerations. Results Probands had significantly worse educational, occupational, economic, and social outcomes; more divorces; and higher rates of ongoing ADHD (22.2% vs 5.1%, P Conclusions The multiple disadvantages predicted by childhood ADHD well into adulthood began in adolescence, without increased onsets of new disorders after 20 years of age. Findings highlight the importance of extended monitoring and treatment of children with ADHD.

Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression.

Abstract: Context: Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited. Objective: To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP). Design: Open-label trial with a sham lead-in phase. Setting: Academic medical center. Patients: Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened. Intervention: Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation. Main Outcome Measures: Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation. Results: A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n=17), 5 (36%) and 5 (36%) after 1 year (n=14), and 7 (58%) and 11 (92%) after 2 years (n =1 2) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase. Conclusions: The findings of this study support the longterm safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP. Trial Registration: clinicaltrials.gov Identifier: NCT00367003

Genome-wide Epigenetic Regulation by Early-Life Trauma

Abstract: CONTEXT Our genome adapts to environmental influences, in part through epigenetic mechanisms, including DNA methylation. Variations in the quality of the early environment are associated with alterations in DNA methylation in rodents, and recent data suggest similar processes in humans in response to early-life adversity. OBJECTIVE To determine genome-wide DNA methylation alterations induced by early-life trauma. DESIGN Genome-wide study of promoter methylation in individuals with severe abuse during childhood. PATIENTS, SETTING, AND MAIN OUTCOME MEASURES Promoter DNA methylation levels were profiled using methylated DNA immunoprecipitation followed by microarray hybridization in hippocampal tissue from 41 French-Canadian men (25 with a history of severe childhood abuse and 16 control subjects). Methylation profiles were compared with corresponding genome-wide gene expression profiles obtained by messenger RNA microarrays. Methylation differences between groups were validated on neuronal and nonneuronal DNA fractions isolated by fluorescence-assisted cell sorting. Functional consequences of site-specific promoter methylation were assessed by luciferase assays. RESULTS We identified 362 differentially methylated promoters in individuals with a history of abuse compared with controls. Among these promoters, 248 showed hypermethylation and 114 demonstrated hypomethylation. Validation and site-specific quantification of DNA methylation in the 5 most hypermethylated gene promoters indicated that methylation differences occurred mainly in the neuronal cellular fraction. Genes involved in cellular/neuronal plasticity were among the most significantly differentially methylated, and, among these, Alsin (ALS2) was the most significant finding. Methylated ALS2 constructs mimicking the methylation state in samples from abused suicide completers showed decreased promoter transcriptional activity associated with decreased hippocampal expression of ALS2 variants. CONCLUSION Childhood adversity is associated with epigenetic alterations in the promoters of several genes in hippocampal neurons. Language: en

A multisite study of the clinical diagnosis of different autism spectrum disorders

Abstract: Context Best-estimate clinical diagnoses of specific autism spectrum disorders (autistic disorder, pervasive developmental disorder–not otherwise specified, and Asperger syndrome) have been used as the diagnostic gold standard, even when information from standardized instruments is available. Objective To determine whether the relationships between behavioral phenotypes and clinical diagnoses of different autism spectrum disorders vary across 12 university-based sites. Design Multisite observational study collecting clinical phenotype data (diagnostic, developmental, and demographic) for genetic research. Classification trees were used to identify characteristics that predicted diagnosis across and within sites. Setting Participants were recruited through 12 university-based autism service providers into a genetic study of autism. Participants A total of 2102 probands (1814 male probands) between 4 and 18 years of age (mean [SD] age, 8.93 [3.5] years) who met autism spectrum criteria on the Autism Diagnostic Interview–Revised and the Autism Diagnostic Observation Schedule and who had a clinical diagnosis of an autism spectrum disorder. Main Outcome Measure Best-estimate clinical diagnoses predicted by standardized scores from diagnostic, cognitive, and behavioral measures. Results Although distributions of scores on standardized measures were similar across sites, significant site differences emerged in best-estimate clinical diagnoses of specific autism spectrum disorders. Relationships between clinical diagnoses and standardized scores, particularly verbal IQ, language level, and core diagnostic features, varied across sites in weighting of information and cutoffs. Conclusions Clinical distinctions among categorical diagnostic subtypes of autism spectrum disorders were not reliable even across sites with well-documented fidelity using standardized diagnostic instruments. Results support the move from existing subgroupings of autism spectrum disorders to dimensional descriptions of core features of social affect and fixated, repetitive behaviors, together with characteristics such as language level and cognitive function.

Preterm Birth and Psychiatric Disorders in Young Adult Life

Abstract: Context: Preterm birth, intrauterine growth restriction, and delivery-related hypoxia have been associated with schizophrenia. It is unclear whether these associations pertain to other adult-onset psychiatric disorders and whether these perinatal events are independent. Objective: To investigate the relationships among gestational age, nonoptimal fetal growth, Apgar score, and various psychiatric disorders in young adult life. Design: Historical population-based cohort study. Setting: Identification of adult-onset psychiatric admissions using data from the National Board of Health and Welfare, Stockholm, Sweden. Participants: All live-born individuals registered in the nationwide Swedish Medical Birth Register between 1973 and 1985 and living in Sweden at age 16 years by December 2002 (n=1 301 522). Main Outcome Measures: Psychiatric hospitalization with nonaffective psychosis, bipolar affective disorder, depressive disorder, eating disorder, drug dependency, or alcohol dependency, diagnosed according to the International Classification of Diseases codes for 8 through 10. Cox proportional hazards regression models were used to estimate hazard ratios and 95% CIs. Results: Preterm birth was significantly associated with increased risk of psychiatric hospitalization in adulthood (defined as16 years of age) in a monotonic manner across a range of psychiatric disorders. Compared with term births (37-41 weeks), those born at 32 to 36 weeks’ gestation were 1.6 (95% CI, 1.1-2.3) times more likely to have nonaffective psychosis, 1.3 (95% CI, 1.1-1.7) times more likely to have depressive disorder, and 2.7 (95% CI, 1.6-4.5) times more likely to have bipolar affective disorder. Those born at less than 32 weeks’ gestation were 2.5 (95% CI, 1.0-6.0) times more likely to have nonaffective psychosis, 2.9 (95% CI, 1.8-4.6) times more likely to have depressive disorder, and 7.4 (95% CI, 2.7-20.6) times more likely to have bipolar affective disorder. Conclusions: The vulnerability for hospitalization with a range of psychiatric diagnoses may increase with younger gestational age. Similar associations were not observed for nonoptimal fetal growth and low Apgar score.

Midlife vs Late-Life Depressive Symptoms and Risk of Dementia: Differential Effects for Alzheimer Disease and Vascular Dementia

Abstract: Context Depression and dementia are common in older adults and often co-occur, but it is unclear whether depression is an etiologic risk factor for dementia. Objective To clarify the timing and nature of the association between depression and dementia. Design We examined depressive symptoms assessed in midlife (1964-1973) and late life (1994-2000) and the risks of dementia, Alzheimer disease (AD), and vascular dementia (VaD) (2003-2009) in a retrospective cohort study. Depressive symptoms were categorized as none, midlife only, late life only, or both. Cox proportional hazards models (age as timescale) adjusted for demographics and medical comorbidities were used to examine depressive symptom category and risk of dementia, AD, or VaD. Setting Kaiser Permanente Medical Care Program of Northern California. Participants Thirteen thousand five hundred thirty-five long-term Kaiser Permanente members. Main Outcome Measure Any medical record diagnosis of dementia or neurology clinic diagnosis of AD or VaD. Results Subjects had a mean (SD) age of 81.1 (4.5) years in 2003, 57.9% were women, and 24.2% were nonwhite. Depressive symptoms were present in 14.1% of subjects in midlife only, 9.2% in late life only, and 4.2% in both. During 6 years of follow-up, 22.5% were diagnosed with dementia (5.5% with AD and 2.3% with VaD). The adjusted hazard of dementia was increased by approximately 20% for midlife depressive symptoms only (hazard ratio, 1.19 [95% CI, 1.07-1.32]), 70% for late-life symptoms only (1.72 [1.54-1.92]), and 80% for both (1.77 [1.52-2.06]). When we examined AD and VaD separately, subjects with late-life depressive symptoms only had a 2-fold increase in AD risk (hazard ratio, 2.06 [95% CI, 1.67-2.55]), whereas subjects with midlife and late-life symptoms had more than a 3-fold increase in VaD risk (3.51 [2.44-5.05]). Conclusions Depressive symptoms in midlife or in late life are associated with an increased risk of developing dementia. Depression that begins in late life may be part of the AD prodrome, while recurrent depression may be etiologically associated with increased risk of VaD.

From Perception to Functional Outcome in Schizophrenia: Modeling the Role of Ability and Motivation

Abstract: CONTEXT Schizophrenia remains a highly disabling disorder, but the specific determinants and pathways that lead to functional impairment are not well understood. It is not known whether these key determinants of outcome lie on 1 or multiple pathways. OBJECTIVE To evaluate theoretically based models of pathways to functional outcome starting with early visual perception. The intervening variables were previously established determinants of outcome drawn from 2 general categories: ability (ie, social cognition and functional capacity) and beliefs/motivation (ie, defeatist beliefs, expressive and experiential negative symptoms). We evaluated an integrative model in which these intervening variables formed a single pathway to poor outcome. DESIGN This was a cross-sectional study that applied structural equation modeling to evaluate the relationships among determinants of functional outcome in schizophrenia. SETTING Assessments were conducted at a Veterans Administration Medical Center. PARTICIPANTS One hundred ninety-one clinically stable outpatients with schizophrenia or schizoaffective disorder were recruited from the community. RESULTS A measurement model showed that the latent variables of perception, social cognition, and functional outcome were well reflected by their indicators. An initial untrimmed structural model with functional capacity, defeatist beliefs, and expressive and experiential negative symptoms had good model fit. A final trimmed model was a single path running from perception to ability to motivational variables to outcome. It was more parsimonious and had better fit indices than the untrimmed model. Further, it could not be improved by adding or dropping connections that would change the single path to multiple paths. The indirect effect from perception to outcome was significant. CONCLUSIONS The final structural model was a single pathway running from perception to ability to beliefs/motivation to outcome. Hence, both ability and motivation appear to be needed for community functioning and can be modeled effectively on the same pathway.

National Trends in the Office-Based Treatment of Children, Adolescents, and Adults With Antipsychotics

Abstract: sonsincreasedfrom0.24to1.83forchildren,0.78to3.76 for adolescents, and 3.25 to 6.18 for adults. The proportion of total visits that included a prescription of antipsychotics increased during this period from 0.16% to 1.07% for youths and from 0.88% to 1.73% for adults. From 2005 to 2009, disruptive behavior disorders were the most common diagnoses in child and adolescent antipsychotic visits, accounting for 63.0% and 33.7%, respectively, while depression (21.2%) and bipolar disorder (20.2%) were the 2 most common diagnoses in adult antipsychotic visits. Psychiatrists provided a larger proportion of the antipsychotic visits for children (67.7%) andadolescents(71.6%)thantoadults(50.3%)(P.001). From2005to2009,antipsychoticswereincludedin28.8% of adult visits and 31.1% of youth visits to psychiatrists. Conclusions: On a population basis, adults make considerably more medical visits with a prescription of antipsychotics than do adolescents or children. Yet antipsychotic treatment has increased especially rapidly among young people, and recently antipsychotics have been prescribed in approximately the same proportion of youth and adult visits to psychiatrists.

Use and abuse of alcohol and illicit drugs in US adolescents: results of the National Comorbidity Survey-Adolescent Supplement.

Abstract: Context Comprehensive descriptions of substance use and abuse trajectories have been lacking in nationally representative samples of adolescents. Objective To examine the prevalence, age at onset, and sociodemographic correlates of alcohol and illicit drug use and abuse among US adolescents. Design Cross-sectional survey of adolescents using a modified version of the Composite International Diagnostic Interview. Setting Combined household and school adolescent samples. Participants Nationally representative sample of 10 123 adolescents aged 13 to 18 years. Main Outcome Measures Lifetime estimates of alcohol and illicit substance use and DSM-IV diagnoses of abuse, with or without dependence. Results By late adolescence, 78.2% of US adolescents had consumed alcohol, 47.1% had reached regular drinking levels defined by at least 12 drinks within a given year, and 15.1% met criteria for lifetime abuse. The opportunity to use illicit drugs was reported by 81.4% of the oldest adolescents, drug use by 42.5%, and drug abuse by 16.4%. The median age at onset was 14 years for alcohol abuse with or without dependence, 14 years for drug abuse with dependence, and 15 years for drug abuse without dependence. The associations observed by age, sex, and race/ethnicity often varied significantly by previous stage of use. Conclusions Alcohol and drug use is common in US adolescents, and the findings of this study indicate that most cases of abuse have their initial onset in this important period of development. Prevention and treatment efforts would benefit from careful attention to the correlates and risk factors that are specific to the stage of substance use in adolescents.

Randomized Trial to Evaluate the Efficacy of Cognitive Therapy for Low-Functioning Patients With Schizophrenia.

Abstract: Context: Low-functioning patients with chronic schizophrenia have high direct treatment costs and indirect costs incurred due to lost employment and productivity and have a low quality of life; antipsychotic medications and psychosocial interventions have shown limited efficacy to promote improved functional outcomes. Objective: To determine the efficacy of an 18-month recovery-oriented cognitive therapy program to improve psychosocial functioning and negative symptoms (avolition-apathy, anhedonia-asociality) in lowfunctioning patients with schizophrenia. Design, Setting, and Participants: A single-center, 18-month, randomized, single-blind, parallel group trial enrolled 60 low-functioning, neurocognitively impaired patients with schizophrenia (mean age, 38.4 years; 33.3% female; 65.0% African American). Interventions: Cognitive therapy plus standard treatment vs standard treatment alone. Main Outcome Measures: The primary outcome measure was the Global Assessment Scale score at 18 months after randomization. The secondary outcomes were scores on the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms at 18 months after randomization. Results: Patients treated with cognitive therapy showed a clinically significant mean improvement in global functioning from baseline to 18 months that was greater than the improvement seen with standard treatment (withingroup Cohen d, 1.36 vs 0.06, respectively; adjusted mean [SE], 58.3 [3.30] vs 47.9 [3.60], respectively; P=.03; between-groupd=0.56). Patients receiving cognitive therapy as compared with those receiving standard treatment also showed a greater mean reduction in avolition-apathy (adjusted mean [SE], 1.66 [0.31] vs 2.81 [0.34], respectively; P=.01; between-group d=�0.66) and positive symptoms (hallucinations, delusions, disorganization) (adjusted mean [SE], 9.4 [3.3] vs 18.2 [3.8], respectively;P=.04; betweengroup d=�0.46) at 18 months. Age was controlled in the analyses, and there were no meaningful group differences in baseline antipsychotic medications (class or dosage) or in medication changes during the course of the trial. Conclusion: Cognitive therapy can be successful in promoting clinically meaningful improvements in functional outcome, motivation, and positive symptoms in lowfunctioning patients with significant cognitive impairment. Trial Registration: clinicaltrials.gov Identifier: NCT00350883

Dopaminergic Mechanisms of Reduced Basal Ganglia Responses to Hedonic Reward During Interferon Alfa Administration

Abstract: Context Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function. Objectives To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior. Design Cross-sectional and longitudinal studies. Setting Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia. Patients Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment. Main Outcome Measures Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa–induced depression, anhedonia, fatigue, and neurotoxicity. Results Patients with HCV receiving interferon alfa for 4 to 6 weeks (n = 14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n = 14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n = 12) exhibited significantly increased 18F-dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration. Conclusions These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release.

Elevated prefrontal cortex γ-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy.

Abstract: Context: Postmortem studies have found evidence of -aminobutyric acid (GABA) deficits in fast-spiking, parvalbumin-positive interneurons in the prefrontal cortex in schizophrenia. Magnetic resonance spectroscopy studies in unmedicated patients have reported glutamine or glutamate-glutamine (Glx) elevations in this region. Abnormalities in these transmitters are thought to play a role in cognitive impairments in the illness. Objective: To measure GABA and Glx levels in vivo in 2 prefrontal brain regions in unmedicated and medicated patients with schizophrenia and healthy controls. Design: Case-control study. Setting: Inpatient psychiatric research unit and associated outpatient clinic. Participants: Sixteen unmedicated patients with schizophrenia, 16 medicated patients, and 22 healthy controls matched for age, sex, ethnicity, parental socioeconomic status, and cigarette smoking. Methods: Proton magnetic resonance spectroscopy with a 3-T system and the J-edited spin-echo difference method. The GABA and Glx levels were measured in the dorsolateral and medial prefrontal cortex and normalized to the simultaneously acquired water signal. Working memory performance was assessed in all subjects. Main Outcome Measures: The GABA and Glx concentrations determined by proton magnetic resonance spectroscopy.

Negative Symptoms and the Failure to Represent the Expected Reward Value of Actions: Behavioral and Computational Modeling Evidence

Abstract: Context Negative symptoms are a core feature of schizophrenia, but their pathogenesis remains unclear. Negative symptoms are defined by the absence of normal function. However, there must be a productive mechanism that leads to this absence. Objective To test a reinforcement learning account suggesting that negative symptoms result from a failure in the representation of the expected value of rewards coupled with preserved loss-avoidance learning. Design Participants performed a probabilistic reinforcement learning paradigm involving stimulus pairs in which choices resulted in reward or in loss avoidance. Following training, participants indicated their valuation of the stimuli in a transfer test phase. Computational modeling was used to distinguish between alternative accounts of the data. Setting A tertiary care research outpatient clinic. Patients In total, 47 clinically stable patients with a diagnosis of schizophrenia or schizoaffective disorder and 28 healthy volunteers participated in the study. Patients were divided into a high-negative symptom group and a low-negative symptom group. Main Outcome Measures The number of choices leading to reward or loss avoidance, as well as performance in the transfer test phase. Quantitative fits from 3 different models were examined. Results Patients in the high-negative symptom group demonstrated impaired learning from rewards but intact loss-avoidance learning and failed to distinguish rewarding stimuli from loss-avoiding stimuli in the transfer test phase. Model fits revealed that patients in the high-negative symptom group were better characterized by an“actor-critic” model, learning stimulus-response associations, whereas control subjects and patients in the low-negative symptom group incorporated expected value of their actions (“Q learning”) into the selection process. Conclusions Negative symptoms in schizophrenia are associated with a specific reinforcement learning abnormality: patients with high-negative symptoms do not represent the expected value of rewards when making decisions but learn to avoid punishments through the use of prediction errors. This computational framework offers the potential to understand negative symptoms at a mechanistic level.

Cost-effectiveness of a Multicondition Collaborative Care Intervention: A Randomized Controlled Trial

Abstract: Context Patients with depression and poorly controlled diabetes mellitus, coronary heart disease (CHD), or both have higher medical complication rates and higher health care costs, suggesting that more effective care management of psychiatric and medical disease control might also reduce medical service use and enhance quality of life. Objective To evaluate the cost-effectiveness of a multicondition collaborative treatment program (TEAMcare) compared with usual primary care (UC) in outpatients with depression and poorly controlled diabetes or CHD. Design Randomized controlled trial of a systematic care management program aimed at improving depression scores and hemoglobin A 1c (HbA 1c ), systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) levels. Setting Fourteen primary care clinics of an integrated health care system. Patients Population-based screening identified 214 adults with depressive disorder and poorly controlled diabetes or CHD. Intervention Physician-supervised nurses collaborated with primary care physicians to provide treatment of multiple disease risk factors. Main Outcome Measures Blinded assessments evaluated depressive symptoms, SBP, and HbA 1c at baseline and at 6, 12, 18, and 24 months. Fasting LDL-C concentration was assessed at baseline and at 12 and 24 months. Health plan accounting records were used to assess medical service costs. Quality-adjusted life-years (QALYs) were assessed using a previously developed regression model based on intervention vs UC differences in HbA 1c , LDL-C, and SBP levels over 24 months. Results Over 24 months, compared with UC controls, intervention patients had a mean of 114 (95% CI, 79 to 149) additional depression-free days and an estimated 0.335 (95% CI, −0.18 to 0.85) additional QALYs. Intervention patients also had lower mean outpatient health costs of $594 per patient (95% CI, −$3241 to $2053) relative to UC patients. Conclusions For adults with depression and poorly controlled diabetes, CHD, or both, a systematic intervention program aimed at improving depression scores and HbA 1c , SBP, and LDL-C levels seemed to be a high-value program that for no or modest additional cost markedly improved QALYs. Trial Registration clinicaltrials.gov Identifier: NCT00468676

Benefits From Antidepressants: Synthesis of 6-Week Patient-Level Outcomes From Double-blind Placebo-Controlled Randomized Trials of Fluoxetine and Venlafaxine

Abstract: Context Some meta-analyses suggest that efficacy of antidepressants for major depression is overstated and limited to severe depression. Objective To determine the short-term efficacy of antidepressants for treating major depressive disorder in youth, adult, and geriatric populations. Data Sources Reanalysis of all intent-to-treat person-level longitudinal data during the first 6 weeks of treatment of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride. Study Selection All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine. Data Extraction Children's Depression Rating Scale–Revised scores (youth population), Hamilton Depression Rating Scale scores (adult and geriatric populations), and estimated response and remission rates at 6 weeks were analyzed for 2635 adults, 960 geriatric patients, and 708 youths receiving fluoxetine and for 2421 adults receiving immediate-release venlafaxine and 2461 adults receiving extended-release venlafaxine. Data Synthesis Patients in all age and drug groups had significantly greater improvement relative to control patients receiving placebo. The differential rate of improvement was largest for adults receiving fluoxetine (34.6% greater than those receiving placebo). Youths had the largest treated vs control difference in response rates (24.1%) and remission rates (30.1%), with adult differences generally in the 15.6% (remission) to 21.4% (response) range. Geriatric patients had the smallest drug-placebo differences, an 18.5% greater rate of improvement, 9.9% for response and 6.5% for remission. Immediate-release venlafaxine produced larger effects than extended-release venlafaxine. Baseline severity could not be shown to affect symptom reduction. Conclusions To our knowledge, this is the first research synthesis in this area to use complete longitudinal person-level data from a large set of published and unpublished studies. The results do not support previous findings that antidepressants show little benefit except for severe depression. The antidepressants fluoxetine and venlafaxine are efficacious for major depressive disorder in all age groups, although more so in youths and adults compared with geriatric patients. Baseline severity was not significantly related to degree of treatment advantage over placebo.

Randomized Trial of Behavior Therapy for Adults With Tourette Syndrome

Abstract: Context Tics in Tourette syndrome begin in childhood, peak in early adolescence, and often decrease by early adulthood. However, some adult patients continue to have impairing tics. Medications for tics are often effective but can cause adverse effects. Behavior therapy may offer an alternative but has not been examined in a large-scale controlled trial in adults. Objective To test the efficacy of a comprehensive behavioral intervention for tics in adults with Tourette syndrome of at least moderate severity. Design A randomized controlled trial with posttreatment evaluations at 3 and 6 months for positive responders. Setting Three outpatient research clinics. Patients Patients (N = 122; 78 males; age range, 16-69 years) with Tourette syndrome or chronic tic disorder were recruited between December 27, 2005, and May 21, 2009. Interventions Patients received 8 sessions of comprehensive behavioral intervention for tics or 8 sessions of supportive treatment for 10 weeks. Patients with a positive response were given 3 monthly booster sessions. Main Outcome Measures Total tic score on the Yale Global Tic Severity Scale and the Clinical Global Impression–Improvement scale rated by a clinician masked to treatment assignment. Results Behavior therapy was associated with a significantly greater mean (SD) decrease on the Yale Global Tic Severity Scale (24.0 [6.47] to 17.8 [7.32]) from baseline to end point compared with the control treatment (21.8 [6.59] to 19.3 [7.40]) (P Conclusion Comprehensive behavior therapy is a safe and effective intervention for adults with Tourette syndrome. Trial Registration clinicaltrials.gov Identifier: NCT00231985

Autism Spectrum Disorders and Autisticlike Traits Similar Etiology in the Extreme End and the Normal Variation

Abstract: Context: Autism spectrum disorders (ASDs) have been suggested to represent the extreme end of a normal distribution of autistic like traits (ALTs). However, the evidence of this notion is inconclus ...

Neural Responses to Affective and Cognitive Theory of Mind in Children With Conduct Problems and Varying Levels of Callous-Unemotional Traits

Abstract: Context Reduced neural responses to others' distress is hypothesized to play a critical role in conduct problems coupled with callous-unemotional traits, whereas increased neural responses to affective stimuli may accompany conduct problems without callous-unemotional traits. Heterogeneity of affective profiles in conduct problems may account for inconsistent neuroimaging findings in this population. Objectives To broaden understanding of neural processing in conduct problems using an affective processing task including an empathy component as well as to explore dimensional contributions of conduct problems symptoms and callous-unemotional traits to variance in affective neural responses. Design Case-control study. Setting On-campus neuroimaging facility. Participants Thirty-one boys with conduct problems (mean age, 14.34 years) and 16 typically developing control subjects (mean age, 13.51 years) matched for age (range, 10-16 years), IQ, socioeconomic status, handedness, and race/ethnicity. Participants were recruited using screening questionnaires in a community-based volunteer sample. Main Outcome Measures Functional magnetic resonance imaging of a task contrasting affective and cognitive theory of mind judgments. Results Relative to typically developing children, children with conduct problems showed reduced activation in right amygdala and anterior insula for affective vs cognitive theory of mind judgments. Furthermore, in the right amygdala, regression analysis within the conduct-problems group showed suppressor effects between ratings of conduct problems and callous-unemotional traits. Specifically, unique variance associated with conduct problems was positively correlated with amygdala reactivity, whereas unique variance associated with callous-unemotional traits was negatively correlated with amygdala reactivity. These associations were not explained by hyperactivity, depression/anxiety symptoms, or alcohol use ratings. Conclusions Childhood conduct problems are associated with amygdala and anterior insula hypoactivity during a complex affective processing task including an empathy component. Suppressor effects between conduct problems and callous-unemotional traits in the amygdala suggest a potential neural substrate for heterogeneity in affective profiles associated with conduct problems.

Suicidal Thoughts and Behavior With Antidepressant Treatment: Reanalysis of the Randomized Placebo-Controlled Studies of Fluoxetine and Venlafaxine

Abstract: Context The US Food and Drug Administration issued a black box warning for antidepressants and suicidal thoughts and behavior in children and young adults. Objective To determine the short-term safety of antidepressants by standard assessments of suicidal thoughts and behavior in youth, adult, and geriatric populations and the mediating effect of changes in depressive symptoms. Data Sources All intent-to-treat person-level longitudinal data of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride. Study Selection All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine. Data Extraction The suicide items from the Children's Depression Rating Scale–Revised and the Hamilton Depression Rating Scale as well as adverse event reports of suicide attempts and suicide during active treatment were analyzed in 9185 patients (fluoxetine: 2635 adults, 960 geriatric patients, 708 youths; venlafaxine: 2421 adults with immediate-release venlafaxine and 2461 adults with extended-release venlafaxine) for a total of 53 260 person-week observations. Data Synthesis Suicidal thoughts and behavior decreased over time for adult and geriatric patients randomized to fluoxetine or venlafaxine compared with placebo, but no differences were found for youths. In adults, reduction in suicide ideation and attempts occurred through a reduction in depressive symptoms. In all age groups, severity of depression improved with medication and was significantly related to suicide ideation or behavior. Conclusions Fluoxetine and venlafaxine decreased suicidal thoughts and behavior for adult and geriatric patients. This protective effect is mediated by decreases in depressive symptoms with treatment. For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment. No evidence of increased suicide risk was observed in youths receiving active medication. To our knowledge, this is the first research synthesis of suicidal thoughts and behavior in depressed patients treated with antidepressants that examined the mediating role of depressive symptoms using complete longitudinal person-level data from a large set of published and unpublished studies.

Effect of Brain Structure, Brain Function, and Brain Connectivity on Relapse in Alcohol-Dependent Patients

Abstract: Context In alcohol-dependent patients, brain atrophy and functional brain activation elicited by alcohol-associated stimuli may predict relapse. However, to date, the interaction between both factors has not been studied. Objective To determine whether results from structural and functional magnetic resonance imaging are associated with relapse in detoxified alcohol-dependent patients. Design A cue-reactivity functional magnetic resonance experiment with alcohol-associated and neutral stimuli. After a follow-up period of 3 months, the group of 46 detoxified alcohol-dependent patients was subdivided into 16 abstainers and 30 relapsers. Setting Faculty for Clinical Medicine Mannheim at the University of Heidelberg, Germany. Participants A total of 46 detoxified alcohol-dependent patients and 46 age- and sex-matched healthy control subjects Main Outcome Measures Local gray matter volume, local stimulus–related functional magnetic resonance imaging activation, joint analyses of structural and functional data with Biological Parametric Mapping, and connectivity analyses adopting the psychophysiological interaction approach. Results Subsequent relapsers showed pronounced atrophy in the bilateral orbitofrontal cortex and in the right medial prefrontal and anterior cingulate cortex, compared with healthy controls and patients who remained abstinent. The local gray matter volume–corrected brain response elicited by alcohol-associated vs neutral stimuli in the left medial prefrontal cortex was enhanced for subsequent relapsers, whereas abstainers displayed an increased neural response in the midbrain (the ventral tegmental area extending into the subthalamic nucleus) and ventral striatum. For alcohol-associated vs neutral stimuli in abstainers compared with relapsers, the analyses of the psychophysiological interaction showed a stronger functional connectivity between the midbrain and the left amygdala and between the midbrain and the left orbitofrontal cortex. Conclusions Subsequent relapsers displayed increased brain atrophy in brain areas associated with error monitoring and behavioral control. Correcting for gray matter reductions, we found that, in these patients, alcohol-related cues elicited increased activation in brain areas associated with attentional bias toward these cues and that, in patients who remained abstinent, increased activation and connectivity were observed in brain areas associated with processing of salient or aversive stimuli.

Brain anatomy and its relationship to behavior in adults with autism spectrum disorder: a multicenter magnetic resonance imaging study.

Abstract: Context There is consensus that autism spectrum disorder (ASD) is accompanied by differences in neuroanatomy. However, the neural substrates of ASD during adulthood, as well as how these relate to behavioral variation, remain poorly understood. Objective To identify brain regions and systems associated with ASD in a large, well-characterized sample of adults. Design Multicenter case-control design using quantitative magnetic resonance imaging. Setting Medical Research Council UK Autism Imaging Multicentre Study (MRC AIMS), with sites comprising the Institute of Psychiatry, Kings College London; the Autism Research Centre, University of Cambridge; and the Autism Research Group, University of Oxford. Participants Eighty-nine men with ASD and 89 male control participants who did not differ significantly in mean age (26 and 28 years, respectively) and full-scale IQ (110 and 113, respectively). Main Outcome Measures (1) Between-group differences in regional neuroanatomy assessed by voxel-based morphometry and (2) distributed neural systems maximally correlated with ASD, as identified by partial least-squares analysis. Results Adults with ASD did not differ significantly from the controls in overall brain volume, confirming the results of smaller studies of individuals in this age group without intellectual disability. However, voxelwise comparison between groups revealed that individuals with ASD had significantly increased gray matter volume in the anterior temporal and dorsolateral prefrontal regions and significant reductions in the occipital and medial parietal regions compared with controls. These regional differences in neuroanatomy were significantly correlated with the severity of specific autistic symptoms. The large-scale neuroanatomic networks maximally correlated with ASD identified by partial least-squares analysis included the regions identified by voxel-based analysis, as well as the cerebellum, basal ganglia, amygdala, inferior parietal lobe, cingulate cortex, and various medial, orbital, and lateral prefrontal regions. We also observed spatially distributed reductions in white matter volume in participants with ASD. Conclusions Adults with ASD have distributed differences in brain anatomy and connectivity that are associated with specific autistic features and traits. These results are compatible with the concept of autism as a syndrome characterized by atypical neural“connectivity.”

Amygdala Volume Changes in Posttraumatic Stress Disorder in a Large Case-Controlled Veterans Group

Abstract: Context Smaller hippocampal volumes are well established in posttraumatic stress disorder (PTSD), but the relatively few studies of amygdala volume in PTSD have produced equivocal results. Objective To assess a large cohort of recent military veterans with PTSD and trauma-exposed control subjects, with sufficient power to perform a definitive assessment of the effect of PTSD on volumetric changes in the amygdala and hippocampus and of the contribution of illness duration, trauma load, and depressive symptoms. Design Case-controlled design with structural magnetic resonance imaging and clinical diagnostic assessments. We controlled statistically for the important potential confounds of alcohol use, depression, and medication use. Setting Durham Veterans Affairs Medical Center, which is located in proximity to major military bases. Patients Ambulatory patients (n = 200) recruited from a registry of military service members and veterans serving after September 11, 2001, including a group with current PTSD (n = 99) and a trauma-exposed comparison group without PTSD (n = 101). Main Outcome Measure Amygdala and hippocampal volumes computed from automated segmentation of high-resolution structural 3-T magnetic resonance imaging. Results Smaller volume was demonstrated in the PTSD group compared with the non-PTSD group for the left amygdala (P = .002), right amygdala (P = .01), and left hippocampus (P = .02) but not for the right hippocampus (P = .25). Amygdala volumes were not associated with PTSD chronicity, trauma load, or severity of depressive symptoms. Conclusions These results provide clear evidence of an association between a smaller amygdala volume and PTSD. The lack of correlation between trauma load or illness chronicity and amygdala volume suggests that a smaller amygdala represents a vulnerability to developing PTSD or the lack of a dose-response relationship with amygdala volume. Our results may trigger a renewed impetus for investigating structural differences in the amygdala, its genetic determinants, its environmental modulators, and the possibility that it reflects an intrinsic vulnerability to PTSD.

Prevention of posttraumatic stress disorder by early treatment: results from the Jerusalem Trauma Outreach And Prevention study.

Abstract: Context Preventing posttraumatic stress disorder (PTSD) is a pressing public health need. Objectives To compare early and delayed exposure-based, cognitive, and pharmacological interventions for preventing PTSD. Design Equipoise-stratified randomized controlled study. Setting Hadassah Hospital unselectively receives trauma survivors from Jerusalem and vicinity. Participants Consecutively admitted survivors of traumatic events were assessed by use of structured telephone interviews a mean (SD) 9.61 (3.91) days after the traumatic event. Survivors with symptoms of acute stress disorder were referred for clinical assessment. Survivors who met PTSD symptom criteria during the clinical assessment were invited to receive treatment. Interventions Twelve weekly sessions of prolonged exposure (PE; n = 63), or cognitive therapy (CT; n = 40), or double blind treatment with 2 daily tablets of either escitalopram (10 mg) or placebo (selective serotonin reuptake inhibitor/placebo; n = 46), or 12 weeks in a waiting list group (n = 93). Treatment started a mean (SD) 29.8 (5.7) days after the traumatic event. Waiting list participants with PTSD after 12 weeks received PE a mean (SD) 151.8 (42.4) days after the traumatic event (delayed PE). Main Outcome Measure Proportion of participants with PTSD after treatment, as determined by the use of the Clinician-Administered PTSD Scale (CAPS) 5 and 9 months after the traumatic event. Treatment assignment and attendance were concealed from the clinicians who used the CAPS. Results At 5 months, 21.6% of participants who received PE and 57.1% of comparable participants on the waiting list had PTSD (odds ratio [OR], 0.21 [95% CI, 0.09-0.46]). At 5 months, 20.0% of participants who received CT and 58.7% of comparable participants on the waiting list had PTSD (OR, 0.18 [CI, 0.06-0.48]). The PE group did not differ from the CT group with regard to PTSD outcome (OR, 0.87 [95% CI, 0.29-2.62]). The PTSD prevalence rates did not differ between the escitalopram and placebo subgroups (61.9% vs 55.6%; OR, 0.77 [95% CI, 0.21-2.77]). At 9 months, 20.8% of participants who received PE and 21.4% of participants on the waiting list had PTSD (OR, 1.04 [95% CI, 0.40-2.67]). Participants with partial PTSD before treatment onset did similarly well with and without treatment. Conclusions Prolonged exposure, CT, and delayed PE effectively prevent chronic PTSD in recent survivors. The lack of improvement from treatment with escitalopram requires further evaluation. Trauma-focused clinical interventions have no added benefit to survivors with subthreshold PTSD symptoms. Trial Registration clinicaltrials.gov Identifier: NCT00146900