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mediating role of depressive symptoms using complete longitudinal person-level data from a large set of published and unpublished studies.

Objective  To determine whether African American individuals would continue to exhibit significantly higher rates of clinical diagnoses of schizophrenia, even after controlling for age, sex, income, site, and education, as well as the presence or absence of serious affective disorder, as determined by experts blinded to race and ethnicity. A secondary objective was to determine if a similar pattern occurred in Latino subjects.

Design  Ethnicity-blinded and -unblinded diagnostic assessments were obtained in 241 African American individuals (mean [SD] age, 34.3 [8.1] years; 57% women), 220 non-Latino white individuals (mean [SD] age, 32.7 [8.5] years; 53% women), and 149 Latino individuals (mean [SD] age, 33.5 [8.0] years; 58% women) at 6 US sites. Logistic regression models were used to determine whether elevated rates of schizophrenia in African American individuals would persist after controlling for various confounding variables including blinded expert consensus diagnoses of serious affective illness.

Settings  Six academic medical centers across the United States.

Participants  Six hundred ten psychiatric inpatients and outpatients.

Main Outcome Measure  Relative odds of unblinded clinical diagnoses of schizophrenia in African American compared with white individuals.

Results  A significant ethnicity/race effect (²₂ = 10.4, P = .01) was obtained when schizophrenia was narrowly defined, controlling for all other predictors. The odds ratio comparing African American with non-Latino white individuals was significant (odds ratio = 2.7; 95% CI, 1.5-5.1). Similar differences between African American and white individuals occurred when schizophrenia was more broadly defined (odds ratio = 2.5; 95% CI, 1.4-4.5). African American individuals did not differ significantly from white individuals in overall severity of manic and depressive symptoms but did evidence more severe psychosis.

Conclusions  African American individuals exhibited significantly higher rates of clinical diagnoses of schizophrenia than non-Latino white subjects, even after controlling for covariates such as serious affective disorder.

Objective  To examine the association between smoking history and cognitive decline in the transition from midlife to old age.

Design  Cohort study.

Setting  The Whitehall II study. The first cognitive assessment was in 1997 to 1999, repeated over 2002 to 2004 and 2007 to 2009.

Participants  Data are from 5099 men and 2137 women in the Whitehall II study, mean age 56 years (range, 44-69 years) at the first cognitive assessment.

Main Outcome Measures  The cognitive test battery was composed of tests of memory, vocabulary, executive function (composed of 1 reasoning and 2 fluency tests), and a global cognitive score summarizing performance across all 5 tests. Smoking status was assessed over the entire study period. Linear mixed models were used to assess the association between smoking history and 10-year cognitive decline, expressed as z scores.

Results  In men, 10-year cognitive decline in all tests except vocabulary among never smokers ranged from a quarter to a third of the baseline standard deviation. Faster cognitive decline was observed among current smokers compared with never smokers in men (mean difference in 10-year decline in global cognition = –0.09 [95% CI, –0.15 to –0.03] and executive function = –0.11 [95% CI, –0.17 to –0.05]). Recent ex-smokers had greater decline in executive function (–0.08 [95% CI, –0.14 to –0.02]), while the decline in long-term ex-smokers was similar to that among never smokers. In analyses that additionally took dropout and death into account, these differences were 1.2 to 1.5 times larger. In women, cognitive decline did not vary as a function of smoking status.

Conclusions  Compared with never smokers, middle-aged male smokers experienced faster cognitive decline in global cognition and executive function. In ex-smokers with at least a 10-year cessation, there were no adverse effects on cognitive decline.

Objective  To compare the copy number intensities of genes associated with GAD67 regulation in the stratum oriens of sectors CA3/2 and CA1 in patients with schizophrenia, patients with bipolar disorder, and healthy controls.

Design  Samples of sectors CA3/2 and CA1 were obtained from patients with schizophrenia, patients with bipolar disorder, and healthy controls. Genomic integrity was analyzed using microarrays, and the copy number intensities identified were correlated with the gene expression profile from a subset of these cases previously reported.

Setting  Harvard Brain Tissue Resource Center at McLean Hospital, Belmont, Massachusetts.

Patients  A total of 15 patients with schizophrenia, 15 patients with bipolar disorder, and 15 healthy controls.

Main Outcome Measures  The copy number intensities for 28 target genes were individually examined using single-nucleotide polymorphism microarrays and correlated with homologous messenger RNA (mRNA) fold changes.

Results  The copy number intensities examined using both microarrays and quantitative real-time polymerase chain reaction for the GAD67 gene were significantly decreased in sector CA3/2 of patients with schizophrenia and patients with bipolar disorder. Other genes associated with GAD67 regulation also showed changes in copy number intensities, and these changes were similar in magnitude and direction to those previously reported for mRNA fold changes in sector CA3/2 but not sector CA1. Moreover, the copy number intensities and mRNA fold changes were significantly correlated for both patients with schizophrenia (r = 0.649; P = .0003) and patients with bipolar disorder (r = 0.772; P = .0002) in sector CA3/2 but not in sector CA1.

Conclusion  Insertions and deletions of genomic DNA in -aminobutyric acid cells at a key locus of the hippocampal circuit are reflected in transcriptional changes in GAD67 regulation that are circuitry-based and diagnosis-specific.

Objective  To investigate this suggestion using follow-up assessments of hospitalization for clinical diagnoses of nonaffective psychotic and other psychiatric disorders.

Design  Longitudinal cohort study of self-reported APSs with outcome assessment of severe mental illness obtained through linkage with a national hospitalization case registry.

Setting  Israel.

Participants  A stratified full probability sample of 4914 persons aged 25 to 34 years who were screened for psychopathology in the 1980s.

Main Outcome Measure  Subsequent psychiatric hospitalization was ascertained using the psychiatric hospitalization registry, with a mean follow-up of 24 years.

Results  After removing subjects with diagnosable psychotic disorders at baseline, 57.2% of the remaining sample reported at least 1 weak (infrequent) APS and 14.3% reported at least 1 strong (frequent) APS in the year preceding the assessment. Self-reported APSs predicted risk of later hospitalization for nonaffective psychotic disorders, mostly during the 5 years after baseline (adjusted odds ratio = 4.31; 95% CI, 2.21-8.41; positive predictive value = 1.27%; population attributable risk fraction = 33%). Also, APSs increased the risk of later hospitalization for other psychiatric disorders, albeit to a lesser extent (adjusted odds ratio = 2.21; 95% CI, 1.02-4.82).

Conclusions  Self-reported APSs signal risk for later nonaffective psychotic disorders but are not clinically useful as predictors. The difference between these population-based data and the high-risk literature in terms of the positive predictive value (1% vs 10%, respectively) and the time window of transition (5 years vs 12 months, respectively) can be attributed to the selective enrichment strategies that produce high-risk samples.

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.

Results  In the medial prefrontal cortex region, 30% elevations were found in GABA (P = .02) and Glx (P = .03) levels in unmedicated patients compared with controls. There were no alterations in the medicated patients or in either group in the dorsolateral prefrontal cortex. Both regions showed correlations between GABA and Glx levels in patients and controls. No correlations with working memory performance were found.

Conclusions  To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies.

Objective  To investigate which medication to administer first to antimanic medication–naive subjects.

Design, Setting, and Participants  The Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments.

Interventions  Subjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 μg/mL), and risperidone (4-6 mg).

Main Outcome Measures  Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement–Mania and the Modified Side Effects Form for Children and Adolescents.

Results  There were 279 antimanic medication–naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) μg/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; ²₁ = 16.9, P < .001) and vs divalproex sodium (68.5% vs 24.0%; ²₁ = 28.3, P < .001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (²₁ = 6.4, P = .011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F_1,212 = 45.5, P < .001; F_1,212 = 39.1, P < .001; and F_1,213 = 191.4, P < .001, respectively) and vs divalproex sodium (F_1,212 = 34.7, P < .001; F_1,212 = 45.3, P < .001; and F_1,213 = 209.4, P < .001, respectively). The thyrotropin level increased in subjects taking lithium (t₆₂ = 11.3, P < .001).

Conclusions  Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects.

Trial Registration  clinicaltrials.gov Identifier: NCT00057681

Objective  To present estimates of 12-month and 30-day prevalence, persistence (12-month prevalence among lifetime cases and 30-day prevalence among 12-month cases), and sociodemographic correlates of commonly occurring DSM-IV disorders among adolescents in the National Comorbidity Survey Replication Adolescent Supplement.

Design  The National Comorbidity Survey Replication Adolescent Supplement is a US national survey of DSM-IV anxiety, mood, behavior, and substance disorders among US adolescents based on face-to-face interviews in the homes of respondents with supplemental parent questionnaires.

Setting  Dual-frame household and school samples of US adolescents.

Participants  A total of 10 148 adolescents aged 13 to 17 years (interviews) and 1 parent of each adolescent (questionnaires).

Main Outcome Measures  The DSM-IV disorders assessed with the World Health Organization Composite International Diagnostic Interview and validated with blinded clinical interviews based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children. Good concordance (area under the receiver operating characteristic curve ≥0.80) was found between Composite International Diagnostic Interview and Schedule for Affective Disorders and Schizophrenia for School-Age Children diagnoses.

Results  The prevalence estimates of any DSM-IV disorder are 40.3% at 12 months (79.5% of lifetime cases) and 23.4% at 30 days (57.9% of 12-month cases). Anxiety disorders are the most common class of disorders, followed by behavior, mood, and substance disorders. Although relative disorder prevalence is quite stable over time, 30-day to 12-month prevalence ratios are higher for anxiety and behavior disorders than mood or substance disorders, suggesting that the former are more chronic than the latter. The 30-day to 12-month prevalence ratios are generally lower than the 12-month to lifetime ratios, suggesting that disorder persistence is due more to episode recurrence than to chronicity. Sociodemographic correlates are largely consistent with previous studies.

Conclusions  Among US adolescents, DSM-IV disorders are highly prevalent and persistent. Persistence is higher for adolescents than among adults and appears to be due more to recurrence than chronicity of child-adolescent onset disorders.

Objective  To study to what extent psychiatric disorders with postpartum onset are early manifestations of an underlying bipolar affective disorder.

Design  Survival analyses were performed in a register-based cohort study linking information from the Danish Civil Registration System and the Danish Psychiatric Central Register.

Setting  Denmark.

Participants  A total of 120 378 women with a first-time psychiatric inpatient or outpatient contact with any type of mental disorder excluding bipolar affective disorder.

Main Outcome Measures  Each woman was followed up individually from the day of discharge, with the outcome of interest being an inpatient or outpatient contact during the follow-up period with a first-time diagnosis of bipolar affective disorder.

Results  A total of 3062 women were readmitted or had an outpatient contact with bipolar affective disorder diagnoses. A postpartum onset of symptoms within 0 to 14 days after delivery predicted subsequent conversion to bipolar disorder (relative risk = 4.26; 95% CI =3.11-5.85). Approximately 14% of women with first-time psychiatric contacts during the first postpartum month converted to a bipolar diagnosis within the 15-year follow-up period compared with 4% of women with a first psychiatric contact not related to childbirth. Postpartum inpatient admissions were also associated with higher conversion rates to bipolar disorder than outpatient contacts (relative risk = 2.16; 95% CI = 1.27-3.66).

Conclusions  A psychiatric episode in the immediate postpartum period significantly predicted conversion to bipolar affective disorder during the follow-up period. Results indicate that the presentation of mental illness in the early postpartum period is a marker of possible underlying bipolarity.

Objective  To determine whether MDMA use is associated with chronic reductions in serotonin signaling in the cerebral cortex of women as reflected by increased serotonin_2A receptor levels.

Design  Cross-sectional case-control study comparing serotonin_2A receptor levels in abstinent female MDMA polydrug users with those in women who did not use MDMA (within-group design assessing the association of lifetime MDMA use and serotonin_2A receptors). Case participants were abstinent from MDMA use for at least 90 days as verified by analysis of hair samples. The serotonin_2A receptor levels in the cerebral cortex were determined using serotonin_2A-specific positron emission tomography with radioligand fluorine 18–labeled setoperone as the tracer.

Setting  Academic medical center research laboratory.

Participants  A total of 14 female MDMA users and 10 women who did not use MDMA (controls). The main exclusion criteria were nondrug-related DSM-IV Axis I psychiatric disorders and general medical illness.

Main Outcome Measures  Cortical serotonin_2A receptor nondisplaceable binding potential (serotonin_2ABP_ND).

Results  MDMA users had increased serotonin_2ABP_ND in occipital-parietal (19.7%), temporal (20.5%), occipitotemporal-parietal (18.3%), frontal (16.6%), and frontoparietal (18.5%) regions (corrected P < .05). Lifetime MDMA use was positively associated with serotonin_2ABP_ND in frontoparietal (β = 0.665; P = .007), occipitotemporal (β = 0.798; P = .002), frontolimbic (β = 0.634; P = .02), and frontal (β = 0.691; P = .008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on serotonin_2ABP_ND.

Conclusions  The recreational use of MDMA is associated with long-lasting increases in serotonin_2A receptor density. Serotonin_2A receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA use produces chronic serotonin neurotoxicity in humans. Given the broad role of serotonin in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications.

Objective  To determine whether comorbid depression in patients with type 2 diabetes increases the risk of development of dementia.

Design  The Diabetes and Aging Study was a cohort investigation that surveyed a racially/ethnically stratified random sample of patients with type 2 diabetes.

Setting  A large, integrated, nonprofit managed care setting in Northern California.

Participants  A sample of 19 239 diabetes registry members 30 to 75 years of age.

Main Outcome Measures  The Patient Health Questionnaire 8, International Classification of Diseases, Ninth Revision (ICD-9) diagnoses of depression, and/or antidepressant prescriptions in the 12 months prior to baseline were used to identify prevalent cases of depression. Clinically recognized dementia was identified among subjects with no prior ICD-9 Clinical Modification (ICD-9-CM) diagnoses of dementia. To exclude the possibility that depression was a prodrome of dementia, dementia diagnoses were only based on ICD-9-CM diagnoses identified in years 3 to 5 postbaseline. The risk of dementia for patients with depression and diabetes relative to patients with diabetes alone was estimated using Cox proportional hazard regression models that adjusted for sociodemographic, clinical, and health risk factors and health use.

Results  During the 3- to 5-year period, 80 of 3766 patients (2.1%) with comorbid depression and diabetes (incidence rate of 5.5 per 1000 person-years) vs 158 of 15 473 patients (1.0%) with diabetes alone (incidence rate of 2.6 per 1000 person-years) had 1 or more ICD-9-CM diagnoses of dementia. Patients with comorbid depression had a 100% increased risk of dementia during the 3 to 5 years postbaseline (adjusted hazard ratio, 2.02; 95% confidence interval, 1.73-2.35).

Conclusion  Depression in patients with diabetes was associated with a substantively increased risk for development of dementia compared with those with diabetes alone.

Objective  To characterize epigenetic signatures of autism in prefrontal cortex neurons.

Design  We performed fluorescence-activated sorting and separation of neuronal and nonneuronal nuclei from postmortem prefrontal cortex, digested the chromatin with micrococcal nuclease, and deeply sequenced the DNA from the mononucleosomes with trimethylated H3K4 (H3K4me3), a histone mark associated with transcriptional regulation. Approximately 15 billion base pairs of H3K4me3-enriched sequences were collected from 32 brains.

Setting  Academic medical center.

Participants  A total of 16 subjects diagnosed as having autism and 16 control subjects ranging in age from 0.5 to 70 years.

Main Outcome Measures  Identification of genomic loci showing autism-associated H3K4me3 changes in prefrontal cortex neurons.

Results  Subjects with autism showed no evidence for generalized disruption of the developmentally regulated remodeling of the H3K4me3 landscape that defines normal prefrontal cortex neurons in early infancy. However, excess spreading of H3K4me3 from the transcription start sites into downstream gene bodies and upstream promoters was observed specifically in neuronal chromatin from 4 of 16 autism cases but not in controls. Variable subsets of autism cases exhibit altered H3K4me3 peaks at numerous genes regulating neuronal connectivity, social behaviors, and cognition, often in conjunction with altered expression of the corresponding transcripts. Autism-associated H3K4me3 peaks were significantly enriched in genes and loci implicated in neurodevelopmental diseases.

Conclusions  Prefrontal cortex neurons from subjects with autism show changes in chromatin structures at hundreds of loci genome-wide, revealing considerable overlap between genetic and epigenetic risk maps of developmental brain disorders.

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.

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

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 low-functioning 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 (within-group Cohen d, 1.36 vs 0.06, respectively; adjusted mean [SE], 58.3 [3.30] vs 47.9 [3.60], respectively; P = .03; between-group d = 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; between-group 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 low-functioning patients with significant cognitive impairment.

Trial Registration  clinicaltrials.gov Identifier: NCT00350883

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.

Objective  To test whether anterior cingulate cortex (ACC) GABA levels, measured by proton magnetic resonance spectroscopy, are decreased in adolescents with MDD. The associations of GABA alterations with the presence and severity of anhedonia were explored.

Design  Case-control, cross-sectional study using single-voxel proton magnetic resonance spectroscopy at 3 T.

Setting  Two clinical research divisions at 2 teaching hospitals.

Participants  Twenty psychotropic medication-free adolescents with MDD (10 anhedonic, 12 female, aged 12-19 years) with episode duration of 8 weeks or more and 21 control subjects group matched for sex and age.

Main Outcome Measures  Anterior cingulate cortex GABA levels expressed as ratios relative to unsuppressed voxel tissue water (w) and anhedonia scores expressed as a continuous variable.

Results  Compared with control subjects, adolescents with MDD had significantly decreased ACC GABA/w (t = 3.2; P < .003). When subjects with MDD were categorized based on the presence of anhedonia, only anhedonic patients had decreased GABA/w levels compared with control subjects (t = 4.08; P < .001; P_Tukey < .001). Anterior cingulate cortex GABA/w levels were negatively correlated with anhedonia scores for the whole MDD group (r = –0.50; P = .02), as well as for the entire participant sample including the control subjects (r = –0.54; P < .001). Anterior cingulate cortex white matter was also significantly decreased in adolescents with MDD compared with controls (P = .04).

Conclusions  These findings suggest that GABA, the major inhibitory neurotransmitter in the brain, may be implicated in adolescent MDD and, more specifically, in those with anhedonia. In addition, use of a continuous rather than categorical scale of anhedonia, as in the present study, may permit greater specificity in evaluating this important clinical feature.

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 = 12) 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 long-term 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

Objectives  To study whether having a first-trimester induced abortion influenced the risk of psychiatric readmission and compare findings with readmission risk in women with mental disorders giving birth.

Design  Survival analyses were performed in a population-based cohort study merging data from the Danish Civil Registration System, the Danish Psychiatric Central Register, and the Danish National Hospital Register from January 1,1994, to December 31, 2007.

Setting  Denmark.

Participants  All women born in Denmark between 1962 and 1992 with a record of 1 or more psychiatric admissions at least 9 months before a first-time first-trimester induced abortion or childbirth.

Main Outcome Measure  Readmission at a psychiatric hospital with any type of mental disorder from 9 months before to 12 months after a first-time first-trimester induced abortion or childbirth.

Results  Relative risk (RR) for readmission risk 9 to 0 months before a first-trimester induced abortion was 0.95 (95% CI, 0.73-1.23) compared with the first year after the abortion. This contrasts with a reduced risk of readmission before childbirth (RR, 0.56; 95% CI, 0.42-0.75) compared with the first year post partum. Proximity to previous psychiatric admission in particular predicted rehospitalization risks in both the abortion and the childbirth group.

Conclusions  Risk of readmission is similar before and after first-time first-trimester abortion, contrasting with a marked increased in risk of readmission post partum. We speculate that recent psychiatric episodes may influence women's decisions to have an induced abortion; however, this decision does not appear to influence the illness course in women with a history of treated mental disorders.

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

Objective  To examine how pathological gamblers represent subjective reward value at a neural level and how this is affected by gambling severity.

Design  Model-based functional magnetic resonance imaging study with patients and control subjects.

Setting  Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf.

Participants  Participants were recruited from the local community by advertisement and through self-help groups. A sample of 16 pathological gamblers (according to the DSM-IV definition) was matched by age, sex, smoking status, income, educational level, and handedness to 16 healthy controls.

Results  Pathological gamblers showed increased discounting of delayed rewards and a trend toward decreased discounting of probabilistic rewards compared with matched controls. At the neural level, a significant group x condition interaction indicated that reward representations in the gamblers were modulated in a condition-specific manner, such that they exhibited increased (delay discounting) and decreased (probability discounting) neural value correlations in the reward system. In addition, throughout the reward system, neuronal value signals for delayed rewards were negatively correlated with gambling severity.

Conclusions  The results extend previous reports of a generally hypoactive reward system in pathological gamblers by showing that, even when subjective reward valuation is accounted for, gamblers still show altered reward representations. Furthermore, results point toward a gradual degradation of mesolimbic reward representations for delayed rewards during the course of pathological gambling.

Objective  To evaluate whether spatial response pattern to sexual stimuli as revealed by a change in the blood oxygen level–dependent signal facilitates the identification of pedophiles.

Design  During functional magnetic resonance imaging, pedophilic and nonpedophilic participants were briefly exposed to same- and opposite-sex images of nude children and adults. We calculated differences in blood oxygen level–dependent signals to child and adult sexual stimuli for each participant. The corresponding contrast images were entered into a group analysis to calculate whole-brain difference maps between groups. We calculated an expression value that corresponded to the group result for each participant. These expression values were submitted to 2 different classification algorithms: Fisher linear discriminant analysis and -nearest neighbor analysis. This classification procedure was cross-validated using the leave-one-out method.

Setting  Section of Sexual Medicine, Medical School, Christian Albrechts University of Kiel, Kiel, Germany.

Participants  We recruited 24 participants with pedophilia who were sexually attracted to either prepubescent girls (n = 11) or prepubescent boys (n = 13) and 32 healthy male controls who were sexually attracted to either adult women (n = 18) or adult men (n = 14).

Main Outcome Measures  Sensitivity and specificity scores of the 2 classification algorithms.

Results  The highest classification accuracy was achieved by Fisher linear discriminant analysis, which showed a mean accuracy of 95% (100% specificity, 88% sensitivity).

Conclusions  Functional brain response patterns to sexual stimuli contain sufficient information to identify pedophiles with high accuracy. The automatic classification of these patterns is a promising objective tool to clinically diagnose pedophilia.

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."

Objective  To identify abnormalities in the expression of oligodendroglial genes and proteins that participate in the formation, maintenance, and integrity of the NOR in SZ.

Design  The messenger RNA (mRNA) expression levels of multiple NOR genes were quantified in 2 independent postmortem brain cohorts of individuals with SZ, and generalizability to protein expression was confirmed. The effect of the ANK3 genotype on the mRNA expression level was tested in postmortem human brain. Case-control analysis tested the association of the ANK3 genotype with SZ. The ANK3 genotype's influence on cognitive task performance and functional magnetic resonance imaging activation was tested in 2 independent cohorts of healthy individuals.

Setting  Research hospital.

Patients  Postmortem samples from patients with SZ and healthy controls were used for the brain expression study (n = 46) and the case-control analysis (n = 272). Healthy white men and women participated in the cognitive (n = 513) and neuroimaging (n = 52) studies.

Main Outcome Measures  The mRNA and protein levels in postmortem brain samples, genetic association with schizophrenia, cognitive performance, and blood oxygenation level–dependent functional magnetic resonance imaging.

Results  The mRNA expression of multiple NOR genes was decreased in schizophrenia. The ANK3 rs9804190 C allele was associated with lower ANK3 mRNA expression levels, higher risk for SZ in the case-control cohort, and poorer working memory and executive function performance and increased prefrontal activation during a working memory task in healthy individuals.

Conclusions  These results point to abnormalities in the expression of genes and protein associated with the integrity of the NOR and suggest them as substrates for the disconnectivity syndrome in SZ. The association of ANK3 with lower brain mRNA expression levels implicates a molecular mechanism for its genetic, clinical, and cognitive associations with SZ.

Objective  To examine the progression of brain changes in first-episode early-onset psychosis and their relationship to diagnosis and prognosis at 2-year follow-up.

Design  Prospective, multicenter, naturalistic, 2-year follow-up study.

Setting  Six child and adolescent psychiatric units in Spain.

Participants  A total of 110 patients and 98 healthy controls were recruited between March 1, 2003, and November 31, 2005. Magnetic resonance imaging of the brain was performed for 61 patients with schizophrenia (n = 25), bipolar disorder (n = 16), or other psychoses (n = 20) and 70 controls (both at baseline and after 2 years of follow-up). Mean age at baseline was 15.5 years (patients) and 15.3 years (controls).

Main Outcome Measures  The GM and cerebrospinal fluid (CSF) volumes in the total brain and frontal, parietal, and temporal lobes.

Results  Compared with controls, patients with schizophrenia showed greater GM volume loss in the frontal lobe during the 2-year follow-up (left: –3.3 vs –0.6 cm³, P = .004; right: –3.7 vs –0.8 cm³, P = .005) and left frontal CSF volume increase (left: 6.7 vs 2.4 cm³, P = .006). In addition to frontal volume, changes for total GM (–37.1 vs –14.5 cm³, P = .001) and left parietal GM (–4.3 vs –2.2 cm³, P = .04) were significantly different in schizophrenic patients compared with controls. No significant differences emerged for patients with bipolar disease. Greater left frontal GM volume loss was related to more weeks of hospitalization, whereas severity of negative symptoms correlated with CSF increase in patients with schizophrenia.

Conclusions  Patients with schizophrenia or other psychoses showed greater loss of GM volume and increase of CSF in the frontal lobe relative to controls. Progressive changes were more evident in patients with schizophrenia than those with bipolar disorder. These changes in specific brain volumes after onset of psychotic symptoms may be related to markers of poorer prognosis.

Objective  To examine the effects of 9-tetrahydrocannabinol (9-THC) and cannabidiol (CBD) on regional brain function during salience processing.

Design  Volunteers were studied using event-related functional magnetic resonance imaging on 3 occasions after administration of 9-THC, CBD, or placebo while performing a visual oddball detection paradigm that involved allocation of attention to infrequent (oddball) stimuli within a string of frequent (standard) stimuli.

Setting  University center.

Participants  Fifteen healthy men with minimal previous cannabis use.

Main Outcome Measures  Symptom ratings, task performance, and regional brain activation.

Results  During the processing of oddball stimuli, relative to placebo, 9-THC attenuated activation in the right caudate but augmented it in the right prefrontal cortex. 9-Tetrahydrocannabinol also reduced the response latency to standard relative to oddball stimuli. The effect of 9-THC in the right caudate was negatively correlated with the severity of the psychotic symptoms it induced and its effect on response latency. The effects of CBD on task-related activation were in the opposite direction of those of 9-THC; relative to placebo, CBD augmented left caudate and hippocampal activation but attenuated right prefrontal activation.

Conclusions  9-Tetrahydrocannabinol and CBD differentially modulate prefrontal, striatal, and hippocampal function during attentional salience processing. These effects may contribute to the effects of cannabis on psychotic symptoms and on the risk of psychotic disorders.

Objective  To explore whether individuals with remitted major depressive disorder had altered neuronal processing of social emotional stimuli.

Design  Cross-sectional design using functional magnetic resonance imaging, combined with a cognitive activation task.

Setting  General community of greater Manchester, England.

Participants  Twenty-five unmedicated participants fully remitted from major depressive disorder and 29 age-matched control subjects.

Main Outcome Measures  Neuronal responses to positive and negative social interaction images vs valence-matched images with less overt social context.

Results  Participants with remitted depression showed attenuated frontopolar response relative to controls for positive and negative images depicting social interactions. For negative social images, participants with remitted depression also showed reduced latero-orbitofrontal response relative to controls.

Conclusions  In the absence of current symptoms, individuals with remitted major depressive disorder showed reduced frontopolar processing of stimuli showing social interactions, a reduction not seen for stimuli showing individual successes and failures and, therefore, not simply an effect of emotional valence. These results suggest a specific trait abnormality in social emotional processing associated with vulnerability to depression, which may have implications for understanding social cognition mechanisms and for developing effective psychological therapies.

Objective  To study whether there are similar genetic and/or environmental etiologies behind ASDs and ALTs.

Design  A nationwide twin study.

Participants  Consenting parents of all Swedish twins aged 9 and 12 years, born between July 1, 1992, and December 31, 2001 (n = 19 208), were interviewed by telephone to screen for child psychiatric conditions, including ASDs.

Main Outcome Measures  Two validated cutoffs for ASDs, 2 cutoffs encompassing the normal variation, and 1 continuous measure of ALTs were used with DeFries-Fulker extreme-end analyses and standard twin study methods.

Results  We discerned a strong correlation between the 4 cutoffs and the full variation of ALTs. The correlation was primarily affected by genes. We also found that the heritability for the 4 cutoffs was similar.

Conclusion  We demonstrate an etiological similarity between ASDs and ALTs in the normal variation and, with results from previous studies, our data suggest that ASDs and ALTs are etiologically linked.

Objective  To determine whether the rate of amygdala growth is abnormal and disproportionate to total brain growth in very young children with autism spectrum disorders (ASDs).

Design  Longitudinal structural magnetic resonance imaging study.

Setting  Neuroimaging and diagnostic assessments were performed at an academic medical center. Participants were recruited from the community.

Participants  Baseline scans were acquired in 132 boys (85 with ASD and 47 control subjects with typical development [TD]; mean age, 37 months). Longitudinal magnetic resonance images were acquired in 70 participants (45 with ASD and 25 TD controls) 1 year later.

Main Outcome Measure  Amygdala volumes and total cerebral volumes (TCVs) were evaluated at both time points, and 1-year growth rates were calculated.

Results  The amygdala was larger in children with ASD at both time points, but the magnitude of enlargement was greater at time 2. The TCV was also enlarged in the children with ASD by the same magnitude at both time points. When we controlled for TCV, amygdala enlargement remained significant at both time points. The rate of amygdala growth during this 1-year interval was faster in children with ASD than in TD controls. The rate of TCV growth did not differ between groups. Post hoc exploratory analyses revealed 3 patterns of amygdala and TCV growth rates in the ASD group.

Conclusions  Disproportionate amygdala enlargement is present by 37 months of age in ASD. The amygdala continues to grow at an increased rate, but substantial heterogeneity exists in amygdala and TCV growth patterns. Future studies aimed at clinical characterization of different growth patterns could have implications for choice and outcomes of treatment and behavioral therapy.

Objective  To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior.

Design  Cross-sectional study. Four FKBP5 single-nucleotide polymorphisms used in previous studies (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. Three diplotypes were derived from 2 major putatively functional haplotypes regulating protein expression that were previously associated with glucocorticoid receptor sensitivity.

Setting  Penitentiary District of Abruzzo-Molise in central Italy.

Participants  A population of 583 male Italian prisoners recruited between 2005 and 2008.

Main Outcome Measures  A comprehensive analysis of aggression and impulsivity was undertaken using the Brown-Goodwin Lifetime History of Aggression (BGHA) questionnaire, the Buss-Durkee Hostility Inventory (BDHI), and the Barratt Impulsiveness Scale (BIS). A history of childhood trauma was investigated with the Childhood Trauma Questionnaire. The interaction between the FKBP5 diplotypes and childhood trauma on measures of aggression was analyzed. Analyses were replicated with a second behavioral measure of aggression: violent behavior in jail. Individual single-nucleotide polymorphism analysis was performed.

Results  Childhood trauma had a significant effect on BGHA and BDHI scores but not on BIS scores. We observed a significant influence of the FKBP5 high-expression diplotype on both a lifetime history of aggressive behavior (BGHA) (P = .012) and violent behavior in jail (P = .025) but only in individuals exposed to childhood trauma, in particular to physical abuse. No main effect of the FKBP5 diplotypes was observed.

Conclusion  These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior.

Objective  To determine the importance of ES definition, measurement, and prevalence in the general population, together with its coexisting conditions.

Design  Cross-sectional telephone study.

Participants  A total of 15 929 individuals representative of the adult general population of 15 states in the United States.

Main Outcome Measures  Interviews were carried out using Sleep-EVAL, a knowledge-based expert system for use in epidemiologic studies, focusing on sleep, as well as physical and mental disorders, according to classification in DSM-IV and the second edition of the International Classification of Sleep Disorders. The interviews elicited information on ES, naps, frequency, duration, impairment, and distress associated with ES symptoms.

Results  Excessive sleepiness was reported by 27.8% (95% CI, 27.1%-28.5%) of the sample. Excessive sleepiness with associated symptoms was found in 15.6% of the participants (95% CI, 15.0%-16.2%). Adding an ES frequency of at least 3 times per week for at least 3 months despite normal sleep duration dropped the prevalence to 4.7% of the sample (95% CI, 4.4%-5.0%). The proportion of individuals having social or professional impairment and psychological distress increased with the frequency of ES symptoms during the week and within the same day. In multivariate models, the number of ES episodes per day and severity of ES were identified as the best predictors for impairment/distress. Prevalence of hypersomnia disorder was 1.5% of the participants (95% CI, 1.3%-1.7%). The most common coexisting conditions were mood and substance use disorders.

Conclusions  Excessive sleepiness is an important problem in the US population, even when using restrictive criteria to define it. Hypersomnia disorder is more prevalent than previously estimated. Excessive sleepiness has to be recognized and given attention by public health authorities, scientists, and clinicians.

Objective  To describe the predictors of emergency department discharge, the emergency mental health assessments, and the follow-up outpatient mental health care of adult Medicaid beneficiaries treated for deliberate self-harm.

Design  A retrospective longitudinal cohort analysis.

Setting  National Medicaid claims data supplemented with county-level sociodemographic variables and Medicaid state policy survey data.

Participants  Adults aged 21 to 64 years who were treated in emergency departments for 7355 episodes of deliberate self-harm, focusing on those who were discharged to the community (4595 episodes).

Main Outcome Measures  Rates and adjusted risk ratios (ARRs) of discharge to the community, mental health assessments in the emergency department, and outpatient mental health visits during the 30 days following the emergency department visit.

Results  Most patients (62.5%) were discharged to the community. Emergency department discharge was directly related to younger patient age (21-31 years vs 45-64 years) (ARR, 1.18 [99% confidence interval {CI}, 1.10-1.25]) and self-harm by cutting (ARR, 1.18 [99% CI, 1.12-1.24]) and inversely related to poisoning (ARR, 0.84 [99% CI, 0.80-0.89]) and recent psychiatric hospitalization (ARR, 0.74 [99% CI, 0.67-0.81]). Approximately one-half of discharged patients (47.5%) received a mental health assessment in the emergency department, and a similar percentage of discharged patients (52.4%) received a follow-up outpatient mental health visit within 30 days. Follow-up mental health care was directly related to recent outpatient mental health care (ARR, 2.30 [99% CI, 2.11-2.50]) and treatment in a state with Medicaid coverage of mental health clinic services (ARR, 1.13 [99% CI, 1.05-1.22]) and inversely related to African American (ARR, 0.86 [99% CI, 0.75-0.96]) and Hispanic (ARR, 0.86 [99% CI, 0.75-0.99]) race/ethnicity.

Conclusion  Most adult Medicaid beneficiaries who present for emergency care for deliberate self-harm are discharged to the community, and many do not receive emergency mental health assessments or follow-up outpatient mental health care.

Objective  To study the association of genetic variants within SLC6A4 with acute and posttraumatic stress symptoms in a civilian cohort with known levels of preexisting trauma and PTSD symptoms collected prior to a shared index traumatic event.

Design  Ongoing longitudinal study.

Setting  On February 14, 2008, a lone gunman shot multiple people on the campus of Northern Illinois University in DeKalb, Illinois, killing 5 and wounding 21. As part of an ongoing longitudinal study on that campus, a cohort of female undergraduate students, interviewed prior to the shooting, completed follow-up trauma-related measures including PTSD symptom severity (follow-up survey was launched 17 days postshooting; n = 691). To obtain DNA, salivary samples were collected from a subset of the original study population based on willingness to participate (n = 276).

Participants  Two hundred four undergraduate women.

Main Outcome Measures  SLC6A4 polymorphisms STin2, 5-HTTLPR, and rs25531 were genotyped in 235 individuals.

Results  We found that although the STin2 variant and 5-HTTLPR alone did not associate with increased PTSD symptoms, rs25531 and the 5-HTTLPR multimarker genotype (combined 5-HTTLPR and rs25531) were associated with significantly increased acute stress disorder symptoms at 2 to 4 weeks postshooting (n = 161; P < .05). This association remained significant when controlling for race and for level of shooting exposure (n = 123; P < .007). The association was most robust with the 5-HTTLPR multimarker genotype and avoidance symptoms (P = .003).

Conclusion  These data suggest that differential function of the serotonin transporter may mediate differential response to a severe trauma. When examined in a relatively homogenous sample with shared trauma and known prior levels of child and adult trauma, the 5-HTTLPR multimarker genotype may serve as a useful predictor of risk for PTSD-related symptoms in the weeks and months following the trauma.

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 < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%.

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.

Objective  Because α4β2 is a key nAChR subtype for nicotinic actions, we investigated the effect of varenicline tartrate, a relatively specific α4β2 partial agonist and antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans.

Design  A double-blind, parallel, randomized, placebo-controlled trial of patients with schizophrenia or schizoaffective disorder to examine the effects of varenicline on biomarkers at 2 weeks (short-term treatment) and 8 weeks (long-term treatment), using a slow titration and moderate dosing strategy for retaining α4β2-specific effects while minimizing adverse effects.

Setting  Outpatient clinics.

Participants  A total of 69 smoking and nonsmoking patients; 64 patients completed week 2, and 59 patients completed week 8.

Intervention  Varenicline.

Main Outcome Measures  Prepulse inhibition, sensory gating, antisaccade, spatial working memory, eye tracking, processing speed, and sustained attention.

Results  A moderate dose of varenicline (1) significantly reduced the P50 sensory gating deficit in nonsmokers after long-term treatment (P = .006), (2) reduced startle reactivity (P = .02) regardless of baseline smoking status, and (3) improved executive function by reducing the antisaccadic error rate (P = .03) regardless of smoking status. A moderate dose of varenicline had no significant effect on spatial working memory, predictive and maintenance pursuit measures, processing speed, or sustained attention by Conners' Continuous Performance Test. Clinically, there was no evidence of exacerbation of psychiatric symptoms, psychosis, depression, or suicidality using a gradual titration (1-mg daily dose).

Conclusions  Moderate-dose treatment with varenicline has a unique treatment profile on core schizophrenia-related biomarkers. Further development is warranted for specific nAChR compounds and dosing and duration strategies to target subgroups of schizophrenic patients with specific biological deficits.

Trial Registration  clinicaltrials.gov Identifier: NCT00492349

Objective  To test the hypotheses that altered DLPFC connectivity is (1) a familial, likely heritable feature of genetic risk for schizophrenia, (2) a novel intermediate phenotype independent of altered DLPFC engagement, and (3) selectively modulated by a polymorphism in ZNF804A.

Design  Cross-sectional case-control study using blood oxygen level–dependent functional magnetic resonance imaging during a working memory task and genotyping of rs1344706 in ZNF804A.

Setting  Research center.

Participants  A total of 402 subjects (153 cognitively normal controls, 171 healthy siblings of patients with schizophrenia, and 78 patients).

Main Outcome Measures  Task-independent and task-dependent physiologic coupling between the DLPFC and other brain "target" regions investigated with (1) seeded connectivity and (2) psychophysiological interaction analysis.

Results  Siblings and patients showed greater DLPFC "inefficiency" than controls. Abnormal DLPFC functional coupling with the hippocampus and, to a lesser degree, the rest of the prefrontal cortex, was observed in patients and siblings when compared with controls using both connectivity analyses. Prefrontal activation and connectivity measures within siblings did not correlate, implying that they were independent phenomena. The ZNF804A genotype significantly modulated DLPFC coupling with the hippocampus and prefrontal cortex but not DLPFC activity in the control group. Similarly, ZNF804A genotype modulated right DLPFC–hippocampal formation coupling in siblings and patients.

Conclusions  Coupling between the DLPFC and hippocampus is compromised in siblings of patients with schizophrenia and is independent of DLPFC engagement. The selective association with a single-nucleotide polymorphism in ZNF804A suggests that this intermediate phenotype proxies a distinct neural system mechanism related to genetic risk for schizophrenia and the biology of this gene.

Objectives  To examine longitudinal trends in health service utilization, spending, and quality of care for depression.

Design  Observational trend study.

Setting  Florida Medicaid enrollees, between July 1, 1996, and June 30, 2006.

Patients  Annual cohorts aged 18 to 64 years diagnosed as having depression.

Main Outcome Measures  Mental health care spending (adjusted for inflation and case mix), as well as its components, including inpatient, outpatient, and medication expenditures. Quality-of-care measures included medication adherence, psychotherapy, and follow-up visits.

Results  Mental health care spending increased from a mean of $2802 per enrollee to $3610 during this period (29% increase). This increase occurred despite a mean decrease in inpatient spending from $641 per enrollee to $373 and was driven primarily by an increase in pharmacotherapy spending (up 110%), the bulk of which was due to spending on antipsychotics (949% increase). The percentage of enrollees with depression who were hospitalized decreased from 9.1% to 5.1%, and the percentage who received psychotherapy decreased from 56.6% to 37.5%. Antidepressant use increased from 80.6% to 86.8%, anxiety medication use was unchanged at 62.7% and 64.4%, and antipsychotic use increased from 25.9% to 41.9%. Changes in quality of care were mixed, with antidepressant use improving slightly, psychotherapy utilization fluctuating, and follow-up visits decreasing.

Conclusions  During a 10-year period, spending for Medicaid enrollees with depression increased substantially, with minimal improvements in quality of care. Antipsychotic use contributed significantly to the increase in spending, while contributing little to traditional measures of quality of care.

Objective  To assess whether growth mixture modeling can provide insights into antidepressant and placebo responses in clinical trials of patients with major depression.

Design  We reanalyzed clinical trials of duloxetine to identify distinct trajectories of Hamilton Scale for Depression (HAM-D) scores during treatment. We analyzed the trajectories in the entire sample and then separately in all active arms and in all placebo arms. Effects of duloxetine hydrochloride, selective serotonin reuptake inhibitor (SSRI), and covariates on the probability of following a particular trajectory were assessed. Outcomes in different trajectories were compared using mixed-effects models.

Setting  Seven randomized double-blind clinical trials of duloxetine vs placebo and comparator SSRI.

Patients  A total of 2515 patients with major depression.

Interventions  Duloxetine and comparator SSRI.

Main Outcome Measure  Total score on the HAM-D.

Results  In the entire sample and in the antidepressant-treated subsample, we identified trajectories of responders (76.3% of the sample) and nonresponders (23.7% of the sample). However, placebo-treated patients were characterized by a single response trajectory. Duloxetine and SSRI did not differ in efficacy, and compared with placebo they significantly decreased the odds of following the nonresponder trajectory. Antidepressant responders had significantly better HAM-D scores over time than placebo-treated patients, but antidepressant nonresponders had significantly worse HAM-D scores over time than the placebo-treated patients.

Conclusions  Most patients treated with serotonergic antidepressants showed a clinical trajectory over time that is superior to that of placebo-treated patients. However, some patients receiving these medications did more poorly than patients receiving placebo. These data highlight the importance of ongoing monitoring of medication risks and benefits during serotonergic antidepressant treatment. They should further stimulate the search for biomarkers or other predictors of responder status in guiding antidepressant treatment.

Trial Registration  clinicaltrials.gov Identifier: NCT00073411

Objective  To evaluate the efficacy of brief and extended buprenorphine hydrochloride–naloxone hydrochloride treatment, with different counseling intensities, for patients dependent on prescription opioids.

Design  Multisite, randomized clinical trial using a 2-phase adaptive treatment research design. Brief treatment (phase 1) included 2-week buprenorphine-naloxone stabilization, 2-week taper, and 8-week postmedication follow-up. Patients with successful opioid use outcomes exited the study; unsuccessful patients entered phase 2: extended (12-week) buprenorphine-naloxone treatment, 4-week taper, and 8-week postmedication follow-up.

Setting  Ten US sites.

Patients  A total of 653 treatment-seeking outpatients dependent on prescription opioids.

Interventions  In both phases, patients were randomized to standard medical management (SMM) or SMM plus opioid dependence counseling; all received buprenorphine-naloxone.

Main Outcome Measures  Predefined "successful outcome" in each phase: composite measures indicating minimal or no opioid use based on urine test–confirmed self-reports.

Results  During phase 1, only 6.6% (43 of 653) of patients had successful outcomes, with no difference between SMM and SMM plus opioid dependence counseling. In contrast, 49.2% (177 of 360) attained successful outcomes in phase 2 during extended buprenorphine-naloxone treatment (week 12), with no difference between counseling conditions. Success rates 8 weeks after completing the buprenorphine-naloxone taper (phase 2, week 24) dropped to 8.6% (31 of 360), again with no counseling difference. In secondary analyses, successful phase 2 outcomes were more common while taking buprenorphine-naloxone than 8 weeks after taper (49.2% [177 of 360] vs 8.6% [31 of 360], P < .001). Chronic pain did not affect opioid use outcomes; a history of ever using heroin was associated with lower phase 2 success rates while taking buprenorphine-naloxone.

Conclusions  Prescription opioid–dependent patients are most likely to reduce opioid use during buprenorphine-naloxone treatment; if tapered off buprenorphine-naloxone, even after 12 weeks of treatment, the likelihood of an unsuccessful outcome is high, even in patients receiving counseling in addition to SMM.

Trial Registration  clinicaltrials.gov Identifier: NCT00316277

Objective  To investigate whether genetic variants of the corticotropin-releasing factor system or their interaction influence the risk of developing AUD in chronic disease populations.

Design  Genotype analysis comprising selected single-nucleotide polymorphisms within the CRHR1 and CRHBP genes in patients with schizophrenia and in a nonschizophrenic psychiatric disease control sample should allow the extraction of predictors of comorbid AUD. Gene expression (messenger RNA) analysis in peripheral blood mononuclear cells was performed to gain the first mechanistic insight.

Setting  An ideal setup for this study was the Göttingen Research Association for Schizophrenia Data Collection of schizophrenic patients, specifically intended to enable association of genetic information with quantifiable phenotypes in a phenotype-based genetic association study.

Patients  A total of 1037 schizophrenic patients (Göttingen Research Association for Schizophrenia sample), 80 nonschizophrenic psychiatric disease controls as a small replicate sample, and a case-control study including 1141 healthy subjects.

Main Outcome Measures  Association of CRHR1 and CRHBP genotypes with the following: (1) AUD; (2) a newly developed alcoholism severity score comprising 5 AUD-relevant variables; and (3) quantitative CRHR1 and CRHBP messenger RNA expression.

Results  An interaction of CRHR1 rs110402 and CRHBP rs3811939 predicts high risk of comorbid AUD in schizophrenic patients (odds ratio = 2.27; 95% confidence interval, 1.56-3.30; P < .001) as well as psychiatric disease controls (odds ratio = 4.02; 95% confidence interval, 0.95-17.05; P = .06) and leads to the highest CRHR1/CRHBP messenger RNA ratio (P = .02; dysbalanced stress axis).

Conclusions  The high predictive value of a genetic interaction within the stress axis for the risk of comorbid AUD may be used for novel preventive and individualized therapeutic approaches.

Objectives  To assess the hypothesis that simple motor tics and comorbid obsessive-compulsive disorders are associated with dysfunction of motor and reward circuits, respectively, and to assess the effects of various antipsychotic medications because they are known to reduce motor tics and interact with dopamine-related reward processing.

Design  Sixty patients with GTS were divided into different subgroups depending on their clinical phenotypes and pharmacological treatments. The GTS patients and healthy control subjects underwent functional magnetic resonance imaging while they performed an instrumental learning task that involved adjusting choices between 2 responses (left- or right-hand movements) based on outcomes (reward or no reward).

Setting  Reference center for GTS, Centre de NeuroImagerie de recherche (CENIR) Paris, France.

Patients  Sixty GTS patients and 50 controls.

Results  Movement-related activation in motor circuits was diminished in GTS patients with simple tics only. Reward-related activation in limbic circuits was independently reduced by the following 2 factors: the presence of associated obsessive-compulsive symptoms (mostly compulsions) and the presence of medication with typical antipsychotics (dopamine receptor antagonists). Computational modeling with standard reinforcement learning algorithms indicated that, for both factors, the diminished reward-related activation could account for the impaired choice performance. Reinforcement learning was not affected by aripiprazole, a recent medication that acts as a partial dopamine agonist.

Conclusions  These results support the hypothesized correspondence between clinical phenotypes and frontal cortex–basal ganglia circuits. Antipsychotic treatment effects comply with formal conceptions that dopamine serves as a teaching signal for reinforcement learning. Furthermore, we suggest that, unlike typical antipsychotics, aripiprazole may preserve reward sensitivity and hence avoid blunting motivational drives.

Objectives  To describe the developmental trajectories of hyperactivity-impulsivity and inattention symptoms and to identify their prenatal, perinatal, and postnatal risk factors.

Design  Birth cohort from the general population.

Setting  Quebec Longitudinal Study of Child Development.

Participants  The sample consisted of 2057 individuals, followed up from age 5 months to 8 years.

Main Outcome Measures  Prenatal, perinatal, and postnatal risk factors assessed at age 5 months were considered predictors of group membership in high hyperactivity-impulsivity and inattention trajectories from age 17 months to 8 years.

Results  The frequency of hyperactivity-impulsivity symptoms tended to slightly decrease with age, whereas the frequency of inattention symptoms substantially increased up to age 6 years. However, trajectories of hyperactivity-impulsivity and inattention symptoms were significantly associated with each other. Risk factors for high trajectories of both types of symptoms were premature birth (adjusted odds ratio [aOR], 1.93; 95% CI, 1.07-3.50), low birth weight (2.11; 1.12-3.98), prenatal tobacco exposure (1.41; 1.03-1.93), nonintact family (1.85; 1.26-2.70), young maternal age at birth of the target child (1.78; 1.17-2.69), paternal history of antisocial behavior (1.78; 1.28-2.47), and maternal depression (1.35; 1.18-1.54).

Conclusions  A large range of early risk factors, including prenatal, perinatal social, and parental psychopathology variables, act independently to heighten the likelihood of having persistently high levels of hyperactivity-impulsivity and inattention symptoms from infancy to middle childhood. Early interventions should be experimented with to provide effective tools for attention-deficit/hyperactivity disorder prevention.

Objective  To evaluate trends in acute care hospitalizations for primary psychiatric diagnoses between 1996 and 2007 in relation to patient-level variables.

Design, Setting, and Participants  The yearly National Hospital Discharge Survey furnished demographic, clinical, and payment data on a probability sample of discharges from short-stay facilities (mean [SD], 448.33 [19.66]), along with weights for extrapolation to population estimates. Discharges with a primary psychiatric diagnosis (mean [SD], 19 535 [2615]) were identified among children (aged 5-13 years), adolescents (aged 14-19 years), adults (aged 20-64 years), and elderly individuals (≥65 years).

Main Outcome Measures  Annual rates of discharges and total days of inpatient care associated with primary psychiatric diagnoses for each age group.

Results  Psychiatric discharges increased for children from 155.54 per 100 000 children in 1996 to 283.04 per 100 000 in 2007 (P = .003); for adolescents, from 683.60 to 969.03 per 100 000 (P = . 001); and for adults, from 921.35 to 995.51 per 100 000 (P = .003) but declined for elderly individuals from 977.63 to 807.55 per 100 000 (P < .001). Total inpatient days increased for children (1845 days per 100 000 in 1996 to 4370 days in 2007; P = .02) and for adolescents (5882 days per 100 000 in 1996 to 8247 days in 2007; P < .001) but decreased for elderly patients (10 348 days per 100 000 in 1996 to 6517 days; P < .001). The proportion of inpatient days paid by private sources declined among children (36%-21%), adolescents (52%-22%), and adults (35%-23%; all P < .001).

Conclusions  Inpatient discharges in short-stay facilities with a primary psychiatric diagnosis rose between 1996 and 2007, most dramatically for youth, but decreased among elderly individuals. Private funding bore a declining share of costs.

Objectives  To examine variation in the prevalence of CD associated with migration from Mexico to the United States and to determine whether this variation is similar for aggressive and nonaggressive CD symptoms and symptom profiles.

Design  The prevalences of CD, different types of CD symptoms, and CD symptom profiles were compared across 3 generations of people of Mexican origin with increasing levels of exposure to American culture: families of origin of migrants (residing in Mexico), children of Mexican migrants raised in the United States, and Mexican-American children of US-born parents.

Setting  General population surveys conducted in Mexico and the United States using the same diagnostic interview.

Participants  Adults aged 18 to 44 years in the household population of Mexico and the household population of people of Mexican descent in the United States.

Main Outcome Measures  Conduct disorder criteria, assessed using the World Mental Health version of the Composite International Diagnostic Interview.

Results  Compared with the risk in families of origin of migrants, risk of CD was lower in the general population of Mexico (odds ratio [OR], 0.54; 95% CI, 0.19-1.51), higher in children of Mexican-born immigrants who were raised in the United States (OR, 4.12; 95% CI, 1.47-11.52), and higher still in Mexican-American children of US-born parents (OR, 7.64; 95% CI, 3.20-18.27). The association with migration was markedly weaker for aggressive than for nonaggressive symptoms.

Conclusions  The prevalence of CD increases dramatically across generations of the Mexican-origin population after migration to the United States. This increase is of larger magnitude for nonaggressive than for aggressive symptoms, consistent with the suggestion that nonaggressive symptoms are more strongly influenced by environmental factors than are aggressive symptoms.

Objective  To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment.

Design, Setting, and Participants  Twin pairs with at least 1 twin with an autism spectrum disorder (ASD) born between 1987 and 2004 were identified through the California Department of Developmental Services.

Main Outcome Measures  Structured diagnostic assessments (Autism Diagnostic Interview–Revised and Autism Diagnostic Observation Schedule) were completed on 192 twin pairs. Concordance rates were calculated and parametric models were fitted for 2 definitions, 1 narrow (strict autism) and 1 broad (ASD).

Results  For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42-0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09-0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28-0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09-0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65-0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16-0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16-0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11-0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD).

Conclusion  Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.

Objective  To systematically evaluate whether prenatal exposure to antidepressant medications is associated with increased risk of ASD.

Design  Population-based case-control study. Medical records were used to ascertain case children and control children and to derive prospectively recorded information on mothers' use of antidepressant medications, mental health history of mothers, and demographic and medical covariates.

Setting  The Kaiser Permanente Medical Care Program in Northern California.

Participants  A total of 298 case children with ASD (and their mothers) and 1507 randomly selected control children (and their mothers) drawn from the membership of the Kaiser Permanente Medical Care Program in Northern California.

Main Outcome Measures  ASDs.

Results  Prenatal exposure to antidepressant medications was reported for 20 case children (6.7%) and 50 control children (3.3%). In adjusted logistic regression models, we found a 2-fold increased risk of ASD associated with treatment with selective serotonin reuptake inhibitors by the mother during the year before delivery (adjusted odds ratio, 2.2 [95% confidence interval, 1.2-4.3]), with the strongest effect associated with treatment during the first trimester (adjusted odds ratio, 3.8 [95% confidence interval, 1.8-7.8]). No increase in risk was found for mothers with a history of mental health treatment in the absence of prenatal exposure to selective serotonin reuptake inhibitors.

Conclusion  Although the number of children exposed prenatally to selective serotonin reuptake inhibitors in this population was low, results suggest that exposure, especially during the first trimester, may modestly increase the risk of ASD. The potential risk associated with exposure must be balanced with the risk to the mother or fetus of untreated mental health disorders. Further studies are needed to replicate and extend these findings.

Objective  To compare the etiology of typical variation in autistic traits with extreme scoring groups (including top 1%) that mimicked the prevalence of diagnosed autism spectrum disorders in the largest twin study of autistic traits to date.

Design  Twin study using phenotypic analysis and genetic model-fitting in the total sample and extreme scoring groups (top 5%, 2.5%, and 1%).

Setting  A nationally representative twin sample from the general population of England.

Participants  The families of 5968 pairs aged 12 years old in the Twins’ Early Development Study.

Main Outcome Measure  Autistic traits as assessed by the Childhood Autism Spectrum Test.

Results  Moderate to high heritability was found for autistic traits in the general population (53% for females and 72% for males). High heritability was found in extreme-scoring groups. There were no differences in heritability among extreme groups or between the extreme groups and the general population. A continuous liability shift toward autistic trait affectedness was seen in the cotwins of individuals scoring in the top 1%, suggesting shared etiology between extreme scores and normal variation.

Conclusion  This evidence of similar etiology across normal variation and the extremes has implications for molecular genetic models of autism spectrum disorders and for conceptualizing autism spectrum disorders as the quantitative extreme of a neurodevelopmental continuum.

Objectives  To test whether adults with combined-type childhood ADHD exhibit cortical thinning and decreased gray matter in regions hypothesized to be related to ADHD and to test whether anatomic differences are associated with a current ADHD diagnosis, including persistent vs remitting ADHD.

Design  Cross-sectional analysis embedded in a 33-year prospective follow-up at a mean age of 41.2 years.

Setting  Research outpatient center.

Participants  We recruited probands with ADHD from a cohort of 207 white boys aged 6 to 12 years. Male comparison participants (n = 178) were free of ADHD in childhood. We obtained magnetic resonance images in 59 probands and 80 comparison participants (28.5% and 44.9% of the original samples, respectively).

Main Outcome Measures  Whole-brain voxel-based morphometry and vertexwise cortical thickness analyses.

Results  The cortex was significantly thinner in ADHD probands than in comparison participants in the dorsal attentional network and limbic areas (false discovery rate < 0.05, corrected). In addition, gray matter was significantly decreased in probands in the right caudate, right thalamus, and bilateral cerebellar hemispheres. Probands with persistent ADHD (n = 17) did not differ significantly from those with remitting ADHD (n = 26) (false discovery rate < 0.05). At uncorrected P < .05, individuals with remitting ADHD had thicker cortex relative to those with persistent ADHD in the medial occipital cortex, insula, parahippocampus, and prefrontal regions.

Conclusions  Anatomic gray matter reductions are observable in adults with childhood ADHD, regardless of the current diagnosis. The most affected regions underpin top-down control of attention and regulation of emotion and motivation. Exploratory analyses suggest that diagnostic remission may result from compensatory maturation of prefrontal, cerebellar, and thalamic circuitry.

Objectives  We sought to determine the association of unipolar and bipolar depression and a history of attempted suicide with mortality due to ischemic heart disease (IHD) and cardiovascular disease (CVD) in young US adults and to examine potential sex differences.

Design  Longitudinal epidemiologic study.

Setting  Nationally representative sample of US adults.

Participants  A total of 7641 US adults aged 17 to 39 years from the 1988-1994 Third National Health and Nutrition Examination Survey.

Main Outcome Measures  Cardiovascular disease and IHD mortality. Unipolar/bipolar depression and a history of attempted suicide were assessed via the Diagnostic Interview Schedule.

Results  After a median follow-up of 14.9 years, a total of 51 subjects (0.67%) died of CVD causes and 28 (0.37%) died of IHD. Depression (538 individuals [7.04%]) and history of attempted suicide (419 [5.48%]) were each associated with an increased risk of IHD death, with adjusted hazard ratios of 3.70 (95% CI, 1.32-10.35) for depression and 7.12 (2.67-18.98) for a history of attempted suicide. Women with depression or a history of attempted suicide had a 3-fold adjusted risk of CVD (adjusted hazard ratio, 3.20 [95% CI, 1.12-9.17]) and a 14-fold adjusted risk of IHD (14.57 [2.65-80.10]). Corresponding figures for men were 2.37 (0.85-6.58) and 3.52 (1.05-11.76).

Conclusion  In adults younger than 40 years, depression and history of attempted suicide are significant independent predictors of premature CVD and IHD mortality in both sexes.

Objective  To examine and compare protein (amyloid and tau) binding in critical brain regions in patients diagnosed as having late-life major depressive disorder (MDD) and healthy control individuals using 2-(1-{6-[(2-[¹⁸F]fluoroethyl)(methyl)-amino]-2-naphthyl}ethylidene) malononitrile ([¹⁸F]FDDNP) positron emission tomography.

Design  A cross-section neuroimaging study using positron emission tomography.

Setting  University of California, Los Angeles.

Patients  Our samples comprised 20 patients diagnosed as having MDD and 19 healthy control individuals of comparable age, sex, and educational level.

Main Outcome Measure  Relative distribution volume in regions of interest was used as the measure of [¹⁸F]FDDNP binding in all study participants.

Results  When compared with controls, [¹⁸F]FDDNP binding was significantly higher overall and in the posterior cingulate and lateral temporal regions in the MDD group.

Conclusions  These findings suggest that neuronal injury associated with higher protein load in critical brain regions might provide a mechanism in the pathophysiologic manifestation of MDD in late life and have implications for the therapeutics of depression in elderly individuals.

Objective  To determine whether high rates of addictive and other psychiatric disorders previously demonstrated in this sample remain disproportionately higher compared with a matched general population sample.

Design  Point-in-time cohort study.

Setting  Pacific Institute for Research and Evaluation, Albuquerque, New Mexico.

Participants  We interviewed convicted first offenders using the Composite International Diagnostic Interview 15 years after referral to a screening program in Bernalillo County, New Mexico. We calculated rates of diagnoses for non-Hispanic white and Hispanic women (n = 362) and men (n = 220) adjusting for missing data using multiple imputation and compared psychiatric diagnoses with findings from the National Comorbidity Survey Replication by sex and Hispanic ethnicity.

Results  Eleven percent of non-Hispanic white women and 12.8% of Hispanic women in the driving while impaired sample reported 12-month alcohol abuse or dependence, compared with 1.0% and 1.8%, respectively, in the National Comorbidity Survey Replication (comparison) sample. Almost 12% of non-Hispanic white men and 17.5% of Hispanic men in the driving while impaired sample reported 12-month alcohol abuse or dependence, compared with to 2.0% and 1.8%, respectively, in the comparison sample. These differences were statistically significant. Rates of drug use disorders and nicotine dependence were also elevated compared with the general population sample, while rates of major depressive disorder and posttraumatic stress disorder were similar.

Conclusion  In this sample, high rates of addictive disorders persisted over 10 years among first offenders and greatly exceeded those found in a general population sample.

Objective  To determine the association between the 10 DSM-IV personality disorders and the persistence of common SUDs in a 3-year prospective study of a national sample.

Design  Data were drawn from participants in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) who had alcohol dependence (n = 1172), cannabis use disorder (n = 454), or nicotine dependence (n = 4017) at baseline and who were reinterviewed 3 years later. Control variables included demographic characteristics, family history of substance disorders, baseline Axis I disorders and treatment status, and prior SUD duration.

Main Outcome Measure  Persistent SUD, defined as meeting full criteria for the relevant SUD throughout the 3-year follow-up period.

Results  Persistent SUD was found among 30.1% of participants with alcohol dependence, 30.8% with cannabis use disorder, and 56.6% with nicotine dependence at baseline. Axis I disorders did not have strong or consistent associations with persistent SUD. In contrast, antisocial personality disorder was significantly associated with persistent alcohol, cannabis, and nicotine use disorders (adjusted odds ratios, 2.46-3.51), as was borderline personality disorder (adjusted odds ratios, 2.04-2.78) and schizotypal personality disorder (adjusted odds ratios, 1.65-5.90). Narcissistic, schizoid, and obsessive-compulsive personality disorders were less consistently associated with SUD persistence.

Conclusions  The consistent findings on the association of antisocial, borderline, and schizotypal personality disorders with persistent SUD indicates the importance of these personality disorders in understanding the course of SUD. Future studies should examine dimensional representations of personality disorders and the role of specific components of these disorders, biological and environmental contributors to these relationships, and potential applications of these findings to treatment development.

Objective  To determine whether mirtazapine would reduce methamphetamine use among MSM who are actively using methamphetamine.

Design  Double-blind, randomized, controlled, 12-week trial of mirtazapine vs placebo conducted from September 5, 2007, to March 4, 2010.

Setting  San Francisco Department of Public Health.

Participants  Participants were actively using, methamphetamine-dependent, sexually active MSM seen weekly for urine sample collection and substance use counseling.

Interventions  Random assignment to daily oral mirtazapine (30 mg) or placebo; both arms included 30-minute weekly substance use counseling.

Main Outcome Measures  The primary study outcome was reduction in methamphetamine-positive urine test results. Secondary outcomes were study medication adherence (by self-report and medication event monitoring systems) and sexual risk behavior.

Results  Sixty MSM were randomized, 85% of follow-up visits were completed, and 56 participants (93%) completed the final visit. In the primary intent-to-treat analysis, participants assigned to the mirtazapine group had fewer methamphetamine-positive urine test results compared with participants assigned to the placebo group (relative risk, 0.57; 95% CI, 0.35-0.93, P = .02). Urine positivity decreased from 67% (20 of 30 participants) to 63% (17 of 27) in the placebo arm and from 73% (22 of 30) to 44% (12 of 27) in the mirtazapine arm. The number needed to treat to achieve a negative weekly urine test result was 3.1. Adherence was 48.5% by medication event monitoring systems and 74.7% by self-report; adherence measures were not significantly different between arms (medication event monitoring systems, P = .82; self-report, P = .92). Most sexual risk behaviors decreased significantly more among participants taking mirtazapine compared with those taking placebo (number of male partners with whom methamphetamine was used, P = .009; number of male partners, P = .04; episodes of anal sex with serodiscordant partners, P = .003; episodes of unprotected anal sex with serodiscordant partners, P = .003; episodes of insertive anal sex with serodiscordant partners, P = .001). There were no serious adverse events related to study drug or significant differences in adverse events by arm (P ≥ .99).

Conclusion  The addition of mirtazapine to substance use counseling decreased methamphetamine use among active users and was associated with decreases in sexual risk despite low to moderate medication adherence.

Trial Registration  clinicalTrials.gov Identifier NCT00497081

Objective  To examine the magnitude of past-year DSM-IV substance-related disorders (alcohol, marijuana, cocaine, inhalants, hallucinogens, heroin, analgesic opioids, stimulants, sedatives, and tranquilizers) among adolescents of white, Hispanic, African American, Native American, Asian or Pacific Islander, and multiple race/ethnicity.

Design  The 2005 to 2008 National Survey on Drug Use and Health.

Setting  Academic research.

Participants  Noninstitutionalized household adolescents aged 12 to 17 years.

Main Outcome Measures  Substance-related disorders were assessed by standardized survey questions administered using the audio computer–assisted self-interviewing method.

Results  Of 72 561 adolescents aged 12 to 17 years, 37.0% used alcohol or drugs in the past year; 7.9% met criteria for a substance-related disorder, with Native Americans having the highest prevalence of use (47.5%) and disorder (15.0%). Analgesic opioids were the second most commonly used illegal drugs, following marijuana, in all racial/ethnic groups; analgesic opioid use was comparatively prevalent among adolescents of Native American (9.7%) and multiple race/ethnicity (8.8%). Among 27 705 past-year alcohol or drug users, Native Americans (31.5%), adolescents of multiple race/ethnicity (25.2%), adolescents of white race/ethnicity (22.9%), and Hispanics (21.0%) had the highest rates of substance-related disorders. Adolescents used marijuana more frequently than alcohol or other drugs, and 25.9% of marijuana users met criteria for marijuana abuse or dependence. After controlling for adolescents' age, socioeconomic variables, population density of residence, self-rated health, and survey year, adjusted analyses of adolescent substance users indicated elevated odds of substance-related disorders among Native Americans, adolescents of multiple race/ethnicity, adolescents of white race/ethnicity, and Hispanics compared with African Americans; African Americans did not differ from Asians or Pacific Islanders.

Conclusions  Substance use is widespread among adolescents of Native American, white, Hispanic, and multiple race/ethnicity. These groups also are disproportionately affected by substance-related disorders.