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mediating role of depressive symptoms using complete longitudinal person-level data from a large set of published and unpublished studies.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