Context  Low-functioning patients with chronic schizophrenia have high direct treatment costs and indirect costs incurred due to lost employment and productivity and have a low quality of life; antipsychotic medications and psychosocial interventions have shown limited efficacy to promote improved functional outcomes.

Objective  To determine the efficacy of an 18-month recovery-oriented cognitive therapy program to improve psychosocial functioning and negative symptoms (avolition-apathy, anhedonia-asociality) in 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

Context  Negative symptoms are a core feature of schizophrenia, but their pathogenesis remains unclear. Negative symptoms are defined by the absence of normal function. However, there must be a productive mechanism that leads to this absence.

Objective  To test a reinforcement learning account suggesting that negative symptoms result from a failure in the representation of the expected value of rewards coupled with preserved loss-avoidance learning.

Design  Participants performed a probabilistic reinforcement learning paradigm involving stimulus pairs in which choices resulted in reward or in loss avoidance. Following training, participants indicated their valuation of the stimuli in a transfer test phase. Computational modeling was used to distinguish between alternative accounts of the data.

Setting  A tertiary care research outpatient clinic.

Patients  In total, 47 clinically stable patients with a diagnosis of schizophrenia or schizoaffective disorder and 28 healthy volunteers participated in the study. Patients were divided into a high-negative symptom group and a low-negative symptom group.

Main Outcome Measures  The number of choices leading to reward or loss avoidance, as well as performance in the transfer test phase. Quantitative fits from 3 different models were examined.

Results  Patients in the high-negative symptom group demonstrated impaired learning from rewards but intact loss-avoidance learning and failed to distinguish rewarding stimuli from loss-avoiding stimuli in the transfer test phase. Model fits revealed that patients in the high-negative symptom group were better characterized by an "actor-critic" model, learning stimulus-response associations, whereas control subjects and patients in the low-negative symptom group incorporated expected value of their actions ("Q learning") into the selection process.

Conclusions  Negative symptoms in schizophrenia are associated with a specific reinforcement learning abnormality: patients with high-negative symptoms do not represent the expected value of rewards when making decisions but learn to avoid punishments through the use of prediction errors. This computational framework offers the potential to understand negative symptoms at a mechanistic level.

Context  Anhedonia, a core symptom of major depressive disorder (MDD) and highly variable among adolescents with MDD, may involve alterations in the major inhibitory amino acid neurotransmitter system of -aminobutyric acid (GABA).

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; PTukey < .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.

Context  Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited.

Objective  To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP).

Design  Open-label trial with a sham lead-in phase.

Setting  Academic medical center.

Patients  Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened.

Intervention  Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation.

Main Outcome Measures  Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation.

Results  A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n = 17), 5 (36%) and 5 (36%) after 1 year (n = 14), and 7 (58%) and 11 (92%) after 2 years (n = 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

Context  Mental health problems are associated with women's reproductive decisions and predict poor mental health outcomes after abortion and childbirth.

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.

Context  Preventing posttraumatic stress disorder (PTSD) is a pressing public health need.

Objectives  To compare early and delayed exposure-based, cognitive, and pharmacological interventions for preventing PTSD.

Design  Equipoise-stratified randomized controlled study.

Setting  Hadassah Hospital unselectively receives trauma survivors from Jerusalem and vicinity.

Participants  Consecutively admitted survivors of traumatic events were assessed by use of structured telephone interviews a mean (SD) 9.61 (3.91) days after the traumatic event. Survivors with symptoms of acute stress disorder were referred for clinical assessment. Survivors who met PTSD symptom criteria during the clinical assessment were invited to receive treatment.

Interventions  Twelve weekly sessions of prolonged exposure (PE; n = 63), or cognitive therapy (CT; n = 40), or double blind treatment with 2 daily tablets of either escitalopram (10 mg) or placebo (selective serotonin reuptake inhibitor/placebo; n = 46), or 12 weeks in a waiting list group (n = 93). Treatment started a mean (SD) 29.8 (5.7) days after the traumatic event. Waiting list participants with PTSD after 12 weeks received PE a mean (SD) 151.8 (42.4) days after the traumatic event (delayed PE).

Main Outcome Measure  Proportion of participants with PTSD after treatment, as determined by the use of the Clinician-Administered PTSD Scale (CAPS) 5 and 9 months after the traumatic event. Treatment assignment and attendance were concealed from the clinicians who used the CAPS.

Results  At 5 months, 21.6% of participants who received PE and 57.1% of comparable participants on the waiting list had PTSD (odds ratio [OR], 0.21 [95% CI, 0.09-0.46]). At 5 months, 20.0% of participants who received CT and 58.7% of comparable participants on the waiting list had PTSD (OR, 0.18 [CI, 0.06-0.48]). The PE group did not differ from the CT group with regard to PTSD outcome (OR, 0.87 [95% CI, 0.29-2.62]). The PTSD prevalence rates did not differ between the escitalopram and placebo subgroups (61.9% vs 55.6%; OR, 0.77 [95% CI, 0.21-2.77]). At 9 months, 20.8% of participants who received PE and 21.4% of participants on the waiting list had PTSD (OR, 1.04 [95% CI, 0.40-2.67]). Participants with partial PTSD before treatment onset did similarly well with and without treatment.

Conclusions  Prolonged exposure, CT, and delayed PE effectively prevent chronic PTSD in recent survivors. The lack of improvement from treatment with escitalopram requires further evaluation. Trauma-focused clinical interventions have no added benefit to survivors with subthreshold PTSD symptoms.

Trial Registration  clinicaltrials.gov Identifier: NCT00146900

Context  The neural basis of excessive delay discounting and reduced risk sensitivity of pathological gamblers with a particular focus on subjective neural reward representations has not been previously examined.

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.

Context  Accurately assessing sexual preference is important in the treatment of child sex offenders. Phallometry is the standard method to identify sexual preference; however, this measure has been criticized for its intrusiveness and limited reliability.

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.

Context  There is consensus that autism spectrum disorder (ASD) is accompanied by differences in neuroanatomy. However, the neural substrates of ASD during adulthood, as well as how these relate to behavioral variation, remain poorly understood.

Objective  To identify brain regions and systems associated with ASD in a large, well-characterized sample of adults.

Design  Multicenter case-control design using quantitative magnetic resonance imaging.

Setting  Medical Research Council UK Autism Imaging Multicentre Study (MRC AIMS), with sites comprising the Institute of Psychiatry, Kings College London; the Autism Research Centre, University of Cambridge; and the Autism Research Group, University of Oxford.

Participants  Eighty-nine men with ASD and 89 male control participants who did not differ significantly in mean age (26 and 28 years, respectively) and full-scale IQ (110 and 113, respectively).

Main Outcome Measures  (1) Between-group differences in regional neuroanatomy assessed by voxel-based morphometry and (2) distributed neural systems maximally correlated with ASD, as identified by partial least-squares analysis.

Results  Adults with ASD did not differ significantly from the controls in overall brain volume, confirming the results of smaller studies of individuals in this age group without intellectual disability. However, voxelwise comparison between groups revealed that individuals with ASD had significantly increased gray matter volume in the anterior temporal and dorsolateral prefrontal regions and significant reductions in the occipital and medial parietal regions compared with controls. These regional differences in neuroanatomy were significantly correlated with the severity of specific autistic symptoms. The large-scale neuroanatomic networks maximally correlated with ASD identified by partial least-squares analysis included the regions identified by voxel-based analysis, as well as the cerebellum, basal ganglia, amygdala, inferior parietal lobe, cingulate cortex, and various medial, orbital, and lateral prefrontal regions. We also observed spatially distributed reductions in white matter volume in participants with ASD.

Conclusions  Adults with ASD have distributed differences in brain anatomy and connectivity that are associated with specific autistic features and traits. These results are compatible with the concept of autism as a syndrome characterized by atypical neural "connectivity."

Context  The US Food and Drug Administration issued a black box warning for antidepressants and suicidal thoughts and behavior in children and young adults.

Objective  To determine the short-term safety of antidepressants by standard assessments of suicidal thoughts and behavior in youth, adult, and geriatric populations and the mediating effect of changes in depressive symptoms.

Data Sources  All intent-to-treat person-level longitudinal data of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride.

Study Selection  All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine.

Data Extraction  The suicide items from the Children's Depression Rating Scale–Revised and the Hamilton Depression Rating Scale as well as adverse event reports of suicide attempts and suicide during active treatment were analyzed in 9185 patients (fluoxetine: 2635 adults, 960 geriatric patients, 708 youths; venlafaxine: 2421 adults with immediate-release venlafaxine and 2461 adults with extended-release venlafaxine) for a total of 53 260 person-week observations.

Data Synthesis  Suicidal thoughts and behavior decreased over time for adult and geriatric patients randomized to fluoxetine or venlafaxine compared with placebo, but no differences were found for youths. In adults, reduction in suicide ideation and attempts occurred through a reduction in depressive symptoms. In all age groups, severity of depression improved with medication and was significantly related to suicide ideation or behavior.

Conclusions  Fluoxetine and venlafaxine decreased suicidal thoughts and behavior for adult and geriatric patients. This protective effect is mediated by decreases in depressive symptoms with treatment. For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment. No evidence of increased suicide risk was observed in youths receiving active medication. To our knowledge, this is the first research synthesis of suicidal thoughts and behavior in depressed patients treated with antidepressants that examined the mediating role of depressive symptoms using complete longitudinal person-level data from a large set of published and unpublished studies.

Context  Rates of clinical diagnoses of schizophrenia in African American individuals appear to be elevated compared with other ethnic groups in the United States, contradicting population rates derived from epidemiologic surveys.

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.

Context  Smoking is a possible risk factor for dementia, although its impact may have been underestimated in elderly populations because of the shorter life span of smokers.

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.

Context  GAD67 regulation involves a network of genes implicated in schizophrenia and bipolar disorder. We have studied the copy number intensities of these genes in specific hippocampal subregions to clarify whether abnormalities of genomic integrity covary with gene expression in a circuitry-based manner.

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.