Objective  To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for suicide attempt (SA) and MDD by investigating common genetic variants in these loci.

Design  Eighty-three tagging single-nucleotide polymorphisms (SNPs) covering the genetic variability of these loci in European populations were assessed in a case-control association design.

Setting  Inpatients and screened control subjects.

Participants  The discovery sample consisted of 394 depressed patients, of whom 113 had SA, and 366 matched healthy control subjects. The replication studies comprised 744 German patients with MDD and 921 African American nonpsychiatric clinic patients, of whom 152 and 119 were positive for SA, respectively.

Interventions  Blood or saliva samples were collected from each participant for DNA extraction and genotyping.

Main Outcome Measures  Associations of SNPs in BDNF and NTRK2 with SA and MDD.

Results  Independent SNPs within NTRK2 were associated with SA among depressed patients of the discovery sample that could be confirmed in both the German and African American replication samples. Multilocus interaction analysis revealed that single SNP associations within this locus contribute to the risk of SA in a multiplicative and interactive fashion (P = 4.7 x 10^–7 for a 3-SNP model in the combined German sample). The effect size was 4.5 (95% confidence interval, 2.1-9.8) when patients carrying risk genotypes in all 3 markers were compared with those without any of the 3 risk genotypes.

Conclusions  Our results suggest that a combination of several independent risk alleles within the NTRK2 locus is associated with SA in depressed patients, further supporting a role of neurotrophins in the pathophysiology of suicide.

Published online February 1, 2010 (doi:10.1001/archgenpsychiatry.2009.201).

Objective  To examine the joint associations of 12 retrospectively reported CAs with the first onset of DSM-IV disorders in the National Comorbidity Survey Replication using substantively complex multivariate models.

Design  Cross-sectional community survey with retrospective reports of CAs and lifetime DSM-IV disorders.

Setting  Household population in the United States.

Participants  Nationally representative sample of 9282 adults.

Main Outcome Measures  Lifetime prevalences of 20 DSM-IV anxiety, mood, disruptive behavior, and substance use disorders assessed using the Composite International Diagnostic Interview.

Results  The CAs studied were highly prevalent and intercorrelated. The CAs in a maladaptive family functioning (MFF) cluster (parental mental illness, substance abuse disorder, and criminality; family violence; physical abuse; sexual abuse; and neglect) were the strongest correlates of disorder onset. The best-fitting model included terms for each type of CA, number of MFF CAs, and number of other CAs. Multiple MFF CAs had significant subadditive associations with disorder onset. Little specificity was found for particular CAs with particular disorders. Associations declined in magnitude with life course stage and number of previous lifetime disorders but increased with length of recall. Simulations suggest that CAs are associated with 44.6% of all childhood-onset disorders and with 25.9% to 32.0% of later-onset disorders.

Conclusions  The fact that associations increased with length of recall raises the possibility of recall bias inflating estimates. Even considering this, the results suggest that CAs have powerful and often subadditive associations with the onset of many types of largely primary mental disorders throughout the life course.

Objective  To examine the multivariate associations of 12 retrospectively reported CAs with persistence of adult DSM-IV disorders in the National Comorbidity Survey Replication.

Design  Cross-sectional community survey.

Setting  Household population in the United States.

Participants  Nationally representative sample of 5692 adults.

Main Outcome Measures  Recency of episodes was assessed separately for each of 20 lifetime DSM-IV mood, anxiety, disruptive behavior, and substance use disorders in respondents with a lifetime history of these disorders using the Composite International Diagnostic Interview. Predictors of persistence were examined using backward recurrence survival models to predict time since most recent episode controlling for age at onset and time since onset.

Results  The CAs involving maladaptive family functioning (parental mental illness, substance use disorder, criminality, family violence, physical and sexual abuse, and neglect) but not other CAs were significantly but modestly related to persistence of mood, substance abuse, and anxiety disorders. Number of maladaptive family functioning CAs had statistically significant, but again substantively modest, subadditive associations with the same outcomes. Exposure to multiple other CAs was significantly associated with persistence of mood and anxiety disorders. Associations remained statistically significant throughout the life course, although the substantive size of associations indicated by simulations showing time to most recent episode would increase by only 1.6% (from a mean of 8.3 years to a mean of 8.4 years) in the absence of CAs.

Conclusions  The overall statistically significant associations of CAs with adult DSM-IV/Composite International Diagnostic Interview disorders are due largely to component associations with onsets rather than with persistence, indirectly suggesting that the greatest focus of public health attention on CAs should be aimed at primary rather than secondary prevention.

Objective  To determine whether hippocampal volume would increase with exercise in humans and whether this effect would be related to improved aerobic fitness.

Design  Randomized controlled study.

Setting  Patients attending a day hospital program or an outpatient clinic.

Patients or Other Participants  Male patients with chronic schizophrenia and matched healthy subjects.

Interventions  Aerobic exercise training (cycling) and playing table football (control group) for a period of 3 months.

Main Outcome Measures  Magnetic resonance imaging of the hippocampus. Secondary outcome measures were magnetic resonance spectroscopy, neuropsychological (Rey Auditory Verbal Learning Test, Corsi block-tapping test), and clinical (Positive and Negative Syndrome Scale) features.

Results  Following exercise training, relative hippocampal volume increased significantly in patients (12%) and healthy subjects (16%), with no change in the nonexercise group of patients (–1%). Changes in hippocampal volume in the exercise group were correlated with improvements in aerobic fitness measured by change in maximum oxygen consumption (r = 0.71; P = .003). In the schizophrenia exercise group (but not the controls), change in hippocampal volume was associated with a 35% increase in the N-acetylaspartate to creatine ratio in the hippocampus. Finally, improvement in test scores for short-term memory in the combined exercise and nonexercise schizophrenia group was correlated with change in hippocampal volume (r = 0.51; P < .05).

Conclusion  These results indicate that in both healthy subjects and patients with schizophrenia hippocampal volume is plastic in response to aerobic exercise.

Objective  To determine whether -3 PUFAs reduce the rate of progression to first-episode psychotic disorder in adolescents and young adults aged 13 to 25 years with subthreshold psychosis.

Design  Randomized, double-blind, placebo-controlled trial conducted between 2004 and 2007.

Setting  Psychosis detection unit of a large public hospital in Vienna, Austria.

Participants  Eighty-one individuals at ultra-high risk of psychotic disorder.

Interventions  A 12-week intervention period of 1.2-g/d -3 PUFA or placebo was followed by a 40-week monitoring period; the total study period was 12 months.

Main Outcome Measures  The primary outcome measure was transition to psychotic disorder. Secondary outcomes included symptomatic and functional changes. The ratio of -6 to -3 fatty acids in erythrocytes was used to index pretreatment vs posttreatment fatty acid composition.

Results  Seventy-six of 81 participants (93.8%) completed the intervention. By study's end (12 months), 2 of 41 individuals (4.9%) in the -3 group and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder (P = .007). The difference between the groups in the cumulative risk of progression to full-threshold psychosis was 22.6% (95% confidence interval, 4.8-40.4). -3 Polyunsaturated fatty acids also significantly reduced positive symptoms (P = .01), negative symptoms (P = .02), and general symptoms (P = .01) and improved functioning (P = .002) compared with placebo. The incidence of adverse effects did not differ between the treatment groups.

Conclusions  Long-chain -3 PUFAs reduce the risk of progression to psychotic disorder and may offer a safe and efficacious strategy for indicated prevention in young people with subthreshold psychotic states.

Trial Registration  clinicaltrials.gov Identifier: NCT00396643

Hypothesis  Chondroitin sulfate proteoglycan–related abnormalities involve glial cells and extracellular matrix pericellular aggregates (perineuronal nets) in the amygdala and entorhinal cortex of subjects with schizophrenia.

Design  Postmortem case-control study.

Setting  The Translational Neuroscience Laboratory at McLean Hospital, Harvard Medical School. Specimens were obtained from the Harvard Brain Tissue Resource Center at McLean Hospital.

Participants  Two separate cohorts of healthy control (n = 15; n = 10) and schizophrenic (n = 11; n = 10) subjects and a cohort of subjects with bipolar disorder (n = 11).

Interventions  Quantitative, immunocytological, and histological postmortem investigations.

Main Outcome Measures  Numerical densities of CSPG-positive glial cells and perineuronal nets, glial fibrillary acidic protein-positive astrocytes, and total numbers of parvalbumin-positive neurons in the deep amygdala nuclei and entorhinal cortex.

Results  In schizophrenia, massive increases in CSPG-positive glial cells were detected in the deep amygdala nuclei (419%-1162%) and entorhinal cortex (layer II; 480%-1560%). Perineuronal nets were reduced in the lateral nucleus of the amygdala and lateral entorhinal cortex (layer II). Numerical densities of glial fibrillary acidic protein-positive glial cells and total numbers of parvalbumin-positive neurons were unaltered. Changes in CSPG-positive elements were negligible in subjects with bipolar disorder.

Conclusions  Marked changes in functionally relevant molecules in schizophrenia point to a pivotal role for extracellular matrix–glial interactions in the pathogenesis of this disease. Disruption of these interactions, unsuspected thus far, may represent a unifying factor contributing to disturbances of neuronal migration, synaptic connectivity, and GABAergic, glutamatergic, and dopaminergic neurotransmission in schizophrenia. The lack of CSPG abnormalities in bipolar disorder points to a distinctive aspect of the pathophysiology of schizophrenia in key medial temporal lobe regions.

Objective  To adjudicate neurocognitive endophenotypes for bipolar disorder.

Design  All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status.

Setting  Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas.

Participants  Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia.

Main Outcome Measure  Neurocognitive test performance.

Results  Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory.

Conclusion  This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.

Objective  To examine if attention disengagement from faces is atypical in the early stages of ASD.

Design  Attention disengagement was tested in a variation of the cued attention task in which participants were required to move their visual attention from face or nonface central fixation stimuli and make a reactive saccade to a peripheral target. The design involved diagnosis as a between-group factor and central fixation stimuli type as a within-group factor.

Setting  Participants were taken from a cohort of patients at a university-based specialized clinic or from a pool of subjects participating in a prospective study of social cognition in ASD.

Participants  Toddlers with ASD (mean age, 32 months [n = 42]) were compared with toddlers with nonautistic developmental delays (mean age, 29 months [n = 31]) and with typically developing toddlers (mean age, 29 months [n = 46]).

Main Outcome Measure  Saccadic reaction time.

Results  Developmentally delayed and typically developing toddlers had more difficulties disengaging visual attention from faces than toddlers with ASD. This effect was not present in response to nonfacial stimuli. These results suggest that toddlers with ASD are not captivated by faces to the same extent as toddlers without ASD and that this effect is not driven by a generalized impairment in disengagement of attention.

Conclusion  The results suggest that face-processing difficulties in toddlers with ASD involve disruption of an attentional mechanism that typically supports deeper processing of these highly socially relevant stimuli.

Objective  To examine the effect of escitalopram on cognitive outcome. We hypothesized that patients who received escitalopram would show improved performance in neuropsychological tests assessing memory and executive functions than patients who received placebo or underwent Problem Solving Therapy.

Design  Randomized trial.

Setting  Stroke center.

Participants  One hundred twenty-nine patients were treated within 3 months following stroke. The 12-month trial included 3 arms: a double-blind placebo-controlled comparison of escitalopram (n = 43) with placebo (n = 45), and a nonblinded arm of Problem Solving Therapy (n = 41).

Outcome Measures  Change in scores from baseline to the end of treatment for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Trail-Making, Controlled Oral Word Association, Wechsler Adult Intelligence Scale–III Similarities, and Stroop tests.

Results  We found a difference among the 3 treatment groups in change in RBANS total score (P < .01) and RBANS delayed memory score (P < .01). After adjusting for possible confounders, there was a significant effect of escitalopram treatment on the change in RBANS total score (P < .01, adjusted mean change in score: escitalopram group, 10.0; nonescitalopram group, 3.1) and the change in RBANS delayed memory score (P < .01, adjusted mean change in score: escitalopram group, 11.3; nonescitalopram group, 2.5). We did not observe treatment effects in other neuropsychological measures.

Conclusions  When compared with patients who received placebo or underwent Problem Solving Therapy, stroke patients who received escitalopram showed improvement in global cognitive functioning, specifically in verbal and visual memory functions. This beneficial effect of escitalopram was independent of its effect on depression. The utility of antidepressants in the process of poststroke recovery should be further investigated.

Trial Registration  clinicaltrials.gov Identifier: NCT00071643

Objective  To determine whether patients with BDD have abnormal patterns of brain activation when visually processing their own face with high, low, or normal spatial resolution.

Design  Case-control study.

Setting  A university hospital.

Participants  Seventeen right-handed medication-free subjects with BDD and 16 matched healthy control subjects.

Intervention  Functional magnetic resonance imaging while viewing photographs of face stimuli. Stimuli were neutral-expression photographs of the patient's own face and a familiar face (control stimuli) that were unaltered, altered to include only high spatial frequency (fine spatial resolution), or altered to include only low spatial frequency (low spatial resolution).

Main Outcome Measure  Blood oxygen level–dependent signal changes in the BDD and control groups during each stimulus type.

Results  Subjects with BDD showed relative hyperactivity in the left orbitofrontal cortex and bilateral head of the caudate for the unaltered own-face vs familiar-face condition. They showed relative hypoactivity in the left occipital cortex for the low spatial frequency faces. Differences in activity in frontostriatal systems but not visual cortex covaried with aversiveness ratings of the faces. Severity of BDD symptoms correlated with activity in frontostriatal systems and visual cortex.

Conclusions  These results suggest abnormalities in visual processing and frontostriatal systems in BDD. Hypoactivation in the occipital cortex for low spatial frequency faces may indicate either primary visual system abnormalities for configural face elements or top-down modulation of visual processing. Frontostriatal hyperactivity may be associated both with aversion and with symptoms of obsessive thoughts and compulsive behaviors.