Objectives  To determine the efficacy and safety of citalopram hydrobromide therapy for repetitive behavior in children with autism spectrum disorders.

Design  National Institutes of Health–sponsored randomized controlled trial.

Setting  Six academic centers, including Mount Sinai School of Medicine, North Shore–Long Island Jewish Health System, University of North Carolina at Chapel Hill, University of California at Los Angeles, Yale University, and Dartmouth Medical School.

Participants  One hundred forty-nine volunteers 5 to 17 years old (mean [SD] age, 9.4 [3.1] years) were randomized to receive citalopram (n = 73) or placebo (n = 76). Participants had autistic spectrum disorders, Asperger disorder, or pervasive developmental disorder, not otherwise specified; had illness severity ratings of at least moderate on the Clinical Global Impressions, Severity of Illness Scale; and scored at least moderate on compulsive behaviors measured with the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders.

Interventions  Twelve weeks of citalopram hydrobromide (10 mg/5 mL) or placebo. The mean (SD) maximum dosage of citalopram hydrobromide was 16.5 (6.5) mg/d by mouth (maximum, 20 mg/d).

Main Outcome Measures  Positive response was defined by a score of much improved or very much improved on the Clinical Global Impressions, Improvement subscale. An important secondary outcome was the score on the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders. Adverse events were systematically elicited using the Safety Monitoring Uniform Report Form.

Results  There was no significant difference in the rate of positive response on the Clinical Global Impressions, Improvement subscale between the citalopram-treated group (32.9%) and the placebo group (34.2%) (relative risk, 0.96; 95% confidence interval, 0.61-1.51; P > .99). There was no difference in score reduction on the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders from baseline (mean [SD], –2.0 [3.4] points for the citalopram-treated group and –1.9 [2.5] points for the placebo group; P = .81). Citalopram use was significantly more likely to be associated with adverse events, particularly increased energy level, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, and dry skin or pruritus.

Conclusion  Results of this trial do not support the use of citalopram for the treatment of repetitive behavior in children and adolescents with autism spectrum disorders.

Trial Registration  clinicaltrials.gov Identifier: NCT00086645

Objective  To produce a broader set of factorial phenotypes that are tested for familiality including core symptoms of schizophrenia and additional indicators of social, work, and educational dysfunction.

Design  The study used psychiatric assessment data collected from several large samples of individuals with schizophrenia who have participated in family or case-control genetic studies (1988-2006) in the Epidemiology-Genetics Program in Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Seventy-three signs and symptoms were selected from direct assessment interviews and consensus diagnostic ratings (integrating interview data, medical records, and informant reports).

Setting  Study participants were recruited from across the United States, and a few additional participants were recruited from Canada, Greece, Italy, Poland, and Israel. Assessments generally were performed in the individuals' homes.

Participants  Forty-three percent of 1199 volunteers had largely white European backgrounds. The remaining individuals were recruited for family and case-control studies with focus on Ashkenazi Jews. All individuals had a consensus diagnosis of schizophrenia (including schizoaffective disorder) using DSM-III or DSM-IV criteria.

Main Outcome Measures  The 73 indicators were subjected to principal components factor analysis, and factor scores representing 9 dimensions were analyzed for familiality.

Results  The 9 factors include the often-reported delusions, hallucinations, disorganization, negative, and affective factors; novel factors included child/adolescent sociability, scholastic performance, disability/impairment, and prodromal factors. All 9 factors demonstrated significant familiality (measured by a heritability statistic), with the highest scores for disability/impairment (0.61), disorganization (0.60), and scholastic performance (0.51).

Conclusions  The factor scores show varying degrees of familiality and may prove useful as quantitative traits and covariates in linkage and association studies.

Objectives  To examine the effects of antipsychotics (clozapine, risperidone, or olanzapine) on the high- vs high- + low-affinity sites of the D₂ and D₃ receptors by comparing the [¹¹C]-(+)-PHNO and [¹¹C]raclopride binding in the D₃ receptor–rich (globus pallidus and ventral striatum) and D₂ receptor–rich (caudate and putamen) regions.

Design  Two sequential studies with different participants and appropriate controls were performed. The first compared the occupancy produced by 3 antipsychotics as measured with [¹¹C]-(+)-PHNO and [¹¹C]raclopride. The second was a double-blind, placebo-controlled experiment to compare the effect of pramipexole (a D₃ receptor–preferring agonist) vs placebo on the increased [¹¹C]-(+)-PHNO signal observed in the globus pallidus of patients.

Setting  Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Participants  Twenty-three patients with schizophrenia and 23 healthy controls.

Main Outcome Measures  Antipsychotic occupancies as measured with [¹¹C]-(+)-PHNO and [¹¹C]raclopride.

Results  The antipsychotic-treated patients showed high occupancies with both [¹¹C]-(+)-PHNO and [¹¹C]raclopride in the dorsal striatum, with [¹¹C]raclopride occupancies about 20% higher. Most strikingly, patients did not show any occupancy with [¹¹C]-(+)-PHNO in the globus pallidus as compared with normal controls or with their own scans using [¹¹C]raclopride. This unblocked [¹¹C]-(+)-PHNO signal was displaced by a single dose of pramipexole.

Conclusions  Antipsychotics block both the high- and low-affinity states of the D₂ receptors across the brain, but antipsychotic treatment does not block the [¹¹C]-(+)-PHNO signal in the D₃ receptor–rich regions, despite the ongoing D₂ receptor blockade. This [¹¹C]-(+)-PHNO signal in regions such as the globus pallidus seems increased despite antipsychotic treatment and is displaceable by a D₃ receptor–preferring agonist. The radiotracer [¹¹C]-(+)-PHNO and the data open up new avenues for exploring the potential therapeutic significance of the D₃ receptor in schizophrenia.

Objective  To examine whether there is an association between depression and various cortisol indicators in a large cohort study.

Design, Setting, and Participants  Data are from 1588 participants of the Netherlands Study of Depression and Anxiety who were recruited from the community, general practice care, and specialized mental health care. Three groups were compared: 308 control subjects without psychiatric disorders, 579 persons with remitted (no current) major depressive disorder (MDD), and 701 persons with a current MDD diagnosis, as assessed using the DSM-IV Composite International Diagnostic Interview.

Main Outcome Measures  Cortisol levels were measured in 7 saliva samples to determine the 1-hour cortisol awakening response, evening cortisol levels, and cortisol suppression after a 0.5-mg dexamethasone suppression test.

Results  Both the remitted and current MDD groups showed a significantly higher cortisol awakening response compared with control subjects (effect size [Cohen d] range, 0.15-0.25). Evening cortisol levels were higher among the current MDD group at 10 pm but not at 11 pm. The postdexamethasone cortisol level did not differ between the MDD groups. Most depression characteristics (severity, chronicity, symptom profile, prior childhood trauma) were not associated with hypothalamic-pituitary-adrenal axis activity except for comorbid anxiety, which tended to be associated with a higher cortisol awakening response. The use of psychoactive medication was generally associated with lower cortisol levels and less cortisol suppression after dexamethasone ingestion.

Conclusions  This large cohort study shows significant, although modest, associations between MDD and specific hypothalamic-pituitary-adrenal axis indicators. Because a higher cortisol awakening response was observed among both subjects with current MDD and subjects with remitted MDD, this may be indicative of an increased biological vulnerability for depression.

Objective  To evaluate the influence of frequent change of residence on risk of attempted and completed suicide among children and adolescents.

Design, Setting, and Participants  We used data from Danish longitudinal population registries to identify all children born from 1978 to 1995 in Denmark; 4160 of these children attempted suicide, and 79 completed suicide at ages 11 to 17 years. We adopted a nested case-control design and recruited 30 controls per case, matched individually on sex, age, and calendar time.

Main Outcome Measure  We used conditional logistic regression to compute the incidence rate ratio for attempted and/or completed suicide associated with the number of previous changes of residence.

Results  We observed a significantly increased risk of attempted suicide associated with changes of living address, and there was an apparent dose-response trend for this association—the more frequent incidence of moving, the higher the risk for attempted suicide. This trend remained the same after controlling for possible confounding factors at birth, ie, birth order, birthplace, link to a father, and parental age at birth. However, it was somewhat attenuated, but still significant, after controlling for the child's own psychiatric morbidity and loss of a mother or father, as well as parental psychiatric history. The observed association was neither modified by sex nor age at the time of moving. Further analyses of suicide completers demonstrated a similar association between change of residence and completed suicide.

Conclusions  Frequent change of residence may induce distress among children and, therefore, increase their risk of suicidal behavior. More research is needed to explore this association.

Objective  To determine whether the unintended declines in depression care persisted for pediatric, young adult, and adult patients.

Design  Time series analyses.

Setting  Ambulatory care settings nationally.

Patients  Pediatric, young adult, and adult cohorts of patients with new episodes of depression (n = 91 748, 70 311, and 630 748 episodes, respectively).

Interventions  Post–FDA advisory trends were compared with expected trends based on preadvisory patterns using a national integrated managed care claims database from July 1999 through June 2007.

Main Outcome Measures  Depression diagnosis; antidepressant, antipsychotic, and anxiolytic prescriptions; and psychotherapy visits.

Results  Changes in pediatric depression care were similar to changes for adults. National diagnosis rates of depression returned to 1999 levels for pediatric patients and below 2004 levels for adults. Primary care providers continued significant reductions in new diagnoses of depression (44% lower for pediatric, 37% lower for young adults, 29% for adults); diagnoses by mental health providers who were not psychiatrists increased. Numbers of prescriptions of anxiolytic and atypical antipsychotic medications did not significantly change from preadvisory trends. Psychotherapy increased significantly for adult, though not pediatric, cases. Selective serotonin reuptake inhibitor use decreased in all cohorts; serotonin-norepinephrine reuptake inhibitor increased for adults.

Conclusions  Diagnosing decreases persist. Substitute care did not compensate in pediatric and young adult groups, and spillover to adults continued, suggesting that unintended effects are nontransitory, substantial, and diffuse in a large national population. Policy actions are required to counter the unintended consequences of reduced depression treatment.

Objective  To identify patterns of gene-environment interplay between externalizing disorders (antisocial behavior and substance use) and several environmental risk factors.

Design  We used quantitative genetic models to examine how genetic and environmental risk for externalizing disorders changes as a function of environmental context.

Setting  Participants were recruited from the community and took part in a daylong assessment at a university laboratory.

Participants  The sample consisted of 1315 male and female twin pairs participating in the assessment of the Minnesota Twin Family Study at age 17 years.

Main Outcome Measures  Multiple measures and informants were used to construct a composite of externalizing disorders and composite measures of 6 environmental risk factors, including academic achievement and engagement, antisocial and prosocial peer affiliations, mother-child and father-child relationship problems, and stressful life events.

Results  A significant gene x environment interaction was detected between each environmental risk factor and externalizing such that greater environmental adversity was associated with increased genetic risk for externalizing.

Conclusions  In the context of environmental adversity, genetic factors become more important in the etiology of externalizing disorders. The consistency of the results further suggests a general mechanism of environmental influence on externalizing disorders regardless of the specific form of the environmental risk.

Objective  To test for an association between GABRA2 and trajectories of externalizing behavior from adolescence to young adulthood and for moderation of genetic effects by parental monitoring.

Design  Data were analyzed from the Child Development Project, with yearly assessments conducted since that time. A saliva sample was collected for DNA at the 2006 follow-up, with a 93% response rate in the target sample. Growth mixture modeling was conducted using Mplus to identify trajectories of externalizing behavior and to test for effects of GABRA2 sequence variants and parental monitoring.

Setting  Nashville and Knoxville, Tennessee, and Bloomington, Indiana.

Participants  A community-based sample of families enrolled at 3 sites as children entered kindergarten in 1987 and 1988. Analyses for the white subset of the sample (n = 378) are reported here.

Main Outcome Measures  Parental monitoring measured at 11 years of age; Child Behavior Checklist youth reports of externalizing behavior at ages 12, 14, 15, 16, 17, 19, 20, 21, and 22 years.

Results  Two classes of externalizing behavior emerged: a stable high externalizing class and a moderate decreasing externalizing behavior class. The GABRA2 gene was associated with class membership, with subjects who showed persistent elevated trajectories of externalizing behavior more likely to carry the genotype previously associated with increased risk of adult alcohol dependence. A significant interaction with parental monitoring emerged; the association of GABRA2 with externalizing trajectories diminished with high levels of parental monitoring.

Conclusions  These analyses underscore the importance of studying genetic effects across development and of identifying environmental factors that moderate risk.

Objective  To identify structural abnormalities in the nonhuman primate brain that may predict increased risk of stress-related neuropsychiatric disorders in human beings.

Design  Rhesus monkeys were divided into 2 groups at birth: a group raised with their mothers and other juvenile and adult animals (mother reared) and a group raised with 3 age-matched monkeys only (peer reared) for the first 6 months of life. Anatomical brain images were acquired in juvenile male and female rhesus monkeys using magnetic resonance imaging.

Setting  National Institutes of Health Animal Center in Poolesville, Maryland.

Subjects  Twenty-eight rhesus monkeys (Macaca mulatta) aged 24 to 30 months were used for the study.

Main Outcome Measures  Volumetric measures of the anterior cingulate cortex, medial prefrontal cortex, hippocampus, corpus callosum, and cerebellar vermis were compared between mother-reared (n = 15) and peer-reared animals (n = 13).

Results  Compared with mother-reared monkeys, we found an enlarged vermis, dorsomedial prefrontal cortex, and dorsal anterior cingulate cortex in peer-reared monkeys without any apparent differences in the corpus callosum and hippocampus.

Conclusions  Peer-rearing during infancy induces enlargement in stress-sensitive brain regions. These changes may be a structural phenotype for increased risk of stress-related neuropsychiatric disorders in human beings.

Objective  To examine changes in β₂*-nAChR availability during acute and prolonged abstinence from tobacco smoking and to determine how changes in β₂*-nAChR availability were related to clinical features of tobacco smoking.

Design  Tobacco smokers participated in up to 4 iodide 123–labeled 5-iodo-A-85380 ([¹²³I]5-IA) single-photon emission computed tomography (SPECT) scans during abstinence at 1 day (n = 7) and 1 (n = 17), 2 (n = 7), 4 (n = 11), and 6 to 12 (n = 6) weeks. Age-matched nonsmokers participated in a single [¹²³I]5-IA SPECT scan. All participants completed 1 magnetic resonance imaging study.

Setting  Academic imaging center.

Participants  Tobacco smokers (n = 19) and an age-matched nonsmoker comparison group (n = 20).

Main Outcome Measure  The [¹²³I]5-IA SPECT images were converted to distribution volume and were analyzed using regions of interest.

Results  Compared with nonsmokers, β₂*-nAChR availability in the striatum, cortex, and cerebellum of smokers was not different at 1 day of abstinence, was significantly higher at 1 week of abstinence, and was not different at 4 or at 6 to 12 weeks of abstinence. In smokers, β₂*-nAChR availability was significantly lower in the cortex and cerebellum at 6 to 12 weeks compared with 1 week of abstinence. In addition, cerebellar β₂*-nAChR availability at 4 weeks of abstinence was positively correlated with craving on the day of the SPECT scan.

Conclusions  These data suggest that higher β₂*-nAChR availability persists up to 1 month of abstinence and normalizes to nonsmoker levels by 6 to 12 weeks of abstinence from tobacco smoking. These marked and persistent changes in β₂*-nAChR availability may contribute to difficulties with tobacco cessation.

Objective  To quantify the distribution and heritability of cortical thickness changes in schizophrenia.

Design  We analyzed a large sample of normal controls, affected patients, and unaffected siblings using a surface-based approach. Cortical thickness was compared between diagnosis groups on a surfacewide node-by-node basis. Heritability related to disease risk was assessed in regions derived from an automated cortical parcellation algorithm by calculating the Risch .

Setting  Research hospital.

Participants  One hundred ninety-six normal controls, 115 affected patients with schizophrenia, and 192 unaffected siblings.

Main Outcome Measure  Regional cortical thickness.

Results  Node-by-node mapping statistics revealed widespread thickness reductions in the patient group, most pronouncedly in the frontal lobe and temporal cortex. Unaffected siblings did not significantly differ from normal controls at the chosen conservative threshold. Risch analysis revealed widespread evidence for heritability for cortical thickness reductions throughout the brain.

Conclusions  To our knowledge, the present study provides the first evidence of broadly distributed and heritable reductions of cortical thickness alterations in schizophrenia. However, since only trend-level reductions of thickness were observed in siblings, cortical thickness per se (at least as measured by this approach) is not a strong intermediate phenotype for schizophrenia.

Objectives  To contextualize metabolic, functional, and clinical parameters and thus to reveal cellular mechanisms related to anhedonia.

Design  The pgACC was investigated using a combined functional magnetic resonance imaging and magnetic resonance spectroscopic approach. Negative blood oxygenation level–dependent (BOLD) activations in the pgACC were assessed during emotional stimulation. Quantitative J-resolved magnetic resonance spectroscopy in the pgACC enabled simultaneous determination of glutamine, glutamate, N-acetylaspartate, glucose, and -aminobutyric acid concentrations. Subjective emotional intensity ratings as well as various clinical parameters were determined.

Setting  The patients were recruited and evaluated in the Department of Psychiatry, University of Zurich, while the measurements were performed in the Institute of Biomedical Engineering, University of Zurich and the Technical University Zurich.

Participants  Nineteen unmedicated patients with MDD and 24 healthy subjects.

Main Outcome Measures  Reduced glutamine levels and lower functional responses in pgACC in anhedonic depressed patients were expected to be the predominant effect of abnormal glutamatergic transmission. It was further tested if, among patients, the ratings of emotional intensity on visual stimulation predicted the amount of metabolic and functional alterations in terms of reduced relative metabolite concentrations and BOLD changes.

Results  Patients with highly anhedonic MDD show decreased glutamine but normal glutamate and -aminobutyric acid concentrations, with glutamine concentrations being dissociated from glucose concentrations. Glutamate and N-acetylaspartate concentrations in pgACC correlate with negative BOLD responses induced by emotional stimulation in MDD; whereas in healthy subjects, negative BOLD responses correlate with -aminobutyric acid instead. Negative BOLD responses as well as glutamate and N-acetylaspartate concentrations correlate with emotional intensity ratings, an anhedonia surrogate, in those with MDD but not in healthy subjects.

Conclusion  Aberrant neuronal activation patterns of the pgACC in anhedonic depression are related to deficits of glutamatergic metabolism.

Objective  To better characterize sequence variability in the BDNF gene by resequencing a genomic DNA region of 22 kilobases that contained all BDNF exons and their flanking regions.

Design  Case-control study.

Setting  University of California, Los Angeles, and University of Miami.

Participants  Two hundred sixty-four controls and 272 Mexican Americans with major depressive disorder (MDD) from Los Angeles who were assessed by the same bilingual clinical research team.

Main Outcome Measures  Identification of novel genetic polymorphisms in the BDNF gene and assessment of their frequencies and associations with MDD or antidepressant response.

Results  We identified 83 novel single-nucleotide polymorphisms (SNPs): 30 in untranslated regions, 4 in coding sequences, 37 in introns, and 12 in upstream regions; 3 of 4 rare novel coding SNPs were nonsynonymous. Association analyses of patients with MDD and controls showed that 6 SNPs were associated with MDD (rs12273539, rs11030103, rs6265, rs28722151, rs41282918, and rs11030101) and 2 haplotypes in different blocks (one including Val66, another near exon VIIIh) were significantly associated with MDD. One recently reported 5' untranslated region SNP, rs61888800, was associated with antidepressant response after adjusting for age, sex, medication, and baseline score on the 21-item Hamilton Depression Rating Scale.

Conclusions  Our data support the concept that extensive resequencing of key candidate genes can lead to the discovery of substantial numbers of new variants. Further studies using larger independent samples are needed to confirm the association of the rs61888800 SNP with antidepressant response.

Trial Registration  clinicaltrials.gov Identifier: NCT00265291

Objective  To compare symptom dimensions of depression as predictors of cardiovascular-related death and events among women with suspected myocardial ischemia.

Design  Cohort study of women with suspected myocardial ischemia who underwent evaluation at baseline for a history of cardiovascular-related problems, depressive symptoms using the Beck Depression Inventory, and coronary artery disease severity via coronary angiography. Principal components analyses (PCAs) of the Beck Depression Inventory items were conducted to examine differential cardiovascular prognosis according to symptom dimensions of depression.

Setting  The Women's Ischemia Syndrome Evaluation (WISE), a multicenter study sponsored by the National Heart, Lung, and Blood Institute to assess cardiovascular function using state-of-the-art techniques in women referred for coronary angiography to evaluate chest pain or suspected myocardial ischemia.

Participants  Five hundred fifty women (mean [SD] age, 58.4 [11.2] years) enrolled in the WISE study and followed up for a median of 5.8 years.

Main Outcome Measures  Cardiovascular-related mortality and events (stroke, myocardial infarction, and congestive heart failure).

Results  When a 3-factor structure from PCA was used, somatic/affective (hazards ratio, 1.35; 95% confidence interval, 1.04-1.74) and appetitive (1.42; 1.21-1.68) but not cognitive/affective (0.89; 0.70-1.14) symptoms predicted cardiovascular prognosis in adjusted multivariate Cox regression analysis. When a 2-factor structure from PCA was used, adjusted results indicated that somatic (hazards ratio, 1.63; 95% confidence interval, 1.28-2.08) but not cognitive/affective (0.87; 0.68-1.11) symptoms predicted worse prognosis.

Conclusions  In a sample of women with suspected myocardial ischemia, somatic but not cognitive/affective depressive symptoms were associated with an increased risk of cardiovascular-related mortality and events. These results support the need to research dimensions of depression in CVD populations and have implications for understanding the connection between depression and CVD.

Objectives  To examine amygdala volume at 2 years with follow-up at 4 years of age in children with autism and to explore the relationship between amygdala volume and selected behavioral features of autism.

Design  Longitudinal magnetic resonance imaging study.

Setting  University medical setting.

Participants  Fifty autistic and 33 control (11 developmentally delayed, 22 typically developing) children between 18 and 35 months (2 years) of age followed up at 42 to 59 months (4 years) of age.

Main Outcome Measures  Amygdala volumes in relation to joint attention ability measured with a new observational coding system, the Social Orienting Continuum and Response Scale; group comparisons including total tissue volume, sex, IQ, and age as covariates.

Results  Amygdala enlargement was observed in subjects with autism at both 2 and 4 years of age. Significant change over time in volume was observed, although the rate of change did not differ between groups. Amygdala volume was associated with joint attention ability at age 4 years in subjects with autism.

Conclusions  The amygdala is enlarged in autism relative to controls by age 2 years but shows no relative increase in magnitude between 2 and 4 years of age. A significant association between amygdala volume and joint attention suggests that alterations to this structure may be linked to a core deficit of autism.

Objective  To gain insight into neuropsychological features that index genetic liability to autism.

Design  Case-control study.

Setting  The general community.

Participants  Thirty-eight high-functioning individuals with autism and parents of autistic individuals, both with and without the BAP (n = 83), as well as control individuals.

Main Outcome Measures  A comprehensive battery of neuropsychological tasks assessing social cognition, executive function, and global vs local processing strategies (central coherence).

Results  Both individuals with autism and parents with the BAP differed from controls on measures of social cognition, with performance in the other 2 domains being more similar to controls.

Conclusions  Data suggest that the social cognitive domain may be an important target for linking phenotype to cognitive process to brain structure in autism and may ultimately provide insight into the genes involved in autism.

Objective  To examine whether peer victimization is associated with psychotic symptoms in a population-based sample of 12-year-olds.

Design  Prospective cohort study.

Setting  Assessment clinic for 12-year-old members of the Avon Longitudinal Study of Parents and Children birth cohort in Bristol, England, where parents had participated since pregnancy and their children completed a range of physical and psychological annual assessments since age 7 years.

Participants  A total of 6437 respondents with complete interviews (mean age, 12.9 years).

Main Outcome Measure  The Psychosis-like Symptoms Interview developed for the study using stem questions, glossary definitions, and rating rules, adapted from the National Institute of Mental Health Diagnostic Interview Schedule for Children–IV and the Schedules for Clinical Assessment in Neuropsychiatry. The interview, carried out by trained psychology graduates, investigated respondents' experience of psychotic symptoms (hallucinations, delusions, and thought disorders) over the previous 6 months.

Results  The risk of psychotic symptoms was increased about 2-fold (odds ratio = 1.94; 95% confidence interval, 1.54-2.44) among victims of bullying at ages 8 and/or 10 years, independent of other prior psychopathology, family adversity, or child's IQ. Similar results were found using mother and teacher reports of victimization. Associations were stronger (up to odds ratio = 4.60; 95% confidence interval, 3.24-6.50) when victimization was chronic or severe (ie, experience of relational as well as overt victimization reported).

Conclusions  Peer victimization in childhood, especially if it is chronic or severe, is associated with psychotic symptoms in early adolescence. These results lend further support to the relevance of psychosocial factors in the etiology of psychotic symptoms in nonclinical populations, which may increase the risk of adult-onset psychotic disorders.

Objective  To compare rates of relapse and time to relapse between short- and long-term treatment with sertraline hydrochloride administered in the luteal phase of the menstrual cycle.

Design  Eighteen-month survival study with a randomized double-blind switch to placebo after 4 or 12 months of sertraline treatment.

Setting  Academic medical center.

Participants  One hundred seventy-four patients with premenstrual syndrome or premenstrual dysphoric disorder.

Main Outcome Measure  Relapse, defined as symptoms returning to the entry criterion level as assessed with daily ratings.

Results  The relapse rate was 41% during long-term treatment compared with 60% after short-term sertraline therapy, with a median time to relapse of 8 months vs 4 months (hazard ratio, 0.58; 95% confidence interval, 0.34-0.98; P = .04). Patients with severe symptoms at baseline were more likely to experience relapse compared with patients in the lower symptom severity group (hazard ratio, 2.02; 95% confidence interval, 1.18-3.41; P = .01) and were more likely to experience relapse with short-term treatment (P = .03). Duration of treatment did not affect relapse in patients in the lower symptom severity group (P = .50). Patients who demonstrated remission were least likely to experience relapse (hazard ratio, 0.22; 95% confidence interval, 0.10-0.45; P < .001). Further analysis comparing relapse in the first 6 months of placebo treatment in each group yielded similar results.

Conclusions  The relapse rate was significantly greater after short-term treatment compared with long-term treatment. The relapse rate was also high during extended drug treatment. Subjects with severe symptoms at baseline were most likely to experience relapse, and relapse occurred more swiftly regardless of treatment duration. These findings suggest that the severity of symptoms at baseline and symptom remission with treatment should be considered in determining the duration of treatment.

Trial Registration  clinicaltrials.gov Identifier: NCT00318773

Objective  To study the relation between white matter integrity and cognition in the general elderly population, using diffusion tensor imaging and taking into account macrostructural white matter changes.

Design  Cross-sectional population-based study.

Setting  A general community in the Netherlands.

Participants  A population-based sample of 860 persons, older than 60 years, free of dementia. We performed multisequence magnetic resonance imaging, which included diffusion tensor imaging, and extensive neuropsychological testing. Fractional anisotropy, mean diffusivity, and directional diffusivities were measured globally in white matter lesions and normal-appearing white matter.

Main Outcome Measures  Performance on neuropsychological tests in the following cognitive domains: memory, executive function, information processing speed, global cognition, and motor speed.

Results  Regardless of macrostructural white matter changes, a higher mean diffusivity or higher axial and radial diffusivities within white matter lesions or normal-appearing white matter were related to worse performance on tasks assessing information processing speed and global cognition. In addition, diffusivity within white matter lesions related to memory, while in normal-appearing white matter, it furthermore related to executive function. Lower mean fractional anisotropy in white matter lesions or normal-appearing white matter related to worse information processing speed and motor speed.

Conclusions  Microstructural integrity of both white matter lesions and normal-appearing white matter is associated with cognitive function, regardless of white matter atrophy and white matter lesion volume. This suggests that measuring white matter integrity has added value beyond macrostructural assessment of white matter changes to study the relation between white matter and cognition.

Objectives  To determine whether patients with a history of well-characterized Lyme disease and persistent cognitive deficit show abnormalities in global or topographic distributions of regional cerebral blood flow (rCBF) or cerebral metabolic rate (rCMR).

Design  Case-controlled study.

Setting  A university medical center.

Participants  A total of 35 patients and 17 healthy volunteers (controls). Patients had well-documented prior Lyme disease, a currently reactive IgG Western blot, prior treatment with at least 3 weeks of intravenous cephalosporin, and objective memory impairment.

Main Outcome Measures  Patients with persistent Lyme encephalopathy were compared with age-, sex-, and education-matched controls. Fully quantified assessments of rCBF and rCMR for glucose were obtained while subjects were medication-free using positron emission tomography. The CBF was assessed in 2 resting room air conditions (without snorkel and with snorkel) and 1 challenge condition (room air enhanced with carbon dioxide, ie, hypercapnia).

Results  Statistical parametric mapping analyses revealed regional abnormalities in all rCBF and rCMR measurements that were consistent in location across imaging methods and primarily reflected hypoactivity. Deficits were noted in bilateral gray and white matter regions, primarily in the temporal, parietal, and limbic areas. Although diminished global hypercapnic CBF reactivity (P < .02) was suggestive of a component of vascular compromise, the close coupling between CBF and CMR suggests that the regional abnormalities are primarily metabolically driven. Patients did not differ from controls on global resting CBF and CMR measurements.

Conclusions  Patients with persistent Lyme encephalopathy have objectively quantifiable topographic abnormalities in functional brain activity. These CBF and CMR reductions were observed in all measurement conditions. Future research should address whether this pattern is also seen in acute neurologic Lyme disease.

Objective  To discuss recent neurobiological studies related to subcomponents of wisdom identified from several published definitions/descriptions of wisdom by clinical investigators in the field, ie, prosocial attitudes/behaviors, social decision making/pragmatic knowledge of life, emotional homeostasis, reflection/self-understanding, value relativism/tolerance, and acknowledgment of and dealing effectively with uncertainty.

Data Sources  Literature focusing primarily on neuroimaging/brain localization and secondarily on neurotransmitters, including their genetic determinants.

Study Selection  Studies involving functional neuroimaging or neurotransmitter functioning, examining human (rather than animal) subjects, and identified via a PubMed search using keywords from any of the 6 proposed subcomponents of wisdom were included.

Data Extraction  Studies were reviewed by both of us, and data considered to be potentially relevant to the neurobiology of wisdom were extracted.

Data Synthesis  Functional neuroimaging permits exploration of neural correlates of complex psychological attributes such as those proposed to comprise wisdom. The prefrontal cortex figures prominently in several wisdom subcomponents (eg, emotional regulation, decision making, value relativism), primarily via top-down regulation of limbic and striatal regions. The lateral prefrontal cortex facilitates calculated, reason-based decision making, whereas the medial prefrontal cortex is implicated in emotional valence and prosocial attitudes/behaviors. Reward neurocircuitry (ventral striatum, nucleus accumbens) also appears important for promoting prosocial attitudes/behaviors. Monoaminergic activity (especially dopaminergic and serotonergic), influenced by several genetic polymorphisms, is critical to certain subcomponents of wisdom such as emotional regulation (including impulse control), decision making, and prosocial behaviors.

Conclusions  We have proposed a speculative model of the neurobiology of wisdom involving frontostriatal and frontolimbic circuits and monoaminergic pathways. Wisdom may involve optimal balance between functions of phylogenetically more primitive brain regions (limbic system) and newer ones (prefrontal cortex). Limitations of the putative model are stressed. It is hoped that this review will stimulate further research in characterization, assessment, neurobiology, and interventions related to wisdom.

Objective  To examine gray matter reduction of the superior temporal gyrus over time in individuals at risk for psychosis and in patients with first-episode psychosis.

Design  Cross-sectional and longitudinal comparisons.

Setting  Personal Assessment and Crisis Evaluation Clinic and Early Psychosis Preventions and Intervention Centre.

Participants  Thirty-five ultrahigh-risk individuals (of whom 12 later developed psychosis [UHRP] and 23 did not [UHRNP]), 23 patients with first-episode psychosis (FEP), and 22 control subjects recruited from the community.

Main Outcome Measures  Volumes of superior temporal subregions (planum polare, Heschl gyrus, planum temporale, and rostral and caudal regions) were measured at baseline and follow-up (mean, 1.8 years) and were compared across groups.

Results  In cross-sectional comparisons, only the FEP group had significantly smaller planum temporale and caudal superior temporal gyrus than other groups at baseline, whereas male UHRP subjects also had a smaller planum temporale than controls at follow-up. In longitudinal comparison, UHRP and FEP patients showed significant gray matter reduction (approximately 2%-6% per year) in the planum polare, planum temporale, and caudal region compared with controls and/or UHRNP subjects. The FEP patients also exhibited progressive gray matter loss in the left Heschl gyrus (3.0% per year) and rostral region (3.8% per year), which were correlated with the severity of delusions at follow-up.

Conclusions  A progressive process in the superior temporal gyrus precedes the first expression of florid psychosis. These findings have important implications for underlying neurobiologic features of emerging psychotic disorders and emphasize the importance of early intervention during or before the first episode of psychosis.

Objective  To determine the functional hierarchical organization of cognitive control within the LPFC in patients with schizophrenia.

Design  Case-control study.

Setting  Hospital-based research units.

Participants  Fifteen schizophrenic patients and 14 controls.

Main Outcome Measures  Behavioral performance and regional brain activity as measured by functional magnetic resonance imaging during a task, varying the amount of information conveyed by episodic and contextual signals.

Results  In patients and healthy controls, activity in caudal LPFC regions varied as episodic and contextual signals, whereas rostral LPFC regions only exhibited an episodic effect. However, patients made more errors than controls when information conveyed by contextual and episodic signals increased. These impairments were related to hypoactivation in caudal LPFC regions and hyperactivation in rostral LPFC regions, respectively. Activation in caudal LPFC regions negatively correlated with the disorganization syndrome score of patients.

Conclusions  In schizophrenic patients, the architecture of cognitive control follows the cascading organization from rostral LPFC regions to caudal LPFC and premotor regions depending on the temporal framing of action and events. We found, however, that immediate contextual signals insufficiently bias the caudal LPFC activity required to select the appropriate behavioral representation. This specific deficit could thus alter the internal consistency of schizophrenic patients' behavior. To compensate for this weakening of contextual influence, schizophrenic patients may inefficiently use temporal episodic information through higher activation in rostral LPFC regions.

Objective  To test the efficacy of 2 nonpharmacological interventions for depression after coronary artery bypass surgery compared with usual care.

Design  A 12-week, randomized, single-blind clinical trial with outcome evaluations at 3, 6, and 9 months.

Setting  Outpatient research clinic at Washington University School of Medicine, St Louis, Missouri.

Patients  One hundred twenty-three patients who met the DSM-IV criteria for major or minor depression within 1 year after surgery.

Intervention  Twelve weeks of cognitive behavior therapy or supportive stress management. Approximately half of the participants were taking nonstudy antidepressant medications.

Main Outcome Measure  Remission of depression, defined as a score of less than 7 on the 17-item Hamilton Rating Scale for Depression.

Results  Remission of depression occurred by 3 months in a higher proportion of patients in the cognitive behavior therapy (71%) and supportive stress-management (57%) arms than in the usual care group (33%) (²₂ = 12.22, P = .002). Covariate-adjusted Hamilton scores were lower in the cognitive behavior therapy (mean [standard error], 5.5 [1.0]) and the supportive stress-management (7.8 [1.0]) arms than in the usual care arm (10.7 [1.0]) at 3 months. The differences narrowed at 6 months, but the remission rates differed again at 9 months (73%, 57%, and 35%, respectively; ²₂ = 12.02, P = .003). Cognitive behavior therapy was superior to usual care at most points on secondary measures of depression, anxiety, hopelessness, stress, and quality of life. Supportive stress management was superior to usual care only on some of the measures.

Conclusions  Both cognitive behavior therapy and supportive stress management are efficacious for treating depression after coronary artery bypass surgery, relative to usual care. Cognitive behavior therapy had greater and more durable effects than supportive stress management on depression and several secondary psychological outcomes.

Trial Registration  clinicaltrials.gov Identifier: NCT00042198

Objective  To study predictive associations between childhood psychopathologic disorders at the age of 8 years and later completed suicides and severe suicide attempts.

Design  Birth cohort study of individuals 8 to 24 years old.

Setting  Finland.

Participants  The sample includes 5302 Finnish people born in 1981 who were examined at the age of 8 years to gather information about psychopathologic conditions, school performance, and family demographics from parents, teachers, and children.

Main Outcome Measures  National register-based lifetime information about completed suicides and suicide attempts that prompted hospital admission.

Results  Of all 24 deaths among males between 8 and 24 years of age, 13 were suicides, whereas of 16 deaths among females, only 2 were suicides. Fifty-four males and females (1%) had either completed suicide or made a serious suicide attempt, defined as a suicide attempt that prompted hospital admission. Of 27 males with completed or serious suicide attempts, 78% screened positive on parent or teacher Rutter scales at the age of 8 years, whereas of 27 females only 11% screened positive. Among males, completed or serious suicide attempt outcome was predicted at the age of 8 years by living in a nonintact family; psychological problems as reported by the primary teacher; or conduct, hyperkinetic, and emotional problems. However, self-reports of depressive symptoms at the age of 8 years did not predict suicide outcome. No predictive associations between the study variables measured at the age of 8 years and suicide outcome were found among females. Male suicide outcome was predicted most strongly by comorbid conduct and internalizing problems.

Conclusions  Most males who completed suicide and/or made serious suicide attempts in adolescence or early adulthood had psychiatric problems by the age of 8 years, indicating a trajectory that persists throughout their lives. However, female severe suicidality is not predicted by psychopathologic disorders at the age of 8 years. The results give additional support to the importance of early detection and treatment of psychiatric problems in males.

Objectives  To determine the role of genetic variation of SLC1A1 in OCD in a large case-control study and to better understand how SLC1A1 variation affects functionality.

Design  A case-control study.

Setting  Publicly accessible SLC1A1 expression and genotype data.

Patients  Three hundred twenty-five OCD probands and 662 ethnically and sex-matched controls.

Interventions  Probands were assessed with the Structured Clinical Interview for DSM-IV, the Yale-Brown Obsessive Compulsive Scale, and the Saving Inventory–Revised. Six single-nucleotide polymorphisms (SNPs) were genotyped. Multiple testing corrections for single-marker and haplotype analyses were performed by permutation.

Results  Gene expression of SLC1A1 is heritable in lymphoblastoid cell lines. We identified 3 SNPs in or near SLC1A1 that correlated with gene expression levels, 1 of which had previously been associated with OCD. Two of these SNPs also predicted expression levels in human brain tissue, and 1 SNP was further functional in reporter gene studies. Two haplotypes at 3 SNPs, rs3087879, rs301430, and rs7858819, were significantly associated with OCD after multiple-testing correction and contained 2 SNPs associated with expression levels. In addition, another SNP correlating with SLC1A1 gene expression, rs3933331, was associated with an OCD-hoarding subphenotype as assessed by 2 independent, validated scales.

Conclusions  Our case-control data corroborate previous smaller family-based studies that indicated that SLC1A1 is a susceptibility locus for OCD. The expression and genotype database–mining approach we used provides a potentially useful complementary approach to strengthen future candidate gene studies in neuropsychiatric and other disorders.

Objectives  To evaluate the pace and reach of the passive dissemination of a promising technology within a national health care system.

Design  Geographic surveillance data study.

Setting  Academic research.

Patients  We tracked the use of prazosin in the treatment of patients diagnosed as having PTSD in the Department of Veterans Affairs during fiscal years 2004 (n = 203 414) and 2006 (n = 319 670).

Main Outcome Measure  The percentage of patients diagnosed as having PTSD who received a prescription for prazosin.

Results  Whereas 37.6% of patients with PTSD treated within the Veterans Affairs Puget Sound Health Care System, Tacoma, Washington, in 2004 were prescribed prazosin, only 18.2% were treated with prazosin at medical centers up to 499 miles (to convert miles to kilometers, multiply by 1.6) away, 6.7% at centers 500 to 999 miles away, 4.0% at centers 1000 to 2499 miles away, and 1.9% at centers 2500 miles away or farther. Adjusting for patient characteristics, patients with PTSD treated up to 499 miles from Puget Sound were about 49% less likely in 2006 and about 63% less likely in 2004 to be prescribed prazosin than their counterparts treated within Puget Sound, while those who were treated 2500 miles away or farther were about 94% less likely in 2006 and about 97% less likely in 2004 to be treated with prazosin than patients within Puget Sound.

Conclusion  Passive diffusion of a new treatment can be rapid in the immediate area in which it is developed, but the geographic gradient of use seems to be steep and enduring even when cost and organizational barriers are minimal.

Objective  The primary objective was to examine the hypothalamic-pituitary-adrenal axis and the subjective and physiologic response to CRH in cocaine-dependent individuals and controls.

Design  A case-control study.

Setting  Subjects were admitted to a General Clinical Research Center for testing and abstinence was verified with a urine drug screening.

Participants  Participants were male controls (n = 23), female controls (n = 24), cocaine-dependent men (n = 28), and cocaine-dependent women (n = 25). Individuals with dependence on other substances (except caffeine or nicotine) or with major depression, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded.

Intervention  Subjects received 1 µg/kg of CRH intravenously.

Main Outcome Measures  Primary outcomes included plasma corticotropin levels, cortisol levels, and heart rate and subjective measurements.

Results  Cocaine-dependent individuals exhibited higher stress (P < .001) and craving for CRH compared with controls. A positive correlation (r_s = 0.51; P < .001) between stress and craving was found in cocaine-dependent subjects. Intravenous CRH elevated heart rates in all groups; however, cocaine-dependent women demonstrated a significantly higher heart rate at all time points (P = .05). Women had higher cortisol responses to CRH (P = .03). No effect of cocaine status was observed. The corticotropin response to CRH was independent of sex and cocaine dependence. Cortisol and corticotropin were positively correlated in the controls and cocaine-dependent men, but not in cocaine-dependent women (r_s = 0.199; P = .4).

Conclusions  There is an increased subjective and heart rate response to CRH and a relationship between stress and craving in cocaine-dependent individuals. The lack of difference in hypothalamic pituitary adrenal axis response between the cocaine-dependent and control groups suggests that the heart rate and subjective responses in the cocaine group may be mediated by sensitization of nonhypothalamic stress-responsive CRH systems.

Objective  To identify cingulate functional circuits that are associated with the severity of nicotine addiction and study how nicotine affects them by means of region-specific resting-state functional magnetic resonance imaging.

Design  Double-blind, placebo-controlled study.

Setting  Outpatient clinics.

Participants  Nineteen healthy smokers.

Intervention  Single-dose (21- or 35-mg) nicotine patch.

Main Outcome Measures  Correlation of nicotine addiction severity and cingulate resting-state functional connectivity, and effects of short-term nicotine administration on connectivity strength.

Results  Clearly separated pathways that correlated with nicotine addiction vs nicotine’s action were found. The severity of nicotine addiction was associated with the strength of dorsal anterior cingulate cortex (dACC)–striatal circuits, which were not modified by nicotine patch administration. In contrast, short-term nicotine administration enhanced cingulate-neocortical functional connectivity patterns, which may play a role in nicotine's cognition-enhancing properties.

Conclusions  Resting-state dACC-striatum functional connectivity may serve as a circuit-level biomarker for nicotine addiction, and the development of new therapeutic agents aiming to enhance the dACC-striatum functional pathways may be effective for nicotine addiction treatment.

Objectives  To investigate the effects of 2 main psychoactive constituents of C sativa, 9-tetrahydrocannabinol (9-THC) and cannabidiol, on regional brain function during verbal paired associate learning.

Design  Subjects were studied on 3 separate occasions using a block design functional magnetic resonance imaging paradigm while performing a verbal paired associate learning task. Each imaging session was preceded by the ingestion of 9-THC (10 mg), cannabidiol (600 mg), or placebo in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject design.

Setting  University research center.

Participants  Fifteen healthy, native English-speaking, right-handed men of white race/ethnicity who had used C sativa 15 times or less and had minimal exposure to other illicit drugs in their lifetime.

Main Outcome Measures  Regional brain activation (blood oxygen level–dependent response), performance in a verbal learning task, and objective and subjective ratings of psychotic symptoms, anxiety, intoxication, and sedation.

Results  9-Tetrahydrocannabinol increased psychotic symptoms and levels of anxiety, intoxication, and sedation, whereas no significant effect was noted on these parameters following administration of cannabidiol. Performance in the verbal learning task was not significantly modulated by either drug. Administration of 9-THC augmented activation in the parahippocampal gyrus during blocks 2 and 3 such that the normal linear decrement in activation across repeated encoding blocks was no longer evident. 9-Tetrahydrocannabinol also attenuated the normal time-dependent change in ventrostriatal activation during retrieval of word pairs, which was directly correlated with concurrently induced psychotic symptoms. In contrast, administration of cannabidiol had no such effect.

Conclusion  The modulation of mediotemporal and ventrostriatal function by 9-THC may underlie the effects of C sativa on verbal learning and psychotic symptoms, respectively.

Objective  To determine the structure of the relationships among psychological mechanisms contributing to paranoia in a transdiagnostic sample.

Design  Cross-sectional design, with relationships between predictor variables and paranoia examined by structural equation models with latent variables.

Setting  Publicly funded psychiatric services in London and the North West of England.

Participants  One hundred seventy-three patients with schizophrenia spectrum disorders, major depression, or late-onset schizophrenia-like psychosis, subdivided according to whether they were currently experiencing paranoid delusions. Sixty-four healthy control participants matched for appropriate demographic variables were included.

Main Outcome Measures  Assessments of theory of mind, jumping to conclusions bias, and general intellectual functioning, with measures of threat anticipation, emotion, self-esteem, and explanatory style.

Results  The best fitting (²₉₆ = 131.69, P = .01; comparative fit index = 0.95; Tucker-Lewis Index = 0.96; root-mean-square error of approximation = 0.04) and most parsimonious model of the data indicated that paranoid delusions are associated with a combination of pessimistic thinking style (low self-esteem, pessimistic explanatory style, and negative emotion) and impaired cognitive performance (executive functioning, tendency to jump to conclusions, and ability to reason about the mental states of others). Pessimistic thinking correlated highly with paranoia even when controlling for cognitive performance (r = 0.65, P < .001), and cognitive performance correlated with paranoia when controlling for pessimism (r = –0.34, P < .001).

Conclusions  Both cognitive and emotion-related processes are involved in paranoid delusions. Treatment for paranoid patients should address both types of processes.

Objective  To determine the prevalence, correlates, and likelihood of treatment for mental and substance use disorders in a population of urban single mothers receiving Temporary Assistance for Needy Families (TANF).

Design  In-person diagnostic assessments were conducted from November 1, 2003, to October 31, 2004.

Setting  Cook County, Illinois.

Participants  Female TANF recipients and residents of Cook County (N = 333) who were randomly sampled during the final 24 months of their eligibility for TANF.

Main Outcome Measure  Prevalence rates of DSM-IV mental and substance use disorders using the World Health Organization's Composite International Diagnostic Interview.

Results  Lifetime prevalence of Composite International Diagnostic Interview disorders was 61.0% (95% confidence interval [CI], 55.7%-66.3%); 12-month prevalence was 46.8% (41.5%-52.2%). Lifetime prevalence of mental disorders was 53.2% (95% CI, 47.8%-58.5%); 12-month prevalence was 44.1% (38.8%-49.5%). Lifetime prevalence of substance use disorders was 29.1% (95% CI, 23.9%-33.8%); 12-month prevalence was 9.0% (6.8%-12.0%). Lifetime prevalence of comorbid mental/substance use disorders was 21.3% (95% CI, 16.9%-25.7%); 12-month prevalence was 6.3% (3.7%-8.9%). Only 21.7% (95% CI, 14.8%-28.5%) of participants with 12-month mental disorders received treatment for mental disorders; 41.4% (22.3%-60.4%) of participants with 12-month substance abuse disorders received treatment for substance use disorders.

Conclusions  Despite the high prevalence of psychiatric and substance use disorders in this population, many remain untreated. The consequences of terminating welfare assistance are worthy of further investigation, given the potential for adverse effects on both mothers and their young children.

Objective  To examine the associations between AAD and MD using fixed-effects modeling to control for confounding and using structural equation models to ascertain the direction of causality.

Design  Data were gathered during the course of the Christchurch Health and Development Study, a 25-year longitudinal study of a birth cohort of children from New Zealand (635 boys, 630 girls).

Setting  General community sample.

Participants  The analysis was based on a sample of 1055 participants with available data on AAD and MD at ages 17 to 18, 20 to 21, and 24 to 25 years.

Main Outcome Measures  Symptom criteria for AAD and MD from the DSM-IV at ages 17 to 18, 20 to 21, and 24 to 25 years as well as measures of life stress, cannabis use, other illicit drug use, affiliation with deviant peers, unemployment, partner substance use, and partner criminality at ages 17 to 18, 20 to 21, and 24 to 25 years.

Results  There were significant (P < .001) pooled associations between AAD and MD. Controlling for confounding factors using conditional fixed-effects models and time-dynamic covariate factors reduced the magnitude of these associations, but they remained statistically significant. Structural equation modeling suggested that the best-fitting causal model was one in which AAD led to increased risk of MD.

Conclusions  The findings suggest that the associations between AAD and MD were best explained by a causal model in which problems with alcohol led to increased risk of MD as opposed to a self-medication model in which MD led to increased risk of AAD.

Objective  To conduct a comprehensive genetic association study of the MANEA locus with CD and CIP.

Design  Genome-wide association study.

Setting  Four university hospitals.

Participants  A total of 3992 individuals from 2 family-based and 2 case-control samples.

Intervention  Participants were classified as having CD or CIP or as a control using the Semi-Structured Assessment for Drug Dependence and Alcoholism. They were genotyped for 11 SNPs spanning MANEA and its surrounding region.

Main Outcome Measure  Association of CD and CIP with individual SNPs and haplotypes.

Results  Cocaine-induced paranoia was associated with 6 SNPs in the European American families and 9 SNPs in the African American families. The strongest evidence in the total sample of families was observed in 3 markers located in the promoter and 3' untranslated regions (P < .001). The association of MANEA SNPs with CD in both family samples was much weaker. In the African American case-control sample, multiple markers were significantly associated with CIP and CD; CIP and CD were also significantly associated with a 2-SNP haplotype in the European American case-control sample. The A allele of the 3' untranslated region SNP rs9387522 was associated with increased risk of CIP in all 4 data sets.

Conclusions  Our findings suggest that CD and associated behaviors may involve biological pathways not typically thought to be associated with brain metabolism.

Objective  To compare amygdala response to varying attention and emotion conditions among adolescents with major depressive disorder (MDD) or anxiety disorders, relative to adolescents with no psychopathology.

Design  Case-control study.

Setting  Government clinical research institute.

Participants  Eighty-seven adolescents matched on age, sex, intelligence, and social class: 26 with MDD (14 with and 12 without anxiety disorders), 16 with anxiety disorders but no depression, and 45 without psychopathology.

Main Outcome Measures  Blood oxygen level–dependent signal in the amygdala, measured by means of event-related functional magnetic resonance imaging. During imaging, participants viewed facial expressions (neutral, fearful, angry, and happy) while attention was constrained (afraid, hostility, and nose-width ratings) or unconstrained (passive viewing).

Results  Left and right amygdala activation differed as a function of diagnosis, facial expression, and attention condition both when patients with comorbid MDD and anxiety were included and when they were excluded (group x emotion x attention interactions, P ≤ .03). Focusing on fearful face–viewing events, patients with anxiety and those with MDD both differed in amygdala responses from healthy participants and from each other during passive viewing. However, both MDD and anxiety groups, relative to healthy participants, exhibited similar signs of amygdala hyperactivation to fearful faces when subjectively experienced fear was rated.

Conclusions  Adolescent MDD and anxiety disorders exhibit common and distinct functional neural correlates during face processing. Attention modulates the degree to which common or distinct amygdala perturbations manifest in these patient groups, relative to healthy peers.

Objective  To evaluate lifetime prevalence and specificity of psychiatric disorders in offspring of parents with BP-I and BP-II.

Design  Offspring aged 6 to 18 years who have parents with BP and community control subjects were interviewed with standardized instruments. All research staff except the statistician were blind to parental diagnoses.

Setting  Parents with BP were recruited primarily through advertisement and outpatient clinics. Control parents were ascertained by random-digit dialing and were group matched for age, sex, and neighborhood to parents with BP.

Participants  Three hundred eighty-eight offspring of 233 parents with BP and 251 offspring of 143 demographically matched control parents.

Main Outcome Measures  Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) Axis I disorders.

Results  Adjusting for demographic factors, living with 1 vs both biological parents, both biological parents' non-BP psychopathology, and within-family correlations, offspring of parents with BP showed high risk for BP spectrum disorders (odds ratio [OR] = 13.4; 95% confidence interval [CI], 2.9-61.6) and any mood (OR = 5.2; 95% CI, 2.3-11.4), anxiety (OR = 2.3; 95% CI, 1.3-4.0), and Axis I (OR = 2.2; 95% CI, 1.5-3.3) disorders. Offspring of parents with BP with high socioeconomic status showed more disruptive behavior disorders and any Axis I disorders than offspring of control parents with high socioeconomic status. Families in which both parents had BP had more offspring with BP than families with only 1 parent with BP (OR = 3.6; 95% CI, 1.1-12.2). More than 75.0% of offspring who developed BP had their first mood episode before age 12 years, with most of these episodes meeting criteria for BP not otherwise specified and, to a lesser degree, major depression.

Conclusions  Offspring of parents with BP are at high risk for psychiatric disorders and specifically for early-onset BP spectrum disorders. These findings further support the familiality and validity of BP in youth and indicate a need for early identification and treatment.

Objective  To determine the effectiveness of an indicated stepped-care prevention program for depression and anxiety disorders in the elderly.

Design  Randomized controlled trial with recruitment between October 1, 2004, and October 1, 2005.

Setting  Thirty-three primary care practices in the northwestern part of the Netherlands.

Participants  A total of 170 consenting individuals, 75 years and older, with subthreshold symptom levels of depression or anxiety who did not meet the full diagnostic criteria for the disorders.

Intervention  Participants were randomly assigned to a preventive stepped-care program (n = 86) or to usual care (n = 84). Stepped-care participants sequentially received a watchful waiting approach, cognitive behavior therapy–based bibliotherapy, cognitive behavior therapy–based problem-solving treatment, and referral to primary care for medication, if required.

Main Outcome Measures  The cumulative incidence of DSM-IV major depressive disorder or anxiety disorder after 12 months as measured using the Mini International Neuropsychiatric Interview.

Results  The intervention halved the 12-month incidence of depressive and anxiety disorders, from 0.24 (20 of 84) in the usual care group to 0.12 (10 of 86) in the stepped-care group (relative risk, 0.49; 95% confidence interval, 0.24 to 0.98).

Conclusions  Indicated stepped-care prevention of depression and anxiety in elderly individuals is effective in reducing the risk of onset of these disorders and is valuable as seen from the public health perspective.

Trial Registration  isrctn.org Identifier: ISRCTN26474556.

Objective  We examine the association between exposure to traumatic events with and without resulting PTSD and the risk of a subsequent suicide attempt in a community sample of urban young adults.

Design  A cohort study followed young adults who had participated in a randomized trial of all first-grade students entering 19 public schools.

Setting  Baltimore, Maryland, an urban setting.

Participants  A total of 1698 young adults (mean age, 21; 47% male; 71% African American) who represented 75% of the original cohort of 2311 persons.

Main Outcome Measure  Relative risk of a subsequent suicide attempt associated with PTSD and with exposure to assaultive and nonassaultive traumas (no PTSD), as estimated using discrete time survival analysis.

Results  Posttraumatic stress disorder was associated with increased risk of a subsequent suicide attempt. The PTSD–suicide attempt association was robust, even after adjustment for a prior major depressive episode, alcohol abuse or dependence, and drug abuse or dependence (adjusted relative risk, 2.7; 95% confidence interval, 1.3-5.5; P < .01). In contrast, exposure to traumatic events without PTSD was not associated with an increased risk of attempted suicide.

Conclusions  Posttraumatic stress disorder is an independent predictor of attempted suicide. Exposure to traumatic events without PTSD is not associated with a later suicide attempt.

Objective  To evaluate the cost-effectiveness of an integrated multidisciplinary diagnostic facility for diagnosing dementia in ambulatory psychogeriatric patients.

Design  Randomized controlled trial with an economic evaluation component.

Setting  The Maastricht Evaluation of a Diagnostic Intervention for Cognitively Impaired Elderly, Maastricht University Hospital, Maastricht, the Netherlands.

Patients  A total of 137 patients who received care in the multidisciplinary diagnostic facility and 93 who received usual care.

Main Outcome Measures  Quality-adjusted life-years (QALYs) as the main outcome measure and cognition and behavioral problems as secondary outcome measures.

Results  Compared with patients receiving usual care, patients who visited the diagnostic facility gained a mean 0.05 QALY at the extra cost of 65. The incremental cost per QALY amounted to 1267. This point estimate lies beneath commonly accepted thresholds and is within an acceptable range of uncertainty. With regard to the secondary analyses, cost-effectiveness results showed a substantial amount of uncertainty and were therefore indecisive.

Conclusion  On the basis of the main cost-per-QALY analysis, the use of the integrated multidisciplinary diagnostic facility is cost-effective for the diagnosis and management of dementia in ambulatory patients.

Trial Registration  clinicaltrials.gov Identifier: NCT00402311

Objective  To examine the biophysical integrity of proteins in critical white and gray matter regions in patients with type 2 diabetes and major depression to understand the pathophysiology of depression in diabetes.

Design  A cross-sectional magnetization transfer study using magnetic resonance imaging. Regions examined included the anterior cingulate, corpus callosum, frontal and occipital white matter, and the caudate and lenticular nuclei.

Setting  A tertiary care university hospital.

Participants  We studied 16 patients diagnosed with type 2 diabetes and major depression, 22 patients diagnosed with diabetes without depression (diabetic controls), and 30 controls without diabetes or major depression (healthy controls).

Main Outcome Measures  Magnetization transfer ratios, a measure of the biophysical structure of proteins in the gray and white matter.

Results  Magnetization transfer ratios were significantly lower bilaterally in the head of the caudate nucleus in the group with diabetes and depression compared with the other 2 groups (P < .001). Diabetic controls had values between the depressed diabetic and healthy control groups. There were no significant differences in magnetization transfer ratios between groups in the other regions examined.

Conclusions  These data indicate that there is an important subcortical biophysical component to depression in patients with type 2 diabetes. This finding has broad implications for the neuronal circuitry underlying mood disorders.