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.