Archives of General Psychiatry recent issues

Archives of General Psychiatry aims to publish the best clinically relevant science in psychiatry. It is the psychiatry journal most frequently cited in scientific literature, and often is cited in the lay press as well. Many of its peer-reviewed original articles deal with the biological origin of mental disorders and pharmaceutical therapy. It is published monthly.

Association Between Cannabis Use and Psychosis-Related Outcomes Using Sibling Pair Analysis in a Cohort of Young Adults [Original Article]

Context  Prospective cohort studies have identified an association between cannabis use and later psychosis-related outcomes, but concerns remain about unmeasured confounding variables. The use of sibling pair analysis reduces the influence of unmeasured residual confounding.

Objective  To explore the association between cannabis use and psychosis-related outcomes.

Design  A sibling pair analysis nested within a prospective birth cohort.

Setting  Births at a Brisbane, Australia, hospital.

Participants  Three thousand eight hundred one young adults born between 1981 and 1984 as part of the Mater-University Study of Pregnancy.

Main Outcome Measures  Cannabis use and 3 psychosis-related outcomes (nonaffective psychosis, hallucinations, and Peters et al Delusions Inventory score) were assessed at the 21-year follow-up. Associations between duration since first cannabis use and psychosis-related outcomes were examined using logistic regression adjusted for sex, age, parental mental illness, and hallucinations at the 14-year follow-up. Within 228 sibling pairs, the association between within-pair differences in duration since first cannabis use and Peters et al Delusions Inventory score was examined with general linear modeling. The potential impact of attrition was examined.

Results  Duration since first cannabis use was associated with all 3 psychosis-related outcomes. For those with duration since first cannabis use of 6 or more years, there was a significantly increased risk of (1) nonaffective psychosis (adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.5), (2) being in the highest quartile of Peters et al Delusions Inventory score (adjusted odds ratio, 4.2; 95% confidence interval, 4.2-5.8), and (3) hallucinations (adjusted odds ratio, 2.8; 95% confidence interval, 1.9-4.1). Within sibling pairs, duration since first cannabis use and higher scores on the Peters et al Delusions Inventory remained significantly associated.

Conclusions  Early cannabis use is associated with psychosis-related outcomes in young adults. The use of sibling pairs reduces the likelihood that unmeasured confounding explains these findings. This study provides further support for the hypothesis that early cannabis use is a risk-modifying factor for psychosis-related outcomes in young adults.

Published online March 1, 2010 (doi:10.1001/archgenpsychiatry.2010.6).

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Association of Genetic Variants in the Neurotrophic Receptor-Encoding Gene NTRK2 and a Lifetime History of Suicide Attempts in Depressed Patients [Original Article]

Context  A consistent body of evidence supports a role of reduced neurotrophic signaling in the pathophysiology of major depressive disorder (MDD) and suicidal behavior. Especially in suicide victims, lower postmortem brain messenger RNA and protein levels of neurotrophins and their receptors have been reported.

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).

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About This Journal [About This Journal]

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This Month in Archives of General Psychiatry [This Month in Archives of General Psychiatry]

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Clark University Vicennial Conference on Psychology and Pedagogy [Art and Images in Psychiatry]

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Overweight, Obesity, and Depression: A Systematic Review and Meta-analysis of Longitudinal Studies [Meta-analysis]

Context  Association between obesity and depression has repeatedly been established. For treatment and prevention purposes, it is important to acquire more insight into their longitudinal interaction.

Objective  To conduct a systematic review and meta-analysis on the longitudinal relationship between depression, overweight, and obesity and to identify possible influencing factors.

Data Sources  Studies were found using PubMed, PsycINFO, and EMBASE databases and selected on several criteria.

Study Selection  Studies examining the longitudinal bidirectional relation between depression and overweight (body mass index 25-29.99) or obesity (body mass index ≥30) were selected.

Data Extraction  Unadjusted and adjusted odds ratios (ORs) were extracted or provided by the authors.

Data Synthesis  Overall, unadjusted ORs were calculated and subgroup analyses were performed for the 15 included studies (N = 58 745) to estimate the effect of possible moderators (sex, age, depression severity). Obesity at baseline increased the risk of onset of depression at follow-up (unadjusted OR, 1.55; 95% confidence interval [CI], 1.22-1.98; P < .001). This association was more pronounced among Americans than among Europeans (P = .05) and for depressive disorder than for depressive symptoms (P = .05). Overweight increased the risk of onset of depression at follow-up (unadjusted OR, 1.27; 95% CI, 1.07-1.51; P < .01). This association was statistically significant among adults (aged 20-59 years and ≥60 years) but not among younger persons (aged <20 years). Baseline depression (symptoms and disorder) was not predictive of overweight over time. However, depression increased the odds for developing obesity (OR, 1.58; 95% CI, 1.33-1.87; P < .001). Subgroup analyses did not reveal specific moderators of the association.

Conclusions  This meta-analysis confirms a reciprocal link between depression and obesity. Obesity was found to increase the risk of depression, most pronounced among Americans and for clinically diagnosed depression. In addition, depression was found to be predictive of developing obesity.

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Increased Synaptic Dopamine Function in Associative Regions of the Striatum in Schizophrenia [Original Article]

Context  A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D₂ receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D₂ receptors is responsible for the antipsychotic action of D₂ receptor antagonists.

Objective  To localize dopaminergic hyperactivity within the striatum in schizophrenia.

Design  Case-control study.

Setting  Inpatient research unit.

Participants  Eighteen untreated patients with schizophrenia and 18 healthy control subjects matched for age, sex, ethnicity, parental socioeconomic status, cigarette smoking, and weight.

Main Outcome Measures  Percentage change in dopamine D₂ receptor availability in striatal subregions within each subject measured by positron emission tomography with carbon 11–labeled raclopride before and during pharmacologically induced dopamine depletion.

Results  In the associative striatum, acute dopamine depletion resulted in a larger increase in D₂ receptor availability in patients with schizophrenia (mean [SD], 15% [7%]) than in control subjects (10% [7%], P = .045), suggesting higher synaptic dopamine concentration. Within the associative striatum, this effect was most pronounced in the precommissural dorsal caudate (15% [8%] in patients vs 9% [8%] in controls, P = .03). No between-group differences were observed in the limbic and sensorimotor striatum.

Conclusions  These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.

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Prediction of Psychosis in Adolescents and Young Adults at High Risk: Results From the Prospective European Prediction of Psychosis Study [Original Article]

Context  Indicated prevention is currently regarded as the most promising strategy to attenuate, delay, or even avert psychosis. Existing criteria need improvement in terms of specificity and individual risk assessment to allow for better targeted and earlier interventions.

Objective  To develop a differential predictive clinical model of transition to first-episode psychosis.

Design  Prospective multicenter, naturalistic field study with a total follow-up time of 18 months.

Setting  Six early-detection outpatient centers in Germany, Finland, the Netherlands, and England.

Participants  Two hundred forty-five help-seeking patients in a putatively prodromal state of psychosis according to either ultra-high-risk (UHR) criteria or the basic symptom–based criterion cognitive disturbances (COGDIS).

Main Outcome Measure  Incidence of transition to psychosis.

Results  At 18-month follow-up, the incidence rate for transition to psychosis was 19%. Combining UHR and COGDIS yielded the best sensitivity. A prediction model was developed and included positive symptoms, bizarre thinking, sleep disturbances, a schizotypal disorder, level of functioning in the past year, and years of education. With a positive likelihood ratio of 19.9, an area under the curve of 80.8%, and a positive predictive value of 83.3%, diagnostic accuracy was excellent. A 4-level prognostic index further classifying the general risk of the whole sample predicted instantaneous incidence rates of up to 85% and allowed for an estimation of time to transition.

Conclusions  The prediction model identified an increased risk of psychosis with appropriate prognostic accuracy in our sample. A 2-step risk assessment is proposed, with UHR and cognitive disturbance criteria serving as first-step criteria for general risk and the prognostic index as a second-step tool for further risk classification of each patient. This strategy will allow clinicians to target preventive measures and will support efforts to unveil the biological and environmental mechanisms underlying progression to psychosis.

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Severe Mental Disorders in Offspring With 2 Psychiatrically Ill Parents [Original Article]

Background  Studies of couples of psychiatric patients with children allow us to calculate the effects of double predispositions on morbid risk in the offspring, which is of interest for molecular genetic research and for genetic counseling.

Objective  To determine the risks in offspring of receiving a diagnosis of schizophrenia, bipolar disorder, unipolar depressive disorder, or any diagnosis from parents who both have received a diagnosis of schizophrenia or bipolar disorder.

Design  National register-based cohort study.

Setting  Denmark.

Participants  A population-based cohort of 2.7 million persons born in Denmark, alive in 1968 or born later than 1968, with a register link to their mother and father and aged 10 years or older in 2007.

Main Outcome Measure  Risk of schizophrenia or bipolar disorder, calculated as cumulative incidences by age 52 years.

Results  The risk of schizophrenia in 270 offspring of 196 parent couples who were both admitted to a psychiatric facility with a diagnosis of schizophrenia was 27.3% (increasing to 39.2% when schizophrenia-related disorders were included) compared with 7.0% in 13 878 offspring from 8006 couples with only 1 parent ever admitted for schizophrenia and 0.86% in 2 239 551 offspring of 1 080 030 couples with neither parent ever admitted. The risk of bipolar disorder was 24.9% in 146 offspring of 83 parent couples who were ever admitted with bipolar disorder (increasing to 36.0% when unipolar depressive disorder was included) compared with 4.4% in 23 152 offspring from 11 995 couples with only 1 parent ever admitted and 0.48% in 2 239 553 offspring of 1 080 030 couples with neither parent ever admitted. Risks of schizophrenia and bipolar disorder in offspring of couples with 1 parent with schizophrenia and the other with bipolar disorder were 15.6% and 11.7%, respectively. The maximal risks of any psychiatric disorders in the offspring of parents both with schizophrenia or both with bipolar disorder were 67.5% and 44.2%, respectively.

Conclusions  Derived risks may be informative for counseling. Patterns of transmission may support evolving assumptions about genetic overlap for traditional categories.

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Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects [Original Article]

Context  Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood.

Objectives  To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects.

Design  Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction.

Setting  Academic medical center.

Patients or Other Participants  Forty-four suicide completers and 33 nonsuicide control subjects of white ethnicity.

Main Outcome Measures  The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain's Wernicke area.

Results  Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter/exon IV compared with nonsuicide control subjects (P < .001). Most of the CpG sites lying in the –300/+500 region, on both strands, had low or no methylation, with the exception of a few sites located near the transcriptional start site that had differential methylation, while genome-wide methylation levels were comparable among the subjects. The mean methylation degree at the 4 CpG sites analyzed by pyrosequencing was always less than 12.9% in the 33 nonsuicide control subjects, while in 13 of 44 suicide victims (30%), the mean methylation degree ranged between 13.1% and 34.2%. Higher methylation degree corresponded to lower BDNF messenger RNA levels.

Conclusions  BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior.

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Decreased Hippocampal Volume in Healthy Girls at Risk of Depression [Original Article]

Context  Researchers have documented that the hippocampus is smaller in individuals with depression than in those without. The temporal or causal association of this reduction in hippocampal volume in depression, however, is not known.

Objective  To test the hypothesis that reduced hippocampal volume precedes and therefore may be implicated in the onset of depression.

Design  We used magnetic resonance imaging to examine brain structure volume in individuals at high and low familial risk of depression. Anatomic images from magnetic resonance imaging were analyzed using both whole-brain voxel-based morphometry and manual tracing of the bilateral hippocampus.

Setting  A research university.

Participants  Fifty-five girls aged between 9 and 15 years: 23 daughters of mothers with recurrent episodes of depression in the daughter's lifetime (high risk) and 32 age-matched daughters of mothers with no history of psychopathology (low risk). None of the girls had any past or current Axis I psychopathology.

Main Outcome Measures  Group differences in voxel-based morphometry brain matter density estimates and traced hippocampal volume.

Results  Voxel-based morphometry analyses indicated that individuals at high risk of depression had significantly less gray matter density in clusters in the bilateral hippocampus (P < .001) than low-risk participants. Tracing yielded a volumetric reduction in the left hippocampus in the high-risk participants (P < .05).

Conclusions  Compared with individuals at low familial risk of the development of depression, high-risk individuals have reduced hippocampal volume, indicating that neuroanatomic anomalies associated with depression may precede the onset of a depressive episode and influence the development and course of this disorder.

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Support for the Vascular Depression Hypothesis in Late-Life Depression: Results of a 2-Site, Prospective, Antidepressant Treatment Trial [Original Article]

Context  Research on vascular depression has used 2 approaches to subtype late-life depression, based on executive dysfunction or white matter hyperintensity severity.

Objective  To evaluate the relationship of neuropsychological performance and white matter hyperintensity with clinical response in late-life depression.

Design  Two-site, prospective, nonrandomized controlled trial.

Setting  Outpatient clinics at Washington University and Duke University.

Participants  A total of 217 subjects aged 60 years or older met DSM-IV criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received vascular risk factor scores, neuropsychological testing, and magnetic resonance imaging; they were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade white matter hyperintensity lesions.

Intervention  Twelve weeks of sertraline treatment, titrated by clinical response.

Main Outcome Measure  Participants' MADRS scores over time.

Results  Baseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (P = .002), language (P = .007), working memory (P = .01), processing speed (P < .001), executive function factor scores (P = .002), and categorical Fazekas ratings (P = .05) predicted MADRS scores, controlling for age, education, age of onset, and race. Controlling for baseline MADRS scores, these factors remained significant predictors of decrease in MADRS scores, except for working memory and Fazekas ratings. Thirty-three percent of subjects achieved remission (MADRS ≤7). Remitters differed from nonremitters in baseline cognitive processing speed, executive function, language, episodic memory, and vascular risk factor scores.

Conclusions  Comprehensive neuropsychological function and white matter hyperintensity severity predicted MADRS scores prospectively over a 12-week treatment course with selective serotonin reuptake inhibitors in late-life depression. Baseline neuropsychological function differentiated remitters from nonremitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with vascular risk factor severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity.

Trial Registration  clinicaltrials.gov Identifier: NCT00045773

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A Placebo-Controlled Trial of Phenelzine, Cognitive Behavioral Group Therapy, and Their Combination for Social Anxiety Disorder [Original Article]

Context  Medication and cognitive behavioral treatment are the best-established treatments for social anxiety disorder, yet many individuals remain symptomatic after treatment.

Objective  To determine whether combined medication and cognitive behavioral treatment is superior to either monotherapy or pill placebo.

Design  Randomized, double-blind, placebo-controlled trial.

Setting  Research clinics at Columbia University and Temple University.

Participants  One hundred twenty-eight individuals with a primary DSM-IV diagnosis of social anxiety disorder.

Interventions  Cognitive behavioral group therapy (CBGT), phenelzine sulfate, pill placebo, and combined CBGT plus phenelzine.

Main Outcome Measures  Liebowitz Social Anxiety Scale and Clinical Global Impression (CGI) scale scores at weeks 12 and 24.

Results  Linear mixed-effects models showed a specific order of effects, with steepest reductions in Liebowitz Social Anxiety Scale scores for the combined group, followed by the monotherapies, and the least reduction in the placebo group (Williams test = 4.97, P < .01). The CGI response rates in the intention-to-treat sample at week 12 were 9 of 27 (33.3%) (placebo), 16 of 34 (47.1%) (CBGT), 19 of 35 (54.3%) (phenelzine), and 23 of 32 (71.9%) (combined treatment) (²₁ = 8.76, P < .01). Corresponding remission rates (CGI = 1) were 2 of 27 (7.4%), 3 of 34 (8.8%), 8 of 35 (22.9%), and 15 of 32 (46.9%) (²₁ = 15.92, P < .01). At week 24, response rates were 9 of 27 (33.3%), 18 of 34 (52.9%), 17 of 35 (48.6%), and 25 of 32 (78.1%) (²₁ = 12.02, P = .001). Remission rates were 4 of 27 (14.8%), 8 of 34 (23.5%), 9 of 35 (25.7%), and 17 of 32 (53.1%) (²₁ = 10.72, P = .001).

Conclusion  Combined phenelzine and CBGT treatment is superior to either treatment alone and to placebo on dimensional measures and on rates of response and remission.

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Magnetic Resonance Imaging of Hippocampal Subfields in Posttraumatic Stress Disorder [Original Article]

Context  Most neuroimaging studies of posttraumatic stress disorder (PTSD) have focused on potential abnormalities in the whole hippocampus, but the subfields of this structure, which have distinctive histological characteristics and specialized functions, have not been investigated. Studies of individual subfields may clarify the role of the hippocampus in PTSD.

Objective  To determine if PTSD is associated with structural alterations in specific subfields of the hippocampus.

Design  Case-control study.

Participants  A total of 17 male veterans with combat trauma and PTSD (mean [SD] age, 41 [12] years) and 19 age-matched male veterans without PTSD who were recruited from the outpatient mental health clinic of the San Francisco Veterans Affairs Medical Center and by advertising in the community.

Interventions  High-resolution magnetic resonance imaging at 4 T.

Main Outcome Measure  Volumes of hippocampal subfields.

Results  Posttraumatic stress disorder was associated with 11.4% (1.5%) (P = .02) smaller mean (SD) cornu ammonis 3 (CA3)/dentate gyrus subfield volumes, irrespective of age-related alterations, whereas other subfields were spared. Age was associated with reduced volume of the CA1 subfield (P = .03). Total hippocampal volume was also reduced in PTSD by a mean (SD) of 6.5% (0.6%) but, related to both PTSD (P = .05) and age (P = .01), was consistent with the measurements in the subfields.

Conclusions  The findings indicate for the first time in humans that PTSD is associated with selective volume loss of the CA3/dentate gyrus subfields, consistent with animal studies, implying that chronic stress suppresses neurogenesis and dendritic branching in these structures.

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Effect of a Purpose in Life on Risk of Incident Alzheimer Disease and Mild Cognitive Impairment in Community-Dwelling Older Persons [Original Article]

Context  Emerging data suggest that psychological and experiential factors are associated with risk of Alzheimer disease (AD), but the association of purpose in life with incident AD is unknown.

Objective  To test the hypothesis that greater purpose in life is associated with a reduced risk of AD.

Design  Prospective, longitudinal epidemiologic study of aging.

Setting  Senior housing facilities and residences across the greater Chicago metropolitan area.

Participants  More than 900 community-dwelling older persons without dementia from the Rush Memory and Aging Project.

Main Outcome Measures  Participants underwent baseline evaluations of purpose in life and up to 7 years of detailed annual follow-up clinical evaluations to document incident AD. In subsequent analyses, we examined the association of purpose in life with the precursor to AD, mild cognitive impairment (MCI), and the rate of change in cognitive function.

Results  During up to 7 years of follow-up (mean, 4.0 years), 155 of 951 persons (16.3%) developed AD. In a proportional hazards model adjusted for age, sex, and education, greater purpose in life was associated with a substantially reduced risk of AD (hazard ratio, 0.48; 95% confidence interval, 0.33-0.69; P < .001). Thus, a person with a high score on the purpose in life measure (score = 4.2, 90th percentile) was approximately 2.4 times more likely to remain free of AD than was a person with a low score (score = 3.0, 10th percentile). This association did not vary along demographic lines and persisted after the addition of terms for depressive symptoms, neuroticism, social network size, and number of chronic medical conditions. In subsequent models, purpose in life also was associated with a reduced risk of MCI (hazard ratio, 0.71; 95% confidence interval, 0.53-0.95; P = .02) and a slower rate of cognitive decline (mean [SE] global cognition estimate, 0.03 [0.01], P < .01).

Conclusion  Greater purpose in life is associated with a reduced risk of AD and MCI in community-dwelling older persons.

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Error in Results in: Efficacy of an Internet-Based Behavioral Intervention for Adults With Insomnia [Correction]

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Matters Arising [Letters to the Editor]

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About This Journal [About This Journal]

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This Month in Archives of General Psychiatry [This Month in Archives of General Psychiatry]

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Pygmalion in Love With His Statue [Art and Images in Psychiatry]

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As the Twig Is Bent, the Tree Inclines: Adult Mental Health Consequences of Childhood Adversity [Commentary]

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Childhood Adversities and Adult Psychiatric Disorders in the National Comorbidity Survey Replication I: Associations With First Onset of DSM-IV Disorders [Original Article]

Context  Although significant associations of childhood adversities (CAs) with adult mental disorders have been documented consistently in epidemiological surveys, these studies generally have examined only 1 CA per study. Because CAs are highly clustered, this approach results in overestimating the importance of individual CAs. Multivariate CA studies have been based on insufficiently complex models.

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.

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Childhood Adversities and Adult Psychiatric Disorders in the National Comorbidity Survey Replication II: Associations With Persistence of DSM-IV Disorders [Original Article]

Context  Although significant associations of childhood adversities (CAs) with adult mental disorders have been widely documented, associations of CAs with onset and persistence of disorders have not been distinguished. This distinction is important for conceptual and practical purposes.

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.

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Hippocampal Plasticity in Response to Exercise in Schizophrenia [Original Article]

Context  Hippocampal volume is lower than expected in patients with schizophrenia; however, whether this represents a fixed deficit is uncertain. Exercise is a stimulus to hippocampal plasticity.

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.

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Long-Chain {omega}-3 Fatty Acids for Indicated Prevention of Psychotic Disorders: A Randomized, Placebo-Controlled Trial [Original Article]

Context  The use of antipsychotic medication for the prevention of psychotic disorders is controversial. Long-chain -3 (omega-3) polyunsaturated fatty acids (PUFAs) may be beneficial in a range of psychiatric conditions, including schizophrenia. Given that -3 PUFAs are generally beneficial to health and without clinically relevant adverse effects, their preventive use in psychosis merits investigation.

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

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Extracellular Matrix-Glial Abnormalities in the Amygdala and Entorhinal Cortex of Subjects Diagnosed With Schizophrenia [Original Article]

Context  Chondroitin sulfate proteoglycans (CSPGs), a main component of the brain extracellular matrix, regulate developmental and adult neural functions that are highly relevant to the pathogenesis of schizophrenia. Such functions, together with marked expression of CSPGs in astrocytes within the normal human amygdala and evidence of a disruption of astrocytic functions in this disease, point to involvement of CSPG-glial interactions in schizophrenia.

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.

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Neurocognitive Endophenotypes for Bipolar Disorder Identified in Multiplex Multigenerational Families [Original Article]

Context  Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes.

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.

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Limited Attentional Bias for Faces in Toddlers With Autism Spectrum Disorders [Original Article]

Context  Toddlers with autism spectrum disorders (ASD) exhibit poor face recognition and atypical scanning patterns in response to faces. It is not clear if face-processing deficits are also expressed on an attentional level. Typical individuals require more effort to shift their attention from faces compared with other objects. This increased disengagement cost is thought to reflect deeper processing of these socially relevant stimuli.

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.

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Escitalopram and Enhancement of Cognitive Recovery Following Stroke [Original Article]

Context  Adjunctive restorative therapies administered during the first few months after stroke, the period with the greatest degree of spontaneous recovery, reduce the number of stroke patients with significant disability.

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

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Abnormalities of Visual Processing and Frontostriatal Systems in Body Dysmorphic Disorder [Original Article]

Context  Body dysmorphic disorder (BDD) is a psychiatric disorder in which individuals are preoccupied with perceived defects in their appearance, often related to their face. Little is known about its pathophysiology, although early research provides evidence of abnormal visual processing.

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.

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About This Journal [About This Journal]

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This Month in Archives of General Psychiatry [This Month in Archives of General Psychiatry]

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Miranda--The Tempest [Art and Images in Psychiatry]

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Decreased Frontal Serotonin2A Receptor Binding in Antipsychotic-Naive Patients With First-Episode Schizophrenia [Original Article]

Context  Postmortem investigations and the receptor affinity profile of atypical antipsychotics have implicated the participation of serotonin_2A receptors in the pathophysiology of schizophrenia. Most postmortem studies point toward lower cortical serotonin_2A binding in schizophrenic patients. However, in vivo studies of serotonin_2A binding report conflicting results, presumably because sample sizes have been small or because schizophrenic patients who were not antipsychotic-naive were included. Furthermore, the relationships between serotonin_2A binding, psychopathology, and central neurocognitive deficits in schizophrenia are unclear.

Objectives  To assess in vivo brain serotonin_2A binding potentials in a large sample of antipsychotic-naive schizophrenic patients and matched healthy controls, and to examine possible associations with psychopathology, memory, attention, and executive functions.

Design  Case-control study.

Setting  University hospital, Denmark.

Participants  A sample of 30 first-episode, antipsychotic-naive schizophrenic patients, 23 males and 7 females, and 30 matched healthy control subjects.

Interventions  Positron emission tomography with the serotonin_2A-specific radioligand fluorine 18–labeled altanserin and administration of a neuropsychological test battery.

Main Outcome Measures  Binding potential of specific tracer binding, scores on the Positive and Negative Syndrome Scale, and results of neuropsychological testing.

Results  Schizophrenic patients had significantly lower serotonin_2A binding in the frontal cortex than did control subjects. A significant negative correlation was observed between frontal cortical serotonin_2A binding and positive psychotic symptoms in the male patients. No correlations were found between cognitive functions and serotonin_2A binding.

Conclusion  The results suggest that frontal cortical serotonin_2A receptors are involved in the pathophysiology of schizophrenia.

Trial Registration  clinicaltrials.gov Identifier: NCT00207064

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Metabolic Testing Rates in 3 State Medicaid Programs After FDA Warnings and ADA/APA Recommendations for Second-Generation Antipsychotic Drugs [Original Article]

Context  In 2003, the Food and Drug Administration (FDA) required a warning on diabetes risk for second-generation antipsychotic (SGA) drugs. The American Diabetes Association (ADA) and American Psychiatric Association (APA) recommended glucose and lipid testing for all patients starting to receive SGA drugs.

Objective  To characterize associations between the combined warnings and recommendations and baseline metabolic testing and SGA drug selection.

Design  Interrupted time-series analysis.

Setting  California, Missouri, and Oregon.

Patients  A total of 109 451 individuals receiving Medicaid who began taking SGA medication and a control cohort of 203 527 patients who began taking albuterol but did not receive antipsychotic medication.

Interventions  Prewarning and postwarning trends in metabolic testing were compared using laboratory claims for the cohort collected January 1, 2002, through December 31, 2005. Changes in SGA prescribing practices were similarly evaluated.

Main Outcome Measures  Monthly rates of baseline serum glucose and lipid testing for SGA-treated and propensity-matched albuterol-treated patients and monthly share of new prescriptions for each SGA drug.

Results  Initial testing rates for SGA-treated patients were low (glucose, 27%; lipids, 10%). The warning was not associated with an increase in glucose testing among SGA-treated patients and was associated with only a marginal increase in lipid testing rates (1.7%; P = .02). Testing rates and trends in SGA-treated patients were not different from background rates observed in the albuterol control group. New prescriptions of olanzapine (higher metabolic risk) declined during the warning period (annual share decline, 19.9%; P < .001). New prescriptions of aripiprazole (lower metabolic risk) increased during the warning period (share increase, 12.1%; P < .001) but may be attributable to the elimination of prior authorization in California during the same time frame. Quetiapine, risperidone, and ziprasidone use were not associated with the warning.

Conclusions  In a Medicaid-receiving population, baseline glucose and lipid testing for SGA-treated patients was infrequent and showed little change following the diabetes warning and monitoring recommendations. A change in SGA drug selection consistent with intentions to reduce metabolic risk was observed.

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National Trends in Psychotropic Medication Polypharmacy in Office-Based Psychiatry [Original Article]

Context  Psychotropic medication polypharmacy is common in psychiatric outpatient settings and, in some patient groups, may have increased in recent years.

Objective  To examine patterns and recent trends in psychotropic polypharmacy among visits to office-based psychiatrists.

Design  Annual data from the 1996-2006 cross-sectional National Ambulatory Medical Care Surveys were analyzed to examine patterns and trends in psychotropic polypharmacy within nationally representative samples of 13 079 visits to office-based psychiatrists.

Setting  Office-based psychiatry practices in the United States.

Participants  Outpatients with mental disorder diagnoses visiting office-based psychiatrists.

Main Outcome Measure  Number of medications prescribed in each visit and specific medication combinations.

Results  There was an increase in the number of psychotropic medications prescribed across years; visits with 2 or more medications increased from 42.6% in 1996-1997 to 59.8% in 2005-2006; visits with 3 or more medications increased from 16.9% to 33.2% (both P < .001). The median number of medications prescribed in each visit increased from 1 in 1996-1997 to 2 in 2005-2006 (mean increase: 40.1%). The increasing trend of psychotropic polypharmacy was mostly similar across visits by different patient groups and persisted after controlling for background characteristics. Prescription for 2 or more antidepressants, antipsychotics, sedative-hypnotics, and antidepressant-antipsychotic combinations, but not other combinations, significantly increased across survey years. There was no increase in prescription of mood stabilizer combinations. In multivariate analyses, the odds of receiving 2 or more antidepressants were significantly associated with a diagnosis of major depression (odds ratio [OR], 3.44; 99% confidence interval [CI], 2.58-4.58); 2 or more antipsychotics, with schizophrenia (OR, 6.75; 99% CI, 3.52-12.92); 2 or more mood stabilizers, with bipolar disorder (OR, 15.46; 99% CI, 6.77-35.31); and 2 or more sedative-hypnotics, with anxiety disorders (OR, 2.13; 99% CI, 1.41-3.22).

Conclusions  There has been a recent significant increase in polypharmacy involving antidepressant and antipsychotic medications. While some of these combinations are supported by clinical trials, many are of unproven efficacy. These trends put patients at increased risk of drug-drug interactions with uncertain gains for quality of care and clinical outcomes.

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Depression Care in the United States: Too Little for Too Few [Original Article]

Objective  To determine the prevalence and adequacy of depression care among different ethnic and racial groups in the United States.

Design  Collaborative Psychiatric Epidemiology Surveys (CPES) data were analyzed to calculate nationally representative estimates of depression care.

Setting  The 48 coterminous United States.

Participants  Household residents 18 years and older (N = 15 762) participated in the study.

Main Outcome Measures  Past-year depression pharmacotherapy and psychotherapy using American Psychiatric Association guideline-concordant therapies. Depression severity was assessed with the Quick Inventory of Depressive Symptomatology Self-Report. Primary predictors were major ethnic/racial groups (Mexican American, Puerto Rican, Caribbean black, African American, and non-Latino white) and World Mental Health Composite International Diagnostic Interview criteria for 12-month major depressive episode.

Results  Mexican American and African American individuals meeting 12-month major depression criteria consistently and significantly had lower odds for any depression therapy and guideline-concordant therapies despite depression severity ratings not significantly differing between ethnic/racial groups. All groups reported higher use of any past-year psychotherapy and guideline-concordant psychotherapy compared with pharmacotherapy; however, Caribbean black and African American individuals reported the highest proportions of this use.

Conclusions  Few Americans with recent major depression have used depression therapies and guideline-concordant therapies; however, the lowest rates of use were found among Mexican American and African American individuals. Ethnic/racial differences were found despite comparable depression care need. More Americans with recent major depression used psychotherapy over pharmacotherapy, and these differences were most pronounced among Mexican American and African American individuals. This report underscores the importance of disaggregating ethnic/racial groups and depression therapies in understanding and directing efforts to improve depression care in the United States.

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Incidence and Risk Patterns of Anxiety and Depressive Disorders and Categorization of Generalized Anxiety Disorder [Original Article]

Context  Controversy surrounds the diagnostic categorization of generalized anxiety disorder (GAD).

Objectives  To examine the incidence, comorbidity, and risk patterns for anxiety and depressive disorders and to test whether developmental features of GAD more strongly support a view of this condition as a depressive as opposed to an anxiety disorder.

Design  Face-to-face, 10-year prospective longitudinal and family study with as many as 4 assessment waves. The DSM-IV Munich Composite International Diagnostic Interview was administered by clinically trained interviewers.

Setting  Munich, Germany.

Participants  A community sample of 3021 individuals aged 14 to 24 years at baseline and 21 to 34 years at last follow-up.

Main Outcome Measures  Cumulative incidence of GAD, other anxiety disorders (specific phobias, social phobia, agoraphobia, and panic disorder), and depressive disorders (major depressive disorder, and dysthymia).

Results  Longitudinal associations between GAD and depressive disorders are not stronger than those between GAD and anxiety disorders or between other anxiety and depressive disorders. Survival analyses reveal that the factors associated with GAD overlap more strongly with those specific to anxiety disorders than those specific to depressive disorders. In addition, GAD differs from anxiety and depressive disorders with regard to family climate and personality profiles.

Conclusions  Anxiety and depressive disorders appear to differ with regard to risk constellations and temporal longitudinal patterns, and GAD is a heterogeneous disorder that is, overall, more closely related to other anxiety disorders than to depressive disorders. More work is needed to elucidate the potentially unique aspects of pathways and mechanisms involved in the etiopathogenesis of GAD. Grouping GAD with depressive disorders, as suggested by cross-sectional features and diagnostic comorbidity patterns, minimizes the importance of longitudinal data on risk factors and symptom trajectories.

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Brain Serotonin and Dopamine Transporter Bindings in Adults With High-Functioning Autism [Original Article]

Context  Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown.

Objective  To determine the occurrence of changes in the binding of serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems.

Design  Using positron emission tomography, we measured the binding of brain serotonin and dopamine transporters in each individual with the radioligands carbon 11 (¹¹C)–labeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([¹¹C](+)McN-5652) and 2β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([¹¹C]WIN-35,428), respectively. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables.

Setting  Participants recruited from the community.

Participants  Twenty men (age range, 18-26 years; mean [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ-matched control subjects.

Results  Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls (P < .05, corrected). Specifically, the reduction in the anterior and posterior cingulate cortices was associated with the impairment of social cognition in the autistic subjects (P < .05, corrected). A significant correlation was also found between repetitive and/or obsessive behavior and interests and the reduction of serotonin transporter binding in the thalamus (P < .05, corrected). In contrast, the dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group (P < .05, corrected in voxelwise analysis). In the orbitofrontal cortex, the dopamine transporter binding was significantly inversely correlated with serotonin transporter binding (r = –0.61; P = .004).

Conclusions  The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Our sample was not characteristic or representative of a typical sample of adults with autism in the community.

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Influence of Environmental Factors in Higher Risk of Sudden Infant Death Syndrome Linked With Parental Mental Illness [Original Article]

Context  Since national risk reduction campaigns have been conducted, sudden infant death syndrome (SIDS) has become increasingly concentrated among disadvantaged families, including those affected by mental illness. However, causal mechanisms specific to this group are poorly understood.

Objectives  To estimate relative risk and compare risk factor prevalence in infants with and without parental psychiatric inpatient history, and to explore effect modification after the 1992 Swedish risk reduction campaign.

Design  National birth cohort. Parental psychiatric admissions, maternal prenatal smoking, obstetric and social risk factors, and cause-specific infant death were ascertained via linkage between national registers.

Setting  The Swedish population, 1978 through 2004.

Participants  All singleton live births (N = 2.5 million).

Main Outcome Measure  Incidence of SIDS.

Results  Risk of SIDS was higher with a history of parental inpatient care, especially if both parents were admitted with any mental illness (odds ratio, 6.8; 95% confidence interval, 4.7-10.0), or if the mother (6.5; 4.9-8.7) or both parents (9.5; 5.5-16.4) had an alcohol/drug disorder. A 2-fold higher risk was also seen if the mother or father was admitted with any psychiatric illness other than alcohol or other drug disorders. Elevated risk persisted even if the last maternal inpatient episode had occurred 5 or more years before the infant's birth. After the national campaign, risk factor prevalence (especially maternal antenatal smoking) remained high in this population, and relative risks therefore increased. During 1992 through 2004, smoking and individual social adversity measures jointly accounted for approximately half the excess risk linked with maternal psychiatric inpatient history, whereas the confounding effects of obstetric factors were minimal.

Conclusions  Tailored approaches are needed to ensure that standard safety advice is effectively communicated to these vulnerable families. In particular, mentally ill pregnant women should be encouraged and better supported to stop smoking. Families with 2 affected parents require particularly strong support. A clearer understanding is needed as to why high risk factor prevalence persists among these parents.

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Error in Dosage and Degree in: A Randomized Placebo-Controlled Clinical Trial of 5 Smoking Cessation Pharmacotherapies [Correction]

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Structural Differences in Adult Orbital and Ventromedial Prefrontal Cortex Predicted by Infant Temperament at 4 Months of Age [Original Article]

Context  The term temperament refers to a biologically based predilection for a distinctive pattern of emotions, cognitions, and behaviors first observed in infancy or early childhood. High-reactive infants are characterized at age 4 months by vigorous motor activity and crying in response to unfamiliar visual, auditory, and olfactory stimuli, whereas low-reactive infants show low motor activity and low vocal distress to the same stimuli. High-reactive infants are biased to become behaviorally inhibited in the second year of life, defined by timidity with unfamiliar people, objects, and situations. In contrast, low-reactive infants are biased to develop into uninhibited children who spontaneously approach novel situations.

Objective  To examine whether differences in the structure of the ventromedial or orbitofrontal cerebral cortex at age 18 years are associated with high or low reactivity at 4 months of age.

Design  Structural magnetic resonance imaging in a cohort of 18-year-olds enrolled in a longitudinal study. Temperament was determined at 4 months of age by direct observation in the laboratory.

Setting  Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital.

Participants  Seventy-six subjects who were high-reactive or low-reactive infants at 4 months of age.

Main Outcome Measure  Cortical thickness.

Results  Adults with a low-reactive infant temperament, compared with those categorized as high reactive, showed greater thickness in the left orbitofrontal cortex. Subjects categorized as high reactive in infancy, compared with those previously categorized as low reactive, showed greater thickness in the right ventromedial prefrontal cortex.

Conclusions  To our knowledge, this is the first demonstration that temperamental differences measured at 4 months of age have implications for the architecture of human cerebral cortex lasting into adulthood. Understanding the developmental mechanisms that shape these differences may offer new ways to understand mood and anxiety disorders as well as the formation of adult personality.

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Brief, Personality-Targeted Coping Skills Interventions and Survival as a Non-Drug User Over a 2-Year Period During Adolescence [Original Article]

Context  Selective interventions targeting personality risk are showing promise in the prevention of problematic drinking behavior, but their effect on illicit drug use has yet to be evaluated.

Objective  To investigate the efficacy of targeted coping skills interventions on illicit drug use in adolescents with personality risk factors for substance misuse.

Design  Randomized controlled trial.

Setting  Secondary schools in London, United Kingdom.

Participants  A total of 5302 students were screened to identify 2028 students aged 13 to 16 years with elevated scores on self-report measures of hopelessness, anxiety sensitivity, impulsivity, and sensation seeking. Seven hundred thirty-two students provided parental consent to participate in this trial.

Intervention  Participants were randomly assigned to a control no-intervention condition or a 2-session group coping skills intervention targeting 1 of 4 personality profiles.

Main Outcome Measures  The trial was designed and powered to primarily evaluate the effect of the intervention on the onset, prevalence, and frequency of illicit drug use over a 2-year period.

Results  Intent-to-treat repeated-measures analyses on continuous measures of drug use revealed time x intervention effects on the number of drugs used (P < .01) and drug use frequency (P < .05), whereby the control group showed significant growth in the number of drugs used as well as more frequent drug use over the 2-year period relative to the intervention group. Survival analysis using logistic regression revealed that the intervention was associated with reduced odds of taking up the use of marijuana (β = –0.3; robust SE = 0.2; P = .09; odds ratio = 0.7; 95% confidence interval, 0.5-1.0), cocaine (β = –1.4; robust SE = 0.4; P < .001; odds ratio = 0.2; 95% confidence interval, 0.1-0.5), and other drugs (β = –0.7; robust SE = 0.3; P = .03; odds ratio = 0.5; 95% confidence interval, 0.3-0.9) over the 24-month period.

Conclusion  This study extends the evidence that brief, personality-targeted interventions can prevent the onset and escalation of substance misuse in high-risk adolescents.

Trial Registration  clinicaltrials.gov Identifier: NCT00344474

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Psychological Treatments of Binge Eating Disorder [Original Article]

Context  Interpersonal psychotherapy (IPT) is an effective specialty treatment for binge eating disorder (BED). Behavioral weight loss treatment (BWL) and guided self-help based on cognitive behavior therapy (CBTgsh) have both resulted in short-term reductions in binge eating in obese patients with BED.

Objective  To test whether patients with BED require specialty therapy beyond BWL and whether IPT is more effective than either BWL or CBTgsh in patients with a high negative affect during a 2-year follow-up.

Design  Randomized, active control efficacy trial.

Setting  University outpatient clinics.

Participants  Two hundred five women and men with a body mass index between 27 and 45 who met DSM-IV criteria for BED.

Intervention  Twenty sessions of IPT or BWL or 10 sessions of CBTgsh during 6 months.

Main Outcome Measures  Binge eating assessed by the Eating Disorder Examination.

Results  At 2-year follow-up, both IPT and CBTgsh resulted in greater remission from binge eating than BWL (P < .05; odds ratios: BWL vs CBTgsh, 2.3; BWL vs IPT, 2.6; and CBTgsh vs IPT, 1.2). Self-esteem (P < .05) and global Eating Disorder Examination (P < .05) scores were moderators of treatment outcome. The odds ratios for low and high global Eating Disorder Examination scores were 2.8 for BWL, 2.9 for CBTgsh, and 0.73 for IPT; for self-esteem, they were 2.4 for BWL, 1.9 for CBTgsh, and 0.9 for IPT.

Conclusions  Interpersonal psychotherapy and CBTgsh are significantly more effective than BWL in eliminating binge eating after 2 years. Guided self-help based on cognitive behavior therapy is a first-line treatment option for most patients with BED, with IPT (or full cognitive behavior therapy) used for patients with low self-esteem and high eating disorder psychopathology.

Trial Registration  clinicaltrials.gov Identifier: NCT00060762

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Mary Frances ("Fran") MacNeil [Announcement]

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About This Journal [About This Journal]

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This Month in Archives of General Psychiatry [This Month in Archives of General Psychiatry]

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The Virgin of the Rocks [Art and Images in Psychiatry]

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Gene-Environment Interactions: Biologically Valid Pathway or Artifact? [From JAMA]

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Functional Neuroanatomy of Visual Masking Deficits in Schizophrenia [Original Article]

Context  Visual masking procedures assess the earliest stages of visual processing. Patients with schizophrenia reliably show deficits on visual masking, and these procedures have been used to explore vulnerability to schizophrenia, probe underlying neural circuits, and help explain functional outcome.

Objective  To identify and compare regional brain activity associated with one form of visual masking (ie, backward masking) in schizophrenic patients and healthy controls.

Design  Subjects received functional magnetic resonance imaging scans. While in the scanner, subjects performed a backward masking task and were given 3 functional localizer activation scans to identify early visual processing regions of interest (ROIs).

Setting  University of California, Los Angeles, and the Department of Veterans Affairs Greater Los Angeles Healthcare System.

Participants  Nineteen patients with schizophrenia and 19 healthy control subjects.

Main Outcome Measure  The magnitude of the functional magnetic resonance imaging signal during backward masking.

Results  Two ROIs (lateral occipital complex [LO] and the human motion selective cortex [hMT+]) showed sensitivity to the effects of masking, meaning that signal in these areas increased as the target became more visible. Patients had lower activation than controls in LO across all levels of visibility but did not differ in other visual processing ROIs. Using whole-brain analyses, we also identified areas outside the ROIs that were sensitive to masking effects (including bilateral inferior parietal lobe and thalamus), but groups did not differ in signal magnitude in these areas.

Conclusions  The study results support a key role in LO for visual masking, consistent with previous studies in healthy controls. The current results indicate that patients fail to activate LO to the same extent as controls during visual processing regardless of stimulus visibility, suggesting a neural basis for the visual masking deficit, and possibly other visual integration deficits, in schizophrenia.

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Brain Monoamine Oxidase A Binding in Major Depressive Disorder: Relationship to Selective Serotonin Reuptake Inhibitor Treatment, Recovery, and Recurrence [Original Article]

Context  Highly significant elevations in regional brain monoamine oxidase A (MAO-A) binding were recently reported during major depressive episodes (MDEs) of major depressive disorder (MDD). The relationship between MAO-A levels and selective serotonin reuptake inhibitor (SSRI) treatment, recovery, and recurrence in MDD is unknown.

Objectives  To determine whether brain MAO-A binding changes after SSRI treatment, whether brain MAO-A binding normalizes in subjects with MDD in recovery, and whether there is a relationship between prefrontal and anterior cingulate cortex MAO-A binding in recovery and subsequent recurrence of MDE.

Design  Case-control study.

Setting  Tertiary care psychiatric hospital.

Participants  Twenty-eight healthy subjects, 16 subjects with an MDE secondary to MDD, and 18 subjects with MDD in recovery underwent carbon 11–labeled harmine positron emission tomography scans. Subjects with MDE were scanned before and after 6 weeks of SSRI treatment. All were otherwise healthy, nonsmoking, and medication free. Subjects with MDD in recovery were followed up for 6 months after MAO-A binding measurement.

Main Outcome Measure  Monoamine oxidase A V_T, an index of MAO-A density, was measured in the prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, dorsal putamen, ventral striatum, thalamus, anterior temporal cortex, midbrain, and hippocampus.

Results  Monoamine oxidase A V_T was significantly elevated in each brain region both during MDE and after SSRI treatment as compared with healthy controls. During recovery, MAO-A V_T was significantly elevated in each brain region; however, those who went on to recurrence had significantly higher MAO-A V_T in the prefrontal and anterior cingulate cortex than those who did not.

Conclusions  Elevated MAO-A binding after SSRI treatment indicates persistence of a monoamine-lowering process not present in health. This provides a strong conceptual rationale for continuing SSRI treatment during early remission. Greater MAO-A binding in the prefrontal and anterior cingulate cortex in subjects with MDD in recovery and its association with subsequent recurrence argue that deficient monoamine neuromodulation may persist into recovery and contribute to recurrence.

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Blood Lead Levels and Major Depressive Disorder, Panic Disorder, and Generalized Anxiety Disorder in US Young Adults [Original Article]

Context  Lead is a ubiquitous neurotoxicant, and adverse cognitive and behavioral effects are well-documented in children and occupationally exposed adults but not in adults with low environmental exposure.

Objective  To investigate the association of current blood lead levels with 3 common psychiatric disorders—major depression, panic, and generalized anxiety—in young adults.

Design  Cross-sectional epidemiologic survey.

Setting  Nationally representative sample of US adults.

Participants  A total of 1987 adults aged 20 to 39 years who responded to the National Health and Nutrition Examination Survey (1999-2004).

Main Outcome Measures  Twelve-month DSM-IV criteria–based diagnoses of major depressive disorder, panic disorder, and generalized anxiety disorder assessed using the Composite International Diagnostic Interview.

Results  The mean (SD) blood lead level was 1.61 (1.72) µg/dL (range, 0.3-37.3 µg/dL) (to convert to micromoles per liter, multiply by 0.0483). Increasing blood lead levels were associated with higher odds of major depression (P = .05 for trend) and panic disorder (P = .02 for trend) but not generalized anxiety disorder (P = .78 for trend) after adjustment for sex, age, race/ethnicity, education status, and poverty to income ratio. Persons with blood lead levels in the highest quintile had 2.3 times the odds of major depressive disorder (95% confidence interval [CI], 1.13-4.75) and 4.9 times the odds of panic disorder (1.32-18.48) as those in the lowest quintile. Cigarette smoking was associated with higher blood lead levels and outcome, but models that excluded current smokers also resulted in significantly increased odds of major depression (P = .03 for trend) and panic disorder (P = .01 for trend) with higher blood lead quintiles.

Conclusions  In these young adults with low levels of lead exposure, higher blood lead levels were associated with increased odds of major depression and panic disorders. Exposure to lead at levels generally considered safe could result in adverse mental health outcomes.

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Personality Change During Depression Treatment: A Placebo-Controlled Trial [Original Article]

Context  High neuroticism is a personality risk factor that reflects much of the genetic vulnerability to major depressive disorder (MDD), and low extraversion may increase risk as well. Both have been linked to the serotonin system.

Objectives  To test whether patients with MDD taking selective serotonin reuptake inhibitors (SSRIs) report greater changes in neuroticism and extraversion than patients receiving inert placebo, and to examine the state effect hypothesis that self-reported personality change during SSRI treatment is merely a change of depression-related measurement bias.

Design  A placebo-controlled trial.

Setting  Research clinics.

Patients  Adult patients with moderate to severe MDD randomized to receive paroxetine (n = 120), placebo (n = 60), or cognitive therapy (n = 60).

Outcome Measures  NEO Five-Factor Inventory and Hamilton Rating Scale for Depression.

Results  Patients who took paroxetine reported greater personality change than placebo patients, even after controlling for depression improvement (neuroticism, P < .001; extraversion, P = .002). The advantage of paroxetine over placebo in antidepressant efficacy was no longer significant after controlling for change in neuroticism (P = .46) or extraversion (P = .14). Patients taking paroxetine reported 6.8 times as much change on neuroticism and 3.5 times as much change on extraversion as placebo patients matched for depression improvement. Although placebo patients exhibited substantial depression improvement (Hamilton Rating Scale for Depression score, –1.2 SD, P < .001), they reported little change on neuroticism (–0.18 SD, P = .08) or extraversion (0.08 SD, P = .50). Cognitive therapy produced greater personality change than placebo (P ≤ .01); but its advantage on neuroticism was no longer significant after controlling for depression (P = .14). Neuroticism reduction during treatment predicted lower relapse rates among paroxetine responders (P = .003) but not among cognitive therapy responders (P = .86).

Conclusions  Paroxetine appears to have a specific pharmacological effect on personality that is distinct from its effect on depression. If replicated, this pattern would disconfirm the state effect hypothesis and instead support the notion that SSRIs' effects on personality go beyond and perhaps contribute to their antidepressant effects.

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Clinical Effectiveness of Individual Cognitive Behavioral Therapy for Depressed Older People in Primary Care: A Randomized Controlled Trial [Original Article]

Context  In older people, depressive symptoms are common, psychological adjustment to aging is complex, and associated chronic physical illness limits the use of antidepressants. Despite this, older people are rarely offered psychological interventions, and only 3 randomized controlled trials of individual cognitive behavioral therapy (CBT) in a primary care setting have been published.

Objective  To determine the clinical effectiveness of CBT delivered in primary care for older people with depression.

Design  A single-blind, randomized, controlled trial with 4- and 10-month follow-up visits.

Patients  A total of 204 people aged 65 years or older (mean [SD] age, 74.1 [7.0] years; 79.4% female; 20.6% male) with a Geriatric Mental State diagnosis of depression were recruited from primary care.

Interventions  Treatment as usual (TAU), TAU plus a talking control (TC), or TAU plus CBT. The TC and CBT were offered over 4 months.

Outcome Measures  Beck Depression Inventory-II (BDI-II) scores collected at baseline, end of therapy (4 months), and 10 months after the baseline visit. Subsidiary measures were the Beck Anxiety Inventory, Social Functioning Questionnaire, and Euroqol. Intent to treat using Generalized Estimating Equation and Compliance Average Causal Effect analyses were used.

Results  Eighty percent of participants were followed up. The mean number of sessions of TC or CBT was just greater than 7. Intent-to-treat analysis found improvements of –3.07 (95% confidence interval [CI], –5.73 to –0.42) and –3.65 (95% CI, –6.18 to –1.12) in BDI-II scores in favor of CBT vs TAU and TC, respectively. Compliance Average Causal Effect analysis compared CBT with TC. A significant benefit of CBT of 0.4 points (95% CI, 0.01 to 0.72) on the BDI-II per therapy session was observed. The cognitive therapy scale showed no difference for nonspecific, but significant differences for specific factors in therapy. Ratings for CBT were high (mean [SD], 54.2 [4.1]).

Conclusion  Cognitive behavioral therapy is an effective treatment for older people with depressive disorder and appears to be associated with its specific effects.

Trial Registration  isrctn.org Identifier: ISRCTN18271323

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Heterogeneity of DSM-IV Major Depressive Disorder as a Consequence of Subthreshold Bipolarity [Original Article]

Context  There is growing evidence that major depressive disorder (MDD) might be overdiagnosed at the expense of bipolar disorder (BPD).

Objectives  To identify a subgroup of subthreshold BPD among DSM-IV MDD, which is distinct from pure MDD regarding a range of validators of bipolarity, and to examine the pattern of these validators among different groups with affective disorders.

Design  Ten-year prospective longitudinal and family study including 3 follow-up waves. Data were assessed with the DSM-IV Munich Composite International Diagnostic Interview.

Setting  Community sample in Munich, Germany.

Participants  A total of 2210 subjects (aged 14-24 years at baseline) who completed the third follow-up.

Main Outcome Measures  Cumulative incidence of pure MDD, BPD, and subthreshold BPD (defined as fulfilling criteria for MDD plus having manic symptoms but never having met criteria for [hypo]mania).

Results  Among 488 respondents with MDD, 286 (58.6%) had pure MDD and 202 (41.4%) had subthreshold BPD (cumulative incidence, 9.3%). Compared with respondents who had pure MDD, respondents with subthreshold BPD were found to have a significantly increased family history of mania, considerably higher rates of nicotine dependence and alcohol use disorders, rates of panic disorder that were twice as high, and a tendency toward higher rates of criminal acts. Prospective analyses showed that subthreshold BPD converted more often into BPD during follow-up, with DSM-IV criterion D (symptoms observable by others) being of critical predictive relevance. With increasing severity of the manic component, rates for diverse validators accordingly increased (eg, alcohol use disorders, parental mania) or decreased (harm avoidance).

Conclusions  Data suggest that MDD is a heterogeneous concept including a large group with subthreshold BPD, which is clinically significant and shares similarities with BPD. Findings might support the need for a broader concept and a more comprehensive screening of bipolarity, which could be substantial for future research and adequate treatment of patients with bipolarity.

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Relationship Between Antiepileptic Drugs and Suicide Attempts in Patients With Bipolar Disorder [Original Article]

Context  On January 31, 2008, the Food and Drug Administration issued an alert regarding increased risk of suicidal thoughts and behavior related to use of antiepileptic drugs (AEDs). On July 10, 2008, a Food and Drug Administration scientific advisory committee voted that, yes, there was a significant positive association between AEDs and suicidality but voted against placing a black box warning on AEDs for suicidality.

Objective  To determine if AEDs increase the risk of suicide attempt in patients with bipolar disorder.

Design  A pharmacoepidemiologic study in which suicide attempt rates were compared before and after treatment and with a medication-free control group. Analyses were restricted to AED and lithium monotherapy.

Setting  We used the PharMetrics medical claims database to study the relationship between the 11 AEDs identified in the FDA alert, and lithium, to suicide attempts.

Main Outcome Measure  Suicide attempts.

Patients  A cohort of 47 918 patients with bipolar disorder with a minimum 1-year window of information before and after the index date of their illness.

Results  Overall, there was no significant difference in suicide attempt rates for patients treated with an AED (13 per 1000 person-years [PY]) vs patients not treated with an AED or lithium (13 per 1000 PY). In AED-treated subjects, the rate of suicide attempts was significantly higher before treatment (72 per 1000 PY) than after (13 per 1000 PY). In patients receiving no concomitant treatment with an antidepressant, other AED, or antipsychotic, AEDs were significantly protective relative to no pharmacologic treatment (3 per 1000 vs 15 per 1000 PY).

Conclusions  Despite Food and Drug Administration reports regarding increased risk of suicidality associated with AED treatment, the current study reveals that, as a class, AEDs do not increase risk of suicide attempts in patients with bipolar disorder relative to patients not treated with an AED or lithium. Use of AEDs reduces suicide attempt rates both relative to patients not receiving any psychotropic medication and relative to their pretreatment levels.

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Disrupted Amygdalar Subregion Functional Connectivity and Evidence of a Compensatory Network in Generalized Anxiety Disorder [Original Article]

Context  Little is known about the neural abnormalities underlying generalized anxiety disorder (GAD). Studies in other anxiety disorders have implicated the amygdala, but work in GAD has yielded conflicting results. The amygdala is composed of distinct subregions that interact with dissociable brain networks, which have been studied only in experimental animals. A functional connectivity approach at the subregional level may therefore yield novel insights into GAD.

Objectives  To determine whether distinct connectivity patterns can be reliably identified for the basolateral (BLA) and centromedial (CMA) subregions of the human amygdala, and to examine subregional connectivity patterns and potential compensatory amygdalar connectivity in GAD.

Design  Cross-sectional study.

Setting  Academic medical center.

Participants  Two cohorts of healthy control subjects (consisting of 17 and 31 subjects) and 16 patients with GAD.

Main Outcome Measures  Functional connectivity with cytoarchitectonically determined BLA and CMA regions of interest, measured during functional magnetic resonance imaging performed while subjects were resting quietly in the scanner. Amygdalar gray matter volume was also investigated with voxel-based morphometry.

Results  Reproducible subregional differences in large-scale connectivity were identified in both cohorts of healthy controls. The BLA was differentially connected with primary and higher-order sensory and medial prefrontal cortices. The CMA was connected with the midbrain, thalamus, and cerebellum. In GAD patients, BLA and CMA connectivity patterns were significantly less distinct, and increased gray matter volume was noted primarily in the CMA. Across the subregions, GAD patients had increased connectivity with a previously characterized frontoparietal executive control network and decreased connectivity with an insula- and cingulate-based salience network.

Conclusions  Our findings provide new insights into the functional neuroanatomy of the human amygdala and converge with connectivity studies in experimental animals. In GAD, we find evidence of an intra-amygdalar abnormality and engagement of a compensatory frontoparietal executive control network, consistent with cognitive theories of GAD.

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Smaller Global and Regional Cortical Volume in Combat-Related Posttraumatic Stress Disorder [Original Article]

Context  Two sets of findings predict smaller cerebral cortical gray matter volume in adult posttraumatic stress disorder (PTSD). Measures of intracranial tissue volume and cerebral tissue volume have been observed to be smaller in adolescents with maltreatment-related PTSD. Second, lower intelligence, a risk factor for PTSD, is associated with smaller cerebral tissue volumes. Nevertheless, to our knowledge, only 1 study has observed globally smaller cerebral tissue volume in adults with PTSD.

Objectives  To apply a recently developed method providing improved estimates of cortical volume and to estimate associations between adult PTSD and selected regional cortical volumes not yet investigated.

Design  Between-group comparison of global and regional cerebral cortical volumes in adult patients with combat-related PTSD and controls.

Setting  Two Department of Veterans Affairs medical centers with large inpatient and outpatient PTSD catchments.

Participants  Ninety-seven combat-exposed veterans of the Vietnam and Persian Gulf wars.

Main Outcome Measure  Global and regional cortical volumes determined using the FreeSurfer software program and the Desikan et al parcellation (modified).

Results  Cerebral cortical volume, thickness, and area were observed to be smaller in association with adult combat-related PTSD. Robust associations were observed between PTSD and smaller cortical volumes in the parahippocampal gyrus, superior temporal cortex, lateral orbital frontal cortex, and pars orbitalis of the inferior frontal gyrus.

Conclusions  Cerebral cortical volume, thickness, and area may be smaller in adult chronic severe PTSD; however, the extracted structural variables did not mediate relations between intelligence and PTSD. The 4 regions exhibiting especially smaller cortical volumes in this sample share involvement in mechanisms subserving "top-down" facilitation of the identification of objects and words. Compromise of these regions may result in difficulty in relearning pretrauma schemata for interpreting the civilian physical and social environments.

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Error in Table in: Role of GABRA2 in Trajectories of Externalizing Behavior Across Development and Evidence of Moderation by Parental Monitoring [Correction]

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