Objective To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for suicide attempt (SA) and MDD by investigating common genetic variants in these loci.
Design Eighty-three tagging single-nucleotide polymorphisms (SNPs) covering the genetic variability of these loci in European populations were assessed in a case-control association design.
Setting Inpatients and screened control subjects.
Participants The discovery sample consisted of 394 depressed patients, of whom 113 had SA, and 366 matched healthy control subjects. The replication studies comprised 744 German patients with MDD and 921 African American nonpsychiatric clinic patients, of whom 152 and 119 were positive for SA, respectively.
Interventions Blood or saliva samples were collected from each participant for DNA extraction and genotyping.
Main Outcome Measures Associations of SNPs in BDNF and NTRK2 with SA and MDD.
Results Independent SNPs within NTRK2 were associated with SA among depressed patients of the discovery sample that could be confirmed in both the German and African American replication samples. Multilocus interaction analysis revealed that single SNP associations within this locus contribute to the risk of SA in a multiplicative and interactive fashion (P = 4.7 x 10–7 for a 3-SNP model in the combined German sample). The effect size was 4.5 (95% confidence interval, 2.1-9.8) when patients carrying risk genotypes in all 3 markers were compared with those without any of the 3 risk genotypes.
Conclusions Our results suggest that a combination of several independent risk alleles within the NTRK2 locus is associated with SA in depressed patients, further supporting a role of neurotrophins in the pathophysiology of suicide.
Published online February 1, 2010 (doi:10.1001/archgenpsychiatry.2009.201).
]]>Objective To examine the joint associations of 12 retrospectively reported CAs with the first onset of DSM-IV disorders in the National Comorbidity Survey Replication using substantively complex multivariate models.
Design Cross-sectional community survey with retrospective reports of CAs and lifetime DSM-IV disorders.
Setting Household population in the United States.
Participants Nationally representative sample of 9282 adults.
Main Outcome Measures Lifetime prevalences of 20 DSM-IV anxiety, mood, disruptive behavior, and substance use disorders assessed using the Composite International Diagnostic Interview.
Results The CAs studied were highly prevalent and intercorrelated. The CAs in a maladaptive family functioning (MFF) cluster (parental mental illness, substance abuse disorder, and criminality; family violence; physical abuse; sexual abuse; and neglect) were the strongest correlates of disorder onset. The best-fitting model included terms for each type of CA, number of MFF CAs, and number of other CAs. Multiple MFF CAs had significant subadditive associations with disorder onset. Little specificity was found for particular CAs with particular disorders. Associations declined in magnitude with life course stage and number of previous lifetime disorders but increased with length of recall. Simulations suggest that CAs are associated with 44.6% of all childhood-onset disorders and with 25.9% to 32.0% of later-onset disorders.
Conclusions The fact that associations increased with length of recall raises the possibility of recall bias inflating estimates. Even considering this, the results suggest that CAs have powerful and often subadditive associations with the onset of many types of largely primary mental disorders throughout the life course.
]]>Objective To examine the multivariate associations of 12 retrospectively reported CAs with persistence of adult DSM-IV disorders in the National Comorbidity Survey Replication.
Design Cross-sectional community survey.
Setting Household population in the United States.
Participants Nationally representative sample of 5692 adults.
Main Outcome Measures Recency of episodes was assessed separately for each of 20 lifetime DSM-IV mood, anxiety, disruptive behavior, and substance use disorders in respondents with a lifetime history of these disorders using the Composite International Diagnostic Interview. Predictors of persistence were examined using backward recurrence survival models to predict time since most recent episode controlling for age at onset and time since onset.
Results The CAs involving maladaptive family functioning (parental mental illness, substance use disorder, criminality, family violence, physical and sexual abuse, and neglect) but not other CAs were significantly but modestly related to persistence of mood, substance abuse, and anxiety disorders. Number of maladaptive family functioning CAs had statistically significant, but again substantively modest, subadditive associations with the same outcomes. Exposure to multiple other CAs was significantly associated with persistence of mood and anxiety disorders. Associations remained statistically significant throughout the life course, although the substantive size of associations indicated by simulations showing time to most recent episode would increase by only 1.6% (from a mean of 8.3 years to a mean of 8.4 years) in the absence of CAs.
Conclusions The overall statistically significant associations of CAs with adult DSM-IV/Composite International Diagnostic Interview disorders are due largely to component associations with onsets rather than with persistence, indirectly suggesting that the greatest focus of public health attention on CAs should be aimed at primary rather than secondary prevention.
]]>Objective To determine whether hippocampal volume would increase with exercise in humans and whether this effect would be related to improved aerobic fitness.
Design Randomized controlled study.
Setting Patients attending a day hospital program or an outpatient clinic.
Patients or Other Participants Male patients with chronic schizophrenia and matched healthy subjects.
Interventions Aerobic exercise training (cycling) and playing table football (control group) for a period of 3 months.
Main Outcome Measures Magnetic resonance imaging of the hippocampus. Secondary outcome measures were magnetic resonance spectroscopy, neuropsychological (Rey Auditory Verbal Learning Test, Corsi block-tapping test), and clinical (Positive and Negative Syndrome Scale) features.
Results Following exercise training, relative hippocampal volume increased significantly in patients (12%) and healthy subjects (16%), with no change in the nonexercise group of patients (–1%). Changes in hippocampal volume in the exercise group were correlated with improvements in aerobic fitness measured by change in maximum oxygen consumption (r = 0.71; P = .003). In the schizophrenia exercise group (but not the controls), change in hippocampal volume was associated with a 35% increase in the N-acetylaspartate to creatine ratio in the hippocampus. Finally, improvement in test scores for short-term memory in the combined exercise and nonexercise schizophrenia group was correlated with change in hippocampal volume (r = 0.51; P < .05).
Conclusion These results indicate that in both healthy subjects and patients with schizophrenia hippocampal volume is plastic in response to aerobic exercise.
]]>Objective To determine whether -3 PUFAs reduce the rate of progression to first-episode psychotic disorder in adolescents and young adults aged 13 to 25 years with subthreshold psychosis.
Design Randomized, double-blind, placebo-controlled trial conducted between 2004 and 2007.
Setting Psychosis detection unit of a large public hospital in Vienna, Austria.
Participants Eighty-one individuals at ultra-high risk of psychotic disorder.
Interventions A 12-week intervention period of 1.2-g/d -3 PUFA or placebo was followed by a 40-week monitoring period; the total study period was 12 months.
Main Outcome Measures The primary outcome measure was transition to psychotic disorder. Secondary outcomes included symptomatic and functional changes. The ratio of -6 to -3 fatty acids in erythrocytes was used to index pretreatment vs posttreatment fatty acid composition.
Results Seventy-six of 81 participants (93.8%) completed the intervention. By study's end (12 months), 2 of 41 individuals (4.9%) in the -3 group and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder (P = .007). The difference between the groups in the cumulative risk of progression to full-threshold psychosis was 22.6% (95% confidence interval, 4.8-40.4). -3 Polyunsaturated fatty acids also significantly reduced positive symptoms (P = .01), negative symptoms (P = .02), and general symptoms (P = .01) and improved functioning (P = .002) compared with placebo. The incidence of adverse effects did not differ between the treatment groups.
Conclusions Long-chain -3 PUFAs reduce the risk of progression to psychotic disorder and may offer a safe and efficacious strategy for indicated prevention in young people with subthreshold psychotic states.
Trial Registration clinicaltrials.gov Identifier:
Hypothesis Chondroitin sulfate proteoglycan–related abnormalities involve glial cells and extracellular matrix pericellular aggregates (perineuronal nets) in the amygdala and entorhinal cortex of subjects with schizophrenia.
Design Postmortem case-control study.
Setting The Translational Neuroscience Laboratory at McLean Hospital, Harvard Medical School. Specimens were obtained from the Harvard Brain Tissue Resource Center at McLean Hospital.
Participants Two separate cohorts of healthy control (n = 15; n = 10) and schizophrenic (n = 11; n = 10) subjects and a cohort of subjects with bipolar disorder (n = 11).
Interventions Quantitative, immunocytological, and histological postmortem investigations.
Main Outcome Measures Numerical densities of CSPG-positive glial cells and perineuronal nets, glial fibrillary acidic protein-positive astrocytes, and total numbers of parvalbumin-positive neurons in the deep amygdala nuclei and entorhinal cortex.
Results In schizophrenia, massive increases in CSPG-positive glial cells were detected in the deep amygdala nuclei (419%-1162%) and entorhinal cortex (layer II; 480%-1560%). Perineuronal nets were reduced in the lateral nucleus of the amygdala and lateral entorhinal cortex (layer II). Numerical densities of glial fibrillary acidic protein-positive glial cells and total numbers of parvalbumin-positive neurons were unaltered. Changes in CSPG-positive elements were negligible in subjects with bipolar disorder.
Conclusions Marked changes in functionally relevant molecules in schizophrenia point to a pivotal role for extracellular matrix–glial interactions in the pathogenesis of this disease. Disruption of these interactions, unsuspected thus far, may represent a unifying factor contributing to disturbances of neuronal migration, synaptic connectivity, and GABAergic, glutamatergic, and dopaminergic neurotransmission in schizophrenia. The lack of CSPG abnormalities in bipolar disorder points to a distinctive aspect of the pathophysiology of schizophrenia in key medial temporal lobe regions.
]]>Objective To adjudicate neurocognitive endophenotypes for bipolar disorder.
Design All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status.
Setting Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas.
Participants Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia.
Main Outcome Measure Neurocognitive test performance.
Results Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory.
Conclusion This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.
]]>Objective To examine if attention disengagement from faces is atypical in the early stages of ASD.
Design Attention disengagement was tested in a variation of the cued attention task in which participants were required to move their visual attention from face or nonface central fixation stimuli and make a reactive saccade to a peripheral target. The design involved diagnosis as a between-group factor and central fixation stimuli type as a within-group factor.
Setting Participants were taken from a cohort of patients at a university-based specialized clinic or from a pool of subjects participating in a prospective study of social cognition in ASD.
Participants Toddlers with ASD (mean age, 32 months [n = 42]) were compared with toddlers with nonautistic developmental delays (mean age, 29 months [n = 31]) and with typically developing toddlers (mean age, 29 months [n = 46]).
Main Outcome Measure Saccadic reaction time.
Results Developmentally delayed and typically developing toddlers had more difficulties disengaging visual attention from faces than toddlers with ASD. This effect was not present in response to nonfacial stimuli. These results suggest that toddlers with ASD are not captivated by faces to the same extent as toddlers without ASD and that this effect is not driven by a generalized impairment in disengagement of attention.
Conclusion The results suggest that face-processing difficulties in toddlers with ASD involve disruption of an attentional mechanism that typically supports deeper processing of these highly socially relevant stimuli.
]]>Objective To examine the effect of escitalopram on cognitive outcome. We hypothesized that patients who received escitalopram would show improved performance in neuropsychological tests assessing memory and executive functions than patients who received placebo or underwent Problem Solving Therapy.
Design Randomized trial.
Setting Stroke center.
Participants One hundred twenty-nine patients were treated within 3 months following stroke. The 12-month trial included 3 arms: a double-blind placebo-controlled comparison of escitalopram (n = 43) with placebo (n = 45), and a nonblinded arm of Problem Solving Therapy (n = 41).
Outcome Measures Change in scores from baseline to the end of treatment for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Trail-Making, Controlled Oral Word Association, Wechsler Adult Intelligence Scale–III Similarities, and Stroop tests.
Results We found a difference among the 3 treatment groups in change in RBANS total score (P < .01) and RBANS delayed memory score (P < .01). After adjusting for possible confounders, there was a significant effect of escitalopram treatment on the change in RBANS total score (P < .01, adjusted mean change in score: escitalopram group, 10.0; nonescitalopram group, 3.1) and the change in RBANS delayed memory score (P < .01, adjusted mean change in score: escitalopram group, 11.3; nonescitalopram group, 2.5). We did not observe treatment effects in other neuropsychological measures.
Conclusions When compared with patients who received placebo or underwent Problem Solving Therapy, stroke patients who received escitalopram showed improvement in global cognitive functioning, specifically in verbal and visual memory functions. This beneficial effect of escitalopram was independent of its effect on depression. The utility of antidepressants in the process of poststroke recovery should be further investigated.
Trial Registration clinicaltrials.gov Identifier:
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.
]]>Objectives To assess in vivo brain serotonin2A 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 serotonin2A-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 serotonin2A binding in the frontal cortex than did control subjects. A significant negative correlation was observed between frontal cortical serotonin2A binding and positive psychotic symptoms in the male patients. No correlations were found between cognitive functions and serotonin2A binding.
Conclusion The results suggest that frontal cortical serotonin2A receptors are involved in the pathophysiology of schizophrenia.
Trial Registration clinicaltrials.gov Identifier:
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.
]]>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.
]]>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.
]]>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.
]]>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.
]]>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.
]]>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.
]]>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:
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:
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.
]]>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 VT, 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 VT was significantly elevated in each brain region both during MDE and after SSRI treatment as compared with healthy controls. During recovery, MAO-A VT was significantly elevated in each brain region; however, those who went on to recurrence had significantly higher MAO-A VT 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.
]]>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.
]]>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.
]]>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:
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.
]]>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.
]]>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.
]]>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.
]]>Objective To examine the effect of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3' untranslated region) on brain function during executive processing in healthy volunteers and patients with schizophrenia. We hypothesized that this variation would have a different effect on prefrontal and striatal activation in schizophrenia, reflecting altered dopamine function.
Design Case-control study.
Setting Psychiatric research center.
Participants Eighty-five subjects, comprising 44 healthy volunteers (18 who were 9-repeat carriers and 26 who were 10-repeat homozygotes) and 41 patients with DSM-IV schizophrenia (18 who were 9-repeat carriers and 23 who were 10-repeat homozygotes).
Main Outcome Measures Regional brain activation during word generation relative to repetition in an overt verbal fluency task measured by functional magnetic resonance imaging. Main effects of genotype and diagnosis on activation and their interaction were estimated with analysis of variance in SPM5.
Results Irrespective of diagnosis, the 10-repeat allele was associated with greater activation than the 9-repeat allele in the left anterior insula and right caudate nucleus. Trends for the same effect in the right insula and for greater deactivation in the rostral anterior cingulate cortex were also detected. There were diagnosis x genotype interactions in the left middle frontal gyrus and left nucleus accumbens, where the 9-repeat allele was associated with greater activation than the 10-repeat allele in patients but not controls.
Conclusions Insular, cingulate, and striatal function during an executive task is normally modulated by variation in the dopamine transporter gene. Its effect on activation in the dorsolateral prefrontal cortex and ventral striatum is altered in patients with schizophrenia. This may reflect altered dopamine function in these regions in schizophrenia.
]]>Objective To determine the role of adjunctive psychotherapy in the treatment of chronically depressed patients with less than complete response to an initial medication trial.
Design This trial compared 12 weeks of (1) continued pharmacotherapy and augmentation with cognitive behavioral analysis system of psychotherapy (CBASP), (2) continued pharmacotherapy and augmentation with brief supportive psychotherapy (BSP), and (3) continued optimized pharmacotherapy (MEDS) alone. We hypothesized that adding CBASP would produce higher rates of response and remission than adding BSP or continuing MEDS alone.
Setting Eight academic sites.
Participants Chronically depressed patients with a current DSM-IV–defined major depressive episode and persistent depressive symptoms for more than 2 years.
Interventions Phase 1 consisted of open-label, algorithm-guided treatment for 12 weeks based on a history of antidepressant response. Patients not achieving remission received next-step pharmacotherapy options with or without adjunctive psychotherapy (phase 2). Individuals undergoing psychotherapy were randomized to receive either CBASP or BSP stratified by phase 1 response, ie, as nonresponders (NRs) or partial responders (PRs).
Main Outcome Measures Proportions of remitters, PRs, and NRs and change on Hamilton Scale for Depression (HAM-D) scores.
Results In all, 808 participants entered phase 1, of which 491 were classified as NRs or PRs and entered phase 2 (200 received CBASP and MEDS, 195 received BSP and MEDS, and 96 received MEDS only). Mean HAM-D scores dropped from 25.9 to 17.7 in NRs and from 15.2 to 9.9 in PRs. No statistically significant differences emerged among the 3 treatment groups in the proportions of phase 2 remission (15.0%), partial response (22.5%), and nonresponse (62.5%) or in changes on HAM-D scores.
Conclusions Although 37.5% of the participants experienced partial response or remitted in phase 2, neither form of adjunctive psychotherapy significantly improved outcomes over that of a flexible, individualized pharmacotherapy regimen alone. A longitudinal assessment of later-emerging benefits is ongoing.
Trial Registration clinicaltrials.gov Identifier:
Objective Using resting-state functional magnetic resonance imaging, we tested the hypothesis that OCD is associated with disturbances in the functional connectivity of primarily ventral corticostriatal regions, measured from coherent spontaneous fluctuations in the blood oxygenation level–dependent (BOLD) signal.
Design Case-control cross-sectional study.
Setting Hospital referral OCD unit and magnetic resonance imaging facility.
Participants A total of 21 patients with OCD (10 men, 11 women) and 21 healthy control subjects matched for age, sex, and estimated intelligence.
Main Outcome Measures Voxelwise statistical parametric maps testing the strength of functional connectivity of 4 striatal seed regions of interest (dorsal caudate nucleus, ventral caudate/nucleus accumbens, dorsal putamen, and ventral putamen) with remaining brain areas.
Results For both groups, there was a clear distinction in the pattern of cortical connectivity of dorsal and ventral striatal regions, consistent with the notion of segregated motor, associative, and limbic corticostriatal networks. Between groups, patients with OCD had significantly increased functional connectivity along a ventral corticostriatal axis, implicating the orbitofrontal cortex and surrounding areas. The specific strength of connectivity between the ventral caudate/nucleus accumbens and the anterior orbitofrontal cortex predicted patients' overall symptom severity (r2 = 0.57; P < .001). Additionally, patients with OCD showed evidence of reduced functional connectivity of the dorsal striatum and lateral prefrontal cortex, and of the ventral striatum with the region of the midbrain ventral tegmental area.
Conclusions This study directly supports the hypothesis that OCD is associated with functional alterations of brain corticostriatal networks. Specifically, our findings emphasize abnormal and heightened functional connectivity of ventrolimbic corticostriatal regions in patients with OCD.
]]>Objective To examine the effects of childhood adversity, adult traumatic events, 5-HTTLPR genotypes, and gene x environment interactions on the etiology of PTSD.
Design A cross-sectional study in which participants in several studies investigating the genetics of substance dependence were also screened for lifetime PTSD. The triallelic system of 5-HTTLPR was genotyped. Logistic regression modeling was used in the analyses.
Setting General community.
Participants Five hundred eighty-two European American and 670 African American individuals who reported experiences of childhood adversity, adult traumatic events, or both.
Main Outcome Measure Diagnosis of PTSD, defined by DSM-IV diagnostic criteria and assessed through the Semi-Structured Assessment for Drug Dependence and Alcoholism interview.
Results Childhood adversity and adult traumatic events both predicted PTSD. Although the 5-HTTLPR genotype alone did not predict the onset of PTSD, it interacted with adult traumatic events and childhood adversity to increase the risk for PTSD, especially for those with high rates of both types of trauma exposure (European American: odds ratio [OR], 2.86; 95% confidence interval [CI], 1.50-5.45; P = .002; African American: OR, 1.88; 95% CI, 1.04-3.40; P = .04; pooled: OR, 2.31; 95% CI, 1.50-3.56; P < .001).
Conclusions Participants who had both childhood adversity and adult traumatic events were more likely to develop lifetime PTSD compared with those who experienced either type of adverse event. The risk was increased in individuals with 1 or 2 copies of the S’ (S) allele compared with the L’ (L) homozygotes. Our study provides additional direct evidence that PTSD is influenced by the interactive effect of environmental and genetic factors.
]]>Objective To determine whether PTSD is associated with cardiovascular health status in patients with heart disease and whether this association is independent of cardiac function.
Design Cross-sectional study.
Setting The Heart and Soul Study, a prospective cohort study of psychological factors and health outcomes in adults with stable cardiovascular disease.
Participants One thousand twenty-two men and women with coronary heart disease.
Main Outcome Measures Posttraumatic stress disorder was assessed using the Computerized Diagnostic Interview Schedule for DSM-IV. Cardiac function was measured using left ventricular ejection fraction, treadmill exercise capacity, and inducible ischemia on stress echocardiography. Disease-specific health status was assessed using the symptom burden, physical limitation, and quality of life subscales of the Seattle Angina Questionnaire. We used ordinal logistic regression to evaluate the association of PTSD with health status, adjusted for objective measures of cardiac function.
Results Of the 1022 participants, 95 (9%) had current PTSD. Participants with current PTSD were more likely to report at least mild symptom burden (57% vs 36%), mild physical limitation (59% vs 44%), and mildly diminished quality of life (62% vs 35%) (all P ≤ .001). When adjusted for cardiovascular risk factors and objective measures of cardiac function, PTSD remained independently associated with greater symptom burden (odds ratio, 1.9; 95% confidence interval, 1.2-2.9; P = .004); greater physical limitation (odds ratio, 2.2; 95% confidence interval, 1.4-3.6; P = .001); and worse quality of life (odds ratio, 2.5; 95% confidence interval, 1.6-3.9; P < .001). Results were similar after excluding participants with depression.
Conclusions Among patients with heart disease, PTSD is more strongly associated with patient-reported cardiovascular health status than objective measures of cardiac function. Future studies should explore whether assessing and treating PTSD symptoms can improve function and quality of life in patients with heart disease.
]]>Objectives To identify structural brain alterations associated with THI and to investigate whether these deficits are associated with posttraumatic stress disorder and depression.
Design Cross-sectional neuroimaging study.
Setting Massachusetts General Hospital and McLean Hospital.
Participants A subsample of Vietnamese ex–political detainees (n = 42) and comparison subjects (n = 16) selected from a community study of 337 ex–political detainees and 82 comparison subjects.
Main Outcome Measures Scores on the Vietnamese versions of the Hopkins Symptom Checklist–25 (HSCL) and Harvard Trauma Questionnaire for depression and posttraumatic stress disorder, respectively; cerebral regional cortical thickness; and manual volumetric morphometry of the amygdala, hippocampus, and thalamus.
Results Ex–political detainees exposed to THI (n = 16) showed a higher rate of depression (odds ratio, 10.2; 95% confidence interval, 1.2-90.0) than those without THI exposure (n = 26). Ex–political detainees with THI had thinner prefrontotemporal cortices than those without THI exposure (P < .001 by the statistical difference brain map) in the left dorsolateral prefrontal and bilateral superior temporal cortices, controlling for age, handedness, and number of trauma/torture events (left superior frontal cortex [SFC], P = .006; left middle frontal cortex, P = .01; left superior temporal cortex [STC], P = .007; right STC, P = .01). Trauma/torture events were associated with bilateral amygdala volume loss (left, P = .045; right, P = .003). Cortical thinning associated with THI in the left SFC and bilateral STC was related to HSCL depression scores in THI-exposed (vs non–THI-exposed) ex–political detainees (left SFC, P for interaction = .007; left STC, P for interaction = .03; right STC, P for interaction = .02).
Conclusions Structural deficits in prefrontotemporal brain regions are linked to THI exposures. These brain lesions are associated with the symptom severity of depression in Vietnamese ex–political detainees.
]]>Objective To determine whether polymorphisms in SLC1A1 are associated with AAP-induced OC symptoms in patients with schizophrenia.
Design A pharmacogenetic case-control association study.
Setting Outpatient schizophrenia clinics.
Patients Clinically stable patients with schizophrenia who were receiving AAP treatment (n = 94; OC group). The OC group consisted of 40 patients with AAP-induced OC symptoms, and the non-OC group consisted of 54 patients who had received AAP for more than 24 months without developing OC symptoms.
Main Outcome Measures Allele, genotype, and haplotype frequencies. The association was tested with a logistic regression model using age, sex, and medication type as covariates.
Results Trends of association were observed in rs2228622 and rs3780412 (nominal P = .01; adjusted permutation P = .07) for the dominant model that was the inheritance model that best fit our data. In the haplotype -based analysis, the A/C/G haplotype at rs2228622-rs3780413-rs3780412 showed a significant association with AAP-induced OC symptoms; this association withstood multiple test correction (nominal P = .01; adjusted permutation P = .04; odds ratio, 3.955; 95% confidence interval, 1.366-11.452, for dominant model).
Conclusions These results suggest that sequence variations in SLC1A1 are associated with susceptibility to AAP-induced OC symptoms. This is the first published pharmacogenetic study on this phenomenon and provides preliminary evidence of the involvement of glutamatergic neurotransmission in the pathogenesis of AAP-induced OC symptoms.
]]>Objective To evaluate the involvement of the orbitofrontal cortex (OFC) in mediating the relationship between PEMCS and substance use.
Design Cross-sectional analyses from the Saguenay Youth Study aimed at evaluating the effects of PEMCS on brain development and behavior among adolescents. Nonexposed adolescents were matched with adolescents exposed prenatally to cigarette smoking by maternal educational level.
Participants and Setting A French Canadian founder population of the Saguenay–Lac-Saint-Jean region of Quebec, Canada.
The behavioral data set included 597 adolescents (275 sibships; 12-18 years of age), half of whom were exposed in utero to maternal cigarette smoking. Analysis of cortical thickness and genotyping were performed using available data from 314 adolescents.
Main Outcome Measures The likelihood of substance use was assessed with the Diagnostic Interview Schedule for Children Predictive Scales. The number of different drugs tried by each adolescent was assessed using another questionnaire. Thickness of the OFC was estimated from T1-weighted magnetic resonance images using FreeSurfer software.
Results Prenatal exposure to maternal cigarette smoking is associated with an increased likelihood of substance use. Among exposed adolescents, the likelihood of drug experimentation correlates with the degree of OFC thinning. In nonexposed adolescents, the thickness of the OFC increases as a function of the number of drugs tried. The latter effect is moderated by a brain-derived neurotrophic factor (BDNF) genotype (Val66Met).
Conclusions We speculate that PEMCS interferes with the development of the OFC and, in turn, increases the likelihood of drug use among adolescents. In contrast, we suggest that, among nonexposed adolescents, drug experimentation influences the OFC thickness via processes akin to experience-induced plasticity.
]]>Objective To assess the relative efficacies of 5 smoking cessation pharmacotherapy interventions using placebo-controlled, head-to-head comparisons.
Design A randomized, double-blind, placebo-controlled clinical trial.
Setting Two urban research sites.
Patients One thousand five hundred four adults who smoked at least 10 cigarettes per day during the past 6 months and reported being motivated to quit smoking. Participants were excluded if they reported using any form of tobacco other than cigarettes; current use of bupropion; having a current psychosis or schizophrenia diagnosis; or having medical contraindications for any of the study medications.
Interventions Participants were randomized to 1 of 6 treatment conditions: nicotine lozenge, nicotine patch, sustained-release bupropion, nicotine patch plus nicotine lozenge, bupropion plus nicotine lozenge, or placebo. In addition, all participants received 6 individual counseling sessions.
Main Outcome Measures Biochemically confirmed 7-day point-prevalence abstinence assessed at 1 week after the quit date (postquit), end of treatment (8 weeks postquit), and 6 months postquit. Other outcomes were initial cessation, number of days to lapse, number of days to relapse, and latency to relapse after the first lapse.
Results All pharmacotherapies differed from placebo when examined without protection for multiple comparisons (odds ratios, 1.63-2.34). With such protection, only the nicotine patch plus nicotine lozenge (odds ratio, 2.34, P < .001) produced significantly higher abstinence rates at 6-month postquit than did placebo.
Conclusion While the nicotine lozenge, bupropion, and bupropion plus lozenge produced effects that were comparable with those reported in previous research, the nicotine patch plus lozenge produced the greatest benefit relative to placebo for smoking cessation.
]]>Objective To identify heritable traits in middle age that contribute to AD.
Design We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. In such a design, the offspring under study are enriched for risk factors of AD but do not yet have the disease.
Setting The Netherlands.
Participants Two hundred six offspring of 92 families with a parental history of late-onset AD and 200 offspring of 97 families without a parental history of AD.
Main Outcome Measures The APOE 4 genotype, vascular factors, production capacity of pro- and anti-inflammatory cytokines upon stimulation with lipopolysaccharide, and circulating markers of inflammation. All outcome measures were assessed in the offspring only and not in the parental generation.
Results More offspring with a parental history of AD carried APOE 4 than those without a parental history of the disease (47% vs 21%, P < .001). Those with a parental history of AD also had higher systolic blood pressures (P = .006), higher diastolic blood pressures (P < .001), and lower ankle brachial indices (P = .005) when compared with offspring without a family history of dementia. Production capacity of pro-inflammatory cytokines in offspring with a parental history of AD was also different, with higher levels of IL-1β (interleukin 1β) (P < .001), IL-1β to IL-1ra ratio (P < .001), tumor necrosis factor (P = .008), IL-6 (P = .04), and interferon (P = .01). All of these positive associations were independent of APOE 4 genotype.
Conclusions Hypertension and the expression of an innate pro-inflammatory cytokine profile in middle age are early risk factors of AD in old age. For the offspring of affected families, it provides clues for screening and preventive strategies, of which blood pressure control can be implemented directly.
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