Objective  To determine whether sociodemographic, clinical, or first-step treatment features predict remission with or intolerance overall or differentially to any 1 of 3 second-step medications after an unsatisfactory outcome with citalopram hydrobromide.

Design  An equipoise stratified randomized study. Participants were recruited from July 17, 2001, through April 20, 2004.

Setting  Public or private sector primary care (n = 18) and psychiatric care (n = 23) settings across the United States.

Participants  Representative outpatients aged 18 to 75 years with nonpsychotic major depressive disorder (N = 727).

Interventions  Sustained-release bupropion hydrochloride was started at 150 mg/d and incrementally increased to 400 mg/d. Sertraline hydrochloride was started at 50 mg/d and incrementally increased to 200 mg/d. Extended-release venlafaxine hydrochloride was started at 37.5 mg/d and incrementally increased to 375 mg/d.

Main Outcome Measures  The 16-item Quick Inventory of Depressive Symptomatology, Self-Rated and the Frequency, Intensity, and Burden of Side Effects Rating.

Results  Remission was more likely among participants who were white, employed, cohabiting or married, or privately insured or who had prior intolerance to citalopram or at least a response to citalopram, and no prior suicide attempts. Remission was less likely among participants with concurrent generalized anxiety, obsessive-compulsive, panic, or posttraumatic stress disorders; social phobia; anxious or melancholic features; or more severe depression. Intolerance was less likely for Hispanic participants, but more likely for participants with previous suicide attempts or intolerance to citalopram.

Participants with concurrent substance use were less likely to remit (odds ratio, 0.37) and more likely not to tolerate extended-release venlafaxine. Intolerance to citalopram was associated with intolerance to sertraline (P = .04).

Conclusions  Clinical, demographic, and treatment history were of little value in recommending 1 medication vs another as a second-step treatment for major depressive disorder. Participants most likely to remit in the second step had less Axis I psychiatric disorder comorbidity, less social disadvantage, and at least a response to citalopram in the first step.

Trial Registration  clinicaltrials.gov Identifier: NCT00021528

Objective  To determine whether this genetic variant is associated with altered brain processing of and behavioral avoidance responses to angry facial expressions.

Design and Participants  A total of 28 white participants (mean age, 29.2 years; 13 women) were screened using the Structured Clinical Interview for DSM-IV to exclude any lifetime Axis I psychiatric disorder and were genotyped for rs4675690, a single-nucleotide polymorphism near CREB1.

Main Outcome Measures  Blood oxygenation level–dependent signal by functional magnetic resonance imaging in the amygdala, insula, anterior cingulate, and orbitofrontal cortex during passive viewing of photographs of faces with emotional expressions. To measure approach and avoidance responses to anger, an off-line key-press task that traded effort for viewing time assessed valuation of angry faces compared with other expressions.

Results  The CREB1-linked single-nucleotide polymorphism was associated with significant differential activation in an extended neural network responding to angry and other facial expressions. The CREB1-associated insular activation was coincident with activation associated with behavioral avoidance of angry faces.

Conclusions  A polymorphism near CREB1 is associated with responsiveness to angry faces in a brain network implicated in processing aversion. Coincident activation in the left insula is further associated with behavioral avoidance of these stimuli.

Objective  To test causal effects of exercise on anxious and depressive symptoms in a population-based sample.

Design  Population-based longitudinal study (1991-2002) in a genetically informative sample of twin families.

Setting  Causal effects of exercise were tested by bivariate genetic modeling of the association between exercise and symptoms of anxiety and depression, correlation of intrapair differences in these traits among genetically identical twins, and longitudinal modeling of changes in exercise behavior and anxious and depressive symptoms.

Participants  A total of 5952 twins from the Netherlands Twin Register, 1357 additional siblings, and 1249 parents. All participants were aged 18 to 50 years.

Main Outcome Measurements  Survey data about leisure-time exercise (metabolic equivalent task hours per week based on type, frequency, and duration of exercise) and 4 scales of anxious and depressive symptoms (depression, anxiety, somatic anxiety, and neuroticism, plus a composite score).

Results  Cross-sectional and longitudinal associations were small and were best explained by common genetic factors with opposite effects on exercise behavior and symptoms of anxiety and depression. In genetically identical twin pairs, the twin who exercised more did not display fewer anxious and depressive symptoms than the co-twin who exercised less. Longitudinal analyses showed that increases in exercise participation did not predict decreases in anxious and depressive symptoms.

Conclusion  Regular exercise is associated with reduced anxious and depressive symptoms in the population at large, but the association is not because of causal effects of exercise.

Objective  To examine the independent and combined effects of depression and APOE 4 on the risk of dementia and its subtypes.

Design  The Honolulu-Asia Aging Study, a population-based prospective cohort study of Japanese American men.

Settings and Participants  Depressive symptoms and presence of the APOE 4 allele were assessed between March 1991 and October 1993 in 1932 cognitively healthy men aged 71 to 90 years. Incident cases of dementia were diagnosed during approximately 6 years of follow-up based on neurologic assessment at 2 repeated examinations (April 1994-April 1996 and October 1997-February 1999).

Main Outcome Measures  Overall dementia, Alzheimer disease, and vascular dementia.

Results  The interaction of depression and APOE 4 was statistically significant in the analytical models. Compared with men with neither APOE 4 nor depression, the risk of dementia in nondepressed men with APOE 4 was not significant (hazard ratio, 1.1; 95% confidence interval [CI], 0.6-1.8); however, depressed men without APOE 4 had a 1.6-fold greater risk (95% CI, 0.8-3.0), whereas depressed men with APOE 4 had a 7.1-fold greater risk (95% CI, 3.0-16.7) of dementia. For subtypes, we found similar increased risks of Alzheimer disease.

Conclusions  The APOE 4 status modifies the association between depressive symptoms and dementia in elderly men. Because individuals with depressive symptoms and the APOE 4 allele had a markedly increased risk of dementia, one might be especially watchful for early signs of dementia in the older person with depression who is also positive for the APOE 4 allele. Because this cohort includes only men, further investigation in women is required.

Objective  To evaluate the long-term efficacy and safety of capsulotomy in OCD.

Design  Noncontrolled, long-term follow-up trial (mean of 10.9 years after surgery).

Setting  University hospital referral center.

Patients  Twenty-five consecutive patients with OCD who underwent capsulotomy from 1988 to 2000.

Intervention  Unilateral or bilateral capsulotomy. Lesions were created by means of radiofrequency heating (thermocapsulotomy) or gamma radiation (radiosurgery, gammacapsulotomy).

Main Outcome Measure  Yale-Brown Obsessive-Compulsive Rating Scale (Y-BOCS) score.

Results  The mean Y-BOCS score was 34 preoperatively and 18 at long-term follow-up (P < .001). Response (defined as ≥35% reduction at long-term follow-up compared with baseline) was seen in 12 patients at long-term follow-up. Nine patients were in remission (Y-BOCS score, <16) at long-term follow-up. Only 3 patients were in remission without adverse effects at long-term follow-up. Response rates did not differ significantly between surgical methods. A mean weight gain of 6 kg was reported in the first postoperative year. Ten patients were considered to have significant problems with executive functioning, apathy, or disinhibition. Six of these 10 patients had received high doses of radiation or had undergone multiple surgical procedures. Results of our magnetic resonance imaging analysis in 11 patients suggest that the OCD symptom reduction may be increased by reducing the lateral extension of the lesions, and a reduction in the medial and posterior extension may limit the risk of adverse effects (ie, smaller lesions may produce better results).

Conclusions  Capsulotomy is effective in reducing OCD symptoms. There is a substantial risk of adverse effects, and the risk may vary between surgical methods. Our findings suggest that smaller lesions are safer and that high radiation doses and multiple procedures should be avoided.

Objective  To examine specific sleep stages, including rapid eye movement (REM) sleep and stages 1 through 4 of non-REM sleep, in relation to overweight in children and adolescents.

Design, Setting, and Participants  A total of 335 children and adolescents (55.2% male; aged 7-17 years) underwent 3 consecutive nights of standard polysomnography and weight and height assessments as part of a study on the development of internalizing disorders (depression and anxiety).

Main Outcome Measures  Body mass index (calculated as weight in kilograms divided by height in meters squared) z score and weight status (normal, at risk for overweight, overweight) according to the body mass index percentile for age and sex.

Results  The body mass index z score was significantly related to total sleep time (β = –0.174), sleep efficiency (β = –0.027), and REM density (β = –0.256). Compared with normal-weight children, overweight children slept about 22 minutes less and had lower sleep efficiency, shorter REM sleep, lower REM activity and density, and longer latency to the first REM period. After adjustment for demographics, pubertal status, and psychiatric diagnosis, 1 hour less of total sleep was associated with approximately 2-fold increased odds of overweight (odds ratio = 1.85), 1 hour less of REM sleep was associated with about 3-fold increased odds (odds ratio = 2.91), and REM density and activity below the median increased the odds of overweight by 2-fold (odds ratio = 2.18) and 3-fold (odds ratio = 3.32), respectively.

Conclusions  Our results confirm previous epidemiological observations that short sleep time is associated with overweight in children and adolescents. A core aspect of the association between short sleep duration and overweight may be attributed to reduced REM sleep. Further studies are needed to investigate possible mechanisms underpinning the association between diminished REM sleep and endocrine and metabolic changes that may contribute to obesity.

Objective  To determine whether CRH variation influences relevant intermediate phenotypes, behavior, and alcohol consumption in rhesus macaques.

Design  We sequenced the rhesus macaque CRH locus (rhCRH) and performed cladistic clustering of haplotypes. In silico analysis, gel shift, and in vitro reporter assays were performed to identify functional variants. Cerebrospinal fluid (CSF) and blood samples were obtained, and levels of CRH and corticotropin (ACTH) were measured by radioimmunoassay. Behavioral data were collected from macaques during infancy. Among adolescent/adult animals, we recorded responses to an unfamiliar conspecific and measured levels of ethanol consumption.

Setting  National Institutes of Health Animal Center.

Participants  Rhesus macaques.

Main Outcome Measures  Animals were genotyped for a single-nucleotide polymorphism disrupting a glucocorticoid response element, rhCRH –2232 C>G, and the effects of this allele on CSF levels of CRH, plasma levels of ACTH, behavior, and ethanol consumption were assessed by analysis of variance.

Results  We show that –2232C>G alters DNAxprotein interactions and confers decreased sensitivity of the CRH promoter to glucocorticoids in vitro. Consistent with the known effects of glucocorticoids on CRH expression in the brain, carriers of the G allele had lower CSF levels of CRH but higher levels of ACTH. Infants carrying the G allele were more exploratory and bold, and among adolescent and adult male macaques, the G allele was associated with exploratory/bold responding to an unfamiliar male. Adults with the C/G genotype also exhibited increased alcohol consumption in the social group, a model for high-risk alcohol-seeking behavior.

Conclusion  Haplotypes that differ in terms of corticosteroid sensitivity have been identified in humans. Our data may suggest that functionally similar CRH variants could influence risk for externalizing disorders in human subjects.

Objective  To quantify preferential attention to the eyes of others at what is presently the earliest point of diagnosis in autism.

Design  We presented the children with 10 videos. Each video showed an actress looking directly into the camera, playing the role of caregiver, and engaging the viewer (playing pat-a-cake, peek-a-boo, etc). Children's visual fixation patterns were measured by eye tracking.

Participants  Fifteen 2-year-old children with autism were compared with 36 typically developing children and with 15 developmentally delayed but nonautistic children.

Main Outcome Measure  Preferential attention was measured as percentage of visual fixation time to 4 regions of interest: eyes, mouth, body, and object. Level of social disability was assessed by the Autism Diagnostic Observation Schedule.

Results  Looking at the eyes of others was significantly decreased in 2-year-old children with autism (P < .001), while looking at mouths was increased (P < .01) in comparison with both control groups. The 2 control groups were not distinguishable on the basis of fixation patterns. In addition, fixation on eyes by the children with autism correlated with their level of social disability; less fixation on eyes predicted greater social disability (r = – 0.669, P < .01).

Conclusions  Looking at the eyes of others is important in early social development and in social adaptation throughout one's life span. Our results indicate that in 2-year-old children with autism, this behavior is already derailed, suggesting critical consequences for development but also offering a potential biomarker for quantifying syndrome manifestation at this early age.

Objective  To compare the efficacy of adjunctive transdermal estradiol with that of adjunctive placebo in the treatment of acute psychotic symptoms.

Design  Randomized, double-blind study.

Setting  Patients were recruited from inpatient acute hospital wards and outpatient clinics of 2 metropolitan Melbourne general hospitals.

Participants  One hundred two women of childbearing age with schizophrenia. All participants were in an acute or chronic phase of their illness; 73 participants were outpatients and the rest were inpatients.

Intervention  Patients were randomized to receive 100 µg of transdermal estradiol (n = 56) or transdermal placebo (n = 46) for 28 days.

Main Outcome Measures  Psychopathological symptoms were assessed weekly with the Positive and Negative Syndrome Scale.

Results  The addition of 100 µg of transdermal estradiol significantly reduced positive (P < .05) and general psychopathological (P < .05) symptoms during the 28-day trial period compared with women receiving antipsychotic medication alone.

Conclusion  Estradiol appears to be a useful treatment for women with schizophrenia and may provide a new adjunctive therapeutic option for severe mental illness.

Trial Registration  clinicaltrials.gov Identifier: NCT00206570

Objective  To examine recent national trends in the provision of psychotherapy by office-based psychiatrists.

Design  Data from the 1996 through 2005 cross-sectional National Ambulatory Medical Care Survey were analyzed to examine trends in psychotherapy provision within nationally representative samples of visits to office-based psychiatrists. Multivariate analyses examined the time trend, adjusting for patient, visit, and setting characteristics. Practice-level analyses examined time trends in the percentage of psychiatrists who provided psychotherapy to all, some, or none of their patients during a typical week.

Setting  Office-based psychiatry practices in the United States.

Participants  Patients with psychiatric diagnoses visiting outpatient psychiatrists.

Main Outcome Measure  Provision of psychotherapy in visits longer than 30 minutes.

Results  Psychotherapy was provided in 5597 of 14 108 visits (34.0% [weighted]) sampled during a 10-year period. The percentage of visits involving psychotherapy declined from 44.4% in 1996-1997 to 28.9% in 2004-2005 (P < .001). This decline coincided with changes in reimbursement, increases in managed care, and growth in the prescription of medications. At the practice level, the decrease in providing psychotherapy corresponded with a decline in the number of psychiatrists who provided psychotherapy to all of their patients from 19.1% in 1996-1997 to 10.8% in 2004-2005 (P = .001). Psychiatrists who provided psychotherapy to all of their patients relied more extensively on self-pay patients, had fewer managed-care visits, and prescribed medications in fewer of their visits compared with psychiatrists who provided psychotherapy less often.

Conclusions  There has been a recent significant decline in the provision of psychotherapy by psychiatrists in the United States. This trend is attributable to a decrease in the number of psychiatrists specializing in psychotherapy and a corresponding increase in those specializing in pharmacotherapy—changes that were likely motivated by financial incentives and growth in psychopharmacological treatments in recent years.

Objective  To determine whether there are initial and progressive gray matter volume deficits in cingulate gyrus subregions in patients with first-episode schizophrenia (FESZ) and patients with first-episode affective psychosis (FEAFF, mainly manic) and their specificity to FESZ or FEAFF.

Design  A naturalistic cross-sectional study at first hospitalization for psychosis and a longitudinal follow-up approximately 11/2 years later.

Setting and Participants  Patients were from a private psychiatric hospital. Thirty-nine patients with FESZ and 41 with FEAFF at first hospitalization for psychosis and 40 healthy control subjects (HCs) recruited from the community underwent high-spatial-resolution MRI, with follow-up scans in 17 FESZ patients, 18 FEAFF patients, and 18 HCs. Individual subjects were matched for age, sex, parental socioeconomic status, and handedness.

Main Outcome Measures  Cingulate gyrus gray matter volumes in 3 anterior subregions (subgenual, affective, and cognitive) and 1 posterior subregion, and whether there was a paracingulate sulcus.

Results  At first hospitalization, patients with FESZ showed significantly smaller left subgenual (P = .03), left (P = .03) and right (P = .005) affective, right cognitive (P = .04), and right posterior (P = .003) cingulate gyrus gray matter subregions compared with HCs. Moreover, at the 11/2-year follow-up, patients with FESZ showed progressive gray matter volume decreases in the subgenual (P = .002), affective (P < .001), cognitive (P < .001), and posterior (P = .02) cingulate subregions compared with HCs. In contrast, patients with FEAFF showed only initial (left, P < .001; right, P = .002) and progressive subgenual subregion abnormalities (P < .001). Finally, patients with FESZ showed a less asymmetric paracingulate pattern than HCs (P = .02).

Conclusions  Patients with FEAFF and FESZ showed differences in initial gray matter volumes and in their progression. Initial and progressive changes in patients with FEAFF were confined to the subgenual cingulate, a region strongly associated with affective disorder, whereas patients with FESZ evinced widespread initial and progressively smaller volumes.

Objective  To determine the long-term effects of an intensive early-intervention program (OPUS) for first-episode psychotic patients.

Design  Single-blinded, randomized, controlled clinical trial of 2 years of an intensive early-intervention program vs standard treatment. Follow-up periods were 2 and 5 years.

Setting  Copenhagen Hospital Corporation and Psychiatric Hospital, Aarhus, Denmark.

Patients  A total of 547 patients with a first episode of psychosis. Of these, 369 patients were participating in a 2-year follow-up, and 301 were participating in a 5-year follow-up. A total of 547 patients were followed for 5 years.

Interventions  Two years of an intensive early-intervention program vs standard treatment. The intensive early-intervention treatment consisted of assertive community treatment, family involvement, and social skills training. Standard treatment offered contact with a community mental health center.

Main Outcome Measures  Psychotic and negative symptoms were recorded. Secondary outcome measures were use of services and social functioning.

Results  Analysis was based on the principles of intention-to-treat. Assessment was blinded for previous treatment allocation. At the 5-year follow-up, the effect of treatment seen after 2 years (psychotic dimension odds ratio [OR], –0.32; 95% confidence interval [CI], – 0.58 to – 0.06; P = .02; negative dimension OR, – 0.45; 95% CI, – 0.67 to – 0.22; P = .001) had equalized between the treatment groups. A significantly smaller percentage of patients from the experimental group were living in supported housing (4% vs 10%, respectively; OR, 2.3; 95% CI, 1.1-4.8; P = .02) and were hospitalized fewer days (mean, 149 vs 193 days; mean difference, 44 days; 95% CI, 0.15-88.12; P = .05) during the 5-year period.

Conclusions  The intensive early-intervention program improved clinical outcome after 2 years, but the effects were not sustainable up to 5 years later. Secondary outcome measures showed differences in the proportion of patients living in supported housing and days in hospital at the 5-year follow-up in favor of the intensive early-intervention program.

Objective  To determine the potential relationship between CB1R signaling and altered GABA neurotransmission in schizophrenia by evaluating CB1R messenger RNA (mRNA) and protein expression in the dorsolateral prefrontal cortex.

Design  In situ hybridization and immunocytochemistry techniques were used to examine the cortical levels of CB1R mRNA and protein, respectively.

Setting  Brain specimens were obtained from autopsies conducted at the Allegheny County Medical Examiner's Office, Pittsburgh, Pennsylvania.

Participants  Postmortem brain specimens from 23 pairs of subjects with schizophrenia and age-, sex-, and postmortem interval–matched comparison subjects, as well as brain specimens from 18 macaque monkeys with long-term exposure to haloperidol, olanzapine, or placebo.

Main Outcome Measures  Optical density measures of CB1R mRNA expression and protein levels and correlations with previously reported glutamic acid decarboxylase 67 and cholecystokinin mRNA measures.

Results  Levels of CB1R mRNA were significantly lower by 14.8% in the subjects with schizophrenia. Similarly, CB1R protein levels, assessed by radioimmunocytochemistry and standard immunocytochemistry, were significantly decreased by 11.6% and 13.9%, respectively. Group differences in CB1R mRNA levels were significantly correlated with those in glutamic acid decarboxylase 67 and cholecystokinin mRNA levels. Expression of CB1R mRNA was not changed in antipsychotic-exposed monkeys, and neither CB1R mRNA levels nor protein levels were affected by potential confounding factors in the subjects with schizophrenia.

Conclusions  This combination of findings suggests the testable hypothesis that reduced CB1R mRNA and protein levels in schizophrenia represent a compensatory mechanism to increase GABA transmission from perisomatic-targeting cholecystokinin interneurons with impaired GABA synthesis.

Objective  To test for an association between candidate genes in the Wnt signaling pathways and disease susceptibility in a family-based bipolar disorder study.

Design  Two hundred twenty-seven tagging single- nucleotide polymorphisms (SNPs) from 34 genes were successfully genotyped. Initial results led us to focus on the gene PPARD, in which we genotyped an additional 13 SNPs for follow-up.

Setting  Nine academic medical centers in the United States.

Participants  Five hundred fifty-four offspring with bipolar disorder and their parents from 317 families.

Main Outcome Measures  Family-based association using FBAT and HBAT (http://www.biostat.harvard.edu/~fbat/default.html; Harvard School of Public Health, Boston, Massachusetts). Exploratory analyses testing for interactions of PPARD SNPs with clinical covariates and with other Wnt genes were conducted with GENASSOC (Stata Corp, College Station, Texas).

Results  In the initial analysis, the most significantly associated SNP was rs2267665 in PPARD (nominal P < .001). This remained significant at P = .05 by permutation after accounting for all SNPs tested. Additional genotyping in PPARD yielded 4 SNPs in 1 haplotype block that were significantly associated with bipolar disorder (P < .01), the most significant being rs9462082 (P < .001). Exploratory analyses revealed significant evidence (P < .01) for interactions of rs9462082 with poor functioning on the Global Assessment Scale (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.85-6.08) and with SNPs in WNT2B (rs3790606: OR, 2.56; 95% CI, 1.67-4.00) and WNT7A (rs4685048: OR, 1.79; 95% CI, 1.23-2.63).

Conclusions  We found evidence for association of bipolar disorder with PPARD, a gene in the Wnt signaling pathway. The consistency of this result with one from the Wellcome Trust Case-Control Consortium encourages further study. If the finding can be confirmed in additional samples, it may illuminate a new avenue for understanding the pathogenesis of severe bipolar disorder and developing more effective treatments.

Objectives  To test the association of selective serotonin reuptake inhibitors and venlafaxine hydrochloride therapy with upper gastrointestinal tract bleeding, to identify subgroups of patients at particularly increased risk, and to explore whether acid-suppressing agents may be effective in minimizing risk.

Design  Nested case-control study.

Setting  General practice database from the United Kingdom.

Participants  One thousand three hundred twenty-one patients with upper gastrointestinal tract bleeding referred to a consultant or hospital and 10 000 control subjects matched for age, sex, and calendar year of the index date.

Main Outcome Measure  Risk of bleeding associated with selective serotonin reuptake inhibitors and effect of acid-suppressing agents.

Results  The percentage of current users of selective serotonin reuptake inhibitors (5.3%) or venlafaxine (1.1%) among case subjects was significantly higher than in matched control subjects (3.0% and 0.3%; adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2-2.1, and OR, 2.9; 95% CI, 1.5-5.6, respectively). An interaction with nonsteroidal anti-inflammatory drugs (OR, 4.8; 95% CI, 2.8-8.3) was observed, in particular among those not using acid-suppressing agents (OR, 9.1; 95% CI, 4.8-17.3) compared with users of these drugs (OR, 1.3; 95% CI, 0.5-3.3). In addition, an interaction with antiplatelet drugs in nonusers of acid-suppressing agents was suggested (OR, 4.7; 95% CI, 2.6-8.3) compared with users of these drugs (OR, 0.8; 95% CI, 0.3-2.5).

Conclusions  Antidepressants with a relevant blockade action on the serotonin reuptake mechanism increase the risk of upper gastrointestinal tract bleeding. The increased risk may be of particular relevance when these drugs are associated with nonsteroidal anti-inflammatory drugs. Our study findings also provide evidence that use of acid-suppressing agents limits such increased risk.

Objective  To examine sociodemographic correlates, rates of DSM-IV Axis I psychiatric disorders, substance use, and treatment seeking among past-year pregnant and postpartum women in the United States.

Design  National survey.

Setting  Face-to-face interviews conducted in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions.

Participants  A total of 43 093 respondents were interviewed, of whom 14 549 were women 18 to 50 years old with known past-year pregnancy status.

Main Outcome Measures  Prevalence of 12-month DSM-IV Axis I psychiatric disorders, substance use, and treatment seeking.

Results  Past-year pregnant and postpartum women had significantly lower rates of alcohol use disorders and any substance use, except illicit drug use, than nonpregnant women. In addition, currently pregnant women had a lower risk of having any mood disorder than nonpregnant women. The only exception was the significantly higher prevalence of major depressive disorder in postpartum than in nonpregnant women. Age, marital status, health status, stressful life events, and history of traumatic experiences were all significantly associated with higher risk of psychiatric disorders in pregnant and postpartum women. Lifetime and past-year treatment-seeking rates for any psychiatric disorder were significantly lower among past-year pregnant than nonpregnant women with psychiatric disorders. Most women with a current psychiatric disorder did not receive any mental health care in the 12 months prior to the survey regardless of pregnancy status.

Conclusions  Pregnancy per se is not associated with increased risk of the most prevalent mental disorders, although the risk of major depressive disorder may be increased during the postpartum period. Groups of pregnant women with particularly high prevalence of psychiatric disorders were identified. Low rates of maternal mental health care underscore the need to improve recognition and delivery of treatment for mental disorders occurring during pregnancy and the postpartum period.

Objective  To test the hypothesis that the CNR1 gene is associated with nicotine dependence.

Design  Genotype-phenotype association study. Ten single-nucleotide polymorphisms were genotyped in the CNR1 gene in 2 independent samples. For the first sample (n = 688), a 3-group case-control design was used to test allele association with smoking initiation and nicotine dependence. For the second sample (n = 961), association was assessed with scores from the Fagerström Test for Nicotine Dependence (FTND).

Settings  Population samples selected from the Mid-Atlantic Twin Registry.

Participants  White patients aged 18 to 65 years who met the criteria of inclusion.

Main Outcome Measures  Fagerström Tolerance Questionnaire and FTND scores.

Results  Significant single-marker and haplotype associations were found in both samples, and the associations were female specific. Haplotype 1-1-2 of markers rs2023239-rs12720071-rs806368 was associated with nicotine dependence and FTND score in the 2 samples (P < .001 and P  = .009, respectively).

Conclusion  Variants and haplotypes in the CNR1 gene may alter the risk for nicotine dependence, and the associations are likely sex specific.

Objective  To investigate whether genetic variations in glutamatergic neurotransmission genes, which are known to alter alcohol effects in rodents, contribute to the genetic basis of alcoholism in humans.

Design  Association analysis of alcohol dependence and haplotype-tagging single nucleotide polymorphisms (SNPs) covering 10 glutamatergic genes. Resequencing of functional domains of these genes identified 204 SNPs. Haplotypes with a frequency of 5% or greater could be discriminated by 21 haplotype-tagging SNPs analyzed for association in 2 independent samples of alcohol-dependent adult patients and controls as well as adolescent trios.

Setting  Four university medical centers in the south of Germany.

Participants  One thousand three hundred thirty-seven patients and 1555 controls (study 1: 544 patients, 553 controls; study 2: 793 patients, 1002 controls). One hundred forty-four trios of 15-year-old adolescents assessed for risky drinking behavior.

Main Outcome Measures  Genotype profiles for GLAST; N-methyl-d-aspartate–receptor subunits NR1, NR2A, and NR2B; MGLUR5; NNOS; PRKG2; CAMK4; the regulatory subunit of PI3K; and CREB were analyzed for association with alcohol dependence using multivariate statistical analysis. Risky adolescent drinking was tested using the transmission disequilibrium test.

Results  Analysis of study 1 revealed that NR2A and MGLUR5 have the greatest relevance for human alcohol dependence among the genes selected with odds ratios of 2.35 and 1.69, respectively. Replication analysis in study 2 confirmed an association of alcohol dependence with NR2A (odds ratio, 2.01) but showed no association with MGLUR5. Combined analysis of study 1 and study 2 exhibited a more significant association on the Cochran-Mantel-Haenszel test (P < .001) for NR2A; NR2A was associated with positive family history, early onset of alcoholism, and maximum number of drinks in adults as well as risky drinking patterns in adolescents.

Conclusion  Genetic variations in NR2A have the greatest relevance for human alcohol dependence among the glutamatergic genes selected for their known alteration of alcohol effects in animal models.

Objective  To achieve a better understanding of the role of the CNR1 gene in the etiology and treatment of alcohol dependence.

Design  The present investigation spans multiple levels of analysis, including receptor binding in postmortem brain tissue, neuroimaging, human laboratory models, and analyses of treatment outcome data.

Results  Findings indicate that the C allele of rs2023239 is associated with greater CB1 binding in the prefrontal cortex, greater alcohol cue–elicited brain activation in the midbrain and prefrontal cortex, greater subjective reward when consuming alcohol, and more positive outcomes after treatment with a medication that targets the mesocorticolimbic neurocircuitry. In addition, there were strong correlations between cue-elicited brain activation and alcohol consumption measures in individuals with the C allele.

Conclusion  Individuals with the C allele may be more susceptible to changes in the mesocorticolimbic neurocircuitry that is involved in the attribution of incentive salience after repeated exposure to alcohol.

Objective  To present results of the first quasi-experimental study, to our knowledge, to evaluate the effects of expanded foster care treatment on the mental and physical health of adult foster care alumni.

Design  We used a quasi-experimental design to compare adult outcomes of alumni of a model private foster care program and 2 public programs. The latter alumni were eligible for but not selected by the private program because of limited openings. Propensity score weights based on intake records were adjusted for preplacement between-sample differences. Personal interviews administered 1 to 13 years after leaving foster care assessed the mental and physical health of alumni.

Setting/Participants  A representative sample of 479 adult foster care alumni who were placed in foster care as adolescents (14-18 years of age) between January 1, 1989, and September 30, 1998, in private (n = 111) or public (n = 368) foster care programs in Oregon and Washington. More than 80% of alumni were traced, and 92.2% of those traced were interviewed.

Intervention  Caseworkers in the model program had higher levels of education and salaries, lower caseloads, and access to a wider range of ancillary services (eg, mental health counseling, tutoring, and summer camps) than caseworkers in the public programs. Youth in the model program were in foster care more than 2 years longer than those in the public programs.

Results  Private program alumni had significantly fewer mental disorders (major depression, anxiety disorders, and substance use disorders), ulcers, and cardiometabolic disorders, but more respiratory disorders, than did public program alumni.

Conclusion  Public sector investment in higher-quality foster care services could substantially improve the long-term mental and physical health of foster care alumni.

Objective  To report the effects of reducing DUP on 2-year course and outcome.

Design  A total of 281 patients with a DSM-IV diagnosis of nonorganic, nonaffective psychosis coming to their first treatment during 4 consecutive years were recruited, of which 231 participated in the 2-year follow-up. A comprehensive early detection (ED) system, based on public information campaigns and low-threshold-psychosis–detecting teams, was introduced in 1 health care area (ED area), but not in a comparable area (no-ED area). Both areas ran equivalent 2-year treatment programs.

Results  First-episode patients from the ED area had a significantly lower DUP, better clinical status, and milder negative symptoms at the start of treatment. There were no differences in treatment received for the first 2 years between the groups. The difference in negative symptoms was maintained at the 1-year follow-up. There was a statistically significant difference in the Positive and Negative Syndrome Scale negative component, cognitive component, and depressive component in favor of the ED group at the 2-year follow-up. Multiple linear regression analyses gave no indication that these differences were due to confounders.

Conclusion  Reducing the DUP has effects on the course of symptoms and functioning, including negative symptoms, suggesting secondary prevention of the negative psychopathologies in first-episode schizophrenia.

Objectives  To evaluate and compare long-term prognoses of adolescent personality disorders and co-occurring Axis I disorders.

Design  Population-based longitudinal study.

Setting  Upstate New York.

Participants  A community sample of 629 adolescents interviewed at a mean age of 13.8 years and again at a mean age of 33.2 years.

Main Outcome Measures  Clinically assessed psychiatric disorders and self-reported attainment and function.

Results  Axis I (mood, anxiety, disruptive behavior, and substance use disorders) and Axis II disorders in adolescence showed risks for negative prognoses lasting 20 years. Co-occurring Axis I and Axis II disorders consistently presented the highest risk, often approximating the sum of the axis-associated risk or even several times the risk of disorders in either axis alone.

Conclusions  Long-term prognoses of Axis I and Axis II disorders are of comparable magnitude and often additive when comorbid. These findings are highly relevant to the current debate over how personality disorders should be handled in DSM-V.

Objectives  To undertake a comprehensive genome-wide linkage study of neuroticism using large study samples that have been measured multiple times and to compare the results between countries for replication and across time within countries for consistency.

Design  Genome-wide linkage scan.

Setting  Twin individuals and their family members from Australia and the Netherlands.

Participants  Nineteen thousand six hundred thirty-five sibling pairs completed self-report questionnaires for neuroticism up to 5 times over a period of up to 22 years. Five thousand sixty-nine sibling pairs were genotyped with microsatellite markers.

Methods  Nonparametric linkage analyses were conducted in MERLIN-REGRESS for the mean neuroticism scores averaged across time. Additional analyses were conducted for the time-specific measures of neuroticism from each country to investigate consistency of linkage results.

Results  Three chromosomal regions exceeded empirically derived thresholds for suggestive linkage using mean neuroticism scores: 10p 5 Kosambi cM (cM) (Dutch study sample), 14q 103 cM (Dutch study sample), and 18q 117 cM (combined Australian and Dutch study sample), but only 14q retained significance after correction for multiple testing. These regions all showed evidence for linkage in individual time-specific measures of neuroticism and 1 (18q) showed some evidence for replication between countries. Linkage intervals for these regions all overlap with regions identified in other studies of neuroticism or related traits and/or in studies of anxiety in mice.

Conclusions  Our results demonstrate the value of the availability of multiple measures over time and add to the optimism reported in recent reviews for replication of linkage regions for neuroticism. These regions are likely to harbor causal variants for neuroticism and its related psychiatric disorders and can inform prioritization of results from genome-wide association studies.

Objective  To determine the efficacy of exposure therapy or trauma-focused cognitive restructuring in preventing chronic PTSD relative to a wait-list control group.

Design, Setting, and Participants  A randomized controlled trial of civilians who experienced trauma and who met the diagnostic criteria for ASD (N = 90) seen at an outpatient clinic between March 1, 2002, and June 30, 2006.

Intervention  Patients were randomly assigned to receive 5 weekly 90-minute sessions of either imaginal and in vivo exposure (n = 30) or cognitive restructuring (n = 30), or assessment at baseline and after 6 weeks (wait-list group; n = 30).

Main Outcome Measures  Measures of PTSD at the 6-month follow-up visit by clinical interview and self-report assessments of PTSD, depression, anxiety, and trauma-related cognition.

Results  Intent-to-treat analyses indicated that at posttreatment, fewer patients in the exposure group had PTSD than those in the cognitive restructuring or wait-list groups (33% vs 63% vs 77%; P = .002). At follow-up, patients who underwent exposure therapy were more likely to not meet diagnostic criteria for PTSD than those who underwent cognitive restructuring (37% vs 63%; odds ratio, 2.10; 95% confidence interval, 1.12-3.94; P = .05) and to achieve full remission (47% vs 13%; odds ratio, 2.78; 95% confidence interval, 1.14-6.83; P = .005). On assessments of PTSD, depression, and anxiety, exposure resulted in markedly larger effect sizes at posttreatment and follow-up than cognitive restructuring.

Conclusions  Exposure-based therapy leads to greater reduction in subsequent PTSD symptoms in patients with ASD when compared with cognitive restructuring. Exposure should be used in early intervention for people who are at high risk for developing PTSD.

Objective  To clarify the changing role of genes and environment in PSU from early adolescence through middle adulthood.

Design  Retrospective assessment by life history calendar, with univariate and bivariate structural modeling.

Setting  General community.

Participants  A total of 1796 members of male-male pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders.

Main Outcome Measures  Levels of use of alcohol, caffeine, cannabis, and nicotine recorded for every year of the respondent's life.

Results  For nicotine, alcohol, and cannabis, familial environmental factors were critical in influencing use in early adolescence and gradually declined in importance through young adulthood. Genetic factors, by contrast, had little or no influence on PSU in early adolescence and gradually increased in their effect with increasing age. The sources of individual differences in caffeine use changed much more modestly over time. Substantial correlations were seen among levels of cannabis, nicotine, and alcohol use and specifically between caffeine and nicotine. In adolescence, those correlations were strongly influenced by shared effects from the familial environment. However, as individuals aged, more and more of the correlation in PSU resulted from genetic factors that influenced use of both substances.

Conclusions  These results support an etiologic model for individual differences in PSU in which initiation and early patterns of use are strongly influenced by social and familial environmental factors while later levels of use are strongly influenced by genetic factors. The substantial correlations seen in levels of PSU across substances are largely the result of social environmental factors in adolescence, with genetic factors becoming progressively more important through early and middle adulthood.

Objectives  To identify replicated genes that facilitate smokers' abilities to achieve and sustain abstinence from smoking (hereinafter referred to as quit-success genes) found in more than 2 genome-wide association (GWA) studies of successful vs unsuccessful abstainers, and, secondarily, to nominate genes for selective involvement in smoking cessation success with bupropion hydrochloride vs nicotine replacement therapy (NRT).

Design  The GWA results in subjects from 3 centers, with secondary analyses of NRT vs bupropion responders.

Setting  Outpatient smoking cessation trial participants from 3 centers.

Participants  European American smokers who successfully vs unsuccessfully abstain from smoking with biochemical confirmation in a smoking cessation trial using NRT, bupropion, or placebo (N = 550).

Main Outcome Measures  Quit-success genes, reproducibly identified by clustered nominally positive single-nucleotide polymorphisms (SNPs) in more than 2 independent samples with significant P values based on Monte Carlo simulation trials. The NRT-selective genes were nominated by clustered SNPs that display much larger t values for NRT vs placebo comparisons. The bupropion-selective genes were nominated by bupropion-selective results.

Results  Variants in quit-success genes are likely to alter cell adhesion, enzymatic, transcriptional, structural, and DNA, RNA, and/or protein-handling functions. Quit-success genes are identified by clustered nominally positive SNPs from more than 2 samples and are unlikely to represent chance observations (Monte Carlo P< .0003). These genes display modest overlap with genes identified in GWA studies of dependence on addictive substances and memory.

Conclusions  These results support polygenic genetics for success in abstaining from smoking, overlap with genetics of substance dependence and memory, and nominate gene variants for selective influences on therapeutic responses to bupropion vs NRT. Molecular genetics should help match the types and/or intensity of antismoking treatments with the smokers most likely to benefit from them.

Objective  To determine whether long-term heavy cannabis use is associated with gross anatomical abnormalities in 2 cannabinoid receptor–rich regions of the brain, the hippocampus and the amygdala.

Design  Cross-sectional design using high-resolution (3-T) structural magnetic resonance imaging.

Setting  Participants were recruited from the general community and underwent imaging at a hospital research facility.

Participants  Fifteen carefully selected long-term (>10 years) and heavy (>5 joints daily) cannabis-using men (mean age, 39.8 years; mean duration of regular use, 19.7 years) with no history of polydrug abuse or neurologic/mental disorder and 16 matched nonusing control subjects (mean age, 36.4 years).

Main Outcome Measures  Volumetric measures of the hippocampus and the amygdala combined with measures of cannabis use. Subthreshold psychotic symptoms and verbal learning ability were also measured.

Results  Cannabis users had bilaterally reduced hippocampal and amygdala volumes (P = .001), with a relatively (and significantly [P = .02]) greater magnitude of reduction in the former (12.0% vs 7.1%). Left hemisphere hippocampal volume was inversely associated with cumulative exposure to cannabis during the previous 10 years (P = .01) and subthreshold positive psychotic symptoms (P < .001). Positive symptom scores were also associated with cumulative exposure to cannabis (P = .048). Although cannabis users performed significantly worse than controls on verbal learning (P < .001), this did not correlate with regional brain volumes in either group.

Conclusions  These results provide new evidence of exposure-related structural abnormalities in the hippocampus and amygdala in long-term heavy cannabis users and corroborate similar findings in the animal literature. These findings indicate that heavy daily cannabis use across protracted periods exerts harmful effects on brain tissue and mental health.

Objective  To assess the association between depressed mood in childhood and alcohol use during adolescence and young adulthood by mood level and sex and race/ethnicity subgroups.

Design  Cohort study of individuals observed during late childhood, early adolescence, and young adulthood.

Setting  Urban mid-Atlantic region of the United States.

Participants  Two successive cohorts of students from 19 elementary schools have been followed up since entry into first grade (1985, cohort I [n = 1196]; 1986, cohort II [n = 1115]). The students were roughly equally divided by sex (48% female) and were predominantly African American (70%). Between 1989 and 1994, annual assessments were performed on students remaining in the public school system, and between 2000 and 2001, approximately 75% participated in an interview at young adulthood (n = 1692).

Main Outcome Measures  Among participants who reported having used alcohol, Cox and multinomial regression analyses were used to assess the association of childhood mood level, as measured by a depression symptom screener, with each alcohol outcome (incident alcohol intoxication, incident alcohol-related problems, and DSM-IV alcohol abuse and dependence).

Results  In adjusted regression analyses among those who drank alcohol, a high level of childhood depressed mood was associated with an earlier onset and increased risk of alcohol intoxication, alcohol-related problems during late childhood and early adolescence, and development of DSM-IV alcohol dependence in young adulthood.

Conclusions  Early manifestations associated with possible depressive conditions in childhood helped predict and account for subsequent alcohol involvement extending across life stages from childhood through young adulthood.

Objective  To conduct autosomal linkage analyses that identify genomic regions that may harbor genes conferring a vulnerability to cannabis use disorders.

Design  In 289 Australian families who participated in the Nicotine Addiction Genetics Project, 423 autosomal markers were genotyped. Families were ascertained for heavy cigarette smoking. Linkage was conducted for DSM-IV cannabis dependence and for a novel factor score representing problems with cannabis use, including occurrence of 3 of 4 abuse criteria (excluding legal problems) and 6 DSM-IV dependence criteria.

Results  A maximum logarithm of odds (LOD) of 3.36 was noted for the cannabis problems factor score on chromosome arm 1p. An LOD of 2.2 was noted on chromosome 4 in the region of the -aminobutyric acid type A gene cluster, including GABRA2, which has been implicated in drug use disorders. For DSM-IV cannabis dependence, a modest LOD score on chromosome 6 (1.42) near cannabinoid receptor 1 (CNR1) was identified. In addition, support for an elevation on chromosome 3, identified in prior independent studies, was noted for the factor score and cannabis dependence (LOD, 1.4).

Conclusions  Genes such as ELTD1 on chromosome 1, in addition to genes on chromosomes 4 (eg, GABRA2) and 6 (eg, CNR1), may be associated with the genetic risk for cannabis use disorders. We introduce a novel quantitative phenotype, a cannabis problems factor score composed of DSM-IV abuse and dependence criteria, that may be useful for future linkage and association studies.

Design  Cohort study with follow-up between 1973 and 2004.

Participants  The entire Swedish population.

Main Outcome Measures  Affective, psychotic, neurotic, and personality disorders as well as dementia and delirium.

Results  Individuals with rheumatic diseases had a higher risk of psychiatric disorders than the general populat