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: NCT00057551

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.

Objective  To investigate whether a potential schizophrenia risk single-nucleotide polymorphism (rs6490121) identified in a recent genome-wide association study negatively influences cognition in patients with schizophrenia and healthy control subjects.

Design  A comparison of both cases and controls grouped according to NOS1 genotype (GG vs AG vs AA) on selected measures of cognition in 2 independent samples. We tested for association between NOS1 rs6490121 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attentional control) in an Irish sample. We then sought to replicate the significant results in a German sample.

Setting  Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy volunteers from the general population were ascertained.

Participants  Patients with DSM-IV–diagnosed schizophrenia and healthy control subjects from independent samples of Irish (cases, n = 349; controls, n = 230) and German (cases, n = 232; controls, n = 1344) nationality.

Results  A main effect of NOS1 genotype on verbal IQ and working memory was observed in the Irish sample where the homozygous carriers of the schizophrenia risk G allele performed poorly compared with the other genotype groups. These findings were replicated in the German sample, again with the GG genotype carriers performing below other genotype groups. Post hoc analysis of additional IQ measures (full-scale and performance IQ) in the German sample revealed that NOS1 GG carriers underperformed on these measures also.

Conclusions  NOS1 is associated with clinically significant variation in cognition. Whether this is a mechanism by which schizophrenia risk is increased (eg, via an influence on cognitive reserve) is yet to be confirmed.

Objective  To evaluate the heritability and conduct genetic linkage analyses of empirically derived, clinically homogeneous schizophrenia subtypes.

Design  Latent class and linkage analysis.

Setting  Taiwanese field research centers.

Participants  The latent class analysis included 1236 Han Chinese individuals with DSM-IV schizophrenia. These individuals were members of a large affected-sibling-pair sample of schizophrenia (606 ascertained families), original linkage analyses of which detected a maximum logarithm of odds (LOD) of 1.8 (z = 2.88) on chromosome 10q22.3.

Main Outcome Measures  Multipoint exponential LOD scores by latent class assignment and parametric heterogeneity LOD scores.

Results  Latent class analyses identified 4 classes, with 2 demonstrating familial aggregation. The first (LC2) described a group with severe negative symptoms, disorganization, and pronounced functional impairment, resembling "deficit schizophrenia." The second (LC3) described a group with minimal functional impairment, mild or absent negative symptoms, and low disorganization. Using the negative/deficit subtype, we detected genome-wide significant linkage to 1q23-25 (LOD = 3.78, empiric genome-wide P = .01). This region was not detected using the DSM-IV schizophrenia diagnosis, but has been strongly implicated in schizophrenia pathogenesis by previous linkage and association studies.Variants in the 1q region may specifically increase risk for a negative/deficit schizophrenia subtype. Alternatively, these results may reflect increased familiality/heritability of the negative class, the presence of multiple 1q schizophrenia risk genes, or a pleiotropic 1q risk locus or loci, with stronger genotype-phenotype correlation with negative/deficit symptoms. Using the second familial latent class, we identified nominally significant linkage to the original 10q peak region.

Conclusion  Genetic analyses of heritable, homogeneous phenotypes may improve the power of linkage and association studies of schizophrenia and thus have relevance to the design and analysis of genome-wide association studies.

Objectives  To quantify the exploratory behavior of individuals with bipolar mania and schizophrenia and to identify distinctive phenotypes of these illnesses.

Design  Static group comparison by the use of a novel human open field paradigm, the human Behavioral Pattern Monitor (BPM).

Setting  Psychiatric hospital.

Participants  Fifteen patients with bipolar mania and 16 patients with schizophrenia were compared with 26 healthy volunteers in the human BPM. The effects of amphetamine sulfate, the selective dopamine transporter inhibitor GBR12909, and the genetic knockdown of the dopamine transporter were compared with controls in the mouse BPM.

Main Outcome Measures  The amount of motor activity, spatial patterns of activity, and exploration of novel stimuli were quantified in both the human and mouse BPMs.

Results  Patients with bipolar mania demonstrated a unique exploratory pattern, characterized by high motor activity and increased object exploration. Patients with schizophrenia did not show the expected habituation of motor activity. Selective genetic or pharmacologic inhibition of the dopamine transporter matched the mania phenotype better than the effects of amphetamine, which has been the criterion standard for animal models of mania.

Conclusions  These findings validate the human open field paradigm and identify defining characteristics of bipolar mania that are distinct from those of schizophrenia. This cross-species study of exploration calls into question an accepted animal model of mania and should help to develop more accurate human and animal models, which are essential to the identification of the neurobiological underpinnings of neuropsychiatric disorders.

Objectives  To estimate the incremental benefit, incremental cost, and net benefit of 2 depression care programs.

Design  Randomized trial comparing 2 interventions with continued usual care, conducted between November 2000 and June 2004.

Setting  Seven primary care clinics of a prepaid health care plan in Washington.

Participants  Consecutive primary care patients starting antidepressant treatment were invited to a telephone assessment 2 weeks later. Of 634 patients with significant depressive symptoms, 600 consented and were randomized.

Interventions  The telephone care management intervention included up to 5 outreach calls for monitoring and support, feedback to treating physicians, and care coordination. The care management plus telephone psychotherapy intervention added an 8-session structured cognitive behavioral therapy program with up to 4 additional calls for reinforcement.

Main Outcome Measures  Independent, blinded telephone assessments at 1, 3, 6, 9, 12, and 18 months included the Symptom Checklist 90 depression scale. Health services costs were measured using health care plan accounting records.

Results  Over 24 months, telephone care management led to a gain of 29 depression-free days (95% confidence interval, –6 to +63) and a $676 increase in outpatient health care costs (95% confidence interval, $596 lower to $1974 higher). The incremental net benefit was negative even if a day free of depression was valued up to $20. Care management plus psychotherapy led to a gain of 46 depression-free days (95% confidence interval, +12 to +80) and a $397 increase in outpatient costs (95% confidence interval, $882 lower to $1725 higher). The incremental net benefit was positive if a day free of depression was valued at $9 or greater.

Conclusion  Compared with current primary care practice, a structured telephone program including care management and cognitive behavioral psychotherapy has significant clinical benefit with only a modest increase in health services cost.

Objective  To assess the association between adherence to the MDP and the incidence of clinical depression.

Design  Prospective study that uses a validated 136-item food frequency questionnaire to assess adherence to the MDP. The MDP score positively weighted the consumption of vegetables, fruit and nuts, cereal, legumes, and fish; the monounsaturated- to saturated-fatty-acids ratio; and moderate alcohol consumption, whereas meat or meat products and whole-fat dairy were negatively weighted.

Setting  A dynamic cohort of university graduates (Seguimiento Universidad de Navarra/University of Navarra Follow-up [SUN] Project).

Participants  A total of 10 094 initially healthy Spanish participants from the SUN Project participated in the study. Recruitment began on December 21, 1999, and is ongoing.

Main Outcome Measure  Participants were classified as having incident depression if they were free of depression and antidepressant medication at baseline and reported a physician-made diagnosis of clinical depression and/or antidepressant medication use during follow-up.

Results  After a median follow-up of 4.4 years, 480 new cases of depression were identified. The multiple adjusted hazard ratios (95% confidence intervals) of depression for the 4 upper successive categories of adherence to the MDP (taking the category of lowest adherence as reference) were 0.74 (0.57-0.98), 0.66 (0.50-0.86), 0.49 (0.36-0.67), and 0.58 (0.44-0.77) (P for trend <.001). Inverse dose-response relationships were found for fruit and nuts, the monounsaturated- to saturated-fatty-acids ratio, and legumes.

Conclusions  Our results suggest a potential protective role of the MDP with regard to the prevention of depressive disorders; additional longitudinal studies and trials are needed to confirm these findings.

Objective  To determine whether resting functional abnormalities found in PTSD are acquired characteristics or familial risk factors.

Design  Cross-sectional design including identical twins discordant for trauma exposure.

Setting  Academic medical center.

Participants  Combat-exposed veterans with PTSD (n = 14) and their identical co-twins not exposed to combat (n = 14) as well as combat-exposed veterans without PTSD (n = 19) and their identical co-twins not exposed to combat (n = 19).

Main Outcome Measures  We used positron emission tomography and fluorodeoxyglucose 18 to examine resting regional cerebral metabolic rate for glucose (rCMRglu).

Results  Veterans with PTSD and their co-twins had significantly higher resting rCMRglu in the dorsal anterior cingulate cortex/midcingulate cortex (dACC/MCC) compared with veterans without PTSD and their co-twins. Resting rCMRglu in the dACC/MCC in unexposed co-twins was positively correlated with combat exposure severity, PTSD symptom severity, and alcohol use in their exposed twins.

Conclusions  Enhanced resting metabolic activity in the dACC/MCC appears to represent a familial risk factor for developing PTSD after exposure to psychological trauma.

Objective  To compare the safety and efficacy of a single-treatment sustained-release naltrexone implant with daily oral naltrexone treatment.

Design  Seventy heroin-dependent volunteers entered a randomized, double-blind, double-placebo controlled trial with a 6-month follow-up period.

Patients  Eligibility criteria were DSM-IV opioid (heroin) dependence; age 18 years or older; willingness to be randomized; residing in the Perth, Western Australia, metropolitan area; and completion of preclinical screening and written consent. A total of 129 eligible participants were identified, and 70 (54%) provided informed consent and were randomized as per the study design.

Intervention  Participants received oral naltrexone, 50 mg/d, for 6 months (plus placebo implants) or a single dose of 2.3 g of naltrexone implant (plus placebo tablets).

Main Outcome Measures  (1) Maintaining therapeutic naltrexone levels above 2 ng/mL; (2) return to regular heroin use (≥4 d/wk); (3) other heroin use and abstinence; (4) use of illicit nonopioid drugs; (5) number of opiate overdoses requiring hospitalization; (6) treatment-related unexpected and expected adverse events; and (7) blood naltrexone levels (ie, pharmacokinetic profile) for recipients of active naltrexone implants.

Results  More participants in the oral vs the implant group had blood naltrexone levels below 2 ng/mL in months 1 (P < .001) and 2 (P = .01); in addition, more oral group participants had returned to regular heroin use by 6 months (P = .003) and at an earlier stage (median [SE], 115 [12.0] days vs 158 [9.4] days). There were 10 trial-related, unexpected adverse events. One serious adverse event, a wound hematoma, was associated with surgical implantation. Naltrexone blood levels in implant recipients were maintained above 1 and 2 ng/mL for 101 (95% confidence interval, 83-119) and 56 (39-73) days, respectively, among men and 124 (88-175) and 43 (16-79) days among women.

Conclusions  The naltrexone implant effectively reduced relapse to regular heroin use compared with oral naltrexone and was not associated with major adverse events.

Clinical Trial Registration  anzctr.org.au Identifier: ACTRN12606000308594

Objectives  To evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence.

Design  A 24-week, phase 2b, randomized, double-blind, placebo-controlled trial with efficacy assessed during weeks 8 to 20 and follow-up to week 24.

Setting  Cocaine- and opioid-dependent persons recruited from October 2003 to April 2005 from greater New Haven, Connecticut.

Participants  One hundred fifteen methadone-maintained subjects (67% male, 87% white, aged 18-46 years) were randomized to vaccine or placebo, and 94 subjects (82%) completed the trial. Most smoked crack cocaine along with using marijuana (18%), alcohol (10%), and nonprescription opioids (44%).

Intervention  Over 12 weeks, 109 of 115 subjects received 5 vaccinations of placebo or succinylnorcocaine linked to recombinant cholera toxin B-subunit protein.

Main Outcome Measure  Semiquantitative urinary cocaine metabolite levels measured thrice weekly with a positive cutoff of 300 ng/mL.

Results  The 21 vaccinated subjects (38%) who attained serum IgG anticocaine antibody levels of 43 µg/mL or higher (ie, high IgG level) had significantly more cocaine-free urine samples than those with levels less than 43 µg/mL (ie, low IgG level) and the placebo-receiving subjects during weeks 9 to 16 (45% vs 35% cocaine-free urine samples, respectively). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the subjects with a high IgG level than in subjects with a low IgG level (53% of subjects vs 23% of subjects, respectively) (P = .048). The most common adverse effects were injection site induration and tenderness. There were no treatment-related serious adverse events, withdrawals, or deaths.

Conclusions  Attaining high (≥43 µg/mL) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters.

Trial Registration  clinicaltrials.gov Identifier: NCT00142857

Objective  To examine the degree to which trait impulsiveness (the tendency to act on cravings and urges rather than to delay gratification) is predicted by baseline µ-receptor availability or the response of this system to a standardized, experientially matched stressor.

Design, Setting, and Patients  Nineteen young healthy male volunteers completed a personality questionnaire (NEO Personality Inventory, Revised) and underwent positron emission tomography scans with the µ-receptor–selective radiotracer carfentanil labeled with carbon 11. Measures of receptor concentrations were obtained at rest and during receipt of an experimentally maintained pain stressor of matched intensity between subjects.

Main Outcome Measures  Baseline receptor levels and stress-induced activation of µ-opioid system neurotransmission compared between subjects scoring above and below the population median on the NEO Personality Inventory, Revised, impulsiveness subscale and the orthogonal dimension (deliberation) expected to interact with it.

Results  High impulsiveness and low deliberation scores were associated with significantly higher regional µ-receptor concentrations and greater stress-induced endogenous opioid system activation. Effects were obtained in the prefrontal and orbitofrontal cortices, anterior cingulate, thalamus, nucleus accumbens, and basolateral amygdala—all regions involved in motivated behavior and the effects of drugs of abuse. Availability of the µ-receptor and the magnitude of stress-induced endogenous opioid activation in these regions accounted for 17% to 49% of the variance in these personality traits.

Conclusions  Individual differences in the function of the endogenous µ-receptor system predict personality traits that confer vulnerability to or resiliency against risky behaviors such as the predisposition to develop substance use disorders. These personality traits are also implicated in psychopathological states (eg, personality disorders) in which variations in the function of this neurotransmitter system also may play a role.

Objective  To document an objective deficit of selective attention in a large sample of children with and without ADHD using spatial orienting paradigms. By stratifying samples according to the gene dosage of a risk haplotype of the dopamine transporter gene (DAT1), we could determine whether genetic factors predict spatial inattention in ADHD.

Design  A case-control design was used.

Setting  Children with ADHD were recruited from clinics or support groups in Ireland. Typically developing children were recruited from schools in and around Dublin, Ireland.

Participants  One hundred fifteen children were recruited (ADHD = 50, control = 65). Groups were matched for age but differed in estimated intelligence.

Intervention  Two versions of a visual spatial orienting task in which attention was directed by valid, neutral, or invalid cues to target locations. Sudden-onset peripheral cues (exogenous) and centrally presented predictive cues (endogenous) were used.

Main Outcome Measures  To isolate an attention deficit in ADHD, groups were first compared using analysis of variance on the spatial orienting tasks. Multiple regression was used to assess the main effect of DAT1 haplotype status (heterozygous vs homozygous) and the interaction of diagnosis and genotype on those variables that discriminated children with and without ADHD.

Results  Children with ADHD displayed deficits in reorienting attention from invalidly cued spatial locations, particularly for targets in the left visual field. DAT1 haplotype status predicted spatial reorienting deficits for left visual field targets (P = .007) but there was also a significant interaction of diagnosis and genotype (P = .02), which revealed the greatest impairment in children with ADHD homozygous for the DAT1 haplotype.

Conclusion  Heterogeneity in selective attention in ADHD can be explained by a replicated genetic risk factor for ADHD, the 10/3 DAT1 haplotype.

Objectives  The primary objectives of the conference were to (1) establish consensus among participants about the design of future clinical trials of deep brain stimulation for disorders of mood, behavior, and thought and (2) develop standards for the protection of human subjects participating in such studies.

Results  Conference participants identified 16 key points for guiding research in this growing field.

Conclusions  The adoption of the described guidelines would help to protect the safety and rights of research subjects who participate in clinical trials of deep brain stimulation for disorders of mood, behavior, and thought and have further potential to benefit other stakeholders in the research process, including clinical researchers and device manufactures. That said, the adoption of the guidelines will require broad and substantial commitment from many of these same stakeholders.

Objective  To identify brain sites differentially targeted by schizophrenia, we applied a high-resolution variant of functional magnetic resonance imaging to clinically characterized patients and matched healthy controls and to a cohort of prodromal subjects who were prospectively followed up. Additionally, to explore the potential confound of medication use, the fMRI variant was applied to rodents receiving an antipsychotic agent.

Design  Cross-sectional and prospective cohort designs.

Setting  Hospital clinic and magnetic resonance imaging laboratory.

Participants  Eighteen patients with schizophrenia, 18 controls comparable in age and sex, and 18 prodromal patients followed up prospectively for 2 years. Ten C57-B mice received an antipsychotic agent or vehicle control.

Main Outcome Measures  Regional cerebral blood volume (CBV), as measured with magnetic resonance imaging, and symptom severity, as measured with clinical rating scales.

Results  In a first between-group analysis that compared patients with schizophrenia with controls, results revealed abnormal CBV increases in the CA1 subfield and the orbitofrontal cortex and abnormal CBV decreases in the dorsolateral prefrontal cortex. In a second longitudinal analysis, baseline CBV abnormalities in the CA1 subfield differentially predicted clinical progression to psychosis from a prodromal state. In a third correlational analysis, CBV levels in the CA1 subfield differentially correlated with clinical symptoms of psychosis. Finally, additional analyses of the human data set and imaging studies in mice suggested that antipsychotic agents were not confounding the primary findings.

Conclusions  Taken as a whole, the results suggest that the CA1 subfield of the hippocampal subregion is differentially targeted by schizophrenia and related psychotic disorders. Interpreted in the context of previous studies, these findings inform underlying mechanisms of illness progression.

Objectives  To provide an estimate of the collective frequency of a set of recurrent or overlapping CNVs in 3 different groups of cases compared with healthy control subjects and to assess whether each CNV is present in more than 1 clinical category.

Design  Case-control study.

Setting  Academic research.

Participants  We investigated 28 candidate loci previously identified by comparative genomic hybridization studies for gene dosage alteration in 247 cases with mental retardation, in 260 cases with autism spectrum disorders, in 236 cases with schizophrenia or schizoaffective disorder, and in 236 controls.

Main Outcome Measures  Collective and individual frequencies of the analyzed CNVs in cases compared with controls.

Results  Recurrent or overlapping CNVs were found in cases at 39.3% of the selected loci. The collective frequency of CNVs at these loci is significantly increased in cases with autism, in cases with schizophrenia, and in cases with mental retardation compared with controls (P < .001, P = .01, and P = .001, respectively, Fisher exact test). Individual significance (P = .02 without correction for multiple testing) was reached for the association between autism and a 350-kilobase deletion located at 22q11 and spanning the PRODH and DGCR6 genes.

Conclusions  Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders.

Objective  To determine the contribution of genetic and environmental influences on the association between monocyte pro-inflammatory state and BD.

Design  A quantitative polymerase chain reaction case-control study of monocytes in bipolar twins. Determination of the influence of additive genetic, common, and unique environmental factors by structural equation modeling (ACE).

Setting  Dutch academic research center.

Participants  Eighteen monozygotic BD twin pairs, 23 dizygotic BD twin pairs, and 18 monozygotic and 16 dizygotic healthy twin pairs.

Main Outcome Measures  Expression levels of monocytes in the previously reported coherent set of 19 genes (signature) reflecting the pro-inflammatory state.

Results  The familial occurrence of the association between the monocyte pro-inflammatory gene-expression signature and BD found in the within-trait/cross-twin correlations (twin correlations) was due to shared environmental factors (ie, both monozygotic and dizygotic ratios in twin correlations approximated 1; ACE modeling data: 94% [95% confidence interval, 53%-99%] explained by common [shared] environmental factors). Although most individual signature genes followed this pattern, there was a small subcluster of genes in which genetic influences could dominate.

Conclusion  The association of the monocyte pro-inflammatory state with BD is primarily the result of a common shared environmental factor.

Objective  To identify genetic and clinical determinants of antidepressant drug treatment outcome in depression.

Design  Genomewide pharmacogenetic association study with 2 independent replication samples.

Setting  We performed a genomewide association study in patients from the Munich Antidepressant Response Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single-nucleotide polymorphisms highly related to outcome in both genomewide association studies was genotyped in a sample of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

Participants  A total of 339 inpatients with a depressive episode (MARS sample), a further 361 inpatients with depression (German replication sample), and 832 outpatients with major depression (STAR*D sample).

Main Outcome Measures  We generated a multilocus genetic variable that described the individual number of alleles of the selected single nucleotide polymorphisms associated with beneficial treatment outcome in the MARS sample ("response" alleles) to evaluate additive genetic effects on antidepressant drug treatment outcome.

Results  Multilocus analysis revealed a significant contribution of a binary variable that categorized patients as carriers of a high vs low number of response alleles in the prediction of antidepressant drug treatment outcome in both samples (MARS and STAR*D). In addition, we observed that patients with a comorbid anxiety disorder combined with a low number of response alleles showed the least favorable outcome.

Conclusion  These results demonstrate the importance of multiple genetic factors combined with clinical features in the prediction of antidepressant drug treatment outcome, which underscores the multifactorial nature of this trait.

Objective  To replicate the interaction between childhood maltreatment and a TAT haplotype formed by rs7209436, rs110402, and rs242924 in CRHR1, predicting adult depression.

Design  Two prospective longitudinal cohort studies.

Setting  England and New Zealand.

Participants  Participants in the first sample were women in the E-Risk Study (N = 1116), followed up to age 40 years with 96% retention. Participants in the second sample were men and women in the Dunedin Study (N = 1037), followed up to age 32 years with 96% retention.

Main Outcome Measure  Research diagnoses of past-year and recurrent major depressive disorder.

Results  In the E-Risk Study, the TAT haplotype was associated with a significant protective effect. In this effect, women who reported childhood maltreatment on the CTQ were protected against depression. In the Dunedin Study, which used a different type of measure of maltreatment, this finding was not replicated.

Conclusions  A haplotype in CRHR1 has been suggested to exert a protective effect against adult depression among research participants who reported maltreatment on the CTQ, a measure that elicits emotional memories. This suggests the hypothesis that CRHR1's protective effect may relate to its function in the consolidation of memories of emotionally arousing experiences.

Objective  To detect global and regional anatomical abnormalities in the amygdala in individuals with psychopathy.

Design  Cross-sectional design using structural magnetic resonance imaging.

Setting  Participants were recruited from high-risk communities (temporary employment agencies) in the Los Angeles, California, area and underwent imaging at a hospital research facility at the University of Southern California.

Participants  Twenty-seven psychopathic individuals as defined by the Hare Psychopathy Checklist–Revised and 32 normal controls matched on age, sex, and ethnicity.

Main Outcome Measures  Amygdala volumes were examined using traditional volumetric analyses and surface-based mesh modeling methods were used to localize regional surface deformations.

Results  Individuals with psychopathy showed significant bilateral volume reductions in the amygdala compared with controls (left, 17.1%; right, 18.9%). Surface deformations were localized in regions in the approximate vicinity of the basolateral, lateral, cortical, and central nuclei of the amygdala. Significant correlations were found between reduced amygdala volumes and increased total and facet psychopathy scores, with correlations strongest for the affective and interpersonal facets of psychopathy.

Conclusions  Results provide the first evidence, to our knowledge, of focal amygdala abnormalities in psychopathic individuals and corroborate findings from previous lesion studies. Findings support prior hypotheses of amygdala deficits in individuals with psychopathy and indicate that amygdala abnormalities contribute to emotional and behavioral symptoms of psychopathy.

Objective  To determine the associations of time since deployment, combat intensity, and posttraumatic stress disorder (PTSD) and depression symptoms with longer-term neuropsychological outcomes in war-deployed soldiers.

Design  Prospective cohort study involving (1) soldiers assessed at baseline (median, 42 days prior to deployment) and following return from Iraq (median, 404 days after return and 885 days since baseline), and (2) soldiers more recently returned from deployment assessed at baseline (median, 378 days prior to deployment) and following return from Iraq (median, 122 days after return and 854 days since baseline assessment).

Setting  Active-duty military installations.

Participants  Two hundred sixty-eight male and female regular active-duty soldiers (164 with 1-year follow-up; 104 recently returned).

Main Outcome Measures  Neuropsychological performances (verbal learning, visual memory, attention, and reaction time).

Results  There was a significant interaction between time and PTSD symptom severity (B= –0.01 [unstandardized], P = .04). Greater PTSD symptoms were associated with poorer attention in soldiers tested at 1-year follow-up (B = 0.01, P = .03) but not in recently returned soldiers. At 1-year follow-up, mean adjusted attention error scores increased by 0.10 points for every 10 points on the PTSD scale. Greater combat intensity was associated with more efficient postdeployment reaction-time performances, regardless of time since deployment (B = 0.48, P = .004), with mean adjusted reaction efficiency scores increasing by 4.8 points for every 10 points on the combat experiences scale. Neither depression nor contextual variables (alcohol use and deployment head injury) were significantly related to neuropsychological outcomes.

Conclusions  In this study of army soldiers deployed to the Iraq war, only PTSD symptoms (among soldiers back from deployment for 1 year) were associated with a neuropsychological deficit (reduced attention). Greater combat intensity was associated with enhanced reaction time, irrespective of time since return.

Objective  To study predictive associations between bullying and victimization in childhood and later psychiatric hospital and psychopharmacologic treatment.

Design  Nationwide birth cohort study from age 8 to 24 years.

Participants  Five thousand thirty-eight Finnish children born in 1981 with complete information about bullying and victimization at age 8 years from parents, teachers, and self-reports.

Main Outcome Measures  National register–based lifetime information about psychiatric hospital treatments and psychopharmacologic medication prescriptions.

Results  When controlled for psychopathology score, frequent victim status at age 8 years among females independently predicted psychiatric hospital treatment and use of antipsychotic, antidepressant, and anxiolytic drugs. Among males, frequent bully-victim and bully-only statuses predicted use of antidepressant and anxiolytic drugs. Frequent bully-victim status among males also predicted psychiatric hospital treatment and use of antipsychotics. However, when the analysis was controlled with total psychopathology score at age 8 years, frequent bully, victim, or bully-victim status did not predict any psychiatric outcomes among males.

Conclusions  Boys and girls who display frequent bullying behavior should be evaluated for possible psychiatric problems, as bullying behaviors in concert with psychiatric symptoms are early markers of risk of psychiatric outcome. Among females, frequent childhood victimization predicts later psychiatric problems irrespective of psychiatric problems at baseline.

Objective  To determine whether adjunctive multifamily psychoeducational psychotherapy would improve outcome for children aged 8 to 12 years with depression or bipolar disorder.

Design  One hundred sixty-five children were studied in a randomized controlled trial of multifamily psychoeducational psychotherapy plus treatment as usual (n = 78) compared with a wait-list control (WLC) condition plus treatment as usual (n = 87). Assessments occurred at baseline and at 6, 12, and 18 months. Intervention occurred between baseline and 6 months for the immediate treatment group and between 12 and 18 months for the WLC group.

Setting  University medical center.

Participants  Children were recruited from mental health and physical health care providers, media contacts, and word of mouth. All had a major mood disorder (major depressive disorder or dysthymic disorder, 30%; bipolar disorder type I, type II, or not otherwise specified, 70%).

Intervention  Children and 1 or more parents participated in eight 90-minute multifamily psychoeducational psychotherapy sessions. Parent and child groups met separately but began and ended sessions together.

Main Outcome Measures  The Mood Severity Index (MSI) combines Mania Rating Scale and Children's Depression Rating Scale–Revised scores.

Results  Multifamily psychoeducational psychotherapy plus treatment as usual was associated with lower MSI scores at follow-up in intent-to-treat analyses compared with WLC plus treatment as usual (MSI: ²₁ = 4.55; P = .03). The WLC group showed a similar decrease in MSI scores 1 year later, when also following their treatment (MSI decrease = 3.24 units per 6 months in the immediate treatment group and 3.50 units per 6 months in the WLC group).

Conclusion  Brief, adjunctive psychoeducational group psychotherapy is associated with improved outcome for children aged 8 to 12 years with major mood disorders.

Trial Registration  clinicaltrials.gov Identifier: NCT00050557

Objectives  To determine whether the following variables were associated with long-term mortality: baseline depression severity, previous MDD episodes, onset of MDD before or after the ACS event, 6 months of sertraline hydrochloride therapy, and mood improvement independent of treatment.

Design  SADHART was a double-blind, placebo-controlled, randomized trial comparing the safety and antidepressant efficacy of sertraline vs placebo in 369 patients with ACS who met criteria for MDD. The trial was completed in June 2000, and follow-up for vital status was completed in September 2007.

Setting  Academic research.

Participants  SADHART participants.

Main Outcome Measures  Vital status was determined in 361 participants (97.8%) during a median follow-up of 6.7 years.

Results  During the study, 75 participants (20.9%) died. Neither previous episodes of MDD, nor onset before or after the index ACS, nor an initial 6 months of sertraline treatment was associated with long-term mortality. Cox proportional hazards regression models showed that baseline MDD severity (hazard ratio, 2.30; 95% confidence interval, 1.28-4.14; P < .006) and failure of MDD to improve substantially during treatment with either sertraline or placebo (hazard ratio, 2.39; 95% confidence interval, 1.39-2.44; P < .001) were strongly and independently associated with long-term mortality. Marked improvement in depression (Clinical Global Impression–Improvement subscale score of 1) was associated with improved adherence to study medication.

Conclusions  Severity of MDD measured within a few weeks of hospitalization for ACS or failure of MDD to improve during the 6 months following ACS predicted more than a doubling of mortality over 6.7 years of follow-up. Because persistent depression increases mortality and decreases medication adherence, physicians need to aggressively treat depression and be diligent in promoting adherence to guideline cardiovascular drug therapy.

Objectives  To test whether common nodes of the cognitive control network exhibit altered activity across functional neuroimaging studies of executive cognition in schizophrenia and to evaluate the direction of these effects.

Data Sources  PubMed database.

Study Selection  Forty-one English-language, peer-reviewed articles published prior to February 2007 were included. All reports used functional neuroimaging during executive function performance by adult patients with schizophrenia and reported whole-brain analyses in standard stereotactic space. Tasks primarily included the delayed match-to-sample, N-back, AX-CPT, and Stroop tasks.

Data Extraction  Activation likelihood estimation modeling reported activation maxima as the center of a 3-dimensional gaussian function in the meta-analysis, with statistical thresholding and correction for multiple comparisons.

Data Synthesis  In within-group analyses, healthy controls and patients activated a similarly distributed cortical-subcortical network, prominently including the dorsolateral prefrontal cortex (PFC), ventrolateral PFC, anterior cingulate cortex (ACC), and thalamus. In between-group analyses, patients showed reduced activation in the left dorsolateral PFC, rostral/dorsal ACC, left thalamus (with significant co-occurrence of these areas), and inferior/posterior cortical areas. Increased activation was observed in several midline cortical areas. Activation within groups varied modestly by task.

Conclusions  Healthy adults and schizophrenic patients activate a qualitatively similar neural network during executive task performance, consistent with the engagement of a general-purpose cognitive control network, with critical nodes in the dorsolateral PFC and ACC. Nevertheless, patients with schizophrenia show altered activity with deficits in the dorsolateral PFC, ACC, and mediodorsal nucleus of the thalamus. Increases in activity are evident in other PFC areas, which could be compensatory in nature.

Objective  To determine the contribution of NRG1 to susceptibility for schizophrenia in a northern Swedish isolated population.

Design  Detailed linkage disequilibrium (LD)–based patient-control association study. This is the first study to type and analyze the 7 Hap_ICE markers and a set of 32 HapMap tagging single-nucleotide polymorphisms (SNPs) that represents variants with a minor allele frequency of at least 1% and fully characterizes the LD structure of the 5' part of NRG1.

Setting  Outpatient and inpatient hospitals.

Participants  A total of 486 unrelated patients with schizophrenia and 514 unrelated control individuals recruited from a northern Swedish isolated population.

Main Outcome Measures  Association between markers and disease.

Results  Analysis of the Hap_ICE markers showed the association of a 7-marker and 2-microsatellite haplotype, different from the haplotypes associated in the Icelandic population and overrepresented in northern Swedish control individuals. Subsequently, a more detailed analysis that included all 37 genotyped SNPs was performed by investigating haplotypic association, dependent and independent of LD block structure. We found significant association with 5 SNPs located in the second intron of NRG1 (.007 ≤ P ≤ .04). Also, 2-, 3-, and 4-SNP windows that comprise these SNPs were associated (P < 3 x 10^–4). One protective haplotype (0% vs 1.8%; P <5 x 10^–5) and 1 disease risk–causing haplotype (40.4% vs 34.9%, P = .02) were defined.

Conclusion  The NRG1 gene contributes to the susceptibility for schizophrenia in the northern Swedish population.

Objectives  To compare remission rates of MD with psychotic features in those treated with a combination of atypical antipsychotic medication plus a serotonin reuptake inhibitor with those treated with antipsychotic monotherapy; and to compare response by age.

Design  Twelve-week, double-blind, randomized, controlled trial.

Setting  Clinical services of 4 academic sites.

Patients  Two hundred fifty-nine subjects with MD with psychotic features randomized by age (<60 or ≥60 years) (mean [standard deviation (SD)], 41.3 [10.8] years in 117 younger adults vs 71.7 [7.8] years in 142 geriatric participants).

Intervention  Target doses of 15 to 20 mg of olanzapine per day plus masked sertraline or placebo at 150 to 200 mg per day.

Main Outcome Measure  Remission rates of MD with psychotic features.

Results  Treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.12-1.47; P < .001); 41.9% of subjects who underwent combination therapy were in remission at their last assessment compared with 23.9% of subjects treated with monotherapy (²₁ = 9.53, P = .002). Combination therapy was comparably superior in both younger (OR, 1.25; 95% CI, 1.05-1.50; P = .02) and older (OR, 1.34; 95% CI, 1.09-1.66; P = .01) adults. Overall, tolerability was comparable across age groups. Both age groups had significant increases in cholesterol and triglyceride concentrations, but statistically significant increases in glucose occurred only in younger adults. Younger adults gained significantly more weight than older subjects (mean [SD], 6.5 [6.6] kg vs 3.3 [4.9] kg, P = .001).

Conclusions  Combination pharmacotherapy is efficacious for the treatment of MD with psychotic features. Future research must determine the benefits vs risks of continuing atypical antipsychotic medications beyond 12 weeks.

Trial Registration  clinicaltrials.gov Identifier: NCT00056472

Objective  To compare sociodemographic and clinical patterns of antidepressant medication treatment in the United States between 1996 and 2005.

Design  Analysis of antidepressant use data from the 1996 (n = 18 993) and 2005 (n = 28 445) Medical Expenditure Panel Surveys.

Setting  Households in the United States.

Participants  Respondents aged 6 years or older who reported receiving at least 1 antidepressant prescription during that calendar year.

Main Outcome Measures  Rate of antidepressant use and adjusted rate ratios (ARRs) of year effect on rate of antidepressant use adjusted for age, sex, race/ethnicity, annual family income, self-perceived mental health, and insurance status.

Results  The rate of antidepressant treatment increased from 5.84% (95% confidence interval [CI], 5.47-6.23) in 1996 to 10.12% (9.58-10.69) in 2005 (ARR, 1.68; 95% CI, 1.55-1.81), or from 13.3 to 27.0 million persons. Significant increases in antidepressant use were evident across all sociodemographic groups examined, except African Americans (ARR, 1.13; 95% CI, 0.89-1.44), who had comparatively low rates of use in both years (1996, 3.61%; 2005, 4.51%). Although antidepressant treatment increased for Hispanics (ARR, 1.75; 95% CI, 1.60-1.90), it remained comparatively low (1996, 3.72%; 2005, 5.21%). Among antidepressant users, the percentage of patients treated for depression did not significantly change (1996, 26.25% vs 2005, 26.85%; ARR, 0.95; 95% CI, 0.83-1.07), although the percentage of patients receiving antipsychotic medications (5.46% vs 8.86%; ARR, 1.77; 95% CI, 1.31-2.38) increased and those undergoing psychotherapy declined (31.50% vs 19.87%; ARR, 0.65; 95% CI, 0.56-0.72).

Conclusions  From 1996 to 2005, there was a marked and broad expansion in antidepressant treatment in the United States, with persisting low rates of treatment among racial/ethnic minorities. During this period, individuals treated with antidepressants became more likely to also receive treatment with antipsychotic medications and less likely to undergo psychotherapy.

Objective  To clarify sources of MD-CAD comorbidity.

Design  Major depression was assessed at the time of the personal interview, and CAD from hospital discharge records and death certificates.

Setting  Swedish population-based twin registry.

Participants  The study included 30 374 twins with a mean age of 57 years.

Main Outcome Measure  Modified DSM-IV diagnosis of MD or diagnosis of CAD.

Results  Lifetime association between MD and CAD was modest (odds ratio, ~1.3). In time-dependent Cox analyses, onset of CAD produced concurrent and ongoing hazard ratios for MD of 2.83 and 1.75. These risks increased if the diagnosis of CAD was restricted to myocardial infarction. Onset of MD increased the concurrent and ongoing hazard ratios for CAD to 2.53 and 1.17. The ongoing CAD risk was strongly associated with depressive severity and recurrence. Twin models showed that the modest comorbidity between MD and CAD in women arose primarily from shared genetic effects, although the genetic correlation was small (+0.16). In men, the source of comorbidity was moderated by age, being environmental in older members and largely genetic in younger members of the sample.

Conclusions  Although the MD-CAD relationship across the lifespan is modest, time-dependent models reveal stronger associations. The sustained effect of CAD onset on MD risk is much stronger than vice versa. The effect of MD on CAD is largely acute, and the longer-term effects are apparently mediated via depressive recurrence. When examined separately, in men, environmental effects, which are often acute, play a large role in MD-CAD comorbidity, whereas in women, chronic effects, which are in part genetic, are more important. In men, genetic sources of MD-CAD comorbidity are more important in younger members of the sample.

Objective  To assess the availability of 4β2*-nAChRs and their relationship to mild cognitive and mild depressive symptoms in vivo in patients with PD.

Design  Crossover comparison between patients with PD and healthy volunteers (control group) using the 4β2*-nAChR–specific radioligand 2-[¹⁸F]fluoro-3-(2[S]-2-azetidinylmethoxy)-pyridine (2-[¹⁸F]FA-85380) and positron emission tomography.

Setting  Departments of Neurology and Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Participants  Twenty-two nonsmoking patients with PD and 9 nonsmoking healthy volunteers.

Main Outcome Measures  Level of 2-[¹⁸F]FA-85380 binding potential (2-FA BP), a measure of 4β2*-nAChR availability. The relationship between severity of cognitive symptoms as rated using the Mini-Mental State Examination and DemTect scale and the level of depressive symptoms as indicated using the Beck Depression Inventory, and 2-FA BP were assessed.

Results  In patients with PD compared with healthy volunteers, there was widespread reduced 2-FA BP, especially in the midbrain, pons, anterior cingulate cortex, frontoparietal cortex, and cerebellum. In subgroups of patients with PD with possible depression, reduced 2-FA BP was most pronounced in the cingulate cortex and frontoparieto-occipital cortex, whereas in patients with PD with mild cognitive impairment, 2-FA BP was reduced in the midbrain, pons, and cerebellum. In patients with PD, the strongest associations between depressive symptoms and reduced 2-FA BP were noted in the anterior cingulate cortex, putamen, midbrain, and occipital cortex. In contrast, cognitive symptoms correlated only weakly with reduced 2-FA BP in the thalamus, midbrain, temporal cortex, hippocampus, and cerebellum.

Conclusions  There is a broad reduction of 4β2*-nAChR availability in patients with PD without clinically manifest dementia or depression compared with healthy volunteers. Reduced 4β2*-nAChR binding in patients with PD within the subcortical and cortical regions is associated with the severity of mild cognitive or depressive symptoms. These results provide novel in vivo evidence for a role of the cholinergic neurotransmission in psychiatric comorbidity of PD.

Objective  To investigate whether prefrontal glutamate levels are higher in patients with type 1 diabetes and whether an elevation is related to lower cognitive performance and depression.

Design  Cross-sectional study.

Setting  General clinical research center.

Participants  One hundred twenty-three patients with adult type 1 diabetes with varying degrees of lifetime glycemic control and 38 healthy participants.

Main Outcome Measures  With the use of proton magnetic resonance spectroscopy, prefrontal glutamate–glutamine–-aminobutyric acid (Glx) levels were compared between patients and control subjects. Relationships between prefrontal Glx levels and cognitive function and between Glx levels and mild depressive symptoms were assessed in patients with type 1 diabetes.

Results  Prefrontal Glx concentrations were 9.0% (0.742 mmol/L; P = .005) higher in adult patients with type 1 diabetes than in healthy control subjects. There were positive linear trends for the effects of lifetime glycemic control on prefrontal Glx levels (P for trend = .002). Cognitive performances in memory, executive function, and psychomotor speed were lower in patients (P = .003, .01, and <.001, respectively) than in control subjects. Higher prefrontal Glx concentrations in patients were associated with lower performance in assessment of global cognitive function (0.11 change in z score per 1-mmol/L increase in Glx) as well as with mild depression.

Conclusions  The high prefrontal glutamate levels documented in this study may play an important role in the genesis of the low cognitive performance and mild depression frequently observed in patients with type 1 diabetes. Therapeutic options that alter glutamatergic neurotransmission may be of benefit in treating central nervous system–related changes in patients with adult type 1 diabetes.

Objective  To delineate the development of cortical asymmetry in children with and without ADHD.

Design  Longitudinal study.

Setting  Government Clinical Research Institute.

Participants  A total of 218 children with ADHD and 358 typically developing children, from whom 1133 neuroanatomical magnetic resonance images were acquired prospectively.

Main Outcome Measures  Cortical thickness was estimated at 40 962 homologous points in the left and right hemispheres, and the trajectory of change in asymmetry was defined using mixed-model regression.

Results  In right-handed typically developing individuals, a mean (SE) increase in the relative thickness of the right orbitofrontal and inferior frontal cortex with age of 0.011 (0.0018) mm per year (t₃₃₇ = 6.2, P < .001) was balanced against a relative left-hemispheric increase in the occipital cortical regions of 0.013 (0.0015) mm per year (t₃₃₇ = 8.1, P < .001). Age-related change in asymmetry in non–right-handed typically developing individuals was less extensive and was localized to different cortical regions. In ADHD, the posterior component of this evolving asymmetry was intact, but the prefrontal component was lost.

Conclusions  These findings explain the way that, in typical development, the increased dimensions of the right frontal and left occipital cortical regions emerge in adulthood from the reversed pattern of childhood cortical asymmetries. Loss of the prefrontal component of this evolving asymmetry in ADHD is compatible with disruption of prefrontal function in the disorder and demonstrates the way that disruption of typical processes of asymmetry can inform our understanding of neurodevelopmental disorders.

Objective  To examine the 24-month course of preschool depression and whether it showed homotypic vs heterotypic continuity or was a developmentally transient phenomenon.

Design  Blindly rated, prospective, 24-month, longitudinal follow-up study.

Setting  Community sites.

Patients  Three hundred six preschoolers aged 3 to 6 years recruited from community sites and oversampled for symptoms of depression.

Main Outcome Measure  Recurrence/stability of depression and predictors of course.

Results  Preschoolers with depression at baseline had the highest likelihood of subsequent depression 12 and/or 24 months later compared with preschoolers with no baseline disorder and with those who had other psychiatric disorders. Preschoolers with depression at baseline were more likely to have later depression rather than other psychiatric disorders. Findings from a logistic regression analysis indicated that when controlling for demographic variables, risk factors, and comorbid disorders, depression during the preschool period and family history of affective disorders were the most robust and significant predictors of later depression.

Conclusions  Preschool depression, similar to childhood depression, is not a developmentally transient syndrome but rather shows chronicity and/or recurrence. Homotypic continuity of preschool MDD during a 24-month period was found. These results underscore the clinical and public health importance of identification of depression as early as preschool. Further follow-up of preschoolers with depression is warranted to inform the longitudinal course throughout childhood.

Objective  To estimate the costs and outcomes of enhanced mental health response to large-scale disasters using the 2005 Gulf storms as a case study.

Design  Decision analysis using state-transition Markov models for 6-month periods from 7 to 30 months after disasters. Simulated movements between health states were based on probabilities drawn from the clinical literature and expert input.

Setting  A total of 117 counties/parishes across Louisiana, Mississippi, Alabama, and Texas that the Federal Emergency Management Agency designated as eligible for individual relief following hurricanes Katrina and Rita.

Participants  Hypothetical cohort, based on the size and characteristics of the population affected by the Gulf storms.

Intervention  Enhanced mental health care consisting of evidence-based screening, assessment, treatment, and care coordination.

Main Outcome Measures  Morbidity in 6-month episodes of mild/moderate or severe mental health problems through 30 months after the disasters; units of service (eg, office visits, prescriptions, hospital nights); intervention costs; and use of human resources.

Results  Full implementation would cost $1133 per capita, or more than $12.5 billion for the affected population, and yield 94.8% to 96.1% recovered by 30 months, but exceed available provider capacity. Partial implementation would lower costs and recovery proportionately.

Conclusions  Evidence-based mental health response is feasible, but requires targeted resources, increased provider capacity, and advanced planning.