Context  Genetic, neuroimaging, and molecular neurobiological evidence support the hypothesis that the disconnectivity syndrome in schizophrenia (SZ) could arise from failures of saltatory conduction and abnormalities at the nodes of Ranvier (NOR) interface where myelin and axons interact.

Objective  To identify abnormalities in the expression of oligodendroglial genes and proteins that participate in the formation, maintenance, and integrity of the NOR in SZ.

Design  The messenger RNA (mRNA) expression levels of multiple NOR genes were quantified in 2 independent postmortem brain cohorts of individuals with SZ, and generalizability to protein expression was confirmed. The effect of the ANK3 genotype on the mRNA expression level was tested in postmortem human brain. Case-control analysis tested the association of the ANK3 genotype with SZ. The ANK3 genotype's influence on cognitive task performance and functional magnetic resonance imaging activation was tested in 2 independent cohorts of healthy individuals.

Setting  Research hospital.

Patients  Postmortem samples from patients with SZ and healthy controls were used for the brain expression study (n = 46) and the case-control analysis (n = 272). Healthy white men and women participated in the cognitive (n = 513) and neuroimaging (n = 52) studies.

Main Outcome Measures  The mRNA and protein levels in postmortem brain samples, genetic association with schizophrenia, cognitive performance, and blood oxygenation level–dependent functional magnetic resonance imaging.

Results  The mRNA expression of multiple NOR genes was decreased in schizophrenia. The ANK3 rs9804190 C allele was associated with lower ANK3 mRNA expression levels, higher risk for SZ in the case-control cohort, and poorer working memory and executive function performance and increased prefrontal activation during a working memory task in healthy individuals.

Conclusions  These results point to abnormalities in the expression of genes and protein associated with the integrity of the NOR and suggest them as substrates for the disconnectivity syndrome in SZ. The association of ANK3 with lower brain mRNA expression levels implicates a molecular mechanism for its genetic, clinical, and cognitive associations with SZ.

Context  Progressive loss of brain gray matter (GM) has been reported in childhood-onset schizophrenia; however, it is uncertain whether these changes are shared by pediatric patients with different psychoses.

Objective  To examine the progression of brain changes in first-episode early-onset psychosis and their relationship to diagnosis and prognosis at 2-year follow-up.

Design  Prospective, multicenter, naturalistic, 2-year follow-up study.

Setting  Six child and adolescent psychiatric units in Spain.

Participants  A total of 110 patients and 98 healthy controls were recruited between March 1, 2003, and November 31, 2005. Magnetic resonance imaging of the brain was performed for 61 patients with schizophrenia (n = 25), bipolar disorder (n = 16), or other psychoses (n = 20) and 70 controls (both at baseline and after 2 years of follow-up). Mean age at baseline was 15.5 years (patients) and 15.3 years (controls).

Main Outcome Measures  The GM and cerebrospinal fluid (CSF) volumes in the total brain and frontal, parietal, and temporal lobes.

Results  Compared with controls, patients with schizophrenia showed greater GM volume loss in the frontal lobe during the 2-year follow-up (left: –3.3 vs –0.6 cm3, P = .004; right: –3.7 vs –0.8 cm3, P = .005) and left frontal CSF volume increase (left: 6.7 vs 2.4 cm3, P = .006). In addition to frontal volume, changes for total GM (–37.1 vs –14.5 cm3, P = .001) and left parietal GM (–4.3 vs –2.2 cm3, P = .04) were significantly different in schizophrenic patients compared with controls. No significant differences emerged for patients with bipolar disease. Greater left frontal GM volume loss was related to more weeks of hospitalization, whereas severity of negative symptoms correlated with CSF increase in patients with schizophrenia.

Conclusions  Patients with schizophrenia or other psychoses showed greater loss of GM volume and increase of CSF in the frontal lobe relative to controls. Progressive changes were more evident in patients with schizophrenia than those with bipolar disorder. These changes in specific brain volumes after onset of psychotic symptoms may be related to markers of poorer prognosis.

Context  The aberrant processing of salience is thought to be a fundamental factor underlying psychosis. Cannabis can induce acute psychotic symptoms, and its chronic use may increase the risk of schizophrenia. We investigated whether its psychotic effects are mediated through an influence on attentional salience processing.

Objective  To examine the effects of 9-tetrahydrocannabinol (9-THC) and cannabidiol (CBD) on regional brain function during salience processing.

Design  Volunteers were studied using event-related functional magnetic resonance imaging on 3 occasions after administration of 9-THC, CBD, or placebo while performing a visual oddball detection paradigm that involved allocation of attention to infrequent (oddball) stimuli within a string of frequent (standard) stimuli.

Setting  University center.

Participants  Fifteen healthy men with minimal previous cannabis use.

Main Outcome Measures  Symptom ratings, task performance, and regional brain activation.

Results  During the processing of oddball stimuli, relative to placebo, 9-THC attenuated activation in the right caudate but augmented it in the right prefrontal cortex. 9-Tetrahydrocannabinol also reduced the response latency to standard relative to oddball stimuli. The effect of 9-THC in the right caudate was negatively correlated with the severity of the psychotic symptoms it induced and its effect on response latency. The effects of CBD on task-related activation were in the opposite direction of those of 9-THC; relative to placebo, CBD augmented left caudate and hippocampal activation but attenuated right prefrontal activation.

Conclusions  9-Tetrahydrocannabinol and CBD differentially modulate prefrontal, striatal, and hippocampal function during attentional salience processing. These effects may contribute to the effects of cannabis on psychotic symptoms and on the risk of psychotic disorders.

Context  Major depressive disorder is associated with impairments in processing emotional stimuli, and residual impairments are observed during remission, possibly indicating trait vulnerability. Stimuli with social context represent a distinct class of emotional stimuli, which in healthy volunteers are associated with specific neural substrates but have not previously been studied relative to vulnerability to depression.

Objective  To explore whether individuals with remitted major depressive disorder had altered neuronal processing of social emotional stimuli.

Design  Cross-sectional design using functional magnetic resonance imaging, combined with a cognitive activation task.

Setting  General community of greater Manchester, England.

Participants  Twenty-five unmedicated participants fully remitted from major depressive disorder and 29 age-matched control subjects.

Main Outcome Measures  Neuronal responses to positive and negative social interaction images vs valence-matched images with less overt social context.

Results  Participants with remitted depression showed attenuated frontopolar response relative to controls for positive and negative images depicting social interactions. For negative social images, participants with remitted depression also showed reduced latero-orbitofrontal response relative to controls.

Conclusions  In the absence of current symptoms, individuals with remitted major depressive disorder showed reduced frontopolar processing of stimuli showing social interactions, a reduction not seen for stimuli showing individual successes and failures and, therefore, not simply an effect of emotional valence. These results suggest a specific trait abnormality in social emotional processing associated with vulnerability to depression, which may have implications for understanding social cognition mechanisms and for developing effective psychological therapies.

Context  Autism spectrum disorders (ASDs) have been suggested to represent the extreme end of a normal distribution of autisticlike traits (ALTs). However, the evidence of this notion is inconclusive.

Objective  To study whether there are similar genetic and/or environmental etiologies behind ASDs and ALTs.

Design  A nationwide twin study.

Participants  Consenting parents of all Swedish twins aged 9 and 12 years, born between July 1, 1992, and December 31, 2001 (n = 19 208), were interviewed by telephone to screen for child psychiatric conditions, including ASDs.

Main Outcome Measures  Two validated cutoffs for ASDs, 2 cutoffs encompassing the normal variation, and 1 continuous measure of ALTs were used with DeFries-Fulker extreme-end analyses and standard twin study methods.

Results  We discerned a strong correlation between the 4 cutoffs and the full variation of ALTs. The correlation was primarily affected by genes. We also found that the heritability for the 4 cutoffs was similar.

Conclusion  We demonstrate an etiological similarity between ASDs and ALTs in the normal variation and, with results from previous studies, our data suggest that ASDs and ALTs are etiologically linked.

Context  Precocious amygdala enlargement is commonly observed in young children with autism. However, the age at which abnormal amygdala enlargement begins and the relative growth trajectories of the amygdala and total brain remain unclear.

Objective  To determine whether the rate of amygdala growth is abnormal and disproportionate to total brain growth in very young children with autism spectrum disorders (ASDs).

Design  Longitudinal structural magnetic resonance imaging study.

Setting  Neuroimaging and diagnostic assessments were performed at an academic medical center. Participants were recruited from the community.

Participants  Baseline scans were acquired in 132 boys (85 with ASD and 47 control subjects with typical development [TD]; mean age, 37 months). Longitudinal magnetic resonance images were acquired in 70 participants (45 with ASD and 25 TD controls) 1 year later.

Main Outcome Measure  Amygdala volumes and total cerebral volumes (TCVs) were evaluated at both time points, and 1-year growth rates were calculated.

Results  The amygdala was larger in children with ASD at both time points, but the magnitude of enlargement was greater at time 2. The TCV was also enlarged in the children with ASD by the same magnitude at both time points. When we controlled for TCV, amygdala enlargement remained significant at both time points. The rate of amygdala growth during this 1-year interval was faster in children with ASD than in TD controls. The rate of TCV growth did not differ between groups. Post hoc exploratory analyses revealed 3 patterns of amygdala and TCV growth rates in the ASD group.

Conclusions  Disproportionate amygdala enlargement is present by 37 months of age in ASD. The amygdala continues to grow at an increased rate, but substantial heterogeneity exists in amygdala and TCV growth patterns. Future studies aimed at clinical characterization of different growth patterns could have implications for choice and outcomes of treatment and behavioral therapy.

Context  Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamic-pituitary-adrenal axis dysregulation.

Objective  To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior.

Design  Cross-sectional study. Four FKBP5 single-nucleotide polymorphisms used in previous studies (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. Three diplotypes were derived from 2 major putatively functional haplotypes regulating protein expression that were previously associated with glucocorticoid receptor sensitivity.

Setting  Penitentiary District of Abruzzo-Molise in central Italy.

Participants  A population of 583 male Italian prisoners recruited between 2005 and 2008.

Main Outcome Measures  A comprehensive analysis of aggression and impulsivity was undertaken using the Brown-Goodwin Lifetime History of Aggression (BGHA) questionnaire, the Buss-Durkee Hostility Inventory (BDHI), and the Barratt Impulsiveness Scale (BIS). A history of childhood trauma was investigated with the Childhood Trauma Questionnaire. The interaction between the FKBP5 diplotypes and childhood trauma on measures of aggression was analyzed. Analyses were replicated with a second behavioral measure of aggression: violent behavior in jail. Individual single-nucleotide polymorphism analysis was performed.

Results  Childhood trauma had a significant effect on BGHA and BDHI scores but not on BIS scores. We observed a significant influence of the FKBP5 high-expression diplotype on both a lifetime history of aggressive behavior (BGHA) (P = .012) and violent behavior in jail (P = .025) but only in individuals exposed to childhood trauma, in particular to physical abuse. No main effect of the FKBP5 diplotypes was observed.

Conclusion  These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior.

Context  Excessive sleepiness (ES) is poorly defined in epidemiologic studies, although its adverse implications for safety, health, and optimal social and vocational functioning have been extensively reported.

Objective  To determine the importance of ES definition, measurement, and prevalence in the general population, together with its coexisting conditions.

Design  Cross-sectional telephone study.

Participants  A total of 15 929 individuals representative of the adult general population of 15 states in the United States.

Main Outcome Measures  Interviews were carried out using Sleep-EVAL, a knowledge-based expert system for use in epidemiologic studies, focusing on sleep, as well as physical and mental disorders, according to classification in DSM-IV and the second edition of the International Classification of Sleep Disorders. The interviews elicited information on ES, naps, frequency, duration, impairment, and distress associated with ES symptoms.

Results  Excessive sleepiness was reported by 27.8% (95% CI, 27.1%-28.5%) of the sample. Excessive sleepiness with associated symptoms was found in 15.6% of the participants (95% CI, 15.0%-16.2%). Adding an ES frequency of at least 3 times per week for at least 3 months despite normal sleep duration dropped the prevalence to 4.7% of the sample (95% CI, 4.4%-5.0%). The proportion of individuals having social or professional impairment and psychological distress increased with the frequency of ES symptoms during the week and within the same day. In multivariate models, the number of ES episodes per day and severity of ES were identified as the best predictors for impairment/distress. Prevalence of hypersomnia disorder was 1.5% of the participants (95% CI, 1.3%-1.7%). The most common coexisting conditions were mood and substance use disorders.

Conclusions  Excessive sleepiness is an important problem in the US population, even when using restrictive criteria to define it. Hypersomnia disorder is more prevalent than previously estimated. Excessive sleepiness has to be recognized and given attention by public health authorities, scientists, and clinicians.

Context  Although concern exists over the quality of emergency mental health services, little is known about the mental health care of adults who are admitted to emergency departments for deliberately harming themselves and then discharged to the community.

Objective  To describe the predictors of emergency department discharge, the emergency mental health assessments, and the follow-up outpatient mental health care of adult Medicaid beneficiaries treated for deliberate self-harm.

Design  A retrospective longitudinal cohort analysis.

Setting  National Medicaid claims data supplemented with county-level sociodemographic variables and Medicaid state policy survey data.

Participants  Adults aged 21 to 64 years who were treated in emergency departments for 7355 episodes of deliberate self-harm, focusing on those who were discharged to the community (4595 episodes).

Main Outcome Measures  Rates and adjusted risk ratios (ARRs) of discharge to the community, mental health assessments in the emergency department, and outpatient mental health visits during the 30 days following the emergency department visit.

Results  Most patients (62.5%) were discharged to the community. Emergency department discharge was directly related to younger patient age (21-31 years vs 45-64 years) (ARR, 1.18 [99% confidence interval {CI}, 1.10-1.25]) and self-harm by cutting (ARR, 1.18 [99% CI, 1.12-1.24]) and inversely related to poisoning (ARR, 0.84 [99% CI, 0.80-0.89]) and recent psychiatric hospitalization (ARR, 0.74 [99% CI, 0.67-0.81]). Approximately one-half of discharged patients (47.5%) received a mental health assessment in the emergency department, and a similar percentage of discharged patients (52.4%) received a follow-up outpatient mental health visit within 30 days. Follow-up mental health care was directly related to recent outpatient mental health care (ARR, 2.30 [99% CI, 2.11-2.50]) and treatment in a state with Medicaid coverage of mental health clinic services (ARR, 1.13 [99% CI, 1.05-1.22]) and inversely related to African American (ARR, 0.86 [99% CI, 0.75-0.96]) and Hispanic (ARR, 0.86 [99% CI, 0.75-0.99]) race/ethnicity.

Conclusion  Most adult Medicaid beneficiaries who present for emergency care for deliberate self-harm are discharged to the community, and many do not receive emergency mental health assessments or follow-up outpatient mental health care.

Context  The serotonin transporter (SLC6A4) has been associated with several stress-related syndromes including posttraumatic stress disorder (PTSD). The ability to detect meaningful associations is largely dependent on reliable measures of preexisting trauma.

Objective  To study the association of genetic variants within SLC6A4 with acute and posttraumatic stress symptoms in a civilian cohort with known levels of preexisting trauma and PTSD symptoms collected prior to a shared index traumatic event.

Design  Ongoing longitudinal study.

Setting  On February 14, 2008, a lone gunman shot multiple people on the campus of Northern Illinois University in DeKalb, Illinois, killing 5 and wounding 21. As part of an ongoing longitudinal study on that campus, a cohort of female undergraduate students, interviewed prior to the shooting, completed follow-up trauma-related measures including PTSD symptom severity (follow-up survey was launched 17 days postshooting; n = 691). To obtain DNA, salivary samples were collected from a subset of the original study population based on willingness to participate (n = 276).

Participants  Two hundred four undergraduate women.

Main Outcome Measures  SLC6A4 polymorphisms STin2, 5-HTTLPR, and rs25531 were genotyped in 235 individuals.

Results  We found that although the STin2 variant and 5-HTTLPR alone did not associate with increased PTSD symptoms, rs25531 and the 5-HTTLPR multimarker genotype (combined 5-HTTLPR and rs25531) were associated with significantly increased acute stress disorder symptoms at 2 to 4 weeks postshooting (n = 161; P < .05). This association remained significant when controlling for race and for level of shooting exposure (n = 123; P < .007). The association was most robust with the 5-HTTLPR multimarker genotype and avoidance symptoms (P = .003).

Conclusion  These data suggest that differential function of the serotonin transporter may mediate differential response to a severe trauma. When examined in a relatively homogenous sample with shared trauma and known prior levels of child and adult trauma, the 5-HTTLPR multimarker genotype may serve as a useful predictor of risk for PTSD-related symptoms in the weeks and months following the trauma.

Context  Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease.

Objectives  To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD.

Design  A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years).

Setting  Memory disorder clinic.

Patients  A total of 137 patients with MCI who underwent lumbar puncture at baseline.

Main Outcome Measure  Conversion to AD dementia.

Results  During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%.

Conclusions  Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.

Context  It has been suggested that attenuated psychotic symptoms (APSs) reported by people who do not have psychotic disorders signal risk for later severe mental illness.

Objective  To investigate this suggestion using follow-up assessments of hospitalization for clinical diagnoses of nonaffective psychotic and other psychiatric disorders.

Design  Longitudinal cohort study of self-reported APSs with outcome assessment of severe mental illness obtained through linkage with a national hospitalization case registry.

Setting  Israel.

Participants  A stratified full probability sample of 4914 persons aged 25 to 34 years who were screened for psychopathology in the 1980s.

Main Outcome Measure  Subsequent psychiatric hospitalization was ascertained using the psychiatric hospitalization registry, with a mean follow-up of 24 years.

Results  After removing subjects with diagnosable psychotic disorders at baseline, 57.2% of the remaining sample reported at least 1 weak (infrequent) APS and 14.3% reported at least 1 strong (frequent) APS in the year preceding the assessment. Self-reported APSs predicted risk of later hospitalization for nonaffective psychotic disorders, mostly during the 5 years after baseline (adjusted odds ratio = 4.31; 95% CI, 2.21-8.41; positive predictive value = 1.27%; population attributable risk fraction = 33%). Also, APSs increased the risk of later hospitalization for other psychiatric disorders, albeit to a lesser extent (adjusted odds ratio = 2.21; 95% CI, 1.02-4.82).

Conclusions  Self-reported APSs signal risk for later nonaffective psychotic disorders but are not clinically useful as predictors. The difference between these population-based data and the high-risk literature in terms of the positive predictive value (1% vs 10%, respectively) and the time window of transition (5 years vs 12 months, respectively) can be attributed to the selective enrichment strategies that produce high-risk samples.

Context  Postmortem studies have found evidence of -aminobutyric acid (GABA) deficits in fast-spiking, parvalbumin-positive interneurons in the prefrontal cortex in schizophrenia. Magnetic resonance spectroscopy studies in unmedicated patients have reported glutamine or glutamate-glutamine (Glx) elevations in this region. Abnormalities in these transmitters are thought to play a role in cognitive impairments in the illness.

Objective  To measure GABA and Glx levels in vivo in 2 prefrontal brain regions in unmedicated and medicated patients with schizophrenia and healthy controls.

Design  Case-control study.

Setting  Inpatient psychiatric research unit and associated outpatient clinic.

Participants  Sixteen unmedicated patients with schizophrenia, 16 medicated patients, and 22 healthy controls matched for age, sex, ethnicity, parental socioeconomic status, and cigarette smoking.

Methods  Proton magnetic resonance spectroscopy with a 3-T system and the J-edited spin-echo difference method. The GABA and Glx levels were measured in the dorsolateral and medial prefrontal cortex and normalized to the simultaneously acquired water signal. Working memory performance was assessed in all subjects.

Main Outcome Measures  The GABA and Glx concentrations determined by proton magnetic resonance spectroscopy.

Results  In the medial prefrontal cortex region, 30% elevations were found in GABA (P = .02) and Glx (P = .03) levels in unmedicated patients compared with controls. There were no alterations in the medicated patients or in either group in the dorsolateral prefrontal cortex. Both regions showed correlations between GABA and Glx levels in patients and controls. No correlations with working memory performance were found.

Conclusions  To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies.

Context  There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents.

Objective  To investigate which medication to administer first to antimanic medication–naive subjects.

Design, Setting, and Participants  The Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments.

Interventions  Subjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 μg/mL), and risperidone (4-6 mg).

Main Outcome Measures  Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement–Mania and the Modified Side Effects Form for Children and Adolescents.

Results  There were 279 antimanic medication–naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) μg/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; 21 = 16.9, P < .001) and vs divalproex sodium (68.5% vs 24.0%; 21 = 28.3, P < .001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (21 = 6.4, P = .011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F1,212 = 45.5, P < .001; F1,212 = 39.1, P < .001; and F1,213 = 191.4, P < .001, respectively) and vs divalproex sodium (F1,212 = 34.7, P < .001; F1,212 = 45.3, P < .001; and F1,213 = 209.4, P < .001, respectively). The thyrotropin level increased in subjects taking lithium (t62 = 11.3, P < .001).

Conclusions  Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects.

Trial Registration  clinicaltrials.gov Identifier: NCT00057681

Context  Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited.

Objective  To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP).

Design  Open-label trial with a sham lead-in phase.

Setting  Academic medical center.

Patients  Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened.

Intervention  Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation.

Main Outcome Measures  Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation.

Results  A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n = 17), 5 (36%) and 5 (36%) after 1 year (n = 14), and 7 (58%) and 11 (92%) after 2 years (n = 12) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase.

Conclusions  The findings of this study support the long-term safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP.

Trial Registration  clinicaltrials.gov Identifier: NCT00367003

Context  Gilles de la Tourette syndrome (GTS) is a hyperkinetic movement disorder with heterogeneous phenotypic expression ranging from simple motor and vocal tics to more complex tics associated with psychiatric comorbidities. The heterogeneity of clinical phenotypes may relate to the dysfunction of distinct frontal cortex–basal ganglia circuits.

Objectives  To assess the hypothesis that simple motor tics and comorbid obsessive-compulsive disorders are associated with dysfunction of motor and reward circuits, respectively, and to assess the effects of various antipsychotic medications because they are known to reduce motor tics and interact with dopamine-related reward processing.

Design  Sixty patients with GTS were divided into different subgroups depending on their clinical phenotypes and pharmacological treatments. The GTS patients and healthy control subjects underwent functional magnetic resonance imaging while they performed an instrumental learning task that involved adjusting choices between 2 responses (left- or right-hand movements) based on outcomes (reward or no reward).

Setting  Reference center for GTS, Centre de NeuroImagerie de recherche (CENIR) Paris, France.

Patients  Sixty GTS patients and 50 controls.

Results  Movement-related activation in motor circuits was diminished in GTS patients with simple tics only. Reward-related activation in limbic circuits was independently reduced by the following 2 factors: the presence of associated obsessive-compulsive symptoms (mostly compulsions) and the presence of medication with typical antipsychotics (dopamine receptor antagonists). Computational modeling with standard reinforcement learning algorithms indicated that, for both factors, the diminished reward-related activation could account for the impaired choice performance. Reinforcement learning was not affected by aripiprazole, a recent medication that acts as a partial dopamine agonist.

Conclusions  These results support the hypothesized correspondence between clinical phenotypes and frontal cortex–basal ganglia circuits. Antipsychotic treatment effects comply with formal conceptions that dopamine serves as a teaching signal for reinforcement learning. Furthermore, we suggest that, unlike typical antipsychotics, aripiprazole may preserve reward sensitivity and hence avoid blunting motivational drives.

Context  Attention-deficit/hyperactivity disorder is an etiologically heterogeneous neurodevelopmental condition with long-term negative outcomes. However, the early developmental course of hyperactivity-impulsivity and inattention symptoms and their association with previous environmental risk factors are still poorly understood

Objectives  To describe the developmental trajectories of hyperactivity-impulsivity and inattention symptoms and to identify their prenatal, perinatal, and postnatal risk factors.

Design  Birth cohort from the general population.

Setting  Quebec Longitudinal Study of Child Development.

Participants  The sample consisted of 2057 individuals, followed up from age 5 months to 8 years.

Main Outcome Measures  Prenatal, perinatal, and postnatal risk factors assessed at age 5 months were considered predictors of group membership in high hyperactivity-impulsivity and inattention trajectories from age 17 months to 8 years.

Results  The frequency of hyperactivity-impulsivity symptoms tended to slightly decrease with age, whereas the frequency of inattention symptoms substantially increased up to age 6 years. However, trajectories of hyperactivity-impulsivity and inattention symptoms were significantly associated with each other. Risk factors for high trajectories of both types of symptoms were premature birth (adjusted odds ratio [aOR], 1.93; 95% CI, 1.07-3.50), low birth weight (2.11; 1.12-3.98), prenatal tobacco exposure (1.41; 1.03-1.93), nonintact family (1.85; 1.26-2.70), young maternal age at birth of the target child (1.78; 1.17-2.69), paternal history of antisocial behavior (1.78; 1.28-2.47), and maternal depression (1.35; 1.18-1.54).

Conclusions  A large range of early risk factors, including prenatal, perinatal social, and parental psychopathology variables, act independently to heighten the likelihood of having persistently high levels of hyperactivity-impulsivity and inattention symptoms from infancy to middle childhood. Early interventions should be experimented with to provide effective tools for attention-deficit/hyperactivity disorder prevention.