Archives of general psychiatry最新文献

Context: Reduced neural responses to others' distress is hypothesized to play a critical role in conduct problems coupled with callous-unemotional traits, whereas increased neural responses to affective stimuli may accompany conduct problems without callous-unemotional traits. Heterogeneity of affective profiles in conduct problems may account for inconsistent neuroimaging findings in this population.

Objectives: To broaden understanding of neural processing in conduct problems using an affective processing task including an empathy component as well as to explore dimensional contributions of conduct problems symptoms and callous-unemotional traits to variance in affective neural responses.

Design: Case-control study.

Setting: On-campus neuroimaging facility.

Participants: Thirty-one boys with conduct problems (mean age, 14.34 years) and 16 typically developing control subjects (mean age, 13.51 years) matched for age (range, 10-16 years), IQ, socioeconomic status, handedness, and race/ethnicity. Participants were recruited using screening questionnaires in a community-based volunteer sample.

Main outcome measures: Functional magnetic resonance imaging of a task contrasting affective and cognitive theory of mind judgments.

Results: Relative to typically developing children, children with conduct problems showed reduced activation in right amygdala and anterior insula for affective vs cognitive theory of mind judgments. Furthermore, in the right amygdala, regression analysis within the conduct-problems group showed suppressor effects between ratings of conduct problems and callous-unemotional traits. Specifically, unique variance associated with conduct problems was positively correlated with amygdala reactivity, whereas unique variance associated with callous-unemotional traits was negatively correlated with amygdala reactivity. These associations were not explained by hyperactivity, depression/anxiety symptoms, or alcohol use ratings.

Conclusions: Childhood conduct problems are associated with amygdala and anterior insula hypoactivity during a complex affective processing task including an empathy component. Suppressor effects between conduct problems and callous-unemotional traits in the amygdala suggest a potential neural substrate for heterogeneity in affective profiles associated with conduct problems.

Context: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.

Objective: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.

Data sources: Primary data.

Study selection: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.

Data extraction: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.

Data synthesis: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01).

Conclusion: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

Context: In alcohol-dependent patients, brain atrophy and functional brain activation elicited by alcohol-associated stimuli may predict relapse. However, to date, the interaction between both factors has not been studied.

Objective: To determine whether results from structural and functional magnetic resonance imaging are associated with relapse in detoxified alcohol-dependent patients.

Design: A cue-reactivity functional magnetic resonance experiment with alcohol-associated and neutral stimuli. After a follow-up period of 3 months, the group of 46 detoxified alcohol-dependent patients was subdivided into 16 abstainers and 30 relapsers.

Setting: Faculty for Clinical Medicine Mannheim at the University of Heidelberg, Germany.

Participants: A total of 46 detoxified alcohol-dependent patients and 46 age- and sex-matched healthy control subjects

Main outcome measures: Local gray matter volume, local stimulus-related functional magnetic resonance imaging activation, joint analyses of structural and functional data with Biological Parametric Mapping, and connectivity analyses adopting the psychophysiological interaction approach.

Results: Subsequent relapsers showed pronounced atrophy in the bilateral orbitofrontal cortex and in the right medial prefrontal and anterior cingulate cortex, compared with healthy controls and patients who remained abstinent. The local gray matter volume-corrected brain response elicited by alcohol-associated vs neutral stimuli in the left medial prefrontal cortex was enhanced for subsequent relapsers, whereas abstainers displayed an increased neural response in the midbrain (the ventral tegmental area extending into the subthalamic nucleus) and ventral striatum. For alcohol-associated vs neutral stimuli in abstainers compared with relapsers, the analyses of the psychophysiological interaction showed a stronger functional connectivity between the midbrain and the left amygdala and between the midbrain and the left orbitofrontal cortex.

Conclusions: Subsequent relapsers displayed increased brain atrophy in brain areas associated with error monitoring and behavioral control. Correcting for gray matter reductions, we found that, in these patients, alcohol-related cues elicited increased activation in brain areas associated with attentional bias toward these cues and that, in patients who remained abstinent, increased activation and connectivity were observed in brain areas associated with processing of salient or aversive stimuli.

Context: Despite the expanding clinical utility of antipsychotics beyond psychotic disorders to include depressive, bipolar, and anxiety disorders, reproductive safety data regarding the neurodevelopmental sequelae of fetal antipsychotic exposure are scarce.

Objective: To examine whether intrauterine antipsychotic exposure is associated with deficits in neuromotor performance and habituation in 6-month-old infants.

Design, setting, and participants: A prospective controlled study was conducted from December 1999 through June 2008 at the Infant Development Laboratory of the Emory Psychological Center examining maternal-infant dyads (N=309) at 6 months postpartum with pregnancy exposure to antipsychotics (n=22), antidepressants (n=202), or no psychotropic agents (n=85). Examiners masked to maternal-infant exposure status administered a standardized neuromotor examination (Infant Neurological International Battery [INFANIB]) that tests posture, tone, reflexes, and motor skills and a visual habituation paradigm using a neutral female face.

Main outcome measures: The INFANIB composite score; number of trials required to achieve a 50% decrease in infant fixation during a visual habituation task; and mean time looking at the stimulus across 10 trials.

Results: Infants prenatally exposed to antipsychotics (mean=64.71) showed significantly lower INFANIB scores than those with antidepressant (mean=68.57) or no psychotropic (mean=71.19) exposure, after controlling for significant covariates (F(2,281)=4.51; P=.01; partial η(2)=0.033). The INFANIB scores were also significantly associated with maternal psychiatric history, including depression, psychosis, and overall severity/chronicity (P's.05) and maternal depression during pregnancy was associated with less efficient habituation (r(245)=0.16; P.02). There were no significant differences regarding habituation between medication exposure groups.

Conclusions: Among 6-month-old infants, a history of intrauterine antipsychotic exposure, compared with antidepressant or no psychotropic exposure, was associated with significantly lower scores on a standard test of neuromotor performance, highlighting the need for further scrutiny of the reproductive safety and neurodevelopmental sequelae of fetal antipsychotic exposure. Disentangling medication effects from maternal illness effects, which also contributed, remains a critical challenge.

Context: Mental disorders have been associated with increased mortality, but the evidence is primarily based on hospital admissions for psychoses. The underlying mechanisms are unclear.

Objectives: To investigate whether the risks of death associated with mental disorders diagnosed in young men are similar to those associated with admission for these disorders and to examine the role of confounding or mediating factors.

Design: Prospective cohort study in which mental disorders were assessed by psychiatric interview during a medical examination on conscription for military service at a mean age of 18.3 years and data on psychiatric hospital admissions and mortality during a mean 22.6 years of follow-up were obtained from national registers.

Setting: Sweden.

Participants: A total of 1,095,338 men conscripted between 1969 and 1994.

Main outcome measure: All-cause mortality according to diagnoses of schizophrenia, other nonaffective psychoses, bipolar or depressive disorders, neurotic and adjustment disorders, personality disorders, and alcohol-related or other substance use disorders at conscription and on hospital admission.

Results: Diagnosis of mental disorder at conscription or on hospital admission was associated with increased mortality. Age-adjusted hazard ratios according to diagnoses at conscription ranged from 1.81 (95% CI, 1.54-2.10) (depressive disorders) to 5.55 (95% CI, 1.79-17.2) (bipolar disorders). The equivalent figures according to hospital diagnoses ranged from 5.46 (95% CI, 5.06-5.89) (neurotic and adjustment disorders) to 11.2 (95% CI, 10.4-12.0) (other substance use disorders) in men born from 1951 to 1958 and increased in men born later. Adjustment for early-life socioeconomic status, body mass index, and blood pressure had little effect on these associations, but they were partially attenuated by adjustment for smoking, alcohol intake, intelligence, educational level, and late-life socioeconomic status. These associations were not primarily due to deaths from suicide.

Conclusion: The increased risk of premature death associated with mental disorder is not confined to those whose illness is severe enough for hospitalization or those with psychotic or substance use disorders.

Context: Hoarding disorder (HD), previously considered a subtype of obsessive-compulsive disorder (OCD), has been proposed as a unique diagnostic entity in DSM-5. Current models of HD emphasize problems of decision-making, attachment to possessions, and poor insight, whereas previous neuroimaging studies have suggested abnormalities in frontal brain regions.

Objective: To examine the neural mechanisms of impaired decision making in HD in patients with well-defined primary HD compared with patients with OCD and healthy control subjects (HCs).

Design: We compared neural activity among patients with HD, patients with OCD, and HCs during decisions to keep or discard personal possessions and control possessions from November 9, 2006, to August 13, 2010.

Setting: Private, not-for-profit hospital.

Participants: A total of 107 adults (43 with HD, 31 with OCD, and 33 HCs).

Main outcome measures: Neural activity as measured by functional magnetic resonance imaging in which actual real-time and binding decisions had to be made about whether to keep or discard possessions.

Results: Compared with participants with OCD and HC, participants with HD exhibited abnormal activity in the anterior cingulate cortex and insula that was stimulus dependent. Specifically, when deciding about items that did not belong to them, patients with HD showed relatively lower activity in these brain regions. However, when deciding about items that belonged to them, these regions showed excessive functional magnetic resonance imaging signals compared with the other 2 groups. These differences in neural function correlated significantly with hoarding severity and self-ratings of indecisiveness and "not just right" feelings among patients with HD and were unattributable to OCD or depressive symptoms.

Conclusions: Findings suggest a biphasic abnormality in anterior cingulate cortex and insula function in patients with HD related to problems in identifying the emotional significance of a stimulus, generating appropriate emotional response, or regulating affective state during decision making.

Context: Although the apolipoprotein E (APOE) ϵ4 allele is a major genetic risk factor for late-onset Alzheimer disease, its effect on hippocampal function during episodic memory is controversial because studies have yielded mixed results. The age of the studied cohorts may contribute to this apparent inconsistency: activation for ϵ4 carriers tends to be increased in studies of older adults but decreased in some studies of younger adults. Consistent with differential age effects, research in transgenic mice suggests that the ϵ4 allele may particularly affect the aging process.

Objective: To define the interactions of age and this allelic variation on brain activation during episodic memory across adult life in healthy individuals.

Design: Functional magnetic resonance imaging (fMRI) using an episodic memory paradigm to test for differences in neuroactivation across APOE genotypes and age groups.

Setting: A federal research institute.

Participants: Healthy white volunteers (APOE ϵ3 homozygotes and ϵ2 and ϵ4 heterozygotes) completed the fMRI task (133 volunteers aged 19-77 years).

Main outcome measure: Memory-related regional blood oxygenation level-dependent (BOLD) activation.

Results: Genotype affected the pattern of change in hippocampal BOLD activation across the adult lifespan: older age was associated with decreased activation in ϵ2 carriers and, to a lesser extent, in ϵ3 homozygotes, but this pattern was not observed in ϵ4 carriers. Among young participants, ϵ4 carriers had less hippocampal activation compared with ϵ3 homozygotes despite similar task performance.

Conclusions: The findings support the hypothesis that aging and APOE allele status have interacting effects on the neural substrate of episodic memory and lend clarification to disparities in the literature. The stepwise decrease in activation with age found among genotype groups resembles the order of susceptibility to Alzheimer disease, suggesting a compensatory neurobiological mechanism in older asymptomatic ϵ4 carriers.

Context: Tics in Tourette syndrome begin in childhood, peak in early adolescence, and often decrease by early adulthood. However, some adult patients continue to have impairing tics. Medications for tics are often effective but can cause adverse effects. Behavior therapy may offer an alternative but has not been examined in a large-scale controlled trial in adults.

Objective: To test the efficacy of a comprehensive behavioral intervention for tics in adults with Tourette syndrome of at least moderate severity.

Design: A randomized controlled trial with posttreatment evaluations at 3 and 6 months for positive responders.

Setting: Three outpatient research clinics.

Patients: Patients (N = 122; 78 males; age range, 16-69 years) with Tourette syndrome or chronic tic disorder were recruited between December 27, 2005, and May 21, 2009.

Interventions: Patients received 8 sessions of comprehensive behavioral intervention for tics or 8 sessions of supportive treatment for 10 weeks. Patients with a positive response were given 3 monthly booster sessions.

Main outcome measures: Total tic score on the Yale Global Tic Severity Scale and the Clinical Global Impression-Improvement scale rated by a clinician masked to treatment assignment.

Results: Behavior therapy was associated with a significantly greater mean (SD) decrease on the Yale Global Tic Severity Scale (24.0 [6.47] to 17.8 [7.32]) from baseline to end point compared with the control treatment (21.8 [6.59] to 19.3 [7.40]) (P < .001; effect size = 0.57). Twenty-four of 63 patients (38.1%) were rated as much improved or very much improved on the Clinical Global Impression-Improvement scale compared with 4 of 63 (6.4%) in the control group (P < .001). Attrition was 13.9%, with no difference across groups. Patients receiving behavior therapy who were available for assessment at 6 months after treatment showed continued benefit.

Conclusion: Comprehensive behavior therapy is a safe and effective intervention for adults with Tourette syndrome.

Trial registration: clinicaltrials.gov Identifier: NCT00231985.