Archives of general psychiatry最新文献

Context: Heightened moral sensitivity seems to characterize patients with obsessive-compulsive disorder (OCD). Recent advances in social cognitive neuroscience suggest that a compelling relationship may exist between this disorder-relevant processing bias and the functional activity of brain regions implicated in OCD.

Objective: To test the hypothesis that patients with OCD demonstrate an increased response of relevant ventromedial prefrontal and orbitofrontal cortex regions in a functional magnetic resonance imaging study of difficult moral decision making.

Design: Case-control cross-sectional study.

Setting: Hospital referral OCD unit and magnetic resonance imaging facility.

Participants: Seventy-three patients with OCD (42 men and 31 women) and 73 control participants matched for age, sex, and education level.

Main outcome measures: Functional magnetic resonance imaging activation maps representing significant changes in blood oxygenation level-dependent signal in response to 24 hypothetical moral dilemma vs nondilemma task vignettes and additional activation maps representing significant linear associations between patients' brain responses and symptom severity ratings.

Results: In both groups, moral dilemma led to robust activation of frontal and temporoparietal brain regions. Supporting predictions, patients with OCD demonstrated significantly increased activation of the ventral frontal cortex, particularly of the medial orbitofrontal cortex. In addition, the left dorsolateral prefrontal cortex and left middle temporal gyrus were more robustly activated in patients with OCD. These results were unexplained by group differences in comorbid affective symptoms. Patients' global illness severity predicted the relative magnitude of orbitofrontal-striatal activation. The severity of "harm/checking" symptoms and "sexual/religious" obsessions predicted the magnitude of posterior temporal and amygdala-paralimbic activation, respectively.

Conclusions: The neural correlates of moral sensitivity in patients with OCD partly coincide with brain regions that are of general interest to pathophysiologic models of this disorder. In particular, these findings suggest that the orbitofrontal cortex together with the left dorsolateral prefrontal cortex may be relevant for understanding the link between neurobiological processes and certain maladaptive cognitions in OCD.

Context: Maintenance antidepressant pharmacotherapy in late life prevents recurrent episodes of major depression. The coverage gap in Medicare Part D could increase the likelihood of reducing appropriate use of antidepressants, thereby exposing older adults to an increased risk for relapse of depressive episodes.

Objectives: To determine whether (1) beneficiaries reduce antidepressant use in the gap, (2) the reduction in antidepressant use is similar to the reduction in heart failure medications and antidiabetics, (3) the provision of generic coverage reduces the risk of reduction of medication use, and (4) medical spending increases in the gap.

Design: Observational before-after study with a comparison group design.

Setting and patients: A 5% random sample of US Medicare beneficiaries 65 years or older with depression (n = 65,223) enrolled in stand-alone Part D plans in 2007.

Main outcome measures: Antidepressant pharmacotherapy, physician, outpatient, and inpatient spending.

Results: Being in the gap was associated with comparable reductions in the use of antidepressants, heart failure medications, and antidiabetics. Relative to the comparison group (those who had full coverage in the gap because of Medicare coverage or low-income subsidies), the no-coverage group reduced their monthly antidepressant prescriptions by 12.1% (95% CI, 9.9%-14.3%) from the pregap level, whereas they reduced use of heart failure drugs and antidiabetics by 12.9% and 13.4%, respectively. Those with generic drug coverage in the gap reduced their monthly antidepressant prescriptions by 6.9% (95% CI, 4.8%-9.1%); this decrease was entirely attributable to the reduction in the use of brand-name antidepressants. Medicare spending on medical care did not increase for either group relative to the comparison group.

Conclusions: The Medicare Part D coverage gap was associated with modest reductions in the use of antidepressants. Those with generic coverage reduced their use of brand-name drugs and did not switch from brand-name to generic drugs. The reduction in antidepressant use was not associated with an increase in nondrug medical spending.

Context: Our genome adapts to environmental influences, in part through epigenetic mechanisms, including DNA methylation. Variations in the quality of the early environment are associated with alterations in DNA methylation in rodents, and recent data suggest similar processes in humans in response to early-life adversity.

Objective: To determine genome-wide DNA methylation alterations induced by early-life trauma.

Design: Genome-wide study of promoter methylation in individuals with severe abuse during childhood. PATIENTS, SETTING, AND MAIN OUTCOME MEASURES: Promoter DNA methylation levels were profiled using methylated DNA immunoprecipitation followed by microarray hybridization in hippocampal tissue from 41 French-Canadian men (25 with a history of severe childhood abuse and 16 control subjects). Methylation profiles were compared with corresponding genome-wide gene expression profiles obtained by messenger RNA microarrays. Methylation differences between groups were validated on neuronal and nonneuronal DNA fractions isolated by fluorescence-assisted cell sorting. Functional consequences of site-specific promoter methylation were assessed by luciferase assays.

Results: We identified 362 differentially methylated promoters in individuals with a history of abuse compared with controls. Among these promoters, 248 showed hypermethylation and 114 demonstrated hypomethylation. Validation and site-specific quantification of DNA methylation in the 5 most hypermethylated gene promoters indicated that methylation differences occurred mainly in the neuronal cellular fraction. Genes involved in cellular/neuronal plasticity were among the most significantly differentially methylated, and, among these, Alsin (ALS2) was the most significant finding. Methylated ALS2 constructs mimicking the methylation state in samples from abused suicide completers showed decreased promoter transcriptional activity associated with decreased hippocampal expression of ALS2 variants.

Conclusion: Childhood adversity is associated with epigenetic alterations in the promoters of several genes in hippocampal neurons.

Context: Schizophrenia is a devastating illness with an indeterminate pathophysiology. Several lines of evidence implicate dysfunction in the thalamus, a key node in the distributed neural networks underlying perception, emotion, and cognition. Existing evidence of aberrant thalamic function is based on indirect measures of thalamic activity, but dysfunction has not yet been demonstrated with a causal method.

Objective: To test the hypothesis that direct physiological stimulation of the cortex will produce an abnormal thalamic response in individuals with schizophrenia.

Design: We stimulated the precentral gyrus with single-pulse transcranial magnetic stimulation (spTMS) and measured the response to this pulse in synaptically connected regions (thalamus, medial superior frontal cortex, insula) using concurrent functional magnetic resonance imaging. The mean hemodynamic response from these regions was fit with the sum of 2 gamma functions, and response parameters were compared across groups.

Setting: Academic research laboratory.

Participants: Patients with schizophrenia and sex- and age-matched psychiatrically healthy subjects were recruited from the community.

Main outcome measure: Peak amplitude of the thalamic hemodynamic response to spTMS of the precentral gyrus.

Results: The spTMS-evoked responses did not differ between groups at the cortical stimulation site. Compared with healthy subjects, patients with schizophrenia showed a reduced response to spTMS in the thalamus (P=1.86 × 10(-9)) and medial superior frontal cortex (P=.02). Similar results were observed in the insula. Sham TMS indicated that these results could not be attributed to indirect effects of TMS coil discharge. Functional connectivity analyses revealed weaker thalamus-medial superior frontal cortex and thalamus-insula connectivity in patients with schizophrenia compared with control subjects.

Conclusions: Individuals with schizophrenia showed reduced thalamic activation in response to direct perturbation delivered to the cortex. These results extend prior work implicating the thalamus in the pathophysiology of schizophrenia and suggest that the thalamus contributes to the patterns of aberrant connectivity characteristic of this disease.

Context: The nature of the relationship of dissociation to posttraumatic stress disorder (PTSD) is controversial and of considerable clinical and nosologic importance.

Objectives: To examine evidence for a dissociative subtype of PTSD and to examine its association with different types of trauma.

Design: A latent profile analysis of cross-sectional data from structured clinical interviews indexing DSM-IV symptoms of current PTSD and dissociation.

Settings: The VA Boston Healthcare System and the New Mexico VA Health Care System.

Participants: A total of 492 veterans and their intimate partners, all of whom had a history of trauma. Participants reported exposure to a variety of traumatic events, including combat, childhood physical and sexual abuse, partner abuse, motor vehicle accidents, and natural disasters, with most participants reporting exposure to multiple types of traumatic events. Forty-two percent of the sample met the criteria for a current diagnosis of PTSD.

Main outcome measures: Item-level scores on the Clinician-Administered PTSD Scale.

Results: A latent profile analysis suggested a 3-class solution: a low PTSD severity subgroup, a high PTSD severity subgroup characterized by elevations across the 17 core symptoms of the disorder, and a small but distinctly dissociative subgroup that composed 12% of individuals with a current diagnosis of PTSD. The latter group was characterized by severe PTSD symptoms combined with marked elevations on items assessing flashbacks, derealization, and depersonalization. Individuals in this subgroup also endorsed greater exposure to childhood and adult sexual trauma compared with the other 2 groups, suggesting a possible etiologic link with the experience of repeated sexual trauma.

Conclusions: These results support the subtype hypothesis of the association between PTSD and dissociation and suggest that dissociation is a highly salient facet of posttraumatic psychopathology in a subset of individuals with the disorder.

Context: Rates of clinical diagnoses of schizophrenia in African American individuals appear to be elevated compared with other ethnic groups in the United States, contradicting population rates derived from epidemiologic surveys.

Objective: To determine whether African American individuals would continue to exhibit significantly higher rates of clinical diagnoses of schizophrenia, even after controlling for age, sex, income, site, and education, as well as the presence or absence of serious affective disorder, as determined by experts blinded to race and ethnicity. A secondary objective was to determine if a similar pattern occurred in Latino subjects.

Design: Ethnicity-blinded and -unblinded diagnostic assessments were obtained in 241 African American individuals (mean [SD] age, 34.3 [8.1] years; 57% women), 220 non-Latino white individuals (mean [SD] age, 32.7 [8.5] years; 53% women), and 149 Latino individuals (mean [SD] age, 33.5 [8.0] years; 58% women) at 6 US sites. Logistic regression models were used to determine whether elevated rates of schizophrenia in African American individuals would persist after controlling for various confounding variables including blinded expert consensus diagnoses of serious affective illness.

Settings: Six academic medical centers across the United States.

Participants: Six hundred ten psychiatric inpatients and outpatients.

Main outcome measure: Relative odds of unblinded clinical diagnoses of schizophrenia in African American compared with white individuals.

Results: A significant ethnicity/race effect (χ(2)(2)=10.4, P=.01) was obtained when schizophrenia was narrowly defined, controlling for all other predictors. The odds ratio comparing African American with non-Latino white individuals was significant (odds ratio=2.7; 95% CI, 1.5-5.1). Similar differences between African American and white individuals occurred when schizophrenia was more broadly defined (odds ratio=2.5; 95% CI, 1.4-4.5). African American individuals did not differ significantly from white individuals in overall severity of manic and depressive symptoms but did evidence more severe psychosis.

Conclusions: African American individuals exhibited significantly higher rates of clinical diagnoses of schizophrenia than non-Latino white subjects, even after controlling for covariates such as serious affective disorder.