Archives of general psychiatry最新文献

CONTEXT Abnormalities in associative memory processes, such as Pavlovian fear conditioning and extinction, have been observed in schizophrenia. The retrieval of fear extinction memories (safety signals) may be particularly affected; although schizophrenic patients can extinguish conditioned fear, they show a deficit in retrieving fear extinction memories after a delay. The neurobiological basis of this abnormality is unknown, but clues have emerged from studies in rodents and humans demonstrating that the ventromedial prefrontal cortex (vmPFC) is a key mediator of extinction memory retrieval. OBJECTIVE To measure autonomic and neural responses during the acquisition and extinction of conditioned fear and the delayed recall of fear and extinction memories in patients with schizophrenia and healthy control participants. DESIGN Cross-sectional case control, functional magnetic resonance imaging study. SETTING Academic medical center. PARTICIPANTS Twenty schizophrenic patients and 17 healthy control participants demographically matched to the patient group. MAIN OUTCOME MEASURES Skin conductance and blood oxygen level-dependent responses. RESULTS During fear conditioning, schizophrenic patients showed blunted autonomic responses and abnormal blood oxygen level-dependent responses, relative to control participants, within the posterior cingulate gyrus, hippocampus, and other regions. Several of these abnormalities were linked to negative symptoms. During extinction learning, patients with schizophrenia and control participants showed comparable autonomic and neural responses. Twenty-four hours after the learning phases, the control subjects exhibited decreased fear and increased vmPFC responses in the extinction (safe) context as expected, indicating successful retention of the extinction memory. In contrast, the schizophrenic patients showed inappropriately elevated fear and poor vmPFC responses in the safe context. CONCLUSION Failure of extinction memory retrieval in schizophrenia is associated with vmPFC dysfunction. In future studies, abnormalities in fear learning and extinction recall may serve as quantitative phenotypes that can be linked to genetic, symptom, or outcome profiles in schizophrenia and those at risk for the disorder.

Context: Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and nonpsychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk.

Objective: To identify single-nucleotide polymorphisms associated with antipsychotic drug–induced weight gain.

Design: Pharmacogenetic association study.

Setting: The discovery cohort was from a US general psychiatric hospital. Three additional cohorts were from psychiatric hospitals in the United States and Germany and from a European antipsychotic drug trial.

Participants: The discovery cohort consisted of 139 pediatric patients undergoing first exposure to SGAs. The 3 additional cohorts consisted of 73, 40, and 92 subjects.

Intervention: Patients in the discovery cohort were treated with SGAs for 12 weeks. Additional cohorts were treated for 6 and 12 weeks.

Main outcome measures: We conducted a genomewide association study assessing weight gain associated with 12 weeks of SGA treatment in patients undergoing first exposure to antipsychotic drugs. We next genotyped 3 independent cohorts of subjects assessed for antipsychotic drug-induced weight gain.

Results: Our genome-wide association study yielded 20 single-nucleotide polymorphisms at a single locus exceeding a statistical threshold of P<10(-5). This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale genome-wide association studies of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight during the 12-week trial. These results were replicated in 3 additional cohorts, with rs489693 demonstrating consistent recessive effects; meta-analysis revealed a genome-wide significant effect (P=5.59 X 10 (-12). Moreover, we observed consistent effects on related metabolic indices, including triglyceride, leptin, and insulin levels.

Conclusions: These data implicate MC4R in extreme SGA-induced weight gain and related metabolic disturbances. A priori identification of high-risk subjects could lead to alternative treatment strategies in this population.

Context: Despite empirical links between sexual revictimization (ie, experiencing 2 or more sexual assaults) and posttraumatic stress disorder (PTSD), to our knowledge, no epidemiological studies document the prevalence of sexual revictimization and PTSD. Establishing estimates is essential to determine the scope, public health impact, and psychiatric sequelae of sexual revictimization.

Objective: To estimate the prevalence of sexual revictimization and PTSD among 3 national female samples (adolescent, college, and adult household probability).

Design: Surveys were used to collect data from the National Women's Study-Replication (2006; college) as well as household probability samples from the National Survey of Adolescents-Replication (2005) and the National Women's Study-Replication (2006; household probability).

Setting: Households and college campuses across the United States.

Participants: One thousand seven hundred sixty-three adolescent girls, 2000 college women, and 3001 household-residing adult women.

Main outcome measures: Behaviorally specific questions assessed unwanted sexual acts occurring over the life span owing to the use of force, threat of force, or incapacitation via drug or alcohol use. Posttraumatic stress disorder was assessed with a module validated against the criterion standard Structured Clinical Interview for DSM-IV.

Results: About 53% of victimized adolescents, 50% of victimized college women, and 58.8% of victimized household-residing women reported sexual revictimization. Current PTSD was reported by 20% of revictimized adolescents, 40% of revictimized college women, and 27.2% of revictimized household-residing women. Compared with nonvictims, odds of meeting past 6-month PTSD were 4.3 to 8.2 times higher for revictimized respondents and 2.4 to 3.5 times higher for single victims.

Conclusions: Population prevalence estimates suggest that 769 000 adolescent girls, 625 000 college women, and 13.4 million women in US households reported sexual revictimization. Further, 154 000 sexually revictimized adolescents, 250 000 sexually revictimized college women, and 3.6 million sexually revictimized household women met criteria for past 6-month PTSD. Findings highlight the importance of screening for sexual revictimization and PTSD in pediatric, college, and primary care settings.

Context: The population of men who display persistent antisocial and violent behavior is heterogeneous. Callous-unemotional traits in childhood and psychopathic traits in adulthood characterize a distinct subgroup.

Objective: To identify structural gray matter (GM) differences between persistent violent offenders who meet criteria for antisocial personality disorder and the syndrome of psychopathy (ASPDP) and those meeting criteria only for ASPD (ASPD-P).

Design: Cross-sectional case-control structural magnetic resonance imaging study.

Setting: Inner-city probation services and neuroimaging research unit in London, England.

Participants: Sixty-six men, including 17 violent offenders with ASPDP, 27 violent offenders with ASPD-P, and 22 healthy nonoffenders participated in the study. Forensic clinicians assessed participants using the Structured Clinical Interview for DSM-IV and the Psychopathy Checklist-Revised.

Main outcome measures: Gray matter volumes as assessed by structural magnetic resonance imaging and volumetric voxel-based morphometry analyses.

Results: Offenders with ASPDP displayed significantly reduced GM volumes bilaterally in the anterior rostral prefrontal cortex (Brodmann area 10) and temporal poles (Brodmann area 20/38) relative to offenders with ASPD-P and nonoffenders. These reductions were not attributable to substance use disorders. Offenders with ASPD-P exhibited GM volumes similar to the nonoffenders.

Conclusions: Reduced GM volume within areas implicated in empathic processing, moral reasoning, and processing of prosocial emotions such as guilt and embarrassment may contribute to the profound abnormalities of social behavior observed in psychopathy. Evidence of robust structural brain differences between persistently violent men with and without psychopathy adds to the evidence that psychopathy represents a distinct phenotype. This knowledge may facilitate research into the etiology of persistent violent behavior.

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD. These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD.

CONTEXT Sustained-release naltrexone implants may improve outcomes of nonagonist treatment of opioid addiction. OBJECTIVE To compare outcomes of naltrexone implants, oral naltrexone hydrochloride, and nonmedication treatment. DESIGN Six-month double-blind, double-dummy, randomized trial. SETTING Addiction treatment programs in St Petersburg, Russia. PARTICIPANTS Three hundred six opioid-addicted patients recently undergoing detoxification. INTERVENTIONS Biweekly counseling and 1 of the following 3 treatments for 24 weeks: (1) 1000-mg naltrexone implant and oral placebo (NI+OP group; 102 patients); (2) placebo implant and 50-mg oral naltrexone hydrochloride (PI+ON group; 102 patients); or (3) placebo implant and oral placebo (PI+OP group; 102 patients). MAIN OUTCOME MEASURE Percentage of patients retained in treatment without relapse. RESULTS By month 6, 54 of 102 patients in the NI+OP group (52.9%) remained in treatment without relapse compared with 16 of 102 patients in the PI+ON group (15.7%) (survival analysis, log-rank test, P < .001) and 11 of 102 patients in the PI+OP group (10.8%) (P < .001). The PI+ON vs PI+OP comparison showed a nonsignificant trend favoring the PI+ON group (P = .07). Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32%-37%) for the PI+OP group (P < .001, Fisher exact test, compared with the NI+OP group). Twelve wound infections occurred among 244 implantations (4.9%) in the NI+OP group, 2 among 181 (1.1%) in the PI+ON group, and 1 among 148 (0.7%) in the PI+OP group (P = .02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy. Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P = .12), and all resolved with antiallergy medication treatment. Other nonlocal-site adverse effects were reported in 8 of 886 visits (0.9%) in the NI+OP group, 4 of 522 visits (0.8%) in the PI+ON group, and 3 of 394 visits (0.8%) in the PI+ON group; all resolved and none were serious. No evidence of increased deaths from overdose after naltrexone treatment ended was found. CONCLUSIONS The implant is more effective than oral naltrexone or placebo. More patients in the NI+OP than in the other groups develop wound infections or local irritation, but none are serious and all resolve with treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00678418.

Context: Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD.

Objectives: To investigate structural connectivity between ventral prefrontal cortex or anterior cingulate cortex areas and the amygdala in GAD and to assess associations with functional connectivity between those areas.

Design: Participants underwent diffusion-tensor imaging and functional magnetic resonance imaging.

Setting: University magnetic resonance imaging facility.

Participants: Forty-nine patients with GAD and 39 healthy volunteer control subjects, including a matched subset of 21 patients having GAD without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education.

Main outcome measures: The mean fractional anisotropy values in the left and right uncinate fasciculus, as measured by tract-based analysis for diffusion-tensor imaging data.

Results: Lower mean fractional anisotropy values in the bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in patients with GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all participants, higher fractional anisotropy values were associated with more negative functional coupling between the pregenual anterior cingulate cortex and the amygdala during the anticipation of aversion.

Conclusions: Reduced structural connectivity of a major frontolimbic pathway suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the anterior cingulate cortex and the amygdala in individuals with reduced structural integrity of the uncinate fasciculus.

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.