Archives of general psychiatry最新文献

CONTEXT Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. OBJECTIVE To study WM growth differences in nonpsychotic siblings of patients with COS. DESIGN Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. SETTING National Institutes of Health Clinical Center, Bethesda, Maryland. PARTICIPANTS Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1 [5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9 [5.3] years; 29 male, 28 female). INTERVENTION Magnetic resonance imaging. MAIN OUTCOME MEASURE White matter growth rates. RESULTS We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P = .004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. CONCLUSIONS In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age.

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: 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 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: Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D(2) receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia.

Objective: To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies.

Data sources: The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011.

Study selection: A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function.

Data extraction: Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables.

Data synthesis: There was a highly significant elevation (P.<001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability (Cohen d=0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used.

Conclusions: The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D(2/3) receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.