Archives of general psychiatry最新文献

Context: Data from animal models demonstrate a link between stress exposure and hypertrophic changes in the amygdala; however, studies of adults with posttraumatic stress disorder (PTSD) have failed to find analogous structural alterations.

Objectives: To compare amygdala volumes between a sample of combat veterans with and without PTSD (analysis 1) and examine whether our observation of larger amygdala volume in individuals with PTSD could be accounted for by the presence of trauma exposure in childhood and the severity of combat exposure in adulthood (analysis 2).

Design: Cross-sectional magnetic resonance imaging.

Setting: Veterans Affairs Palo Alto Health Care System Inpatient Trauma Recovery Program and Veterans Affairs New England Health Care System Outpatient PTSD program.

Participants: Ninety-nine combat-exposed veterans from the Vietnam Conflict or the Persian Gulf War who had been exposed to substantial military operational stress.

Main outcome measures: Amygdala volume adjusted for total cerebral volume, Life Events Checklist, and the Combat Exposure Scale.

Results: Analysis 1 indicated that combat-exposed individuals with PTSD exhibited larger total amygdala volume compared with their non-PTSD counterparts (99 individuals, P = .047). Analysis 2 indicated that greater severity of combat exposure (87 individuals, P = .02), as well as the interaction between the presence of early life trauma and the severity of combat exposure (87 individuals, P = .008), were significantly associated with smaller total amygdala volume. The PTSD diagnosis continued to explain larger amygdala volume (87 individuals, P = .006).

Conclusions: Posttraumatic stress disorder is associated with enlarged amygdala volume, above the variance accounted for by a history of early life trauma and severity of adult trauma exposure. The discrepancy between our and prior findings may be explained by variability in these trauma indices in previous investigations. These findings support additional study of amygdala structure in human stress disorders and further delineation of the role of early and adult trauma on associated neurologic changes.

Context: Proneness to overgeneralization of self-blame is a core part of cognitive vulnerability to major depressive disorder (MDD) and remains dormant after remission of symptoms. Current neuroanatomical models of MDD, however, assume general increases of negative emotions and are unable to explain biases toward emotions entailing self-blame (eg, guilt) relative to those associated with blaming others (eg, indignation). Recent functional magnetic resonance imaging (fMRI) studies in healthy participants have shown that moral feelings such as guilt activate representations of social meaning within the right superior anterior temporal lobe (ATL). Furthermore, this area was selectively coupled with the subgenual cingulate cortex and adjacent septal region (SCSR) during the experience of guilt compared with indignation. Despite its psychopathological importance, the functional neuroanatomy of guilt in MDD is unknown.

Objective: To use fMRI to test the hypothesis that, in comparison with control individuals, participants with remitted MDD exhibit guilt-selective SCSR-ATL decoupling as a marker of deficient functional integration.

Design: Case-control study from May 1, 2008, to June 1, 2010.

Setting: Clinical research facility.

Participants: Twenty-five patients with remitted MDD (no medication in 16 patients) with no current comorbid Axis I disorders and 22 controls with no personal or family history of MDD.

Main outcome measures: Between-group difference of ATL coupling with a priori SCSR region of interest for guilt vs indignation.

Results: We corroborated the prediction of a guilt-selective reduction in ATL-SCSR coupling in MDD vs controls (familywise error-corrected P=.001 over the region of interest) and revealed additional medial frontopolar, right hippocampal, and lateral hypothalamic areas of decoupling while controlling for medication status and intensity of negative emotions. Lower levels of ATL-SCSR coupling were associated with higher scores on a validated measure of overgeneralized self-blame (67-item Interpersonal Guilt Questionnaire).

Conclusions: Vulnerability to MDD is associated with temporofrontolimbic decoupling that is selective for self-blaming feelings. This provides the first neural mechanism ofMDD vulnerability that accounts for self-blaming biases.

Context: Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function.

Objectives: To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior.

Design: Cross-sectional and longitudinal studies.

Setting: Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia.

Patients: Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment.

Main outcome measures: Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa-induced depression, anhedonia, fatigue, and neurotoxicity.

Results: Patients with HCV receiving interferon alfa for 4 to 6 weeks (n = 14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n = 14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n = 12) exhibited significantly increased 18F-dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration.

Conclusions: These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release.

Context: Despite the frequent occurrence of depressive symptoms among older adults, especially women, little is known about the long-term course of late-life depressive symptoms.

Objective: To characterize the natural course of depressive symptoms among older women (from the young old to the oldest old) followed up for almost 20 years.

Design: Using latent-class growth-curve analysis, we analyzed women enrolled in an ongoing prospective cohort study (1988 through 2009).

Setting: Clinic sites in Baltimore, Maryland; Minneapolis, Minnesota; the Monongahela Valley near Pittsburgh, Pennsylvania; and Portland, Oregon.

Participants: We studied 7240 community-dwelling women 65 years or older.

Main outcome measure: The Geriatric Depression Scale short form (score range, 0-15) was used to routinely assess depressive symptoms during the follow-up period.

Results: Among older women, we identified 4 latent classes during 20 years, with the predicted probabilities of group membership totaling 27.8% with minimal depressive symptoms, 54.0% with persistently low depressive symptoms, 14.8% with increasing depressive symptoms, and 3.4% with persistently high depressive symptoms. In an adjusted model for latent class membership, odds ratios (ORs) for belonging in the increasing depressive symptoms and persistently high depressive symptoms classes, respectively, compared with a group having minimal depressive symptoms were substantially and significantly (P < .05) elevated for the following variables: baseline smoking (ORs, 4.69 and 7.97), physical inactivity (ORs, 2.11 and 2.78), small social network (ORs, 3.24 and 6.75), physical impairment (ORs, 8.11 and 16.43), myocardial infarction (ORs, 2.09 and 2.41), diabetes mellitus (ORs, 2.98 and 3.03), and obesity (ORs, 1.86 and 2.90).

Conclusions: During 20 years, almost 20% of older women experienced persistently high depressive symptoms or increasing depressive symptoms. In addition, these women had more comorbidities, physical impairment, and negative lifestyle factors at baseline. These associations support the need for intervention and prevention strategies to reduce depressive symptoms into the oldest-old years.

CONTEXT The single-nucleotide polymorphism rs1344706 in the gene ZNF804a has been associated with schizophrenia and with quantitative phenotypic features, including brain structure volume and the core symptoms of schizophrenia. OBJECTIVE To evaluate associations of rs1344706 with brain structure and the core symptoms of schizophrenia. DESIGN Case-control analysis of covariance. SETTING University-based research hospital. PARTICIPANTS Volunteer sample of 335 individuals with schizophrenia spectrum disorders (306 with core schizophrenia) and 198 healthy volunteers. MAIN OUTCOME MEASURES Cerebral cortical gray matter and white matter (WM) volumes (total and frontal, parietal, temporal, and occipital lobes), lateral ventricular cerebrospinal fluid volume, and symptom severity from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms divided into 3 domains: psychotic, negative, and disorganized. RESULTS The rs1344706 genotype produced significant main effects on total, frontal, and parietal lobe WM volumes (F = 3.98, P = .02; F = 4.95, P = .007; and F = 3.08, P = .05, respectively). In the schizophrenia group, rs1344706 produced significant simple effects on total (F = 3.93, P = .02) and frontal WM volumes (F = 7.16, P < .001) and on psychotic symptom severity (F = 6.07, P = .003); the pattern of effects was concordant with risk allele carriers having larger volumes and more severe symptoms of disease than nonrisk homozygotes. In the healthy volunteer group, risk allele homozygotes had increased total WM volume compared with nonrisk allele carriers (F = 4.61, P = .03), replicating a previously reported association. CONCLUSIONS A growing body of evidence suggests that the risk allele of rs1347706 is associated with a distinctive set of phenotypic features in healthy volunteers and individuals with schizophrenia. Our study supports this assertion by finding that specific genotypes of the polymorphism are associated with brain structure volumes in individuals with schizophrenia and healthy volunteers and with symptom severity in schizophrenia.

Context: There are limited data on the manifestations of mania in general community samples of adolescents.

Objective: To present the prevalence and clinical correlates of mania with and without depressive episodes in a representative sample of US adolescents.

Design: Cross-sectional survey of adolescents using a modified version of the Composite International Diagnostic Interview.

Participants: Ten thousand one hundred twentythree adolescents aged 13 to 18 years identified in household and school settings.

Main outcome measures: Mania/hypomania with or without depression among those who met DSM-IV criteria for bipolar I or II disorder or major depressive disorder.

Results: Two and a half percent of youth met criteria for lifetime bipolar I or II disorder and 1.7%, for mania only. Twelve-month rates of mania with and without depression were 2.2% and 1.3%, respectively. There was a nearly 2-fold increase in rates of mania from ages 13-14 to 17-18 years. Mania with depression was associated with a greater number of all indictors of clinical severity including symptom number and severity, role disability, severe impairment, comorbidity, and treatment compared with depression alone, whereas correlates of mania were similar among those with mania with or without depression.

Conclusions: The increasing prevalence of bipolar disorder with increasing age and the comparable rate of bipolar disorder with those of adult samples highlight adolescence as the peak period of onset of mania. The clinical significance of mania plus depression as demonstrated by a 1 in 5 suicide attempt rate and nearly 2 months per year of role impairment in adolescence has important implications for early intervention. The evidence for independence of mania from depression warrants additional scrutiny in the diagnostic nomenclature and etiologic dissection of bipolar disorder.

CONTEXT Among depressed individuals not receiving medication in controlled trials, 40% to 60% respond to cognitive therapy (CT). Multiple previous studies suggest that activity in the subgenual anterior cingulate cortex (sgACC; Brodmann area 25) predicts outcome in CT for depression, but these results have not been prospectively replicated. OBJECTIVE To examine whether sgACC activity is a reliable and robust prognostic outcome marker of CT for depression and whether sgACC activity changes in treatment. DESIGN Two inception cohorts underwent assessment with functional magnetic resonance imaging using different scanners on a task sensitive to sustained emotional information processing before and after 16 to 20 sessions of CT, along with a sample of control participants who underwent testing at comparable intervals. SETTING A hospital outpatient clinic. PATIENTS Forty-nine unmedicated depressed adults and 35 healthy controls. MAIN OUTCOME MEASURES Pretreatment sgACC activity in an a priori region in response to negative words was correlated with residual severity and used to classify response and remission. RESULTS As expected, in both samples, participants with the lowest pretreatment sustained sgACC reactivity in response to negative words displayed the most improvement after CT (R2 = 0.29, >75% correct classification of response, >70% correct classification of remission). Other a priori regions explained additional variance. Response/remission in cohort 2 was predicted based on thresholds from cohort 1. Subgenual anterior cingulate activity remained low for patients in remission after treatment. CONCLUSIONS Neuroimaging provides a quick, valid, and clinically applicable way of assessing neural systems associated with treatment response/remission. Subgenual anterior cingulate activity, in particular, may reflect processes that interfere with treatment (eg, emotion generation) in addition to its putative regulatory role; alternately, its absence may facilitate treatment response.

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.