Classical conditioning features prominently in many etiological accounts of panic disorder. According to such accounts, neutral conditioned stimuli present during panic attacks acquire panicogenic properties. Conditioned stimuli triggering panic symptoms are not limited to the original conditioned stimuli but are thought to generalize to stimuli resembling those co-occurring with panic, resulting in the proliferation of panic cues. The authors conducted a laboratory-based assessment of this potential correlate of panic disorder by testing the degree to which panic patients and healthy subjects manifest generalization of conditioned fear.
Nineteen patients with a DSM-IV-TR diagnosis of panic disorder and 19 healthy comparison subjects were recruited for the study. The fear-generalization paradigm consisted of 10 rings of graded size presented on a computer monitor; one extreme size was a conditioned danger cue, the other extreme a conditioned safety cue, and the eight rings of intermediary size created a continuum of similarity from one extreme to the other. Generalization was assessed by conditioned fear potentiating of the startle blink reflex as measured with electromyography (EMG).
Panic patients displayed stronger conditioned generalization than comparison subjects, as reflected by startle EMG. Conditioned fear in panic patients generalized to rings with up to three units of dissimilarity to the conditioned danger cue, whereas generalization in comparison subjects was restricted to rings with only one unit of dissimilarity.
The findings demonstrate a marked proclivity toward fear overgeneralization in panic disorder and provide a methodology for laboratory-based investigations of this central, yet understudied, conditioning correlate of panic. Given the putative molecular basis of fear conditioning, these results may have implications for novel treatments and prevention in panic disorder.
The purpose of the analysis was to examine the temporal course of improvement in symptoms of posttraumatic stress disorder (PTSD) and substance use disorder among women in outpatient substance abuse treatment.
Participants were 353 women randomly assigned to 12 sessions of either trauma-focused or health education group treatment. PTSD and substance use assessments were conducted during treatment and posttreatment at 1 week and after 3, 6, and 12 months. A continuous Markov model was fit on four defined response categories (nonresponse, substance use response, PTSD response, or global response [improvement in both PTSD and substance use]) to investigate the temporal association between improvement in PTSD and substance use symptom severity during the study's treatment phase. A generalized linear model was applied to test this relationship over the follow-up period.
Subjects exhibiting nonresponse, substance use response, or global response tended to maintain original classification; subjects exhibiting PTSD response were significantly more likely to transition to global response over time, indicating maintained PTSD improvement was associated with subsequent substance use improvement. Trauma-focused treatment was significantly more effective than health education in achieving substance use improvement, but only among those who were heavy substance users at baseline and had achieved significant PTSD reductions.
PTSD severity reductions were more likely to be associated with substance use improvement, with minimal evidence of substance use symptom reduction improving PTSD symptoms. Results support the self-medication model of coping with PTSD symptoms and an empirical basis for integrated interventions for improved substance use outcomes in patients with severe symptoms.
Amygdala dysfunction is theorized to give rise to poor fear conditioning, which in turn predisposes to crime, but it is not known whether poor conditioning precedes criminal offending. This study prospectively assessed whether poor fear conditioning early in life predisposes to adult crime in a large cohort.
Electrodermal fear conditioning was assessed in a cohort of 1,795 children at age 3, and registration for criminal offending was ascertained at age 23. In a case-control design, 137 cohort members with a criminal record were matched on gender, ethnicity, and social adversity with 274 noncriminal comparison members. Statistical analyses compared childhood fear conditioning for the two groups.
Criminal offenders showed significantly reduced electrodermal fear conditioning at age 3 compared to matched comparison subjects.
Poor fear conditioning at age 3 predisposes to crime at age 23. Poor fear conditioning early in life implicates amygdala and ventral prefrontal cortex dysfunction and a lack of fear of socializing punishments in children who grow up to become criminals. These findings are consistent with a neurodevelopmental contribution to crime causation.
To understand disorder-unique and common pathophysiology, studies in multiple patient groups with overlapping symptoms are needed. Deficits in emotion processing and hyperarousal symptoms are prominent features of bipolar disorder, attention deficit hyperactivity disorder (ADHD), and severe mood dysregulation. The authors compared amygdala response during emotional and nonemotional ratings of neutral faces in youths with these disorders as well as a group of healthy comparison youths.
Blood-oxygen-level-dependent (BOLD) signal in the amygdala was examined in children with bipolar disorder (N=43), ADHD (N=18), and severe mood dysregulation (N=29) and healthy comparison subjects (N=37). During functional magnetic resonance imaging (fMRI), participants attended to emotional and nonemotional aspects of neutral faces.
While rating subjective fear of neutral faces, youths with ADHD demonstrated left amygdala hyperactivity relative to the other three groups, whereas youths with severe mood dysregulation demonstrated hypoactivity.
These findings support the role of unique neural correlates in face-emotion processing among youths with bipolar disorder, ADHD, and severe mood dysregulation.
Dopamine D2 receptor antagonism is a unifying property of all antipsychotic drugs in clinical use. Remarkably, the effector molecules through which these medications exert their actions remain poorly characterized. Increasing attention is being focused on Akt/glycogen synthase kinase-3 (GSK-3) and wingless (Wnt) signaling pathways, which have been associated with schizophrenia in a number of genetic and postmortem studies. Antipsychotic medications may treat symptoms of psychosis, at least in part, through modulation of levels and activity of Akt, GSK-3, and Wnt-related intracellular signaling. The authors review evidence that Akt/GSK-3 and Wnt-related pathways are involved in the pathogenesis of schizophrenia as well as details of intracellular events related to these molecules mediated by both typical and atypical antipsychotic medications. Further study of Akt/GSK-3 and Wnt signaling may ultimately lead to alternative therapeutics of schizophrenia-related disorders.
]]>Evidence suggests that chronic high levels of behavioral inhibition are a precursor of social anxiety disorder. The authors sought to identify early risk factors for, and developmental pathways to, chronic high inhibition among school-age children and the association of chronic high inhibition with social anxiety disorder by adolescence.
A community sample of 238 children was followed from birth to grade 9. Mothers, teachers, and children reported on the children's behavioral inhibition from grades 1 to 9. Lifetime history of psychiatric disorders was available for the subset of 60 (25%) children who participated in an intensive laboratory assessment at grade 9. Four early risk factors were assessed: female gender; exposure to maternal stress during infancy and the preschool period; and at age 4.5 years, early manifestation of behavioral inhibition and elevated afternoon salivary cortisol levels.
All four risk factors predicted greater and more chronic inhibition from grades 1 to 9, and together they defined two developmental pathways. The first pathway, in girls, was partially mediated by early evidence of behavioral inhibition and elevated cortisol levels at age 4.5 years. The second pathway began with exposure to early maternal stress and was also partially mediated by childhood cortisol levels. By grade 9, chronic high inhibition was associated with a lifetime history of social anxiety disorder.
Chronic high levels of behavioral inhibition are associated with social anxiety disorder by adolescence. The identification of two developmental pathways suggests the potential importance of considering both sets of risk factors in developing preventive interventions for social anxiety disorder.
The present review addresses the outcome of bulimia nervosa, effect variables, and prognostic factors.
A total of 79 study series covering 5,653 patients suffering from bulimia nervosa were analyzed with regard to recovery, improvement, chronicity, crossover to another eating disorder, mortality, and comorbid psychiatric disorders at outcome. Forty-nine studies dealt with prognosis only. Final analyses on prognostic factors were based on 4,639 patients.
Joint analyses of data were hampered by a lack of standardized outcome criteria. There were large variations in the outcome parameters across studies. Based on 27 studies with three outcome criteria (recovery, improvement, chronicity), close to 45% of the patients on average showed full recovery of bulimia nervosa, whereas 27% on average improved considerably and nearly 23% on average had a chronic protracted course. Crossover to another eating disorder at the follow-up evaluation in 23 studies amounted to a mean of 22.5%. The crude mortality rate was 0.32%, and other psychiatric disorders at outcome were very common. Among various variables of effect, duration of follow-up had the largest effect size. The data suggest a curvilinear course, with highest recovery rates between 4 and 9 years of follow-up evaluation and reverse peaks for both improvement and chronicity, including rates of crossover to another eating disorder, before 4 years and after 10 years of follow-up evaluation. For most prognostic factors, there was only conflicting evidence.
One-quarter of a century of specific research in bulimia nervosa shows that the disorder still has an unsatisfactory outcome in many patients. More refined interventions may contribute to more favorable outcomes in the future.
The purpose of this investigation was to compare three types of treatment for binge eating disorder to determine the relative efficacy of self-help group treatment compared to therapist-led and therapist-assisted group cognitive-behavioral therapy.
A total of 259 adults diagnosed with binge eating disorder were randomly assigned to 20 weeks of therapist-led, therapist-assisted, or self-help group treatment or a waiting list condition. Binge eating as measured by the Eating Disorder Examination was assessed at baseline, at end of treatment, and at 6 and 12 months, and outcome was assessed using logistic regression and analysis of covariance (intent-to-treat).
At end of treatment, the therapist-led (51.7%) and the therapist-assisted (33.3%) conditions had higher binge eating abstinence rates than the self-help (17.9%) and waiting list (10.1%) conditions. However, no between-group differences in abstinence rates were observed at either of the follow-up assessments. The therapist-led condition also showed more reductions in binge eating at end of treatment and follow-up assessments compared to the self-help condition, and treatment or waiting period completion rates were higher in the therapist-led (88.3%) and waiting list (81.2%) conditions than in the therapist-assisted (68.3%) and self-help (59.7%) conditions.
Therapist-led group cognitive-behavioral treatment for binge eating disorder led to higher binge eating abstinence rates, greater reductions in binge eating frequency, and lower attrition compared to group self-help treatment. Although these findings indicate that therapist delivery of group treatment is associated with better short-term outcome and less attrition than self-help treatment, the lack of group differences at follow-up suggests that self-help group treatment may be a viable alternative to therapist-led interventions.
Although attention deficit hyperactivity disorder (ADHD) in adults is associated with significant morbidity and dysfunction and afflicts both sexes, relatively few imaging studies have examined female subjects and none have had sufficient power to adequately examine sex differences. The authors examined sex differences in the neural functioning of adults with ADHD during performance of a verbal working memory task.
The participants were 44 adults with ADHD matched on age, sex, and estimated IQ to 49 comparison subjects. Accuracy and reaction time on an N-back task were measured to assess working memory. The blood-oxygen-level-dependent functional MRI response was used as a measure of neural activity.
A group-by-sex analysis of variance showed no between-group differences in either reaction time or percent correct for the working memory task. For both sexes combined, the adults with ADHD showed less activity than comparison subjects in prefrontal regions. However, sex-by-group analyses revealed an interaction, such that male ADHD subjects showed significantly less activity in right frontal, temporal, and subcortical regions and left occipital and cerebellar regions relative to male comparison subjects, whereas female ADHD subjects showed no differences from female comparison subjects. Exploratory correlation analyses revealed negative associations between working-memory-related activation and number of hyperactive symptoms for men and number of inattentive symptoms for women.
Male but not female adults with ADHD showed significantly altered patterns of neural activity during a verbal working memory task. Men and women showed different associations between neural activity and ADHD symptoms.
The purpose of the present study was to evaluate the efficacy of divalproex for reducing aggressive behavior among children 6 to 13 years old with attention deficit hyperactivity disorder (ADHD) and a disruptive disorder whose chronic aggression was underresponsive to a prospective psychostimulant trial.
Children received open stimulant treatment during a lead-in phase that averaged 5 weeks. Agent and dose were assessed weekly and modified to optimize response. Children whose aggressive behavior persisted at the conclusion of the lead-in phase were randomly assigned to receive double-blind, flexibly dosed divalproex or a placebo adjunctive to stimulant for 8 weeks. Families received weekly behavioral therapy throughout the trial. The primary outcome measure was the proportion of children whose aggressive behavior remitted, defined by post-trial ratings of negligible or absent aggression.
A significantly higher proportion of children randomly assigned to divalproex met remission criteria (eight out of 14 [57%]) than those randomly assigned to placebo (two out of 13 [15%]). Divalproex was generally well tolerated.
Among children with ADHD whose chronic aggressive behavior is refractory to optimized stimulant treatment, the addition of divalproex increases the likelihood that aggression will remit. A larger trial is necessary to specify with greater precision the magnitude of benefit for adjuvant divalproex.
The traumatic loss of an unborn child by induced termination of pregnancy because of fetal malformation is a major life event that causes intense maternal grief. Increasing evidence supports the hypothesis that the same neural structures involved in the experience of physical pain are involved in the experience of social pain and loss.
To investigate neural activation patterns related to acute grief, the authors conducted a functional MRI study of 12 post-termination women and 12 noninduced women who delivered a healthy child. Brain activation was measured while participants viewed pictures of happy baby, happy adult, and neutral adult faces.
Relative to comparison women, post-termination women showed greater activation in the middle and posterior cingulate gyrus, the inferior frontal gyrus, the middle temporal gyrus, the thalamus, and the brainstem in response to viewing happy baby faces. Functional connectivity between the cingulate gyrus and the thalamus during the processing of happy baby faces was significantly stronger in post-termination women.
Overall, acute grief after the loss of an unborn child was closely related to the activation of the physical pain network encompassing the cingulate gyrus, the inferior frontal gyrus, the thalamus, and the brainstem. To the authors' knowledge, the stronger functional thalamocingulate connectivity in post-termination women is the first in vivo demonstration of an involvement of the neural maternal attachment network in grief after the loss of an unborn child.
This randomized controlled trial tested the effectiveness of an 18-month mentalization-based treatment (MBT) approach in an outpatient context against a structured clinical management (SCM) outpatient approach for treatment of borderline personality disorder.
Patients (N=134) consecutively referred to a specialist personality disorder treatment center and meeting selection criteria were randomly allocated to MBT or SCM. Eleven mental health professionals equal in years of experience and training served as therapists. Independent evaluators blind to treatment allocation conducted assessments every 6 months. The primary outcome was the occurrence of crisis events, a composite of suicidal and severe self-injurious behaviors and hospitalization. Secondary outcomes included social and interpersonal functioning and self-reported symptoms. Outcome measures, assessed at 6-month intervals, were analyzed using mixed effects logistic regressions for binary data, Poisson regression models for count data, and mixed effects linear growth curve models for self-report variables.
Substantial improvements were observed in both conditions across all outcome variables. Patients randomly assigned to MBT showed a steeper decline of both self-reported and clinically significant problems, including suicide attempts and hospitalization.
Structured treatments improve outcomes for individuals with borderline personality disorder. A focus on specific psychological processes brings additional benefits to structured clinical support. Mentalization-based treatment is relatively undemanding in terms of training so it may be useful for implementation into general mental health services. Further evaluations by independent research groups are now required.
Anorexia nervosa has been consistently associated with increased mortality, but whether this is true for other types of eating disorders is unclear. The goal of this study was to determine whether anorexia nervosa, bulimia nervosa, and eating disorder not otherwise specified are associated with increased all-cause mortality or suicide mortality.
Using computerized record linkage to the National Death Index, the authors conducted a longitudinal assessment of mortality over 8 to 25 years in 1,885 individuals with anorexia nervosa (N=177), bulimia nervosa (N=906), or eating disorder not otherwise specified (N=802) who presented for treatment at a specialized eating disorders clinic in an academic medical center.
Crude mortality rates were 4.0% for anorexia nervosa, 3.9% for bulimia nervosa, and 5.2% for eating disorder not otherwise specified. All-cause standardized mortality ratios were significantly elevated for bulimia nervosa and eating disorder not otherwise specified; suicide standardized mortality ratios were elevated for bulimia nervosa and eating disorder not otherwise specified.
Individuals with eating disorder not otherwise specified, which is sometimes viewed as a "less severe" eating disorder, had elevated mortality risks, similar to those found in anorexia nervosa. This study also demonstrated an increased risk of suicide across eating disorder diagnoses.
Maternal depression is relatively common during pregnancy. The authors examined whether maternal antenatal depressed mood increased the risk of schizophrenia and other psychoses among offspring with and without a familial history of psychosis.
In the Northern Finland 1966 birth cohort, mothers of 12,058 children were asked at mid-gestation at the antenatal clinic if they felt depressed. The offspring were followed for over 30 years, and subsequent schizophrenia and other psychoses were detected using the Finnish Hospital Discharge Register, which was also used for identifying psychosis in the parents. Familial risk for psychosis was considered as a genetic risk factor and mothers' depressed mood as an environmental or genetic risk factor.
The risk for schizophrenia was higher in the offspring with both maternal depressed mood during pregnancy and parental psychosis (OR=9.4, 95% CI=4.2–20.9 adjusted for sex and perinatal complications) than in those with a depressed mother but without parental psychosis (OR=1.0, 95% CI=0.6–1.8) or those without maternal depression and with a psychotic parent (OR=2.6, 95% CI=1.2–5.4). The reference group was birth cohort members without maternal antenatal depression and without parental psychosis.
Maternal depressed mood during pregnancy per se is unlikely to increase the risk for schizophrenia in the offspring but may affect subjects with a family history for psychosis. This finding could be an example of a gene-environment or possibly a gene-gene interaction in the development of schizophrenia. Mothers' antenatal depression may act as additive factor for subjects vulnerable to schizophrenia.
Animal studies assessing mechanisms of self-starvation under conditions of stress and diet suggest a pivotal role for the mesolimbic reward system in the maintenance of core symptoms in anorexia nervosa, which is corroborated by initial empirical evidence in human studies. The authors examined activity in the ventral striatal system in response to disease-specific stimuli in women with acute anorexia nervosa.
Participants were 14 women with acute anorexia nervosa and 14 matched healthy comparison women who underwent functional magnetic resonance imaging (fMRI) during evaluation of visual stimuli depicting a female body with underweight, normal weight, and overweight canonical whole-body features according to standardized body mass indices. Participants were required to process each stimulus in a self-referring way. Ratings for each weight category were used as the control task.
Behaviorally, women with anorexia nervosa provided significantly higher positive ratings in response to underweight stimuli than in response to normal-weight stimuli, while healthy comparison women showed greater preference for normal-weight stimuli relative to underweight stimuli. Functionally, ventral striatal activity demonstrated a highly significant group-by-stimulus interaction for underweight and normal-weight stimuli. In women with anorexia nervosa, activation was higher during processing of underweight stimuli compared with normal-weight stimuli. The reverse pattern was observed in healthy comparison women.
These findings are consistent with predictions in animal studies of the pivotal role of the human reward system in anorexia nervosa and thus support theories of starvation dependence in maintenance of the disorder.
Prevention of late-life depression, a common, disabling condition with often poor outcomes in primary care, requires identification of seniors at highest risk of incident episodes. The authors examined a broad range of clinical, functional, and psychosocial predictors of incident depressive episodes in a well-characterized cohort of older primary care patients.
In this observational cohort study, patients age ≥65 years without current major depression, recruited from practices in general internal medicine, geriatrics, and family medicine, received annual follow-up assessments over a period of 1 to 4 years. Of 617 enrolled subjects, 405 completed the 1-year follow-up evaluation. The Structured Clinical Interview for DSM-IV (SCID) determined incident major depressive episodes. Each risk indicator's predictive utility was examined by calculating the risk exposure rate, incident risk ratio, and population attributable fraction, leading to determination of the number needed to treat in order to prevent incident depression.
A combination of risks, including minor or subsyndromal depression, impaired functional status, and history of major or minor depression, identified a group in which fully effective treatment of five individuals would prevent one new case of incident depression.
Indicators routinely assessed in primary care identified a group at very high risk for onset of major depressive episodes. Such markers may inform current clinical care by fostering the early detection and intervention critical to improving patient outcomes and may serve as the basis for future studies refining the recommendations for screening and determining the effectiveness of preventive interventions.
The literature provides evidence of a strong relationship between greater stress and memory loss, but few studies have examined this relationship with both variables measured over time. The authors sought to determine the prospective association between subjective and objective measures of chronic stress and rate of memory decline in cognitively normal and mildly impaired older adults.
This longitudinal study was conducted at a university research center and included 61 cognitively normal subjects and 41 subjects with mild cognitive impairment (ages 65–97). Fifty-two subjects were followed for up to 3 years (mean=2 years) and received repeated stress and cognitive assessments. Exclusion criteria were dementia, significant medical or psychiatric conditions, and medication use (e.g., corticosteroids) that might affect cortisol level or cognitive functioning. The main outcome measure was a regression-based slope reflecting performance change on tests of global cognition and episodic memory as a function of baseline diagnosis, recent life events, and salivary cortisol. Examiners were blind to stress ratings and cortisol levels at the time of cognitive testing.
Higher event-based stress ratings collected over the follow-up period were associated with faster cognitive decline in subjects with mild cognitive impairment but not in cognitively normal subjects. In contrast, higher cortisol levels were associated with slower cognitive decline in subjects with mild cognitive impairment but not in cognitively normal subjects.
Chronic stress affects cognitive functioning differently in cognitively normal subjects and those with mild cognitive impairment. Cortisol, while likely to have neurotoxic effects over time, may enhance cognitive functioning in older adults compromised by existing cognitive deficits.
The authors sought to evaluate the clinical efficacy of dialectical behavior therapy compared with general psychiatric management, including a combination of psychodynamically informed therapy and symptom-targeted medication management derived from specific recommendations in APA guidelines for borderline personality disorder.
This was a single-blind trial in which 180 patients diagnosed with borderline personality disorder who had at least two suicidal or nonsuicidal self-injurious episodes in the past 5 years were randomly assigned to receive 1 year of dialectical behavior therapy or general psychiatric management. The primary outcome measures, assessed at baseline and every 4 months over the treatment period, were frequency and severity of suicidal and nonsuicidal self-harm episodes.
Both groups showed improvement on the majority of clinical outcome measures after 1 year of treatment, including significant reductions in the frequency and severity of suicidal and nonsuicidal self-injurious episodes and significant improvements in most secondary clinical outcomes. Both groups had a reduction in general health care utilization, including emergency visits and psychiatric hospital days, as well as significant improvements in borderline personality disorder symptoms, symptom distress, depression, anger, and interpersonal functioning. No significant differences across any outcomes were found between groups.
These results suggest that individuals with borderline personality disorder benefited equally from dialectical behavior therapy and a well-specified treatment delivered by psychiatrists with expertise in the treatment of borderline personality disorder.