Objective: This follow-up study reports on 19 of 36 male participants in the Minnesota Semi-Starvation Experiment. As systematic data were obtained for only 3 months of controlled nutritional rehabilitation following 6 months of semi-starvation, the follow-up aim was to re-examine the acute effects and inquire into possible long term physical and psychosocial effects from undergoing semi-starvation. The experiment has been a source of information for understanding eating disorders, particularly anorexia nervosa. Therefore, another aim was to examine the relevance of any starvation-induced symptomatic changes to eating disorders. Method: Semi-structured phone interviews were employed to explore 1) physical and psychological consequences of semi-starvation and nutritional rehabilitation 2) eating and weight changes during and since completion of the experiment, and 3) quality of the participants’ lives following completion of the experiment. Results: Participants proceeded to lead interesting and productive lives, free of life-long adverse effects. Personality differences, inferred from the Minnesota Multiphasic Personality Inventory, likely influenced the severity of the psychopathological reactions to starvation. Many participants reported maintaining a higher than normal weight and had abnormal eating habits for many months and even years before returning to “normal” state. Discussion: Reestablishment of normal body weight took significantly longer than suggested in the original experiment, and might therefore constitute a factor contributing to the extended course of illness and tendency to relapse in eating disorders. The preservation of energy and normal to high activity levels in the presence of signs of severe weight loss and starvation and body image disturbances seen in anorexia nervosa were not observed nor reported in the Minnesota Semi-starvation Experiment.

Objective: 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.Method: 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.Results: 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.Conclusions: 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.

Bulimia nervosa is characterized by consuming large amounts of food over a defined period with a loss of control over the eating. This is followed by a compensatory behavior directed at eliminating the consumed calories, usually vomiting. Current treatments include antidepressants and/or behavioral therapies. Consensus exists that these treatments are not very effective and are associated with high relapse rates. We review evidence from literature and present original data to evaluate the hypothesis that bulimia involves alterations in vago-vagal function. Evidence in support of this include (1) laboratory studies consistently illustrate deficits in meal size, meal termination, and satiety in bulimia; (2) basic science studies indicate that meal size and satiation are under vagal influences; (3) anatomical, behavioral and physiological data suggest that achieving satiety and the initiation of emesis involve common neural substrates; (4) abnormal vagal and vago-vagal reflexive functions extend to non-eating activational stimuli; and (5) studies from our laboratory modulating vagal activation have shown significant effects on binge/vomit frequencies and suggest a return of normal satiation. We propose a model for the pathophysiology of bulimia based upon de-stabilization of a bi-stable positive vago-vagal feedback loop. This model is not meant to be complete, but rather to stimulate anatomical, psychobiological, and translational neuroscience experiments aimed at elucidating the pathophysiology of bulimia and developing novel treatment strategies.

The most widespread eating disorders, anorexia nervosa and bulimia nervosa, are potentially serious disorders with high morbidity and mortality primarily affecting young women. The disorders are related; often there are no clear boundaries between the two disorders. Recent advances have been made in defining the interplay of risk factors leading to the disorders. These include various biologic and genetic factors, such as personality and comorbid psychiatric symptoms. Although there have also been advances in the treatment of the disorders, much more research is needed, particularly in anorexia nervosa, to define effective treatments.

The bilateral vagus nerves (Cranial X) provide both afferent and efferent connections between the viscera and the caudal medulla. The afferent branches increasingly are being recognized as providing significant input to the central nervous system for modulation of complex behaviors. In this paper, we review evidence from our laboratory that increases in vagal afferent activity are involved in perpetuating binge-eating and vomiting in bulimia nervosa. Preliminary findings are also presented which suggest that a subgroup of depressions may have a similar pathophysiology.Two main approaches were used to study the role of vagal afferents. Ondansetron (ONDAN), a 5-HT3 antagonist, was used as a pharmacological tool for inhibiting or reducing vagal afferent neurotransmission. Second, somatic pain detection thresholds were assessed for monitoring a physiological process known to be modulated by vagal afferents, including the gastric branches involved in meal termination and satiety. High levels of vagal activity result in an increase in pain detection thresholds. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Positron Emission Tomography (PET) was used to identify higher cortical brain areas activated by vagal stimulation produced by proximal gastric distention in normal eating subjects.Double-blind treatment of severe bulimia nervosa subjects with ONDAN resulted in a rapid and significant decrease in binge-eating and vomiting compared to placebo controls. The decrease in abnormal eating episodes was accompanied by a return of normal satiety. Pain detection thresholds measured weekly over the course of the treatment protocol were found to dynamically fluctuate in association with bulimic episodes. Thresholds were the most elevated during periods of short-term abstinence from the behaviors, suggesting that not engaging in a binge/vomit episode is accompanied by an increase in vagal activity. ONDAN also resulted in abolition of the fluctuations in pain thresholds. Depressive symptoms in these subjects also were reduced by ONDAN. Like pain thresholds, depressive symptoms varied dynamically with the bulimic behaviors, with BDI scores increasing (more depressed) as more time elapsed since the last bulimic episode. PET studies indicated that mechanical distention of the stomach with a balloon (a non-nutritive stimulus) was associated with the activation of several brain loci, including those associated with vagal activation (parabrachial nucleus), emotive aspects of eating (lateral inferior frontal and orbitofrontal), and depressive symptoms (anterior cingulate).The results of the ONDAN study in bulimia nervosa subjects suggest that cyclic increases in vagal activity drive the urge to binge-eat and vomit. The alterations in vagal firing patterns are possibly a physiological adaptation to the high levels of vagal stimulation initially provided by voluntarily binge-eating and vomiting for weight control. The depressive symptoms that occur in association with the urge to binge-eat are also likely due to the cyclic increase in vagal activity. This suggestion is supported by the reduction of depressive symptoms during ONDAN treatment in bulimia subjects and PET imaging studies in normal eating subjects showing that brain loci classically involved in depression are activated by vagal stimulation administered by mechanical gastric distention. In normal eating individuals, depressions accompanying visceral diseases may also be vagally mediated. Ondansetron and other drugs known to modulate vagal activity may be helpful in treating depressions of this origin.

Bipolar disorder (BD) is one of the most heritable psychiatric conditions and is associated with high suicide risk. To explore the reasons for this link, this study examined the interaction between traumatic stress and BD polygenic risk score in relation to suicidal ideation, suicide attempt, and nonsuicidal self-injury (NSSI) in adolescent and young adult offspring and relatives of persons with BD (BD-relatives) compared with adolescent and young adult offspring of individuals without psychiatric disorders (controls).Data were collected from 4 sites in the United States and 1 site in Australia from 2006 through 2012. Generalized estimating equation models were used to compare rates of ideation, attempts, and NSSI between BD-relatives (n = 307) and controls (n = 166) and to determine the contribution of demographic factors, traumatic stress exposure, lifetime mood or substance (alcohol/drug) use disorders, and BD polygenic risk score.After adjusting for demographic characteristics and mood and substance use disorders, BD-relatives were at increased risk for suicidal ideation and attempts but not for NSSI. Independent of BD-relative versus control status, demographic factors, or mood and substance use disorders, exposure to trauma within the past year (including bullying, sexual abuse, and domestic violence) was associated with suicide attempts (p = .014), and BD polygenic risk score was marginally associated with attempts (p = .061). Importantly, the interaction between BD polygenic risk score and traumatic event exposures was significantly associated with attempts, independent of demographics, relative versus control status, and mood and substance use disorders (p = .041).BD-relatives are at increased risk for suicide attempts and ideation, especially if they are exposed to trauma and have evidence of increased genetic vulnerability.

Background: The rapidly expanding gambling business has resulted in an increasing number of gamblers, and the problem is likely to get worse in the future. Traditionally, mood and gambling symptoms have been known to overlap. In the,present review we attempt to examine the diagnostic associations and implications for treatment.Method: Selected published papers on the frequencies of mood disorders among patients who have gambling disorder or gambling disorder among patients who have mood disorder have been reviewed. Recently emerging new treatment methods for gambling disorder have been reviewed and a brief summary has been added.Results: SCID based study results show a close link between gambling and mood disorders. The prevalence of manic disorder reaches to approximately one fourth of the pathological gambling disorder population. The prevalence of depression is much higher, reaching to over half of the population in some studies. Limitations: The studies included in the present paper involve inpatients, outpatients, subjects recruited through advertisements and prison populations. Thus the data need to be interpreted as such. Standardized assessment instruments are not used in all studies. Methodological issues such as primary or secondary nature of depression have not been addressed adequately in these studies. The findings, however, offer new insights for the assessment and treatment of complicated gambling disorder cases.Conclusions: A high prevalence rate of manic and depressive disorders has been recorded among pathological gambling disorder patients. A rational treatment approach to each defined subset of complicated gambling disorder is discussed. Published by Elsevier B.V.

OBJECTIVE:The prevalence of body dysmorphic disorder in patients with anorexia nervosa is unknown. We hypothesized that body dysmorphic disorder would be underdiagnosed in patients with anorexia nervosa and that comorbidity with body dysmorphic disorder would result in greater overall dysfunction.METHOD:Forty-one patients with DSM-IV anorexia nervosa completed the Body Dysmorphic Disorder Questionnaire, a self-report screen for body dysmorphic disorder. A follow-up interview was conducted using a reliable clinician-administered semistructured diagnostic instrument for DSM-IV body dysmorphic disorder. Delusionality about appearance was assessed using a validated semistructured interview. Comorbid DSM-IV diagnoses, number of hospitalizations and suicide attempts were obtained by means of a detailed diagnostic interview.RESULTS:Sixteen (39%) of the 41 patients with anorexia nervosa were diagnosed with comorbid body dysmorphic disorder unrelated to weight concerns. The anorexia nervosa patients with body dysmorphic disorder had significantly lower overall functioning and higher levels of delusionality than the anorexic patients without body dysmorphic disorder.DISCUSSION:These preliminary results suggest that body dysmorphic disorder may be relatively common among patients with anorexia nervosa. The presence of comorbid body dysmorphic disorder may indicate a more severe form of illness.

A large body of basic science research provides evidence for the involvement of peripheral afferent branches of the vagus in a wide range of functions including, but not limited to, control of meal termination, memory storage, exploratory behaviors, sleep, and modulation of somatic pain detection. The implications of these basic science findings to human behavior in general, and to psychiatric disorders in specific, have just recently become the subject of clinical investigations. The overall goal of this workshop is to present existing evidence supporting vagal afferent involvement in both the pathophysiology of bulimia nervosa and in human memory storage. Two different methods for modulation of peripheral vagal neurotransmission will be presented and discussed-namely the use of ondansetron (Zofran) as a pharmacological modulator of vagal activity and the implantation of Vagal Nerve Stimulators (Cyberonics) for direct unilateral electrical stimulation of vagal fibers. Investigators from the University of Minnesota will present physiological (Dr. Faris), clinical outcome (Dr. Eckert), and neuroanatomical (Dr. Hartman) findings supporting vagal involvement in the perpetuation of both primary bulimic symptoms and also depressive symptoms in severely ill bulimia nervosa patients using ondansetron treatment to modulate vagal activity. Dr. Jensen will present data demonstrating an enhancement of memory in human subjects by direct vagal nerve stimulation at specific stimulation frequencies. This workshop will provide a timely presentation of potential vagal involvement in the pathophysiology of psychiatric disorders.

OBJECTIVE:This paper addresses the lack of a standard protocol for pharmacotherapy trials for patients with bulimia nervosa (BN) and anorexia nervosa (AN).METHOD:Twenty-two surveys were sent to established researchers in the field of eating disorders to elicit their opinions regarding medication trials, including baseline laboratory tests, the optimal length/frequency of medication management sessions, and the information that should or should not be included in these sessions.RESULTS:Sixteen of 22 researchers completed and returned the survey. Their answers are the basis of the data presented.DISCUSSION:We propose a battery of screening laboratory tests for both conditions. We suggest 30-45-min initial medication management sessions in both AN and BN trials with 15-min follow-ups to be held weekly for AN subjects, and weekly for 2 weeks, then biweekly for 2 weeks, then monthly, for BN subjects. We also recommend that published trials should include explicit details of medication management.

BackgroundSeveral lines of evidence have led us to postulate that afferent vagal hyperactivity could be an important factor in the pathophysiology of the eating disorder bulimia nervosa. Ondansetron is a peripherally active antagonist of the serotonin receptor 5-HT3, and is marketed for prevention of vagally-mediated emesis caused by cancer chemotherapeutic agents. We investigated the effects of ondansetron on bulimic behaviours in patients with severe and chronic bulimia nervosa in a randomised, double-blind, placebo-controlled study.MethodsWe enrolled patients with severe bulimia nervosa (at least seven coupled binge/vomit episodes per week). The patients were otherwise healthy, their weight was normal, and they were not receiving medical or psychiatric treatment. During the first week of the study, patients recorded all eating-behaviour events to establish a baseline. In the second week, all patients received placebo, but were told that they were receiving either placebo or active drug. At the end of this single-blind phase, patients were randomly assigned placebo or ondansetron (24 mg daily) for a further 4 weeks. The primary outcome measure was the number of binge/vomit episodes per week. Data were analysed by intention to treat.Findings29 patients met the inclusion criteria, of whom 28 completed the baseline study, and 26 completed the single-blind placebo week. 12 patients were assigned placebo, and 14 ondansetron; one patient in the ondansetron group dropped out owing to accidental injury. During the 4th week of double-blind treatment, mean binge/vomit frequencies were 13·2 per week (SD 11·6) in the placebo group, versus 6·5 per week (3·9) in the ondansetron group (estimated difference 6·8 [95% CI 4·0–9·5]; p<0·0001). The ondansetron group also showed significant improvement, compared with the placebo group, in two secondary indicators of disease severity. The amount of time spent engaging in bulimic behaviours was decreased on average by 7·6 h per week in the ondansetron group, compared with 2·3 h in the placebo group (estimated difference 5·1 [0·6–9·7]). Similarly, the number of normal meals and snacks increased on average by 4·3 normal eating episodes without vomiting per week in the ondansetron group, compared with 0·2 in the placebo group (estimated difference 4·1 [1·0–7·2]).InterpretationThe decrease in binge-eating and vomiting under ondansetron treatment was not achieved by compensatory changes in eating behaviour such as by a smaller number of binges of longer duration, or by not eating, or by binge-eating without vomiting. Instead, our findings indicate a normalisation of the physiological mechanism(s) controlling meal termination and satiation. Since meal termination and satiety are mainly vagally mediated functions, since binge-eating and vomiting produce intense stimulation of vagal afferent fibres, and since ondansetron and other 5-HT3 antagonists decrease afferent vagal activity, the symptom improvement may result from a pharmacological correction of abnormal vagal neurotransmission.

OBJECTIVE:We previously reported elevated serum levels of the cytokines interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) in patients with anorexia nervosa (AN). We investigated the cellular production of these two cytokines and of interferon-gamma (IFN-gamma), interleukin-1alpha (IL-1alpha), and tumor necrosis factor-alpha (TNF-alpha) in subjects with AN, bulimia nervosa (BN), and obesity as well as in normal-weight control subjects.METHODS:Supernatant fluids from isolated peripheral blood mononuclear cells (PBMC) incubated with and without concanavalin A (ConA) were assayed for cytokine concentrations by enzyme-linked immunosorbent assay (ELISA).RESULTS:Significant differences across the four groups were found in the stimulated cellular production of IFN-gamma and IL-6. Stimulated IFN-gamma production was elevated in the AN group compared to controls. IL-6 production was significantly elevated in obese subjects relative to the two normal-weight groups, BN and controls, and tended to be higher in the AN group than in the controls, but not significantly so. IL-1alpha production was greater in obese subjects.CONCLUSION:The findings of increased IFN-gamma production and a tendency toward increased IL-6 production (both of which suppress food intake in animals) in individuals who severely restrict food intake suggest a potential role for these cytokines in the pathogenesis of AN. Elevated IL-6 and IL-1alpha production by PBMC in obese individuals requires further investigation to determine if these cytokines contribute to the development or perpetuation of obesity.

Subjects with bulimia nervosa (BN) have been shown to exhibit abnormal satiety responses. Short-term satiety is largely mediated by afferent vagal activity. Activation of afferent vagal fibers has also been found to stimulate a descending pain inhibitory pathway that leads to elevation in somatosensory pain thresholds. Therefore, the study of pain thresholds in BN subjects may lead to a better understanding of afferent vagal function in this disorder. In this preliminary study, pressure pain thresholds were assessed in nine subjects with BN on 3 consecutive days during a binge-eating and vomiting (B/V) episode, during a normal meal, and after an overnight fast. A significant time versus condition effect was found with a significant change in the pain threshold in BN subjects under the B/V condition only. These data are consistent with the hypothesis that vagal afferent activation by a B/V episode also activates the descending pain inhibitory pathway.

Background: Conflicting data have been published regarding pain threshold in subjects with anorexia nervosa (AN), with some studies indicating elevated pain threshold and others indicating normal thresholds. Previous research has indicated the presence of elevated pain threshold in eating disorder subjects with binge-eating behavior. Methods: In this study pressure pain detection thresholds (PDT) (assessed by a pressure analgesiometer) in binge-eating/purging and restricting subtypes of AN subjects were compared to control subjects. Results: PDT was elevated in AN compared to control subjects at baseline. There was no difference in PDT between the subgroups of AN subjects. Conclusions: The etiology of elevated PDT in AN subjects is most likely different from the etiology of elevated PDT in bulimia nervosa subjects.

Many researchers have questioned whether patients with bulimia nervosa (BN) have more prominent impulsive or compulsive traits and whether eating disorders should be considered to be obsessivel compulsive (OC) spectrum disorders. It this paper we compare the extent to which individuals with BN and binge eating disorder (BED) exhibit both OC and impulsive traits. Thirty-one women with BN and 39 women with BED were enrolled in this study. Psychiatric diagnoses were made using the Structured Clinical Interview for DSM-III-R and participants completed a number of questionnaires (including one developed by the authors) to assess impulsive and OC traints. Compared to the BED group, the BN group reported spending significantly more time being preoccupied

Serum leptin levels are low in untreated anorexia nervosa, but studies of the exact relationship between leptin and body weight and the impact of refeeding in anorectics are limited. Therefore, we studied serum leptin, insulin-like growth factor I, and other endocrine parameters in female anorectics before and after gaining weight and in female normal body weight controls. Leptin levels in untreated anorectics were significantly lower than those in normal body weight controls (3.6 +/- 1.6 vs. 12.0 +/- 6.9 ng/mL; P < 0.001), and they uncoupled from body weight in a nonlinear relationship, suggesting a threshold effect at lowest body weights. Leptin increased significantly with refeeding (5.6 +/- 3.8 ng/mL; P < 0.01). The significant linear correlations of leptin with body mass index in the anorectics after weight gain and in normal body weight controls (r = 0.69; P < 0.001 and r = 0.76; P < 0.001, respectively) are consistent with a normal physiological increase in leptin with weight gain. Leptin and insulin-like growth factor I were highly correlated, even after controlling for body weight (r = 0.63; P = 0.001) during starvation, but were no longer significantly correlated after body weight gain in the anorectics or the normal body weight controls. Further studies are necessary to elucidate the relationship of leptin to neuroendrocrine abnormalities seen in starvation and to determine a possible contribution of leptin to difficulties with weight restoration in anorexia nervosa.

The assessment of personality variables measured by the Minnesota Multiphasic Personality Inventory (MMPI), was compared in a sample of 52 female inpatients with anorexia nervosa at the time of hospitalization, discharge from hospital, and 10 years after treatment. Admission MMPI scores were significantly higher than scores both at discharge and 10 years later. There were no significant overall differences between discharge and follow-up evaluation. Discharge, but not admission, MMPI scores were positively correlated with 10-year follow-up study on seven of 10 clinical MMPI scales (all but hypochondriasis, masculinity/femininity, and hypomania). At follow-up evaluation, eating disorder poor outcome was associated with higher MMPI scores. There was no significant difference on admission MMPI scores between the four outcome groups; however, patients who recovered had a greater decrease in MMPI scores at the 10-year follow-up study compared with poor outcome patients. The long-term outcome of anorexia nervosa was largely unrelated to the severity of psychopathology during the acute phase of the illness. These results suggest that persistent personality features are best measured following treatment of acute symptomatology of anorexia nervosa.

Bulimia nervosa, a chronic psychiatric disorder, is characterized by frequent episodes of binge eating followed by purging (usually in the form of self-induced vomiting) with a loss of volitional control over these behaviors. This disorder occurs in 3% to 5% of young women.1Our research group has previously suggested that the pathophysiological characteristics driving the abnormal behaviors involve an increase in the basal tone of the vagus nerve as a result of repeated and aggressive stimulation of the gastric branch of the vagus nerve by binge eating and vomiting.2This hypothesis led us to treat a total of 5 women who met theDSM-III-Rcriteria for bulimia nervosa (binge-purge subtype) with ondansetron hydrochloride (a 5-hydroxytryptamine type 3 receptor antagonist that pharmacologically decreases vagal transmission3). All of these patients were considered to have severe bulimia nervosa due to the chronicity of the disease, a history of previous drug

Complement plays important roles in host immune defences, and recent studies suggest that adipose tissue is an important site of production for some complement proteins. Starvation has been associated with low complement levels, but studied populations have usually had concomitant opportunistic infections or other conditions which might affect complement levels. To determine the impact of body weight and changes in body weight on serum complement, we investigated levels of complement proteins in otherwise healthy patients with a wide range of body weights, including patients with anorexia nervosa before and after treatment, obese dieters before and after weight loss, and normal weight controls. We found that complement proteins of the alternative pathway (C3, B, and D), alternative pathway haemolytic activity (AP50) and the inhibitors H and I were low in starving anorectics and normalized with weight gain. C3a levels were comparable in anorectics at low weight and after weight gain, indicating that low serum complement levels were attributable to hypoproduction and not complement cascade activation with consumption. Further, levels of C3, B, AP50, H and I, but not D, were higher than controls in obese patients and decreased toward normal after weight loss. Overall, percentage of ideal body weight, changes in body weight, and serum transferrin were each highly correlated with serum levels of complement proteins. We conclude that levels of alternative pathway complement components are determined in part by factors that influence body weight and by weight changes, possibly due to changes in production in adipose tissue or at other sites.