Increased mortality in bulimia nervosa and other eating disorders.

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.

De-stabilization of the positive vago-vagal reflex in bulimia nervosa.

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.

Evidence for a vagal pathophysiology for bulimia nervosa and the accompanying depressive symptoms.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Pathological gambling and mood disorders: clinical associations and treatment implications.

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.

Body dysmorphic disorder in patients with anorexia nervosa: prevalence, clinical features, and delusionality of body image.

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.

Effect of ondansetron, a 5-HT3 receptor antagonist, on the dynamic association between bulimic behaviors and pain thresholds.

Thresholds for detection of both pressure and thermal pain are elevated in patients with bulimia nervosa. The present study was aimed at determining (1) if pressure pain detection thresholds (PDT) varied dynamically with the primary disease symptoms of binge eating and vomiting and (2) if the elevation in PDT was effected by treatment with ondansetron (ONDAN), a 5-HT3 receptor antagonist. PDT was defined as the mean of the minimal amount of pressure (measured in g) perceived as painful when exerted by a 1 mm2 blunted point onto the center of the ventral surface of the ungual phalanx of digits 2-5 of the non-dominant hand. Fourteen female patients with severe bulimia nervosa (currently >seven binge/vomit episodes per week; > 2 years illness duration) served as participants. PDT were evaluated at weekly intervals during the course of ongoing treatment studies (double-blind and 'open' label) investigating the therapeutic effects of ONDAN. Data were analyzed by random regression analyses, allowing for the repeated-measures and non-orthogonal design. Data collected from 14 patients under the no-drug condition indicated that PDT increased over the interval between binge/vomit episodes, with significant elevations occurring at times when patients had naturally exceeded their average inter-binge interval. Eleven of these 14 patients underwent 4 weeks of ONDAN treatment. Under this drug condition, the time since the last binge/vomit episode was no longer a significant predictor of PDT. These patients also experienced a significant reduction in the frequency of bulimic behaviors, a finding reported in detail elsewhere. The above finding from untreated patients support the involvement of a common underlying mechanism driving both the increase in pain detection thresholds and the occurrence of the next bulimic episode. This possibility is further supported by the findings that ONDAN treatment is associated with a significant moderation of both variables. The effect of ONDAN may be mediated by blockade of afferent vagal neurotransmission, although other mechanisms must be considered.