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.

The use of cholecystokinin as an adjunctive treatment for toxin ingestion.

STUDY OBJECTIVE: To determine if pharmacologic trapping of ingested toxins in the stomach using cholecystokinin (CCK) in addition to activated charcoal (AC) decreases the absorption of ingested toxins. METHODS: We performed a two-phase study that was prospective, randomized, blinded, and placebo-controlled, using a subtoxic acetaminophen (APAP) animal model. Eight adult beagle dogs were studied to detect a 20% decrease in 4h APAP levels with a power of 80%. A control arm using APAP at 100 mg/kg without AC or CCK was first performed. APAP levels were drawn at 0.5, 1, 1.5, 2, 4, 8, and 24 h. This was repeated in a CCK dose finding phase using a 60-min CCK infusion (4 vs. 8 pmol/kg/min) starting at 30 min post-APAP ingestion. Once the optimal CCK dose was established, animals in the treatment phase received AC and a 1 h infusion of CCK (vs. placebo). The efficacy of CCK when started at 30 and 60 min post-APAP ingestion was tested. RESULTS: In the dose finding arm 8 pmol/kg/min was well tolerated and also reduced maximum APAP levels by a mean of 49% from control. This dose was then used for the treatment phase. Four-hour APAP levels, maximum APAP levels, and area under the curve (AUC) were measured. No significant differences were found between placebo and CCK arms at either the 30 or 60 min postingestion interventions. CONCLUSIONS: In this model, CCK infusion did not decrease the absorption of APAP. Adding charcoal to the model overcame the suggested beneficial effect of CCK alone in the dosing arm.

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.