Involvement of the vagus nerves and associated CNS pathways in psychiatric disorders
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 our research is to present existing evidence supporting vagal afferent involvement in the pathophysiology of bulimia nervosa. Investigators from the University of Minnesota (Faris, et. al), have found supporting supporting evidence for vagal involvement in the perpetuation of both primary bulimic symptoms and also depressive symptoms in severely ill bulimia nervosa patients using ondansetron (Zofran®) treatment to modulate vagal activity.
Effect of decreasing afferent vagal activity with ondansetron (Zofran®)
Bulimia nervosa is an eating disorder that affects 2–3% of young women. The most common form of the disorder involves frequent episodes of binge-eating followed by self-induced vomiting, accompanied by a definite feeling of loss of control over the behavior, and by distortions of body image (as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV]). Outcome studies indicate that the illness becomes chronic in a substantial proportion of patients with bulimia nervosa. Depending on the criteria, 20–50% will still have symptoms of the disorder at 5 year follow-up, irrespective of treatment history. Factors responsible for the initiation of the pathological behaviors of the disorder involve the pressure society places on young women to maintain a slim, “attractive” physique. Accordingly, in most cases, bulimic behaviors start as voluntary acts directed towards weight control. In individuals who develop diagnosable bulimia nervosa, the voluntary control decreases at some point, and patients feel driven to engage in binge eating and vomiting. The mechanism responsible for perpetuating bulimia nervosa is unknown.
Several 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 behaviors in patients with severe and chronic bulimia nervosa in a randomized, double-blind, placebo-controlled study.
Use of ondansetron (Zofran®) in bulimia nervosa
Several facts necessitated our development of a unique dosing schedule for ondansetron, including the drug's short half-life of 3 hours after oral administration, the episodic nature of the urge to engage in bulimic behaviors, and the variable daily pattern of binge-eating and vomiting between patients. The aim was to maximize the likelihood that effective concentrations of ondansetron in blood would occur at behaviorally symptomatic times. Patients were instructed to take one capsule (containing 4mg of active drug or placebo) whenever they felt an urge to binge-eat or to vomit and to try to restrain themselves for 30 minutes. If urges were either constant or not clearly defined, patients were instructed to take doses 30 minutes before consuming food. They were to take a total of six capsules per day, but had the option to alter the timing to maximize any perceived effect. Each patient was encouraged to take a total of 24mg per day.
Ondansetron, (Zofran®) is produced and distributed by Glaxo-Wellcome. The drug has been approved for use in the United States and elsewhere around the world. To learn more about the drug's chemical structure and its interactions and side-effects please visit either Glaxo-Wellcome online or the Physicians Desk Reference online.
We are pleased to offer any further assistance you may need regarding the dosing schedule for ondansetron. Feel free to contact us via any means, our contact information is available at the bottom of each page.
SOMATIC PAIN DETECTION THRESHOLDS AND VAGAL ACTIVITY IN BULIMIA NERVOSA PATIENTS
Bulimia nervosa (BN) patients do not experience normal satiety, a process largely mediated by the vagus nerve. Also, somatic pain detection thresholds (PDT) are elevated in BN. Available evidence indicates that vagal stimulation can result in elevated PDT. Thus, an increase in vagal activity would provide an unifying mechanism to account for both of these alterations. We have previously reported that PDT rise dynamically as a function of time elapsed since the last binge/vomit (B/V) episode and ondansetron (ONDAN), a 5 HT 3 antagonist known to dampen the responsivity of the vagus nerve, moderated both this dynamic increase (PAIN 77, 297, 1998) and reduced B/V frequencies (see Eckert et al abstract). To determine if these findings apply to a more general population of BN subjects, first, data collected on 25 bulimic patients were analyzed to determine if the duration of the inter-binge interval was significantly correlated with the weekly frequency of binge/vomit episodes. Second, data from a second larger sample of bulimia nervosa patients (n=47) were analyzed to determine if PDT was significantly related to binge/vomit frequencies. The time elapsed since the last bulimic episode was negatively correlated with the total number of bulimic episodes during the preceding week (p<0.04). That is, at the time of pain testing, those subjects with the highest weekly rates of binge/vomiting were statistically likely to have more recently engaged in a B/V episode. Application of this finding to the larger patient population indicated a highly significant negative relationship between PDT and binge/vomit frequencies (p <0.0001). These findings suggest that perpetuation of the B/V behaviors may arise from the fact that engaging in the behaviors corrects vagal neurotransmission. Conversely, not engaging in the behaviors is associated with a worsening of the underlying physiology and associated mood (Hartman et al.).
SYMPTOMS OF DEPRESSION IN BULIMIA MAY BE MEDIATED THROUGH CNS VAGAL PROJECTIONS
It was of interest to determine if vagal activity could influence mood in bulimia in addition to perpetuating the binge/vomit (B/V) cycle (see Faris and Eckert abstracts). In our double blind study average Beck Depression scores were significantly reduced by ondansetron (ONDAN) compared to placebo (p<0.05). More importantly, in untreated bulimic subjects, Beck Depression Scores were positively correlated with 'time since last binge' (P< 0.02), indicating that depressive symptoms are least severe immediately following a B/V episode and become worse as one approaches the time for the next B/V episode. Thus, the symptoms of depression also appear coupled to increases in afferent vagal activity as measured by pain detection thresholds (PDT). We have now shown in a small group of bulimic subjects that following 8 mg of ONDAN, reductions in subjective feelings of depression (as measured by visual analog scores) are correlated with an acute (1 hour post drug) reduction in vagal afferent activity (as measured by PDT).
Meal Pattern Record
We devised this form as a tool to help measure bulimic behaviors within our patient population. We are pleased to provide it here for your use due to popular demand. Please feel free to download a copy.
Contact Information
eating@umn.edu
phone - 1-800-600-8636 - 612-626-4034
fax - 612-624-8935
Address:
University of Minnesota, Dept. of Psychiatry
MMC 392 Mayo, 420 Delaware St. S.E.
Minneapolis, MN 55455