Pharmacotherapy for Patients With Eating Disorders
Pharmacotherapy for Patients With Eating Disorders
Eating disorders, including anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED), remain one of the most complex and clinically challenging groups of mental disorders in our nomenclature. There are no easy solutions, and the bottom line of this article is that pharmacological agents are not the primary treatment of choice. Although a number of agents have been found in randomized controlled trials to be beneficial, they are by and large insufficient as stand-alone treatments. Space does not allow a comprehensive overview of this topic, but the reader is referred to a recent review by Steinglass and Walsh (2004). In addition, the revised American Psychiatric Association practice guidelines for the treatment of eating disorders (APA, 2000) and the recently released National Institute of Clinical Excellence (NICE) Guidelines (2004) are useful resources regarding the use of drug therapy within the context of a comprehensive treatment approach.
No pharmacological agents have ever been shown in double-blind, placebo-controlled trials to significantly improve AN when given outside a structured, inpatient program. Food remains the "drug of choice" for this population, for reasons that will be elaborated below. Of course, administering food in the interest of weight restoration is much easier said than done, given the profound denial and resistance typical of this disorder. There are a handful of drugs found to be statistically better than placebo in randomized controlled trials, but there is little clinical significance of these findings. Lithium (Eskalith, Lithobid) was shown in one controlled trial to be statistically better than placebo in a small group of patients being treated at the National Institute of Mental Health on an intensive, highly structured, specialized treatment unit (Gross et al., 1981). However, the effect was small, and eating disorder specialists generally deem the potential risks of lithium treatment in this population to be far greater than the possible benefits, largely due to the danger of lithium toxicity secondary to dehydration and electrolyte imbalances from starvation, compulsive exercising and/or purging. Another study found amitriptyline (Elavil) statistically better than placebo for patients who are both bulimic and anorexic, while cyproheptadine (Periactin) was better for restricting anorexia (Halmi et al., 1986). However, other studies have had mixed results.
Although the use of antidepressant medications in AN seems theoretically sound, the results from randomized controlled trials have been dismal. In addition, the cardiac effects of tricyclic antidepressants include prolongation of the QTC interval, which can already be prolonged in patients with AN, a setup for sudden death. Selective serotonin reuptake inhibitors might seem applicable given their safety profile and usefulness in major depression and obsessive-compulsive disorder, as well as the profound central serotonergic disturbances reported in AN (Brewerton, 1995; Brewerton and Jimerson, 1996). Fluoxetine (Prozac) has been shown to have absolutely no effect on weight, body image, anxiety or mood in low-weight patients with AN (Attia et al., 1998). However, once patients are weight-recovered, one controlled trial indicated that relapse (which is common) can be significantly reduced with fluoxetine in comparison to placebo, presumably due to its antiobsessional effects (Kaye et al., 2001).
It is essential for the clinician to understand that the reason fluoxetine, or any monoamine reuptake inhibitor, cannot work in low-weight patients is because central 5-HT levels are profoundly depleted in these individuals as a direct result of starvation and weight loss (Brewerton, 1995; Brewerton and Jimerson, 1996; Kaye et al., 1988). The effectiveness of SSRIs depends not only on having sufficient central 5-HT available for release and reuptake-inhibition, but also on essential amino acid precursor (l-tryptophan) availability (via a balanced meal plan) to allow continued 5-HT-synthesis following weight recovery. This is well-established as a result of many tryptophan-depletion studies.
There is excitement in the field about the possibility of using olanzapine (Zyprexa) and other atypical antipsychotics in low-weight patients with AN. Olanzapine acts in part via postsynaptic 5-HT2-antagonism, so it bypasses the presynaptic apparatus altogether and does not depend on l-tryptophan availability. Olanzapine's propensity toward enhanced appetite and weight gain, as well as its antianxiety, antiobsessional and antidepressant properties, makes it theoretically an excellent drug for AN, especially the restricting subtype. It also increases sleep and decreases motor activity, thereby conserving energy expenditure. Open trials and case reports are promising (La Via et al., 2000; Malina et al., 2003; Powers et al., 2002), but no controlled trials have been completed as of yet. Adult patients often resist or refuse to take olanzapine because of its weight gain and soporific effects; however, in children and adolescents, parents can ensure compliance. Very low doses are usually sufficient to attain the desired effect (i.e., 0.625 mg/day to 5.0 mg/day). There are no long-term follow-up data, but once weight restoration is achieved, olanzapine can be tapered and usually stopped as fluoxetine "kicks in" for prophylaxis. If needed, a very low dose of a relatively weight-neutral atypical antipsychotic agent, such as quetiapine (Seroquel), ziprasidone (Geodon) or aripiprazole (Abilify) may be a helpful adjunct as recovery progresses, especially when there is significant comorbidity. However, this remains speculative and untested, and most patients do not need continued antipsychotic treatment following full weight recovery. The propensity for olanzapine and other atypical antipsychotics to induce hyperglycemia, diabetes mellitus and extrapyramidal side effects certainly requires monitoring and caution, but their use must be weighed against the significant psychiatric and medical morbidity and mortality associated with AN.