Paul F. Aravich
>In light of the connections drawn between Obsessive complusive disorder (OCD) and the triad/anorexia in terms of Serotonin functions, could you critique/elaborate on the studies that found both positive and negative outcomes for treatment with Serotonin reuptake inhibitiors? (could you give special attention to those studies which showed no improvement with SRIs, since this type of evidence presents a challenge to your model?)
Thank you so much for your kind remarks regarding our research program on anorexia nervosa. Thank you also for your support for animal modeling in psychiatric research. I am sorry my response is delayed. One thing is for sure about a cyberspace conference: my delay can't be blamed on weather or air travel problems!
You ask a provocative and timely question regarding the mixed effects of serotonin reuptake inhibitors (SRIs) in the treatment of anorexia nervosa and note that the negative studies present a challenge to our model system in particular and to the serotonergic view of anorexia nervosa in general. Here is my response.
Numerous authors suggest that anorexia nervosa is a "compulsive behavior" disorder potentially linked to obsessive-compulsive disorder (OCD). Kaye et al. have been among the promoters of this view. The predominate neurochemical view of OCD emphasizes serotonergic dysfunction, since serotonin reuptake inhibitors (SRIs) have clear clinical efficacy. The latency of their anti-OCD effect, however, is considerably longer than that for their anti-depressant effect.
According to the OCD view of anorexia nervosa, SRIs should also be effective in the treatment of this disorder. As you correctly note, beneficial effects have been reported in some but not all studies. It is important to recognize, however, that a significant fraction of OCD patients are also resistant to SRI pharmacotherapy. It is also important to note that indirect-acting serotonin agonists promote serotonin binding to virtually all of the more than 14 serotonin receptors. Further research is needed to identify the specific receptor sites responsible for the anti-obessional effects of SRIs. This will allow us to design more specific agents to target those sites in both OCD and anorexia nervosa. It is obvious that human psychiatric disorders are highly complex. This is precisely why animal modeling is so critically needed. It allows us to focus on key elements of an otherwise complex system. The model system we utilize is particularly well suited to this problem area since the data we and others have generated indicate its validity as a model of anorexia nervosa and since the data of Altemus et al. demonstrate its efficacy as a model of OCD.
Yet another issue to consider is that an anorexic is not an anorexic. Thus, it is important to identify sub-populations who may be more responsive to various treatment strategies. While the DSM-IV distinguishes between the restricting and binge-purging subtypes, more research is needed to distinguish other sub-populations of anorexics. These include, e.g., those with substantial depression vs. OCD co-morbidity, and those who exercise at high levels vs. those who do not. According to this view, treatments that fail in one sub-population may actually be effective in others. From our point of view, high-exercising anorexics with significant OCD co-morbidity are a potentially important sub-population to target with SRI therapy. Yet another sub-population to consider is those that have recovered from anorexia nervosa, which has a high relapse rate. Recent data in abstract form from Kaye's group suggest that SRIs may be useful in this regard.
Yet another important issue is that much of the pharmacological research on the treatment of anorexia nervosa has focused on food intake control mechanisms at the level of the hypothalamus. It is clear, however, that anorexia nervosa is much more than a food intake problem. The OCD view of anorexia stands in direct contrast to the simple food intake view since, from an ingestive point of view, SRIs are actually contraindicated. Instead, the OCD view emphasizes serotonin dysfunction "above" the level of the hypothalamus. Once again, animal research is needed to more clearly define this substrate.
As a result of these considerations, we conclude that there is a great need for more animal and clinical research on serotonin in anorexia nervosa. As of now, it is difficult to make firm conclusions from a relatively limited set of controlled SRI trials. This comment does not ignore the fact that anorexia nervosa is a complex disorder with multiple social, psychological and biological factors. Nor does it ignore the need for better psychotherapeutic approaches to the problem. It does indicate, however, that there is a compelling rationale to continue a focus on serotonin in anorexia nervosa.
Thank you again for your interest in our work.