5-HT has a well-confirmed role in the regulation of eating behaviour. In animals and in humans, manipulations that increase 5-HT neurotransmission lead to reduced eating behaviour, whereas those that reduce 5-HT activity precipitate compulsive or binge eating.20
These tendencies lead to the expectation that anorexia nervosa, in its restrictive form, should coincide with increased 5-HT tone, whereas syndromes characterized by binge eating (such as anorexia nervosa binge–purge type or bulimia nervosa) should correspond with reduced 5-HT activity. Studies of the 5-HT system in patients with clinical EDs are only partly consistent with these expectations.
At first blush, findings in women with active anorexia nervosa appear to contradict the expectation articulated here, because they indicate reduced 5-HT tone: decreased platelet binding of serotonin uptake inhibitors,21
blunted prolactin (PRL) and cortisol responses to 5-HT agonists and partial agonists,22
reduced cerebrospinal fluid (CSF) levels of 5-HT metabolite23
and decreased platelet monoamine oxidase (MAO) activity.24
However, Kaye et al23
have documented that CSF 5-hydroxyindoleacetic acid (5-HIAA) in forms of anorexia nervosa characterized by binge eating is lower than that in restrictive forms of the disorder, a finding that associates bulimic symptomatology with an expected reduction in 5-HT tone. Furthermore, findings in people who have recovered fully from anorexia nervosa reveal that data from actively ill individuals may be deceptive: following restoration of full weight, former patients with anorexia nervosa reportedly display normal PRL responses to the 5-HT-releasing agent, d-fenfluramine,25
as might indicate improvement of a state-related 5-HT abnormality. Furthermore, Kaye et al26
and Kaye and Frank27
have noted that fully recovered former patients with anorexia nervosa display elevated
CSF 5-HIAA and elevated 5-HT1A
receptor binding, measured by positron emission tomography (PET). These findings suggest that anorexia nervosa may actually correspond to a primary state of increased 5-HT tone, which is then masked during active illness by malnutrition-induced reductions
in 5-HT activity. Indeed, Kaye et al26,27
have proposed that findings in the active stages of illness distort the existence of an underlying hyperserotonergic trait in the pathophysiology of anorexia nervosa. The same group has recently reported findings from PET studies in fully weight-recovered women who formerly had anorexia nervosa that may also be compatible with a general “5-HT overactivity hypothesis.” These findings suggest reduced 5-HT2A
receptor binding in mesial temporal regions and cingulate and sensorimotor cortical regions28
and could reveal a compensation resulting from exposure to increased extracellular levels of 5-HT.
Findings in patients with active bulimia nervosa are compatible with a “low 5-HT tone hypothesis” in the sense that they associate the syndrome with abnormally low 5-HT turnover and neurotransmission and establish the 5-HT system as a potential site of action for the antecedent effects of dieting in binge episodes. Patients with active bulimia nervosa display decreased CSF 5-HIAA (at least when they binge at high frequency29
), reduced platelet binding of 5-HT uptake inhibitors,30,31
reduced central transporter availability32
and blunted neuroendocrine responses to 5-HT precursors and 5-HT agonists/partial agonists, such as meta-chlorophenylpiperazine (m-CPP).33,34,35
Furthermore, tryptophan- depletion paradigms that use dietary manipulations to lower brain tryptophan and 5-HT synthesis have been shown to exacerbate bulimic symptoms in patients with active bulimia nervosa36
and to lead to the transient reappearance of such symptoms in fully recovered individuals.37
Findings in individuals who have recovered fully from bulimia nervosa, however, suggest a more complicated picture: in 2 studies, recovery from bulimia nervosa is reported to coincide with normal endocrine responses after 5-HT agonists.38,39
In a third study, based on PET techniques, findings suggest persistent reductions in postsynaptic 5-HT2A
receptor activity following recovery from bulimia nervosa.40
A fourth set of results, from 23 women who had recovered fully from bulimia nervosa, suggest abnormally high CSF 5-HIAA (i.e., increased 5-HT metabolism) compared with a group of women with normal eating habits.38
These last findings parallel those obtained in women who had recovered from anorexia nervosa and support the concept that, setting disorder sequelae aside, anorexia nervosa and bulimia nervosa may both involve elevated 5-HT activity. This is possible, but we caution that the findings of Kaye et al38
indicating heightened 5-HT metabolism following recovery from bulimia nervosa may be confounded by weight discrepancies between a heavier clinical group and a lighter nonclinical group, which could partly explain the higher 5-HT metabolism observed in the group with bulimia nervosa.
At best, the available 5-HT findings lend themselves to ambiguous interpretation, with the results probably reflecting differences related to measurement, stages of illness, brain regions and other factors. Supportable generalizations, nonetheless, appear to include the following: anorexia nervosa and bulimia nervosa implicate general alterations in brain 5-HT function; there is evidence of serotonergic dysregulation, with no sweeping unidirectional tendency (toward elevation or reduction) emerging in either disorder; and compared with findings in restrictive ED variants, which imply some propensity toward increased 5-HT tone, serotonergic tendencies in binge-eating syndromes appear to be inconsistently skewed toward reduction of 5-HT activity.