Serotonin: Implications for the Etiology & Treatment of Eating Disorders

by Walter H. Kaye, M.D., Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania & Michael Strober, Ph.D., Professor of Psychiatry, Neuropsychiatric Institute and Hospital, UCLA School of Medicine, Los Angeles, California
Reprinted from Eating Disorders Review
May/June 1999 Volume 10, Number 3
©1999 Gürze Books

Anorexia nervosa (AN) and bulimia nervosa (BN) have complex etiologies that are shaped by developmental, social, and biological processes. While the exact nature of these interactive processes is still not completely understood, there is limited evidence that cultural factors are the primary, or at least the most formidable, determinants of these disorders. However, dieting behavior and the drive toward thinness are quite common in industrialized countries throughout the world, where eating disorders are most prevalent. But, at the same time, AN and BN affect only a small proportion of women.

Genetic influences

Emerging evidence suggests that both AN and BN are familial disorders with strong biological correlates. For example, the results of family and twin studies have pointed to significant genetic influences in the etiology of both disorders. Family studies have shown that the prevalence of eating disorders is 7 to 12 times higher among relatives of AN and BN probands than among controls. Significantly higher concordance rates reported among monozygotic (MZ) compared to dizygotic (DZ) AN and BN twins have suggested substantial genetic influence in the observed familiality. Indeed, heritability estimates indicate that approximately 55% to 80% of the variance in the occurrence of AN and BN can be traced to genetic factors.

Earlier theories about the biological expression of the observed genetic liability questioned whether people with AN had an underlying pituitary or hypothalamic disorder. More recently, as mechanisms of neurotransmitter modulation in appetitive behaviors have become better understood, researchers have begun to suspect that some disturbances of neurotransmitter function may be involved in causing AN and/or BN. It is important to emphasize that monoamine or neuropeptide disturbances could themselves be consequences of either dietary abnormalities or other premorbid traits that contribute to a vulnerability to develop AN or BN. One way to tease apart cause and effect related to neurotransmitter disturbances is to study people with AN or BN at various stages in their illness, that is, while they are symptomatic and after they recover.

Serotonin’s role

Among all the different transmitters, there has been particular interest in the role that serotonin (5-HT) may play in AN and BN. That is because disturbances in brain serotonin pathways have been implicated in behaviors typically found in people with eating disorders, such as disturbance of feeding, mood and impulse regulation, and obsessionality. A substantial number of studies have shown alterations in serotonin activity in the ill state. While less well studied, it is of considerable interest that these serotonin disturbances appear to persist after recovery in both AN and BN. In addition, 4 of 6 studies have shown that people with AN have a modest but increased frequency of a gene that codes for an abnormal serotonin receptor. Finally, people with AN and BN respond to antidepressants in placebo-controlled trials. In such studies, antidepressants, including selective serotonin reuptake inhibitors (SSRIs), have been effective for reducing binge eating and vomiting in people with BN.

Both recovered AN and BN women have been found to have elevated levels of cerebrospinal fluid (CSF) concentrations of 5-HIAA, the major serotonin metabolite. (In contrast, low levels of CSF 5-HIAA are associated with impulsive and non-premeditated aggressive behaviors, which cut across traditional diagnostic boundaries.) Behaviors noted after recovery from AN and BN, such as obsessions with symmetry, exactness, and perfectionism, and negative affect, tend to be opposite in character to behaviors displayed by people with low 5-HIAA levels. These data support the hypothesis that the increased CSF 5-HIAA concentrations in AN and BN may be associated with exaggerated anticipatory overconcern with negative consequences (i.e., “harm avoidance”), while the lack of such concerns may explain impulsive, aggressive acts that are associated with low CSF 5-HIAA levels. In fact, it is conceivable that people with AN might starve themselves in order to reduce brain serotonergic activity, and in this way, temporarily make themselves feel better.

Etiologic vulnerability

It is possible that a disturbance of serotonin activity may create a vulnerability for the expression of a cluster of symptoms that are common to both AN and BN. The possibility of a common vulnerability for AN and BN may seem puzzling, given well-recognized differences in behavior between these disorders. However, recent family and biological studies suggest that patients with AN and BN have a shared etiologic vulnerability. Other factors that are independent of a vulnerability for the development an eating disorder may contribute to the development of eating disorders subgroups. For example, people with restricting-type AN have extraordinary self-restraint and self-control. The risk for obsessive-compulsive personality disorder is elevated only in this eating disorder subgroup and in their families, suggesting a shared transmission with restricting-type AN. In other words, an additional vulnerability for behavioral over-control, and rigid, inflexible mood states, combined with a vulnerability for an eating disorder, may result in an increased risk for developing restricting-type AN.

SSRIs and Mood Regulation

Another fact suggesting that serotonin plays an important role in eating disorders is that SSRIs are sometimes helpful in reducing weight- and shape-related preoccupations in individuals with this disorder. It has been theorized that these medications do not simply increase or decrease the general level of serotonin activity. Rather, they may help the serotonin system to more precisely modulate mood and impulse control.

One confounding issue is that people with AN do not seem to respond well to SSRIs when they are malnourished and underweight. The lack of response to SSRIs in malnourished patients may be due to the fact that SSRIs are effective only when there is enough serotonin in the brain for these drugs to work in the first place. In fact, the precursor of serotonin is tryptophan, an essential amino acid that is present in certain foods. Although it is difficult to eat a diet that does not contain at least some tryptophan, one way is to reduce the body’s level of tryptophan and thereby serotonin. This results in reduced tryptophan availability to the CNS and reduced serotonin activity. Consistent with this view, it has been shown that people with AN have reduced serotonergic activity when they are malnourished and underweight.

To summarize this point, SSRI medication works by blocking reuptake of serotonin in the synapse, but because there may be so little serotonin in the synapse of starving brains, SSRI medication may not be effective in the underweight state. Available data suggest that SSRI medications may be more effective for preventing relapse and reducing obsessionality when they are administered after weight restoration in women with AN.


Emerging data suggest that disturbances of serotonin activity may create a vulnerability for the expression of symptoms that are common to both AN and BN, and thus may contribute to the etiology of these disorders. The effects of several antidepressant medications, particularly SSRIs, used to treat BN and weight-restored patients with AN, are consistent with serotonin’s mechanisms in BN. When patients are underweight, the SSRIs do not seem to be effective for reducing the symptoms of AN. This lack of effect may reflect the fact that the medications need a certain amount of serotonin in brain synapses for them to work, and that starving brains are deficient in serotonin. However, once brain serotonin is regained, SSRIs may reduce relapse in AN.


Brewerton TD. Toward a unified theory of serotonin dysregulation in eating and related disorders. Psychoneuroendocrinology 20:561-590, 1995.

Bulik CM, Sullivan PF, Kendler KS: Heritability of binge eating and bulimia nervosa. Biol Psychiatry 44:1210, 1998.

Jimerson DC, Wolfe BE, Metzger ED, et al. Decreased serotonin function in bulimia nervosa. Arch Gen Psychiatry 54:529-534, 1997.

Kaye WH, Greeno CG, Moss H, et al. Alterations in serotonin activity and psychiatric symptoms after recovery from bulimia nervosa. Arch Gen Psychiatry 55:927, 1998.

Lilenfeld LR, Kaye WH, Greeno CG, et al. A controlled family study of anorexia nervosa and bulimia nervosa. Psychiatric disorders in first-degree relatives and effects on proband comorbidity. Arch Gen Psychiatry 55:603, 1998.

Strober M. Family-genetic studies of eating disorders. J Clin Psychiatry 52:9, 1991.

Strober M, Freeman R, Lampert C, Diamond J, Kaye W. A controlled family study of anorexia nervosa and bulimia nervosa: evidence of shared liability and transmission of partial syndromes. Am J Psychiatry (submitted for publication).

Michael Strober, Ph.D.

Professor of Psychiatry, Neuropsychiatric Institute and Hospital, UCLA School of Medicine, Los Angeles, California

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