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Serotonin:
Implications for the Etiology & Treatment of Eating
Disorders
Reprinted from Eating
Disorders Review
By Walter H. Kaye, M.D. & Michael Strober, Ph.D.
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.
Conclusion
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.
References
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).
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