Melatonin Disturbances in Anorexia Nervosa and

Bulimia Nervosa

Sidney H. Kennedy
(Accepted 18 November 1993)

The pineal gland releases melatonin into the blood stream in response to sympathetic
noradrenergic stimulation of pinealocytes. This process is inhibited by light via the
retino-hypothalamic-pineal pathway. Hence melatonin is predominantly released in
darkness. Because serotonin is a precursor of melatonin, the intake of dietary tryp-
tophan may also influence melatonin levels. Although the exact physiological role of
melatonin in humans is unclear, it appears to be implicated in reproductive physiology,
especially in terms of the onset of menarche. Low levels of melatonin also occur in
depression. In this review, studies of melatonin in patients with anorexia nervosa and
bulimia nervosa are considered in relation to potential abnormalities of noradrenergic
function and circadian rhythm. The influence ofweight loss, binging and purging, and
depression on melatonin is discussed. Other studies involving the assessment of mel-
atonin in relation to menstrual function are required. 0 7994 by john Wiley & Sons, lnc.

Disturbances of cognition, psychological development, affect, perceptual functions in-

cluding taste, hunger, and satiety, as well as neurobiological and metabolic abnormal-
ities have all been implicated in etiological investigations of anorexia nervosa (AN) or
bulimia nervosa (BN; Anderson & Kennedy, 1992). In many instances abnormalities are
due to the secondary consequences of prolonged fasting and/or purging. The extent to
which these abnormalities perpetuate AN and BN is unclear but is of much importance
in understanding the course and outcome of these often chronic disorders.
The purpose of this paper is to: (1) selectively review the neurophysiology and func-
tional aspects of the pineal gland and melatonin (MT) particularly in those areas that
have potential relevance to AN and BN, (2) summarize what is known about MT pro-
duction and release in AN and BN, and (3) discuss the potential relevance of these
findings and their implications for future research.

Sidney H. Kennedy, M.D., F.R.C.P. (C),i s Professor of Psychiatry and Head of the Psychosomatic Medicine
Program at the University of Toronto, Research Director, Department of Psychiatry, and Head, Program for
Eating Disorders, The Toronto Hospital. Address reprint requests to Dr. Kennedy at the Department of
Psychiatry, The Toronto Hospital, 200 Elizabeth Street, ENB-235, Toronto, Canada M5G 2C4.

lnternationai Joornai of Eating Disorders, Vol. 16, No. 3, 257-265 (1994)

0 1994 by John Wiley & Sons, Inc. CCC 027fi-3478/94/030257-09
258 Kennedy

NEUROPHYSIOLOGICALAND FUNCTIONAL ASPECTS OF MT

With the development of valid and reliable assay techniques for the measurement of
MT (Lewy & Markey, 1978; Brown et al., 1983) and its principal metabolite 6-hydroxy-
melatonin sulfate (aMT6s); Aldhous & Arendt, 1988), researchers have elucidated how
neurological mechanisms under sympathetic control are responsible for MT release. The
output of MT from the pineal gland is sensitive to light conditions, providing a marker
of diurnal or circadian rhythm (Moore & Klein, 1974; Lynch, Wurtman, Moskowitz,
Archer, & Ho, 1975). Because serotonin is a precursor of MT in the pineal gland, the
relationship between dietary tryptophan intake and MT output has also attracted inter-
est as a possible index of the serotonin system. Both the amount and circadian rhythm
of MT output have been investigated in a number of physical and psychiatric conditions
including major depression and reproductive dysfunction.

links to Noradrenergic Function

Neural control of this ”neuroendocrine transduction” process occurs through periph-

eral sympathetic innervation of the pineal gland with both a and p noradrenergic input
(Lewy, 1984a). This neural pathway has been confirmed in humans using pharmaco-
logical probes with specific noradrenergic actions. For example, the p antagonists pro-
pranolol and atenolol block nocturnal MT release (Vaughan et al., 1976; Cowen, Green,
Graham-Smith, & Braddock, 1983) as do both the a2 agonist clonidine (Lewy, Siever,
Uhde, & Markey, 1986), and the a1antagonist prazosin (Checkley & Palazidou, 1988).In
contrast, the a2 antagonist ”ORG 370” increases MT release although the p receptor
agonist isoproterenol could not be given safely to humans at a high enough dose to
enhance MT release (Lewy, 1984a).

Circadian Rhythm
Under normal conditions, the pineal gland secretes MT in a circadian pattern with
peak blood levels occurring during the night whereas daytime levels are low or below
detectable values (Lewy, 1984b). This rhythm is sensitive to environmental and behav-
ioral changes, as seen following transmeridian travel (Arendt et al., 1987; Claustrat,
Brun, David, Sassolas, & Chazot, 1992) or in shift workers (Waldhauser, Vierhapper, &
Pirich, 1986; Sack, Bloor, & Lewy, 1992).

Links to Dietary Intake and Restriction

Because MT is produced in the pineal gland from serotonin, there has also been
considerable interest in the effect of both tryptophan intake and serotonin uptake block-
ade on MT output. Investigators have reported increased MT or aMT6s output in re-
sponse to the serotonin reuptake inhibitor fluvoxamine (Demisch, Gerbaldo, & De-
misch, 1988) and to both intravenous (Demisch et al., 1991) and oral (Levitt, Brown,
Kennedy, & Stern, 1991) L-tryptophan.
The effect of dietary depletion of tryptophan or other essential amino acids on MT
release is less clear. Despite evidence from animal studies that reduced food intake
results in elevated plasma MT levels (Chik, Ho, & Brown, 1987), human volunteers who
restricted food intake for 3 weeks showed no significant elevation in nocturnal MT
Melatonin Disturbances 259

(Anderson, Gartside, & Cowen, 1990). In fact, acute tryptophan depletion resulted in
decreased nocturnal MT secretion (Zimmerman et al., 1993). On the other hand, Meyer,
Steyn, and Moncrieff (1990) reported a significant daytime elevation of aMT6s in vol-
unteers after 72 hours of calorie restriction.

MT as a Marker in Major Depression

There is also considerable interest in MT output in patients with mood disorders. A
reduced nocturnal rise in serum or plasma MT has been reported in most (Wetterberg,
1978; Beck-Friis, Von Rosen, Kjellman, Ljumgren, & Wetterberg, 1984; Brown et al.,
1985) but not all (Thompson, Franey, Arendt, & Checkley, 1988) studies involving pa-
tients with major depression. A reciprocal relationship between MT and cortisol output
has also been proposed (Wetterberg, Beck-Friis, Aperia, & Petterson, 1979). In addition,
several authors have reported a significant increase in levels of serum MT during the
manic state among patients with biopolar affective disorder (Lewy, Wehr, Gold, &
Goodwin, 1979; Kennedy, Tighe ,McVey, & Brown, 1989).Reports that antidepressant
drugs, including desipramine (Thompson, 1985; Sack & Lewy, 1986; Kennedy & Brown,
1992) and monoamine oxidase inhibitors (Murphy, Tamarkin, Sunderland, Garrick, &
Cohen, 1986; Kennedy, Davis, Brown, Ford, & DSouza, in press), increase MT output
have been advanced in support of a norepinephrine depletion hypothesis in major
depression (Checkley & Palazidou, 1988).
Therefore, measurement of serum MT or urinary aMT6s may yield indirect evidence
of disturbances in (1) circadian rhythm, (2) noradrenergic innervation of the pineal
gland, (3) tryptophan availability for conversion to serotonin and MT within the pineal
gland, and (4) depressed mood state.

POTENTIAL RELEVANCE OF MT TO A N A N D B N

Neuroendocrine and Neurotransmitter Disturbances

Changes in many hormonal circadian rhythms have been described in both AN and
BN (Kennedy & Garfinkel, 1987; Goldbloom & Kennedy, 1993). Various physiological
disturbances, including amenorrhea and abnormal temperature regulation, that occur in
patients with eating disorders are thought to be hypothalamic in origin (Russell, 1979).
Similar neuroendocrine abnormalities including hypercortisolism and a blunted corti-
cotropic response to corticoptropin releasing factor (CRF) occur in patient groups with
both AN and major depressive disorder (Gold, Loriaux, Roy, Kellner, et al., 1986; Gold,
Loriaux, Roy, Kling, et al., 1986). There is also evidence to suggest that measures of
peripheral noradrenergic function are most abnormal in those depressed patients who
display overactivity of the hypothalamic pituitary adrenal axis Oimerson, Insel, Reus, &
Kopiu, 1983; Rubin, Price, Charney, & Heninger, 1985).
Particularly in seasonal breeding animals the duration and amount of MT released are
influenced by the light-dark cycle. A photic response from the suprachiasmatic nucleus
(SCN) is mediated via the retino-hypothalamic-pineal axis and this is believed to switch
on or off reproductive function (Karsch et al., 1984; Tamarkin, Baird, & Almeide, 1985).
The mechanism of action of MT is thought to occur at the hypothalamic level because
administration of exogenous MT has been shown to produce a reduction in gonadotro-
pin releasing hormone (Gn-RH) receptor function (Lang, Aubert, Conne, Bradtke, &
260 Kennedy

Sizonenko, 1983) as well as an enhanced luteinizing hormone (LH) pulsatile response

(Cagnacci, Elliott, & Yen, 1991).Further support for a link between MT and reproductive
function comes from studies of central precocious puberty in children (Waldhauser,
Boepple, Schemper, Mansfield, & Crowley, 1991) in whom serum MT is significantly
lower than age-matched prepubertal children. Changes in MT levels during the men-
strual cycle have also been described, although findings are inconsistent (Sizonenko &
Lang, 1988). Of particular relevance to anorexic women is the report by Laughlin,
Loucks, and Yen (1991) comparing MT profiles in amenorrheic and cycling female ath-
letes. Although both groups had elevated daytime MT levels, only the amenorrheic
subgroup displayed elevated nocturnal MT output that was associated with a 2-hour
delay in offset.
MT Output and Rhythm in AN and BN
The original reports on MT secretion in AN and BN were inconsistent. Dalery, Claus-
trat, Brun, and De Villard (1985)and Baranowska, Soszynski, Misiorowski, Doroket, and
Witkowski (1986) reported normal plasma MT levels in AN patients whereas Birau,
Alexander, Bertholdt, and Meyer (1984) reported significantly reduced MT levels among
AN subjects compared with controls. In contrast Brambilla et al. (1988)reported signif-
icantly higher MT secretion in AN subjects compared with both obese and control
groups.
Toronto Studies of MT Output in A N and BN
In an attempt to resolve the question of whether or not AN and BN patients display
disturbances in either circulating levels or circadian rhythm of MT, we have undertaken
a series of studies over recent years.
In the initial study involving three groups of eating disorder patients (11 with a
diagnosis of AN, 10 with AN and BN, and 12 with BN) as well as 10 control subjects
there were no differences in overnight levels of serum MT among the groups. However,
when AN and BN subjects were subdivided according to the presence or absence of
concomitant major depression, there were significantly lower elevations in nocturnal MT
levels among those with concurrent MD compared with the nondepressed group. Di-
vision of subjects according to current weight (those above and below 85% of average
body weight) yielded no difference among groups (Kennedy, Garfinkel, Parienti, Costa,
& Brown, 1989).
In a subsequent report, urinary aMT6s levels for daytime (6 a.m. to 6 p.m.) and
nighttime (6 p.m. to 6. a.m.) were compared among the same three patient populations
and controls (Kennedy, Brown, Garfinkel, McVey, Costa, & Parienti, 1990).Again, there
were no differences in aMT6s levels between AN and BN patients and controls, although
in all cases nighttime output was significantly higher than daytime output. This latter
finding suggests that normal circadian rhythm was preserved in these groups of pa-
tients. There was also a significantly lower nocturnal aMT6s output among the de-
pressed subgroup.
In addition to providing support for reduced MT output during major depression (in
this case depression that is comorbid with AN or BN) these two studies also provide
support for the measurement of urinary aMT6s as a practical, less intrusive, and valid
index of pineal function.
To further evaluate the effect of weight change in AN, 9 AN patients completed
overnight serum MT sampling on two occasions when the mean levels of body weight
were 74% and 85'% of matched population average weights. There was no significant
Melatonin Disturbances 261

change in MT levels between the two sampling points and at neither time was there a
significant difference from an age-matched female control group (Kennedy, Brown,
McVey, & Garfinkel, 1990), again suggesting that low weight alone does not alter MT
release. Bearn et al. (1988) reported similar findings in AN patients before and after
weight restoration.
How is it possible to reconcile differences between these seemingly consistent find-
ings, which suggest that neither low weight nor weight change alter MT levels, and the
report by Brambilla et al. (1988)of elevated MT levels in AN? We hypothesized that acute
starvation and not low weight might be responsible for elevated nocturnal levels of MT.
We, therefore, carried out a further study involving 23 female AN patients (11of whom
were also actively binging and purging) who were admitted to an intense hospital
treatment program for metabolic and weight correction (Kennedy, Brown, Ford, & Ra-
levski, 1993). In this study, daytime and nighttime urinary aMT6s levels were evaluated
on the day of admission (when subjects were most acutely starved and in some cases
metabolically unstable), and again after 7 and 14 days. Results indicated a significant
elevation of daytime aMT6s output in the AN + BN group on the day of admission
compared with both AN and control groups, suggesting a disturbance in circadian
rhythms among acutely symptomatic AN patients who were also binging and purging.
This AN + BN group also demonstrated significantly greater overall aMT6s output over
24 hours on the day of admission to hospital compared with themselves after a further
7 or 14 days in hospital, and compared with AN patients who did not binge or purge,
as well as with control subjects.
This study again supports the conclusion that low weight patients with AN do not
have abnormal amounts or rhythm of MT output. However, the subgroup of AN pa-
tients who concurrently binge and purge display abnormalities of both rhythm and
amount of MT released. These findings are similar to reports in male alcoholic patients
(Murialdo et al., 1991) where increased daytime MT output occurred during the acute
withdrawal state.

POTENTIAL RELEVANCE OF THESE FINDINGS

In general, MT levels appear to be less susceptible to variation in response to stress
(Vaughan et al., 1979) than other hormones such as cortisol. This is borne out in several
studies involving low weight anorexic patients who have commenced a refeeding treat-
ment program. Depressed anorexic and bulimic patients consistently demonstrate a
lower MT output compared with those who do not have concurrent major depression.
These findings are in agreement with the literature on major depression and may be
used in conjunction with other genetic investigations (Kassett et a]., 1989) to support
differences between depressed and nondepressed eating disorder patients. A logical
extension of this finding would be to hypothesize that those eating disorder patients
with low MT may respond preferentially to antidepressant therapies. This has not been
evaluated as yet.
Disturbances in both output and rhythm of MT in acutely symptomatic anorexic
patients who are also binging and purging distinguish this group of patients from
restricting anorexics. There is evidence to suggest that weight restored bulimic anorexic
patients display underactivity of both serotonergic (Kaye, Ebert, Gwirtsman, & Weiss,
1984) and noradrenergic (Kaye, Ballenger, et al., 1990)pathways. Thus, the elevated MT
output may indicate increased neurotransmitter activity in either or both systems during
acute binge eating and purging. This hypothesis is further supported by the observation
262 Kennedy

that resting metabolic rate (which is influenced by noradrenergic function) is normal in

symptomatic bulimic patients but decreases in asymptomatic bulimics (Black, Kennedy,
Kaplan, Levitt, Allard, & Anderson 1991).
Alterations in MT output may also influence the symptom profiles of patients with AN
or BN. Abnormally elevated daytime levels could be expected to cause dysphoric mood
and daytime sleepiness (Lieberman, 1986), further disrupting the individual's ability to
reestablish normal patterns of eating, sleeping, and activity patterns. Other neuropep-
tides including neuropeptide Y (NPY) and peptide YY (PYY) are both potent stimulators
of feeding in animals (Morley, Levine, Grace, & Kneip, 1985; Stanley, Kyrkouli, Lam-
pert, & Leibowitz, 1986) and may inhibit noradrenergically mediated MT secretion (01-
cese, 1991).High levels of both NPY and PYY have been reported in weight restored and
nonbinging AN patients (Kaye, Berrettini, Gwirtsman, & George, 1990). Further studies
of symptomatic and asymptomatic weight restored AN patients in whom these neu-
ropeptides and MT or its metabolite aMT6s are measured would be of considerable
interest. It is also possible that elevated daytime aMT6s levels may reflect increased
tryptophan intake during binge eating, resulting in a higher output of aMT6s.
Finally, because of the association between MT output and reproductive function,
further detailed evaluation of sex hormones and MT during and after amenorrhea may
help to clarify the course of reproductive function among AN patients.
The author would like to acknowledge the collaborative support of Dr. Gregory M. Brown
throughout these studies and for advice on an earlier version of this manuscript. Dr. Kennedy was
supported by the Ontario Mental Health Foundation.

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