Effects of Acute Tryptophan Depletion on Mood
in Bulimia Nervosa
Walter H. Kaye, Kelly A. Gendall, Madelyn H. Fernstrom, John D. Fernstrom,
Claire W. McConaha, and Theodore E. Weltzin
Background: The present study investigated the role of
serotonin in the pathophysiology of bulimia nervosa (BN)
by studying the affective and appetitive responses of
women ill with BN to an acute tryptophan depletion (ATD)
paradigm.
Methods: Twenty-two women with BN and 16 healthy
control women (CW) were studied on 2 separate days
during the follicular stage of the menstrual cycle. Participants drank a control mix of essential amino acids
(100 g ⫹ 4.6 g tryptophan) on one day and a tryptophan
deficient (100 g ⫺ 4.6 g tryptophan) mixture (ATD) on the
other in a double-blind fashion. Mood/appetite ratings and
blood samples were taken at baseline and at intervals up
to 420 minutes. Participants were then presented with an
array of foods and were allowed to binge and vomit if they
desired.
Results: CW and BN women had a similar and significant
reduction in plasma tryptophan levels and the tryptophan:
LNAA ratio after ATD. After ATD, the BN women had a
significantly greater increase in peak (minus baseline)
depression, mood lability, sadness and desire to binge
compared to the CW. BN subjects and CW had similar
peak changes in mood after the control amino acid
mixture. BN subjects and CW consumed similar amounts
of food after the two amino acid treatments.
Conclusions: Women with BN seem more vulnerable to
the mood lowering effects of ATD, suggesting they have
altered modulation of central 5-HT neuronal systems.
Biol Psychiatry 2000;47:151–157 © 2000 Society of Biological Psychiatry
Key Words: Bulimia nervosa, tryptophan depletion, serotonin, mood
From the Western Psychiatric Institute and Clinic, University of Pittsburgh Medical
Center, Pittsburgh, Pennsylvania.
Address reprint requests to Walter H. Kaye, Western Psychiatric Institute and
Clinic, University of Pittsburgh Medical Center, 3811 O’Hara St, Pittsburgh,
PA 15213-2593.
Received January 11, 1999; revised April 20, 1999; accepted April 22, 1999.
© 2000 Society of Biological Psychiatry
Introduction
B
ulimia nervosa (BN) is a disorder that most commonly occurs in adolescent women who are of normal
body weight (American Psychiatric Association 1994).
BN is characterized by binge eating, purging, and a
distorted body image, and is often associated with neuroendocrine abnormalities (Gwirtsman et al 1983) as well
as comorbid depression, anxiety and obsessions (Lilenfeld
et al 1998).
The pathophysiology of BN is poorly understood. One
hypothesis postulated that bingeing behavior is precipitated by a reduction in serotonin (5-HT) activity in the
brain (Jimerson et al 1990; Kaye et al 1988). This notion
is based on several types of experimental evidence. First,
in general, reducing transmission across brain 5-HT synapses by pharmacologic means is known to stimulate food
intake (Blundell 1984). Second, several studies support the
possibility that ill BN women have reduced 5-HT activity
as suggested by blunting of prolactin response after drugs
with serotonergic actions (Brewerton et al 1992; Goldbloom et al 1990; Jimerson et al 1997; Levitan et al 1997).
Whereas one study found BN subjects had normal levels
of the 5-HT metabolite 5-hydroxyindoleacetic acid (5HIAA) in cerebrospinal fluid (Kaye et al 1990), another
study found this metabolite was low in subjects who
binged more than twice daily (Jimerson et al 1992). Third,
numerous double-blind, placebo controlled studies have
found that a wide range of antidepressant medications are
effective in reducing binge and purge frequency (Mitchell
et al 1993; Walsh 1991). It is important to note that
antidepressants with noradrenergic activity also are efficacious in BN suggesting that other neurotransmitter
systems may also be involved.
The development of the acute tryptophan depletion
(ATD) paradigm is of interest because this method has
been reputed to transiently reduce brain 5-HT synthesis
and release in humans (Delgado et al 1990; Young et al
1985). The synthesis of 5-HT depends on the availability
of its amino acid precursor, tryptophan. Tryptophan is
transported across the blood brain barrier by a competitive
transport mechanism and is converted to 5-HT by trypto0006-3223/00/$20.00
PII S0006-3223(99)00108-0
152
W.H. Kaye et al
BIOL PSYCHIATRY
2000;47:151–157
phan hydroxylase. Because tryptophan hydroxylase is
normally only half saturated with its substrate, manipulations that lower the supply of tryptophan to the brain
reliably reduce 5-HT synthesis (Biggio et al 1974; Fernstrom and Wurtman 1971; Moja et al 1989; Young et al
1989). The ATD paradigm has been used to manipulate
5-HT production through the ingestion of a tryptophan
deficient amino acid mixture or diet (Young 1991). This
technique relies on the occurrence of protein synthesis;
normally when a protein meal is ingested, a large proportion of the digested large neutral amino acids (LNAA) are
synthesized into labile protein stores in the muscle and
liver. When a tryptophan deficient protein mixture is
ingested, tryptophan is drawn from the circulation, enabling synthesis of labile protein stores to continue with
the net result being a reduced plasma tryptophan:LNAA
ratio. The tryptophan depletion technique can lower
plasma tryptophan by 70% to 80% after 5 hours (Young et
al 1985). It has been estimated that such a reduction in
plasma tryptophan can reduce central 5-HT levels by 60%
to 70% (Moja et al 1989). The behavioral effects of ATD
include the instigation of depressive symptoms in normal
(Smith et al 1997; Young et al 1985), remitted depressed
(Delgado et al 1990), and obsessive-compulsive (Barr et al
1994) individuals. In addition, recent findings suggest that
women may be more susceptible to the mood lowering
effects of ATD than men (Smith et al 1997). Fewer studies
have measured the effects of ATD on appetite; no changes
were found in healthy women in a study by Oldman et al
(1994), whereas Young et al (1985) found a decline in
protein intake after ATD.
We hypothesized that the ATD experimental treatment
should precipitate or facilitate bingeing and dysphoric
mood in BN women. Previous studies from our group
found that ATD increased irritability, labile mood, retarded affect, and caloric intake in BN women (Weltzin et
al 1994a, 1995). By contrast, Oldman et al (1995) found
no significant effects of tryptophan depletion on mood,
appetite, or food intake in women with BN who were
abstinent from binge eating and purging. The purpose of
this study was to replicate and extend our initial findings
in a larger sample of BN and healthy control women.
Methods and Materials
Participants
Twenty-two women who met criteria for DSM-IV (American
Psychiatric Association 1994) BN were recruited from the eating
disorders unit of Western Psychiatric Institute and Clinic for this
study. For comparison purposes, 16 healthy control women
(CW) matched to the BN women for age and weight, were
recruited from the staff of Western Psychiatric Institute and
Clinic and through advertisements. These subjects were a com-
bination of those previously reported and new subjects. Results
from 10 BN and 10 CW have been previously reported (Weltzin
et al 1995). This study reports on an additional 12 BN and 6 CW
subjects. All participants provided written informed consent
before commencement of the study, and the study obtained
approval from the University Institutional Review Board on the
Use of Humans as Experimental Subjects. Depression was
measured using the Beck Depression Inventory (Beck et al
1961). BN women were medication free for at least 4 weeks
before the study.
ATD Procedure
Participants were studied within the first 10 days after the onset
of their most recent menstrual period. Each subject was studied
during a sequential two-day period on 2 separate occasions. On
the first day, subjects ate standardized meals consisting of 1500
calories (kcal) (27 g protein and 164 mg tryptophan). No food
was consumed after 9:00 PM. On the second day, an indwelling
venous catheter was inserted into the antecubital vein at 6:30 AM.
At 8:00 AM, participants drank an amino acid (AA) mixture
within 5 minutes. Blood samples were drawn at 7:30 AM
(baseline) and 1, 2, 4, and 7 hours after ingestion of the AA
mixture. The subjects were allowed water but no food until 3:00
PM.
Psychological Testing
Psychological state was assessed at baseline and 2, 4, and 7 hours
after ingestion of the AA mixtures using ratings adapted from
those previously described (Asberg et al 1978; Murphy et al
1982; Overall et al 1962). Ratings were conducted by two
Psychiatrists (TEW and WHK) who were blind to the treatment
condition. At each time-point, using a 6-point scale, a number of
psychological variables were assessed including: anxiety, depression, mood lability, obsessionality, irritability, and desire to
overeat and purge. Peak changes in mood ratings (peak change
from baseline at 4 or 7 hours after AA ingestion) were compared
for each individual mood rating.
Assessment of Feeding
At 1500 hours, subjects were presented with food choices to
assess the effects of ATD on feeding behavior. The original
subjects (10 BN and 10 CW) previously reported by Weltzin et
al (1995) selected their own food from a vending apparatus in the
Human Feeding Laboratory (HFL) (Weltzin et al 1991). The
vending apparatus in the HFL contained 38 different food and
drink items. The food items represented typical binge and non
binge foods and are described in detail elsewhere (Kaye et al
1992). Food items were weighed before dispensing so that the
amount of calories and macronutrients consumed could be
calculated from the uneaten food. The vending machine could be
restocked so that a virtually unlimited amount of food was
available. The participants were instructed to select as much of
any of the foods they wanted and were allowed to binge and
vomit if they so desired.
The new 12 BN and 6 CW subjects were given similar
Tryptophan Depletion in Bulimia
BIOL PSYCHIATRY
2000;47:151–157
153
Table 1. Participant Characteristics
Variable
Age (years)
BMI
% Average body weight
% Low lifetime average weight
% High lifetime average weight
Age of illness onset (years)
Binge frequency (times per week)
Purge frequency (times per week)
Dieting frequency (times per week)
Beck Depression Inventory
CW (n ⫽ 19)
BN (n ⫽ 22)
t
p
24.5 ⫾ 5.6
22.0 ⫾ .3
105.1 ⫾ 9.2
95.2 ⫾ 7.2
109.2 ⫾ 9.3
—
—
—
—
1.8 ⫾ 2.4
21.2 ⫾ 5.0
21.2 ⫾ .4
99.9 ⫾ 11.3
90.6 ⫾ 5.8
121.1 ⫾ 21.0
15.9 ⫾ 4.5
9.9 ⫾ 6.7
14.9 ⫾ 6.9
6.3 ⫾ 11.5
18.6 ⫾ 10.8
1.5
1.0
1.2
0.8
1.9
—
—
—
—
4.4
0.10
0.3
0.3
0.4
0.07
—
—
—
—
0.0001
Values are mean ⫾ SD.
instructions to those above, but did not use the HFL procedure.
Rather, they were presented with a selection of packaged foods,
on a tray, consisting of a wide range of normal meal foods
(chicken, beef, cottage cheese, yogurt, bread, vegetables, fruit,
beverages) and items that are typically preferred during binge
eating episodes such as cookies, chocolate, chips, and ice cream
(Hadigan et al 1989). Again, food items were weighed before
being given to subjects so that the amount of calories and
macronutrients consumed could be calculated from the uneaten
food. The total energy content of the food provided on the trays
was set at 3705 kilocalories.
AA Mixtures
Using a counterbalanced, double-blind design, two AA mixtures
were administered. Both AA mixtures were formulated in our
laboratory using purified AA (Ajinomoto USA, Teaneck NJ) by
a method reported in detail elsewhere (Weltzin et al 1994a). Each
mixture contained a total of 100 g of the following essential and
nonessential AA: L-alanine; L-arginine; L-cysteine; L-glycine; Lhistidine; L-isoleucine; L-leucine; lysine; L-methionine; L-phenylalanine; L-proline; L-serine; L-threonine; L-tyrosine; and Lvaline. The ATD mixture did not contain tryptophan (the 0 g
tryptophan mixture or “active” mixture), whereas the control
mixture did contain tryptophan (the 4.6 g tryptophan mixture or
“control mixture”). The addition of 4.6 g of tryptophan has
previously been shown to prevent a reduction in the plasma
tryptophan:LNAA ratio (Weltzin et al 1994a).
Plasma AA Measurements
Total plasma tryptophan concentrations were quantified fluorometrically (Denckla et al 1967). The plasma levels of other
LNAAs (phenylalanine, tyrosine, leucine, isoleucine and valine)
were measured using a Beckman Model 63000 AA analyzer,
equipped with a fluorometer to detect O-phthalaldehyde-derivatized AA. Plasma samples were precipitated with sulfosalicylic
acid (50 mg/ml plasma), and the supernatant passed through 0.22
mm centrifuge filters (Microfilterfuge Tubes, Rainin Instruments, Woburn, MA). Aminoethyl cysteine was added as an
internal standard before sample precipitation (Fernstrom et al
1987). Mean plasma tryptophan:LNAA ratio responses after the
control and the deficient amino acid drinks were calculated from
the sum of measurements taken at 1, 2, 4, and 7 hours. The
change in the tryptophan:LNAA ratio was calculated by subtracting the baseline ratio from the calculated mean plasma tryptophan:LNAA response.
Data Analysis and Statistics
Analyses were conducted both within and between groups.
Group comparisons for age and weight were done using group
t-tests. Plasma tryptophan levels and the ratio of tryptophan to
the sum of LNAA (Tryptophan: LNAA ratio) were analyzed by
repeated measures ANOVA and Tukey’s post hoc t tests.
Comparisons of plasma tryptophan and tryptophan:LNAA ratios,
after AA ingestion, to those at baseline were done using
Newman–Keuls (NK) multiple comparison procedure. Because
of a lack of normal distributions, feeding and mood data were
analyzed using nonparametric procedures for paired (Wilcoxon
signed ranks test) and group comparisons (Mann–Whitney U
test). Regression analyses were undertaken to determine if
changes in mood and appetite were associated with BECK
scores. Correlational analyses were used to examine any relationships between changes in tryptophan:LNAA ratios and
changes in mood variables. All the data are presented as mean ⫾
standard deviation.
Results
Participant Characteristics
There were no significant differences between the two
groups for most demographic variables (Table 1). The BN
women were slightly, but not significantly, younger than
the CW women, and there was a trend for the BN group to
have a greater percent high lifetime average weight. The
BN women had significantly elevated levels of depression
compared to the control women.
Amino Acid Patterns and Mood and Behavior
Ratings
Baseline levels of tryptophan and the tryptophan:LNAA
ratios were similar in CW and BN subjects (see Table 2).
154
W.H. Kaye et al
BIOL PSYCHIATRY
2000;47:151–157
Table 2. Plasma Amino Acids and Mood Ratings: Absolute Mean Baseline Measurements and Peak Changes after a Control
Amino Acid Mixture and after Acute Tryptophan Depletion (ATD)
Control women (n ⫽ 16)
Variable
Plasma amino acids
Tryptophan (nmol/ml)
Tryptophan/LNAA ratio
Mood states
Anxious
Depressed
Mood lability
Obsessional
Irritable
Desire to overeat
Desire to purge
Women with bulimia nervosa
Baseline
Control
ATD
Baseline
Control
ATD
60 ⫾ 13
0.13 ⫾ 0.03
⫹134 ⫾ 62
⫹0.03 ⫾ 0.05
⫺35.6 ⫾ 9.2e
⫺0.11 ⫾ 0.03e
53 ⫾ 16
0.13 ⫾ 0.04
⫹158 ⫾ 60.4
⫺0.01 ⫾ 0.03
⫺29 ⫾ 9.7e
⫺0.12 ⫾ 0.03e
0.5 ⫾ 0.7
0.1 ⫾ 0.5
0⫾0
0⫾0
0.3 ⫾ 0.6
0⫾0
11.2 ⫾ 24.2
⫺0.5 ⫾ 0.8
⫹0.3 ⫾ 0.9
⫹0.1 ⫾ 0.5
⫹0.2 ⫾ 0.5
⫺0.06 ⫾ 1.1
⫹0.3 ⫾ 0.7
⫹7.2 ⫾ 11.8
⫺0.3 ⫾ 0.6
⫹0.3 ⫾ 0.8
⫹0 ⫾ 0
⫹0 ⫾ 0
⫹0.8 ⫾ 1.5d
⫹0.1 ⫾ 0.5
⫺2.1 ⫾ 27.2
1.5 ⫾ 1.6a
0.9 ⫾ 0.9a
0.05 ⫾ 0.2
1.0 ⫾ 1.4b
0.5 ⫾ 1.2
0.3 ⫾ 0.9
12.6 ⫾ 18.2
⫺0.2 ⫾ 1.4
⫹0.2 ⫾ 1.1
⫹0.3 ⫾ 0.9
⫺0.4 ⫾ 1.1
⫹0.2 ⫾ 1.5
⫹0.5 ⫾ 0.9
⫹9.2 ⫾ 22
⫹0.2 ⫾ 1.1
⫹1.2 ⫾ 1.3b
⫹0.9 ⫾ 1.2c,d
⫹0.2 ⫾ 1.0
⫹1.7 ⫾ 1.9d
⫹1.0 ⫾ 1.2a
⫹18.9 ⫾ 30b,d
Values are mean ⫾ SD. In Control and ATD columns, ⫹ indicates an increase compared to baseline and ⫺ indicates a decrease compared to baseline.
For between group comparisons (CW vs. BN Women), group t comparing the same condition: ap ⬍ .05, bp ⬍ .01, cp ⬍ .001.
For within group comparisons (control vs. ATD), paired t: dp ⬍ .05, ep ⬍ .001.
Similarly, amino acid levels after both interventions were
similar for the CW and BN groups. In both CW and BN
groups, ATD produced a significant decline in plasma
tryptophan concentrations (58% and 55%, respectively)
and in the plasma tryptophan:LNAA ratio compared with
the ingestion of a control amino acid mixture (85% and
92%, respectively).
At baseline, the BN women had significantly higher
ratings of anxiety, depression, and obsessionality than the
controls (Table 2). For mood levels after both interventions, baseline values were subtracted from peak values
(change score). Compared to their response to the control
amino acid mixture, BN women had significantly higher
levels of mood lability, irritability, and desire to purge
after ATD. By contrast, CW only had a significant
increase in irritability after ATD as compared to the
control amino acid mixture.
After ATD, the BN women showed significantly elevated changes in depression, mood lability and desire to
overeat and purge compared to the CW women. There
were no significant differences in mood changes between
BN and CW women after the control amino acid mixture.
Regression analyses indicated that changes in mood and
appetite ratings after ATD were not associated with the
higher Beck Depression Inventory scores in the BN
women compared to the CW women (F ⫽ 0.24, p ⫽ .63).
Correlational analyses also failed to reveal significant
relationships between peak changes in tryptophan:LNAA
ratios and peak changes in any of the mood variables in the
CW or in the BN groups.
Test Meal Intake
There were no significant differences in the intake of
calories or the intake of any macro nutrients between the
two amino acid treatments for either group.
Discussion
This paper confirms and expands previous reports (Weltzin et al 1994b, 1995) that found that ATD increased
negative mood states in BN women compared to healthy
controls. Specifically, we found increased susceptibility to
depression, mood liability, and desire to overeat and purge
after ATD in women with BN compared to controls. These
data suggest that women with BN are vulnerable to the
mood lowering effects of tryptophan depletion. This corroborates results from other studies that have shown that
individuals predisposed to other, possibly serotonergically-mediated psychiatric disorders are particularly susceptible to the depressant effects of tryptophan depletion (Benkelfat et al 1994; Moreno et al 1995; Young et
al 1985).
We found that ATD produced mild irritability in healthy
CW. Other investigators have also found that the ATD
paradigm can have mild mood-lowering effects in healthy
individuals who do not have psychiatric diagnoses (Barr et
al 1997; Smith et al 1987, 1997; Young et al 1985).
Studies that have not found this have used a relatively low
dose of amino acids (Delgado et al 1989; Moreno et al
1995; Oldman et al 1994; Saloman et al 1997) or demonstrated differential effects in males and females (Ellenbogan et al 1996). ATD was associated with an increased
desire to overeat and purge in the BN women. Despite
these self reports, food intake was not increased in the BN
women after ATD.
Differences in the test meal presentation may explain
discrepant findings between this current study and our
previous report (Weltzin et al 1995), that did find increased food intake after ATD. In the current investigation, presentation of a set selection of foods on a tray may
have been more inhibiting than the previously used HFL
procedure that permitted access to a virtually unlimited
Tryptophan Depletion in Bulimia
amount of food. It should also be noted that the small
proportion of patients that completed the test-meal procedure may have limited the ability to detect changes in food
intake, that tend to be modest after ATD (Oldman et al
1995; Young et al 1988). Alternatively, although reduced
5-HT activity may contribute to negative affect and desire
to eat in BN women, it may not in itself be sufficient to
precipitate binge eating. The presence of certain other
mediating circumstances, such as a high degree of food
deprivation, distorted cognitions or perceived negative
experiences of the self or of interpersonal interactions
(Heatherton 1991; Powell et al 1996), may be necessary to
mediate binge eating in the context of reduced 5-HT
activity. In addition, the laboratory setting may have been
inhibiting for some subjects.
What mechanisms could explain the sensitivity of BN
patients to tryptophan depletion? It is thought that aberrations in nutritional status (Laessle et al 1988) or dieting
can reduce tryptophan availability (Anderson et al 1990;
Goodwin et al 1990; Walsh et al 1995; Weltzin et al 1995;
Wolfe et al 1997). Baseline plasma tryptophan levels and
tryptophan ratios were similar between eating disordered
women and controls. Thus, it is unlikely that reduced
availability of tryptophan at baseline for conversion to
5-HT accounted for our findings. Still, it is possible that
there were differences in bioavailable tryptophan stores
that may not have been evident in plasma.
Several studies have shown that women with BN have
an altered neuroendocrine response to 5-HT agents (Brewerton et al 1992; Goldbloom et al 1990; Halmi et al 1993;
Jimerson et al 1997; Levitan et al 1997; McBride et al
1991). Our group (Kaye et al 1998) has found that 5-HT
abnormalities persist after recovery from BN. In addition,
a recent study showed that a dysphoric response to ATD
persisted in remitted BN women (Smith et al 1999).
Together these studies suggest that a disturbance of 5-HT
neuronal function may be trait-related and contribute to
the pathogenesis of BN. We hypothesize that the 5-HT
neuronal system in individuals with BN is inherently
unstable and poorly modulated. This instability results in
the 5-HT system fluctuating erratically rather than having
a more precise compensation that buffers the effects of
diet or stress as is found in the control women. Dieting (or
ATD) may then cause a reduction of 5-HT signal transmission in BN subjects that, in turn, may contribute to
binge eating and dysphoric mood (Jimerson et al 1992;
Kaye et al 1988). In line with our theory, Jimerson et al
(1992) have proposed a model in which individuals with
BN may binge eat as a means of self-modulating 5-HT
activity. In brief, binge episodes may increase the tryptophan:LNAA ratio in plasma, that in turn increases tryptophan availability to the brain, resulting in increased 5-HT
synthesis and release (Fernstrom et al 1971, 1972, 1978).
BIOL PSYCHIATRY
2000;47:151–157
155
Thus, individuals with BN may use dieting and binge
eating to modulate an unstable 5-HT system. In summary,
people with an inherent modulatory defect in 5-HT function may be prone to develop an eating disorder. Because
of their modulatory 5-HT defect, they cannot respond
appropriately and precisely to stress or stimuli, or modulate their affective states. They may learn that extremes of
dietary intake, by effects on plasma TRP, are a means by
which they can crudely modulate their brain 5-HT functional activity.
Overall, the present study adds to the expanding body of
evidence suggesting that aberrations in serotonergic modulation exist in individuals with BN. The tryptophan
depletion paradigm demonstrates that the mood of BN
women is sensitive to acute changes in 5-HT activity.
Further investigations using larger samples may be required to elucidate the definitive effects of tryptophan
depletion on appetite and food intake in eating disordered
women.
Financial support: NIMH #2 R01 MH 42984-04; “The Neurobiology of
Feeding Behavior in Bulimia.”
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