Altered Response to Meta-Chlorophenylpiperazine
in Anorexia Nervosa: Support for a Persistent
Alteration of Serotonin Activity After Short-Term
Weight Restoration
Guido K. Frank,1 Walter H. Kaye,1* Theodore E. Weltzin,2 James Perel,1
Howard Moss,3 Claire McConaha,1 and Christine Pollice1
1
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
2
University of Wisconsin, Madison, Wisconsin
3
Temple University, Philadelphia, Pennsylvania
Accepted 29 August 2000
Abstract: Objective: Patients with anorexia nervosa (AN) have disturbances of appetite
and behaviors, such as dysphoria, inhibition, and obsessions, that could be related to
altered serotonin activity. To investigate such relationships, we administered metachlorophenylpiperazine (m-CPP), a relatively serotonin-specific drug. Methods: To avoid the
confounding effects of malnutrition or weight loss, we studied 12 patients with restrictingtype AN between 5 and 17 days after a return to a normal weight and while on a stable
dietary intake. We compared them to 12 healthy control women (CW). m-CPP was administered double blind and placebo controlled. Results: Although weight restored, AN women
had lower body weight and increased ratings for depression and obsessionality compared
with CW. After m-CPP, AN women had an elevation in mood and a reduction in body image
distortion when compared with placebo. After m-CPP, groups had similar cortisol, adrenocorticotropin (ACTH), and growth hormone responses whereas AN women had an uncertain
reduction in prolactin response. Discussion: These data support other studies that suggest that
altered serotonin activity persists after weight restoration in AN patients. The finding that
m-CPP temporarily improved mood and reduced body image distortions supports the hypothesis that altered serotonin activity may contribute to the pathophysiology of AN. © 2001
by John Wiley & Sons, Inc. Int J Eat Disord 30: 57–68, 2001.
Key words: anorexia nervosa; serotonin; m-CPP; OCD
*Correspondence to: Walter H. Kaye, University of Pittsburgh, Western Psychiatric Institute and Clinic, 3811
O’Hara Street, Room E-724, Pittsburgh, PA 15213. E-mail: kayewh@msx.upmc.edu
Grant sponsor: NIMH; Grant number: MH 46001 01A1; Grant sponsor: the Children’s Hospital Clinical
Research Center, Pittsburgh, Pennsylvania; Grant number: 5M01RR00084; Grant sponsor: Christina BarzFoundation, Essen, Germany.
© 2001 by John Wiley & Sons, Inc.
Prod. #1662
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Frank et al.
INTRODUCTION
Anorexia nervosa (AN) is characterized by a refusal to maintain body weight over a
minimal weight normal for age and height; an intense fear of gaining weight or becoming
fat, even though underweight; and a disturbance in the way in which one’s body weight,
size, or shape is experienced (e.g., the person claims to “feel fat” even when emaciated.
American Psychiatric Association [APA], 1994).
Alterations of the serotonin neurotransmitter system may contribute to the pathophysiology of AN (Brewerton & Jimerson, 1996; Wolfe, Metzger & Jimerson, 1997; Walsh &
Devlin, 1998). An increase in intrasynaptic serotonin reduces food consumption (Leibowitz & Alexander, 1998; Blundell, 1984). Several serotonin receptors and sites for serotonergic action involved in feeding and satiety have been identified (Simansky 1996;
Leibowitz & Alexander, 1998). Altered brain serotonin activity could play a role in increased satiety and weight loss in AN patients. In addition, more than 50 years of investigations suggest that anorexics tend to be inhibited, rigid, perfectionistic, and obsessional
(Palmer & Jones, 1939). Such traits may be premorbid and persist after recovery (Kaye et
al., 1992; Casper, 1990, Srinivasagam et al., 1995).
Underweight anorexics may have diminished serotonin activity (Walsh & Devlin, 1998;
Kaye, Gendall, & Stober, 1998). In contrast, increased levels of cerebrospinal fluid (CSF)
5-hydroxy indoleacetic acid (5-HIAA), the major metabolite of serotonin, has been found
after long-term recovery that could be a premorbidly existing trait. Low levels of CSF
5-HIAA are associated with impulsive and aggressive behavior (Asberg, Traskman, &
Thoren, 1976; Van Praag, 1983; Linnoila et al., 1983), whereas behaviors in anorexic patients tend to be the opposite of those in impulsive and aggressive patients.
One tool that can be used to investigate the relationships between brain serotonin
activity and behavior is meta-chlorophenylpiperazine (m-CPP). m-CPP binds as an agonist at the 5HT1C and 5HT2C (Graeff, 1996), as an antagonist at the 5HT2B (Thomas,
Gager, Holland, Brown, & Wood, 1996), and as a partial agonist at the 5HT2A (Willins &
Meltzer, 1997) and 5HT3 (Hoyer, Neijt, & Karpf, 1989; Kahn & Wetzler, 1991) receptor
sites in the brain. m-CPP may also act at presynaptic serotonin transporter sites in humans
(Baumann, Mash, & Staley, 1995). It binds potently to alpha-2 adrenergic receptors, but
weakly to dopamine and muscarinic cholinergic receptors (Hamik & Peroutka, 1989).
m-CPP is a relatively selective serotonin agonist that can be used to assess serotonin
functional activity in humans.
To reduce the confounding effects of malnutrition and low weight, we studied a group
of subjects who had previously been underweight with AN and who, at the time of this
study, had been restored to a normal body weight in an inpatient treatment program. We
studied anorectic patients who restricted, but did not binge.
METHODS
Subjects
Subjects (all female) were hospitalized for treatment on the Eating Disorders Unit of
Western Psychiatric Institute and Clinic, University of Pittsburgh, and gave informed
consent for the study. All subjects were medication free for at least 30 days prior to any
study.
m-CPP and Anorexia Nervosa
59
Twelve patients with AN (short-term weight-restored anorexics) were recruited. At the
time of admission to the Eating Disorders Unit, they had met criteria for AN as described
in the 4th ed. of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; APA,
1994) and were at 74 ± 6% of average body weight (ABW, range 62–81% ABW). These
anorexic patients gained weight in the hospital (21 ± 6% of ABW, range 13–32% ABW)
over 71 ± 16 days (range 56–104 days). Anorexics were studied 12 ± 4 days (range 5–17
days) after attaining their target weight (95 ± 2% ABW, range 92–99% ABW). At the time
of the study, all AN subjects were consuming 40 to 60 kcal/kg of caloric intake per day.
All were food restrictors. None binged, but 3 purged by vomiting or abusing laxatives
prior to hospitalization. All anorexic patients were amenorrheic on admission and none
had resumption of menses at the time of this study.
Twelve healthy control women (CW) were admitted to a clinical laboratory on the same
inpatient unit the night prior to the study. None had significant current or past psychiatric
or medical diseases or any symptoms of an eating disorder according to DSM-IV criteria.
All had normal menstrual cycles and were studied during the early follicular phase of the
menstrual cycle.
Study Design
Subjects were not permitted to eat or smoke from midnight until the study was completed. At 7:30 a.m., an intravenous catheter was inserted in an antecubital vein and kept
open with a heparinized 5% dextrose solution. After 1 hr of adaptation, blood samples
were obtained at −30, −15, and at 0 min. Then the subject ingested capsules containing 0.5
mg/kg m-CPP or placebo. Blood samples were obtained at 15, 30, 60, 90, 120, 150, 180, and
240 min. After blood sampling was complete, the intravenous catheter was removed.
Subjects were given m-CPP and placebo in random order. For AN subjects, there were
3 ± 3 days between studies. For CW, there were 3 ± 2 days between studies.
Assessments of Mood and Behavior
Standardized Assessments of Depression, Anxiety, and Obsessive-Compulsive Disorder
(OCD)
Both groups of subjects were interviewed within a week of this study by a trained rater
who was a Ph.D. psychologist. This trained rater administered the Hamilton Anxiety and
Depression Rating Scales. Obsessive-compulsive features were assessed by a trained rater
who administered the Yale-Brown Obsessive Compulsive Scale (YBOCS; Goodman et al.,
1989, Goodman et al., 1989) after excluding core anorexic traits as described by Kaye et al.
(1992).
Psychiatric Assessment of Behavioral Response to m-CPP and Placebo
Ratings of psychological state on the morning prior to the m-CPP or placebo challenge
and after the administration of m-CPP and placebo were done by two methods. First,
behavioral states were assessed by two psychiatrists (TEW and WHK) who were blind to
whether m-CPP or placebo had been administered. These assessments were done at
baseline and at 90 and 180 min after m-CPP or placebo administration. These psychological ratings were adapted from those previously described in the literature (Asberg,
Montgomery, Perris, Schalling, & Sedvall, 1978; Murphy, Pickar, & Alterman, 1982; Overall & Gorham, 1962). At each time point, the following psychological states were assessed
60
Frank et al.
using a 6-point scale: anxiety, depression, euphoria, body image distortion, and obsessive
thinking. In this scale, 0 denotes the absence of a behavior. The numbers 1 through 6
denote increasingly more pronounced symptoms with each number anchored by a descriptive phrase. Peak changes were determined by taking the largest deviation from
baseline at either 90 or 180 min after ingestion of m-CPP or placebo and subtracting the
baseline score. For body image distortion, we devised a similar 0–6-point scale of relative
intensity and preoccupation with fears of being fat (0, not present; 2, feels fat, but can
believe possibility that really is not too fat; 4, feels too fat, unshakable belief that she is too
fat, but able to concentrate on other thoughts; 6, relentless and continuous preoccupation
with feeling too fat, unshakable belief that she is too fat, unable to concentrate on other
thoughts).
Subject Self-Assessment of Behavioral Response to m-CPP and Placebo
Second, subjects self-rated their moods at baseline and at 30-min intervals for 12 hr
after receiving m-CPP or placebo on a 24-item self-rating scale with extremes from 0 (not
present) to 6 (very marked).
Assays
Methods used to measure plasma cortisol (Kao, Voina, Nichols, & Horton, 1975), adrenocorticotropin (ACTH), growth hormone (Odell, Rayford, & Ross, 1967), and prolactin
(Sinha, Selby, Lewis, & Vanderlaan, 1973) have been previously described. The sensitivity
and interassay coefficient of variation (CV) for cortisol were 1 ␮g/dl and 2.69, respectively; for ACTH, 5 pg/nl and 1.56, respectively; for growth hormone, 5 ng/ml and 2.30,
respectively; and for prolactin, 1 ng/ml and 2.86, respectively.
Statistical Procedures
Statistical analysis was carried out using BMDP statistical software (Dixon, 1985). Hormonal concentrations for ACTH, cortisol, growth hormone, and prolactin were analyzed
by using the following methods. First, baseline levels (determined by averaging hormone
concentration for the day of m-CPP and placebo for the three prechallenge blood draws
[×30, −15, and 0 min]) were compared using group t tests for between-group comparisons
(anorexics vs. controls). Second, to determine the increase in hormone secretion in response to m-CPP, the area under the curve (AUC) was calculated using the trapezoidal
method. The AUC for the placebo condition was then subtracted from the m-CPP condition. Third, an analysis of variance (ANOVA) with a repeated measures design was
used to determine the response to drug (m-CPP vs. placebo) in the two diagnostic groups
(anorexics vs. controls), with respect to mean response and trends over time.
Psychological symptoms were analyzed using the following methods. First, diagnostic
group differences for baseline and peak change (peak minus baseline) assessments were
done using group t tests and ANOVA using the baseline values as covariates (ANCOVA).
Second, drug condition difference for peak change and peak change compared with
baseline were determined separately for each diagnostic group using paired t tests. Third,
repeated measures ANOVA was used to examine group and drug effects over time for
self-ratings of mood. However, nonnormally distributed values were also assessed using
Mann-Whitney U tests and exact significant levels. Values are expressed as M ± SD.
m-CPP and Anorexia Nervosa
61
Table 1. Comparison of 12 normal control women and 12 short-term
weight-restored women with anorexia nervosa
Age
Percent ABW
Percent high ABW
Percent low ABW
Age of onset
Age of menarche
Y-BOCS
Hamilton Depression
Hamilton Anxiety
Controls
Anorexics
t
p
21 ± 3
101 ± 9
105 ± 8
93 ± 6
17 ± 2
95 ± 2
97 ± 14
69 ± 8
15 ± 3
13 ± 1
22 ± 5
15 ± 10
13 ± 5
4.85
2.44
1.75
8.15
.0001
.03
.1
.0001
1.24
9.64
4.48
4.91
NS
.0001
.001
.0001
14 ± 2
3±3
1±3
4±3
Note: ABW = average body weight; YBOCS = Yale-Brown Obsessive Compulsive Scale.
RESULTS
Short-term recovered anorexics weighed significantly less and were younger than control subjects (Table 1). In the past, short-term recovered anorexics, in comparison to
controls, had a significantly lower lifetime low percent body weight and a trend toward
having a lower lifetime high percent body weight. Subjects had similar ages of menarche.
Plasma m-CPP Concentrations
Plasma m-CPP levels were obtained at 60, 120, 180, and 240 min for 9 anorexics and 11
controls. A repeated measure ANOVA showed no difference between plasma m-CPP
levels for Drug × Time interaction between these two groups (df = 3.54, F = 1.22, p = .31).
Hormonal Response
In terms of mean baseline values (combining the three baseline values for the day of the
m-CPP and the day of the placebo), the anorexics had significantly reduced prolactin and
cortisol levels and a trend toward elevated growth hormone compared with the controls
(Table 2).
By repeated measures ANOVA, there was no difference for prolactin for Drug × Time
× Group (df = 8,176, F = 1.12, p = .35). However, calculation of net AUC (the difference
Table 2. Hormonal values for 12 healthy control women and 12 short-term weight-recovered
women with anorexia nervosa
Baseline prolactin (ng/ml)
Prolactin (ng/ml/240 min AUC)
Baseline cortisol (␮g/dl)
Cortisol (␮g/dl/240 min AUC)
Baseline ACTH (pg/ml)
ACTH (pg/ml/240 min AUC)
Baseline growth hormone (ng/ml)
Growth hormone (ng/ml/240 min AUC)
Controls
Anorexics
t
p
8.1 ± 3.0
743 ± 509
16.9 ± 7.1
643 ± 615
19.6 ± 6.2
1002 ± 1782
1.3 ± 1.7
176 ± 245
4.2 ± 2.6
345 ± 353
11.8 ± 3.6
460 ± 373
15.9 ± 5.9
696 ± 1026
3.5 ± 3.8
79 ± 231
3.31
2.22
2.23
.88
1.48
.50
1.82
1.00
.003
.04
.04
NS
NS
NS
.09
NS
Note: AUC = area under the curve; ACTH = adrenocorticotropin.
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Frank et al.
between the response to m-CPP and the placebo response) revealed that short-term
weight-restored anorexics had a significantly blunted prolactin response after m-CPP
compared with CW (Table 2).
Drug × Time × Group interaction was not significant for ACTH (df = 8,168, F = 0.61,
p = NS), cortisol (df = 8,176, F = .26, p = NS), or growth hormone (df = 8,176, F = 1.17,
p = .32). The AUC for cortisol, ACTH, and growth hormone response was similar between
groups (Table 2).
Mood and Behavioral Response
Standardized Assessments of Depression, Anxiety, and OCD
Compared with CW, the AN subjects had significantly elevated baseline ratings on the
Hamilton Anxiety and the Hamilton Depression Rating Scale and on the YBOCS (Table 1).
Psychiatric Assessment of Behavioral Response to m-CPP and Placebo
Data were nonnormally distributed and Mann-Whitney U tests were applied for group
comparisons. The mean baseline assessments on the morning before administration of
m-CPP or placebo showed that the AN subjects, compared with CW, had significantly
higher scores for anxiety (2.0 ± 1.1 vs. 0.6 ± 0.7, U = 16.0, p = .001), depression (1.9 ± 1.2
vs. 0.3 ± .05, U = 13.0, p < .001), body image distortion (2.4 ± 1.4 vs. 0 ± 0, U = 12.0,
p < .001), and obsessional thoughts (1.7 ± 1.6 vs. 0.1 ± 0.3, U = 32.5, p = .02).
We calculated change scores (peak score after m-CPP or placebo minus the baseline
score). Given the marked baseline differences in mood between anorexics and controls,
only the change scores are presented (Figure 1). After administration m-CPP compared
with placebo, anorexic subjects had a significantly greater reduction in body image distortions (U = 33.0, p = .02). Between groups, after m-CPP compared with placebo, anorexics tended to be less anxious compared with controls (U = 43.0, p = .06), were less
depressed (U = 36.0, p = .04), and had decreased body image distortions (U = 12.0,
p < .001). After a conservative Bonferroni correction for multiple comparisons, body image
distortions were still significantly reduced (p < .004).
Subject Self-Assessment of Behavioral Response to m-CPP and Placebo
For subject self-rating of changes in mood and behavior, repeated measures ANOVAs
showed a significant Group × Drug × Time difference for only two of the self-ratings of
behavioral states. That is, after m-CPP, anorexics had an increase in elation (df = 7,154,
F = 2.48, p = .02) and feeling strange (df = 7,154, F = 3.58, p = .001).
Compared with the CW (n = 12), the AN women (n = 12, Table 3) had significantly
higher baseline values for feeling anxious (t = 3.09, p = .01), depressed (t = 3.02, p = .01),
irritable (t = 2.61, p = .02), difficulty concentrating (t = 2.43, p = .02), and sad (t = 3.10,
p = .01).
We compared differences between baseline value and change at 120 min after m-CPP
versus the change at 120 min after placebo within groups. For anorexic patients, the peak
effects of m-CPP on elation occurred at 120 min (Table 3; t = 2.31, p = .03). At 120 min after
administration of m-CPP, anorexics had a significant increase in feeling strange (t = 2.62,
p = .02). For healthy women, there were no significant m-CPP minus placebo changes
from baseline at 120 min (Table 3).
We compared between-group differences in terms of change at 120 min after m-CPP
minus the change at 120 min after placebo. We found that anorexics had significantly
m-CPP and Anorexia Nervosa
63
Figure 1: Bar graphs showing change scores for anxiety, depression, body image distortion, and
obsessive thoughts. Letters indicate significant changes compared with baseline. a: p < .05, b: p < .01.
NC = control women, ST = short-term weight-recovered anorexic women. Shaded bar = metachlorophenylpiperazine; black bar = placebo.
greater elation (t = 2.46, p = .03) and felt more strange (t = 2.52, p = .03). This effect
persisted when taking into account the baseline values as covariates (F = 5.41, p = .03 for
elation, F = 7.95, p = .01 for strange). In addition, AN women also felt less anxious after
taking baseline values into account as covariates (F = 4.26, p = .05). After a conservative
correction for multiple testing (Bonferroni), a tendency toward increased elation (p = .07)
still persisted. In part, values were normally and nonnormally distributed. Nonparametric
testing resulted in significant group differences between AN patients and CW after
m-CPP for being less anxious (U = 32.5, p = .02), more elated (U = 36, p = .04), and a
tendency for an increased feeling of strange or unreal (U = 39.5, p = .06). After Bonferroni
correction for multiple testing, there was at a trend toward significance for anxiety (p = .1).
Correlations
There were no significant relationships for either short-term weight-restored anorexics
or controls between the prolactin AUC and current weight, age, baseline assessments,
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Frank et al.
Table 3. Self-assessment of behavioral mood states in 12 healthy control women and 12
short-term weight-recovered women with anorexia nervosa
Short-Term Weight-Recovered
Patients with Anorexia Nervosa
Behavioral States
Baseline
Change from Baseline
at 120 Min for
Response to m-CPP
Minus Response to
Placebo
Anxious
Difficulty concentrating
Depressed
Elated (better than usual)
Irritable
Sad
Strange or unreal
1.19 ± 0.98*
1.17 ± 1.10*
1.21 ± 1.21*
0.15 ± 0.29
0.73 ± 0.63*
0.96 ± 0.92*
0.10 ± 0.25
0.42 ± 2.07
−0.25 ± 2.01
−0.42 ± 0.79
1.33 ± 1.83** , ***
−0.50 ± 0.67
−0.33 ± 0.65
1.58 ± 1.98** , ***
Healthy Control Women
Baseline
Change from Baseline
at 120 Min
for Response to m-CPP Minus
Response to Placebo
0.23 ± 0.45
0.33 ± 0.46
0.13 ± 0.31
0.13 ± 0.25
0.19 + 0.36
0.10 ± 0.25
0.06 ± 0.22
−0.17 ± 0.58
0.08 ± 1.24
0.00 ± 0.00
0.00 ± 0.43
−0.08 ± 0.52
−0.08 ± 0.29
0.00 ± 0.44
*Significant (p < .05) between-group difference for mean baseline values (group t test). **Significant (p < .05)
within-group difference when comparing baseline value to change at 120 min after m-CPP minus the change at
120 min after placebo. ***Significant (p < .05) between-group difference comparing change at 120 min after
m-CPP minus the change at 120 min after placebo taking baseline into account as covariate (ANCOVA).
changes in anxiety, depression, elation, body image distortion, or obsessionality. In NC
self-assessments, however, depression correlated positively with anxiety (.7, p = .01),
sadness (.8, p < .01), and irritability (.7, p < .01), and feeling strange correlated with feeling
elated (.6, p = .06). In short-term recovered anorexics, depression correlated with sadness
(.9, p < .01) and with irritability (.5, p = .07), but not with anxiety; feeling strange was
positively correlated with elation (.6, p = .02) and with anxiety (.6, p = .053).
DISCUSSION
After m-CPP administration, anorexics had evidence of a blunted prolactin response,
but normal cortisol, ACTH, and growth hormone response. m-CPP was associated with
increased elation and feeling strange in short-term weight-restored anorexics, as well
as with a reduction in dysphoric mood and body image distortion. These data extend
previous observations that suggest that anorexics have an alteration in brain serotonin
activity that persists after weight recovery.
Target Behavioral Symptoms
After short-term weight restoration, anorexic patients had elevations of baseline symptoms of depression, anxiety, and obsessionality. m-CPP administration was associated
with a reduction in dysphoric mood states. In fact, AN subjects had an elevation of mood
on two separate scales (psychiatric rater and self-assessment). It is well recognized that
restrictor anorexics are intense, serious, and inhibited people and that the response to
m-CPP was particularly unusual for many of them. Clinically, we noticed that many of the
AN subjects were less emotionally constricted and introverted on m-CPP.
We were surprised to find that some anorexic patients had a reduction of distortions of
body image and the feeling of being too fat. No scales, to our knowledge, have been
m-CPP and Anorexia Nervosa
65
devised to assess changes in body image distortion in response to a drug challenge. The
scale we devised has not been standardized. Still, we found that 9 of the 12 restricting-type
anorexic subjects had less preoccupation with feeling too fat after administration of
m-CPP. We are not certain whether this change was secondary to elevated mood or
reduced inhibition or to some direct effect of the m-CPP on obsessions about body image
distortion. Because the scale has not been standardized and because of the existence of a
significant baseline difference, this finding has to be viewed with caution.
A previous study investigating m-CPP after weight restoration in AN patients found no
behavioral alterations compared with CW (Hadigan, Walsh, Buttinger, & Hollander,
1995). Whereas in our study, weight-restored anorexics showed a decrease in depressive
feelings, that study reported a tendency toward more depressed mood in both AN women
and CW. In Hadigan et al.’s study, however, subjects were entered at a lower weight, they
were not distinguished by anorexia subgroup, and different instruments were used for
psychological assessment, which might have contributed to the observed differences. In
addition, CW were not studied in the same phase of the menstrual cycle and gonadal
hormone levels may have influenced the response to m-CPP (Rubinow, Schmidt, & Roca,
1998).
There has been interest in similarities between AN and OCD patients. Many OCD
patients have increased obsessions and anxiety after oral or intravenous administration of
m-CPP in most (Zohar, Mueller, Insel, Zohar-Kadouch, & Murphy, 1987; Hollander et al.,
1992; Brooks et al., 1998), but not all, studies (Charney, Goodman, & Price, 1988; Goodman
et al., 1995). These data suggest that although AN and OCD patients may have a similarity
of certain symptoms, they have a difference in pathophysiology in regard to serotonin
function. In addition, people with AN and bulimia nervosa (BN) may have differential
responses to m-CPP after weight restoration. BN subjects had a dysphoric response to
administration of m-CPP (Kaye, Greeno, et al., 1998) and short-term weight-restored
bulimic-type anorexics had an increase in anger, tension, and distress after m-CPP (Brewerton et al., 1992; Brewerton & Jimerson, 1996).
Hormones: Baseline and m-CPP Response
After m-CPP administration, AN patients, compared with CW, had blunted prolactin
secretion by calculation of AUC, but not by repeated measures ANOVA. Other studies
found a blunted prolactin response to m-CPP in ill and short-term weight-recovered
anorexics (Brewerton & Jimerson, 1996; Hadigan et al., 1995). It is important to note that
altered prolactin response has also been found in other disorders such as BN, OCD, and
subjects with antisocial and borderline personality disorder (Charney, Goodman, & Price,
1988; Hollander et al., 1992; Moss, Yao, & Pauzak, 1990; Stein, et al., 1996).
We found that AN women had reduced baseline cortisol levels, but a normal cortisol
response to m-CPP. Reduced basal cortisol concentrations after short-term recovery in AN
patients have been noted elsewhere (Gold et al., 1986). Hadigan et al. (1995) found reduced cortisol response to m-CPP prior to but not after weight restoration. It could be
speculated that the baseline reduction of cortisol in our study may have altered central
5-HT receptor densities (Lopez, Vazquez, Chalmers, & Watson, 1997), and thus affected
the behavioral response to m-CPP. More unspecific serotonin challenges using d-fenfluramine in weight-recovered AN patients (mixed subtypes) did not show alterations in
hormonal response compared with controls in one study (O’Dwyer, Lucey, & Russell,
1996), but blunted plasma cortisol after a test meal in another (Ward, Brown, Lightman,
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Frank et al.
Campbell, & Treasure, 1998). However, both studies did not control for d-fenfluramine
plasma levels, and one study did not have a placebo condition.
Limitations
AN patients were significantly younger and weighed less than CW. However, these
mean differences were small (4 years of age and 6% ABW), and no correlation was found
between these demographic variables and outcome measures. AN women were studied
soon after weight restoration, a time when they are hypermetabolic and must eat at least
50% more than controls in order to maintain their weight (Weltzin, Fernstrom, Hansen,
McConaha, & Kaye, 1991). A hypermetabolic state might also have suppressed the prolactin response to m-CPP (Goodwin, Fairburn, & Cowen, 1987). All AN women were
amenorrheic. Estradiol has been shown to stimulate prolactin synthesis (Chan, Means, &
O’Malley, 1978), suppress the release of tuberoinfundibular dopamine (which inhibits
prolactin, Crowley, 1982), and increase prolactin secretion through its effects on serotonergic neuronal activity (Johnson & Crowley, 1983). Reduced sex steroid activity could
have contributed to reduced baseline prolactin and prolactin response to m-CPP.
After Bonferroni correction for multiple testing, only tendencies toward statistical significance persisted, except for body image distortions. However, the reported results
consistently occurred in self and clinical rater reports and suggest decreased anxiety and
depressive feelings and increased elation. A Type 1 error appears unlikely for the observed changes in response to m-CPP administration. Comorbid lifetime psychiatric diagnoses were not assessed so that the influence of other psychopathology on these results
cannot be determined.
CONCLUSIONS
The mechanism responsible for elevated mood and/or reduced behavioral inhibition
after m-CPP administration is uncertain. Several serotonin receptors have been implicated
in the modulation of inhibition, anxiety, and obsessionality (Cowen, 1991; Peroutka et al.,
1989; Fuller, 1992). A reduced prolactin response to m-CPP in the studied weight-restored
AN women raises the possibility of a reduction in activity of the postsynaptic 5HT1C
or 5-HT2C receptor. Data suggest that these receptors may be responsible for central
prolactin response (Aulakh, Hill, & Murphy, 1992; Fone, Austin, Topham, Kennett, &
Punhani, 1998; Gleason & Shannon, 1998) and for eating behavior and emotional states
(Heisler, Chu, & Tecott, 1998; Sargent, Sharpley, Williams, Goodall, & Cowen, 1997). In
the future, specific brain imaging studies have to identify receptors specifically involved
in prolactin response.
It has been our experience that third and fourth party providers tend to conceptualize
AN as a disorder primarily caused by psychosocial factors, despite its high morbidity and
mortality. This study suggests that AN patients have disturbances that persist after
weight recovery. These data contribute to the argument that patients with AN require
medical and psychiatric intervention up to and beyond mere weight restoration.
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