Reduced 5-HT2A Receptor Binding after Recovery
from Anorexia Nervosa
Guido K. Frank, Walter H. Kaye, Carolyn C. Meltzer, Julie C. Price, Phil Greer,
Claire McConaha, and Kelli Skovira
Background: Several lines of evidence suggest that a
disturbance of serotonin neuronal pathways may contribute to the pathogenesis of anorexia nervosa (AN). This
study applied positron emission tomography (PET) to
investigate the brain serotonin 2A (5HT2A) receptor,
which could contribute to disturbances of appetite and
behavior in AN.
Methods: To avoid the confounding effects of malnutrition, we studied 16 women recovered from AN (REC AN,
⬎1 year normal weight, regular menstrual cycles, no
bingeing or purging) compared with 23 healthy control
women (CW) using [18F]altanserin, a specific 5-HT2A
receptor antagonist on PET imaging.
Results: REC AN women had significantly reduced
[18F]altanserin binding relative to CW in mesial temporal
(amygdala and hippocampus), as well as cingulate cortical regions. In a subset of subjects (11 CW and 16 REC
AN), statistical parametric mapping (SPM) confirmed
reduced mesial temporal cortex 5HT2A receptor binding
and, in addition, showed reduced occipital and parietal
cortex binding.
Conclusions: This study extends research suggesting that
altered 5-HT neuronal system activity persists after recovery from AN and may be related to disturbances of mesial
temporal lobe function. Altered 5-HT neurotransmission
after recovery also supports the possibility that this may
be a trait-related disturbance that contributes to the
pathophysiology of AN. Biol Psychiatry 2002;52:
896 –906 © 2002 Society of Biological Psychiatry
Key Words: Anorexia nervosa, serotonin, receptor, limbic
system
Introduction
A
norexia nervosa (AN) is a disorder that most often
has its onset during adolescence in young women and
is invariably characterized by the relentless pursuit of
From the Department of Psychiatry, Western Psychiatric Institute and Clinic (GKF,
WHK, CM, KS), and Department of Radiology, Presbyterian University
Hospital (CCM, JCP, PG), University of Pittsburgh, School of Medicine,
Pittsburgh, Pennsylvania.
Address reprint requests to Walter H. Kaye, M.D., University of Pittsburgh,
Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh PA
15213.
Received November 7, 2001; revised February 15, 2002; accepted February 21, 2002.
© 2002 Society of Biological Psychiatry
thinness, obsessive fears of being fat, and emaciation.
Consequently, AN has the highest mortality among the
psychiatric disorders (Sullivan 1995). Depression, anxiety,
and obsessive– compulsive behaviors are common. People
with AN tend to have a characteristic cluster of personality
and temperament traits including perfectionism, over control, rigidity, and harm avoidance (Palmer and Jones
1939). Such behaviors may be traits because they occur
premorbidly and persist after weight and eating normalize
(Casper 1990; Klump et al 2000; Srinivasagam et al 1995).
The etiology of AN is presumed to be complex and has
traditionally been thought to be influenced by developmental and social factors (Garner 1993; Treasure and
Campbell 1994); however, the stereotypic clinical presentation, gender distribution, and age of onset suggest a
biologic vulnerability. Recent studies show that AN is
familial (Lilenfeld et al 1998; Strober et al 2000) with
three large-scale, community-based twin studies suggesting that eating disorders have a heritability of between 0.5
and 0.8 (Bulik et al 1998). The clustering of the disorder
in families may be related in part to a genetic transmission
of risk.
A considerable number of animal and human studies
suggest that altered central nervous system serotonin
(5-HT) activity may contribute to the appetitive and
behavioral alterations found in AN. For example, increased intrasynaptic 5-HT, or directly activated 5-HT
receptors, tend to reduce food consumption (Blundell
1984; Leibowitz and Shor-Posner 1986), and alterations in
5-HT activity be implicated in disturbances of mood and
impulse control (Higley and Linnoila 1997; Kaye 1997;
Lucki 1998; Mann 1999). In fact, most studies have shown
that ill AN patients have disturbances (i.e., a reduction) of
central 5-HT activity (Kaye et al 1988; Walsh et al 1998;
Wolfe et al 1997).
Behavioral or 5-HT disturbances in ill AN patients may
be a consequence of malnutrition or premorbid traits that
contribute to a vulnerability to develop AN. Determining
whether abnormalities are a consequence or a potential
antecedent of pathologic feeding behavior is a major
question in the study of eating disorders. It is impractical
to study AN prospectively because of the young age of
onset and difficulty in premorbid identification of people
0006-3223/02/$22.00
PII S0006-3223(02)01378-1
Serotonin Receptor Activity in Anorexia
who will develop the disorder. Another strategy is to study
women who are recovered from AN. Any persistent
psychobiological abnormalities might be trait related and
potentially contribute to the pathogenesis of this disorder.
In fact, increased levels of cerebrospinal fluid (CSF)
5-hydroxy indoleacetic acid (5-HIAA), the major metabolite of 5-HT, have been found after long-term recovery
from AN (Kaye et al 1991). Other studies of recovered AN
found reduced appetite suppression in response to the
5-HT challenge drug D-fenfluramine (Ward et al 1998),
but normal 5-HT-related endocrine secretion (O’Dwyer et
al 1996; Ward et al 1998).
The 5-HT neurotransmitter system is widespread
throughout the brain, (Nieuwenhuys et al 1988), and the
loci of CNS pathophysiology responsible for serotonin and
behavioral abnormalities in people with AN are unknown.
Positron emission tomography (PET) technologies hold
the promise of understanding previously inaccessible brain
5-HT function in vivo and its dynamic relationship with
human behaviors. In this study, the radioligand [18F]altanserin, a specific 5-HT2A receptor antagonist, was used
together with PET imaging to determine whether the
5-HT2A receptor system was altered in women who were
recovered from AN. The 5-HT2A receptor system is of
potential interest in AN because it has been implicated in
the modulation of feeding (inducing hypophagia), mood,
and anxiety as well as in antidepressant efficacy (Bonhomme and Esposito 1998; De Vry and Schreiber 2000;
Simansky 1996; Stockmeier 1997). In addition, some but
not all studies have found differences in allele frequencies
of the 5-HT2A receptor in AN (Hinney et al 2000).
Because 5-HT2A receptors are in high concentrations in
the cortex, this study sought to determine whether PET
could identify alterations of specific cortical brain regions
in AN.
Recently, we showed in a group of women recovered
from bulimia nervosa (REC BN) reduced cortical 5-HT2A
receptor binding that was significant in the orbital frontal
cortex (Kaye et al 2001). Women with AN and BN share
increased CSF 5-HIAA after recovery (Kaye et al 1998a,
1998b). Thus, we hypothesized that postsynaptic cortical
5-HT2A receptor densities would be downregulated in
response to the suggested 5-HT hyperactivity in AN after
recovery (Rioux et al 1999; Roth et al 1998) similar to our
previous finding in REC BN. We hypothesized that, if
regional cortical alterations occur in AN, they are most
likely to be present in frontal or limbic regions because
such regions have been particularly implicated in the modulation of mood and impulse control (McAllister 1992).
Methods and Materials
Sixteen women who had recovered from restricting type AN
(REC RAN) were recruited. No subject had a history of bingeing
or purging. Subjects were previously treated in the eating
BIOL PSYCHIATRY
2002;52:896 –906
897
disorders treatment program at the Western Psychiatric Institute
and Clinic (Pittsburgh, PA) or were recruited through advertisements. All subjects underwent four levels of screening: 1) a brief
phone screening; 2) an intensive screening assessing psychiatric
history, lifetime weight, and exercise and menstrual cycle history
as well as eating pattern and exercise history for the past 12
months; 3) a comprehensive assessment using structured and
semistructured interviews; and 4) a face-to-face interview with a
psychiatrist. To be considered “recovered,” subjects had to 1)
maintain a weight above 85% average body weight (Metropolitan Life Insurance Company 1959); 2) have regular menstrual
cycles; and 3) have not binged, purged, or engaged in significant
restrictive eating patterns for at least 1 year before the study.
Additionally, subjects must not have used psychoactive medication such as antidepressants or met criteria for alcohol or drug
abuse or dependence, major depressive disorder or severe anxiety
disorder within 3 months of the study. Twenty-one healthy
control women (CW) were recruited through local advertisements. The CW had no history of an eating disorder or any
psychiatric, medical, or neurologic illness. They had no firstdegree relative with an eating disorder. They had normal menstrual cycles and had been within normal weight range since
menarche.
This study was conducted according to local institutional
review board regulations, and all subjects gave written informed
consent. The PET imaging was performed during the first 10
days of the follicular phase for all subjects. Subjects were
admitted to a research laboratory on the eating disorders unit of
Western Psychiatric Institute and Clinic at 9:00 pm of the day
before the PET study for adaptation to the laboratory and for
psychologic assessments. The PET study was done the next day.
All subjects had the same standardized, monoamine controlled
(low protein) breakfast on the morning of the study.
Blood was drawn for assessment of ␤-hydroxybutyrate
(BHBA), a plasma ketone body that is relatively sensitive to
reflecting the presence of starvation (Fichter et al 1990), as well
as for evaluation of gonadal hormone levels (estradiol, E2). The
Structured Clinical Interview for DSM-IV Axis I Disorders (First
et al 1996) was used to assess the lifetime prevalence of Axis I
psychiatric disorders, and the Structured Interview for Anorexia
and Bulimia (Fichter et al 1998) to assess lifetime diagnosis of an
eating disorder. These interviews were administered by a trained
masters- or doctoral-level clinical interviewer and blindly reviewed by a psychiatrist or trained PhD-level psychologist, who
validated final DSM-IV Axis I diagnoses. Current psychopathology was assessed with a battery of standardized instruments
including the Beck Depression Inventory (Beck et al 1961), the
Spielberger State–Trait Anxiety Inventory (Spielberger et al
1970), the Frost Multidimensional Perfectionism Scale (Frost et
al 1990), and the Temperament and Character Inventory (Cloninger et al 1994) for assessment of harm avoidance, novelty
seeking, and reward dependence.
All subjects underwent magnetic resonance (MR) imaging
before the PET scan on a Signa 1.5 Tesla scanner (GE Medical
Systems, Milwaukee, WI) using a standard head coil. A volumetric spoiled gradient recalled (SPGR) sequence (TE ⫽ 5, TR
⫽ 25, flip angle ⫽ 40°, NEX ⫽ 1; field of view ⫽ 24 cm, image
matrix ⫽ 256 ⫻ 192 pixels) acquired in the coronal plane was
898
BIOL PSYCHIATRY
2002;52:896 –906
used to guide region of interest (ROI) selection. Fast spin-echo
T2 and proton density weighted images were also routinely
acquired to exclude significant neuropathology. Pixels that corresponded to scalp and calvarium were removed from the SPGR
MR images (Sandor and Leahy 1997), and the MR and PET
image data were then coregistered (Woods et al 1993).
The 5-HT2A receptor–specific radioligand [18F]altanserin
was used and synthesized as described by Lemaire et al (1991).
Subjects were studied using two PET scanners, ECAT HR⫹ and
951R/31 (CTI PET Systems, Knoxville, TN) because the 951RPET scanner was replaced by the HR⫹ during the course of this
study. The 951R/31 acquires 31 slices over a 108-mm axial field
of view (FOV). The HR⫹ scanner acquires 63 continuous slices
over a 152-mm axial FOV. All subjects were studied in two
dimensional (2D) imaging mode (septa extended). Under these
conditions, the 951R/31 has a point source resolution in air
reconstructed (without smoothing) of approximately 6.0 mm
full-width at half-maximum (FWHM) in the in-plane, and 5.0
mm FWHM in the axial orientation (Spinks et al 1992). In 2D,
the HR⫹ scanner has an approximated in-plane resolution of 4.9
mm (1–10 cm radius) at FWHM, and an axial resolution of 4.4
mm FWHM (Brix et al 1997). All REC AN women were studied
on the HR⫹ PET scanner. Eleven CW were studied on the HR⫹
scanner and 12 were studied on the 951R PET scanner. Data on
the 12 CW studied with the 951R PET scanner were previously
published (Kaye et al 2001).
The CW studies on the HR⫹ and the 951R PET scanners had
similar age and body mass index (BMI). A comparison of
regional 5-HT2A receptor binding potential values between CW
sub groups using nonparametric Mann–Whitney U tests yielded
similar binding across groups, with a U value range between 5
and 52, and corresponding p values between 0.9 and 0.2. For
example, CW values were as follows: prefrontal cortex, 2.41 ⫾
0.2 (HR⫹ scanner) and 2.40 ⫾ 0.3 (951R scanner), U ⫽ 50, p ⫽
.8; mesial temporal cortex, 1.64 ⫾ 0.2 (HR⫹ scanner) and 1.70
⫾ 0.2 (951R scanner), U ⫽ 46, p ⫽ .6. Because these two groups
of CW were similar, and because the methods for 5HT2A
binding assessment used relative measures (regional binding
divided by the binding in a reference region, discussed below),
the data on CW were combined.
Subjects were positioned with the head oriented parallel to the
cantomeatal line. A softened thermoplastic mold with generous
holes for eyes, nose, and ears was fitted closely around the head
and attached to the headholder to minimize subject motion. A
10-min transmission scan was obtained and used for attenuation
correction. Following bolus intravenous injection of 10 mCi
high-specific activity (ⱖ1.04 Ci/␮mol) [18F]altanserin, dynamic
emission scanning with arterial blood sampling was performed
until 90 min postinjection. The arterial input function was
determined by approximately 35 0.5-mL hand-drawn samples
collected over the scanning interval (including 20 samples in the
initial 2 min postinjection). Blood samples were centrifuged and
the plasma radioactivity concentration measured (Cobra II,
Packard Instruments, Cleveland, OH). Additionally, 3-mL blood
samples were acquired at 2, 10, 30, 60, and 90 min after
[18F]altanserin injection and used to determine the fraction of
unmetabolized [18F]altanserin (of total plasma radioactivity
concentration) using high-performance liquid chromatography
G.K. Frank et al
(HPLC). Plasma data were corrected for the presence of radiolabeled metabolites of [18F]altanserin using the HPLC data
(Lopresti et al 1998). The PET data were also corrected for
radioactive decay and scatter and reconstructed with a Hanning
window and a cutoff at 0.8 of the Nyquist rate.
The ROIs were hand drawn on the coregistered MR images
and applied to the dynamic PET data to generate time-activity
curves. The following ROIs were selected: prefrontal cortex
(Brodmann’s area [BA] 10), medial orbital frontal cortex (BA
11), lateral orbital frontal cortex (BA 47), mesial temporal cortex
(amygdalo– hippocampal complex), lateral temporal cortex (BA
21), supragenual cingulate (BA 24/32, five planes superior to
anterior most part of genu corporis callosi), pregenual cingulate
(BA 24/32, anterior to anterior most part of genu of the corpus
callosum), and subgenual cingulate (BA 25, inferior to the genu
of the corpus callosum), parietal cortex (BA 7), and sensorimotor
cortex (BA 1,2,3,4). We also performed ROI sampling of the
cerebellum, and this was used as the reference region because of
the low concentration of 5-HT2A receptors (Pazos et al 1987).
The ROIs were expressed as the mean of left and right values. All
subjects were assigned a number at the local PET facility, and
imaging data were analyzed blindly. The data on 12 CW from the
951R scanner had previously been assessed similarly under blind
conditions (Kaye et al 2001). For the kinetic analyses, the Logan
graphic method was applied based on sampled ROI data from 8
to 90 min following [18F]altanserin injection. The regression
slope value (distribution volume, DV) for each ROI was calculated (Logan et al 1990). The cerebellar data were assumed to
represent free and nonspecifically bound radioactivity concentrations. The ratio of regional [18F]altanserin binding (DV ROI)
in relation to cerebellar [18F]altanserin binding (DV Cer) was
calculated (DVROI/DVCer ⫽ Dvratio, DVR), and the DVR was
used as a specific binding measure (Smith et al 1998). Recent
literature suggests that the cerebellum is not totally devoid of
5HT2A receptors (Dwivedi and Pandey 1998; Staley et al 2001).
Although the number of such cerebellar 5HT2A receptors is low,
an influence on ROI-specific binding could not be excluded. We
therefore also compared the cerebellar DV between groups.
The ROI-based data analysis may be confounded by how
individual regions are drawn, as well as by potentially missing
areas of binding alterations due to a limited number of assessed
ROIs. Thus, an additional analysis using statistical parametric
mapping was performed on all subjects studied on the HR⫹
scanner, using Statistical Parametric Mapping (SPM) software
(Frackowiak et al 1997; Friston 1995). We created DVR images
for all subjects on the HR⫹ scanner by applying the Logan
modeling method on a pixel-by-pixel basis for each PET image
and dividing each pixel by the cerebellar binding value (Smith et
al 1998). All MR images were normalized to the Montreal
Neurologic Institute (MNI, Canada) standard brain that is derived
from 152 subjects (Evans et al 1993). The normalized DVR
images were then smoothed with a Gaussian filter (12 mm
FWHM). Statistical parametric maps were created based on the
t statistic (Friston 1995), assigning a p value to each voxel
(probability image). An initial uncorrected p value of ⬍0.05 was
selected as threshold for display in the probability image.
Regions considered significant had to be either of significant
Serotonin Receptor Activity in Anorexia
BIOL PSYCHIATRY
2002;52:896 –906
899
Table 1. Demographic Variables between Groups and Behavioral Assessment Data
CW (n ⫽ 23)
Age (years)
Current BMI
AN onset (years of age)
Duration of recovery (years)
Estradiol (pmol/mL)
Plasma BHBA (␮mol/mL)
Drive for Thinness (EDI)
Depression (BDI)
Perfectionism (MPS)
Novelty seeking (TCI)
Harm avoidance (TCI)
Reward dependence (TCI)
State anxiety (STAI)
Trait anxiety (STAI)
REC AN (n ⫽ 16)
Mean
SD
Mean
SD
U
Exact Sig.
25.3
21.4
—
—
35
100
0.6
1
54
21
12
20
26
28
5.3
1.3
—
—
26
103
1.2
1.5
13
5
4
2
5
7
24.5
20.5
14.2
4.3
74
42
15.3 (12)
3.3 (12)
101 (12)
20 (12)
15 (12)
16 (12)
32 (12)
38 (12)
6.1
1.8
2.9
3.3
51
14
6.4
3.6
29
7
8
4
7
10
155
105
—
—
28.5
31
14.5
87.5
28.5
109
87
59
78
53.5
.4
.024
—
—
.1
.1
⬍.001
.047
⬍.001
.5
.15
.01
.04
.04
(12) indicates that only 12 of the REC AN women completed self-assessment questionnaires. Group comparison by
Mann–Whitney U test.
CW, healthy comparison women; REC AN, recovered anorexic women; Sig., significance; BMI, body mass index; BHBA,
beta hydroxy butryic acid; EDI, Eating Disorders Inventory; TCI, Temperament and Character Inventory; BDI, Beck Depression
Inventory; STAI, State and Trait Anxiety Inventory.
cluster size or voxel significance (p ⬍ .05) after correction for
multiple comparisons.
We also assessed, in an exploratory analysis, possible structural differences between groups, because such alterations theoretically could confine 5-HT receptor distribution findings. We
used SPGR images and compared these by group with the
voxel-based morphometry tool kit (VBM) within SPM (Ashburner and Friston 2000). In short, this analysis is a voxelwise
comparison of the local concentration of gray and white matter.
For this approach, SPGR images from each subject were aligned
to a vertical, midsagittal plane (Woods et al 1992) and spatially
transformed into the MNI standard reference atlas described
above. All images were separated into GM, WM, and CSF.
Differences in between-subject global activity were removed by
analysis of covariance (ANCOVA) on a pixel-by-pixel basis with
global counts as the covariate. The resulting image data were
then convolved with a three-dimensional Gaussian filter (12 mm
FWHM). Groups were compared using t statistic– based parametric maps and multiple comparison corrections as above.
The SPSS statistical software package (Barcikowski 1984)
was used for all other statistical analyses. Because of the
relatively small sample size, between-group comparisons were
made with nonparametric Mann–Whitney U two independent
samples tests calculating two-sided exact significance levels.
Multiple comparisons were corrected using the Bonferroni correction. Correlations were examined with Spearman correlation
coefficients. Factors that were considered possible confounds of
5-HT2A receptor binding were explored with analyses of covariance (ANCOVA). To assess possible seasonal influences on
5HT2A binding, we compared the distribution of PET scans over
the 12 months between groups using a chi-square test. All values
are expressed as mean ⫾ SD. As level of significance a p value
of p ⬍ .05 was selected.
Results
Demographic Variables and Behavioral
Assessments
The REC AN and CW women were of similar ages (Table
1). Although current BMI was significantly lower in REC
AN, the mean difference was less than 1 BMI unit. Subject
groups had similar plasma BHBA values, a measure of
ketone body metabolism, suggesting REC AN were not
starving. In addition, plasma E2 was similar between groups.
The REC AN subjects scored significantly higher on
drive for thinness, perfectionism, state and trait anxiety,
and depressive symptoms (Table 1). Groups did not differ
significantly on harm avoidance or novelty seeking; however, reward dependence was significantly reduced in
REC AN. Eight subjects of the REC AN group had a
confirmed history of major depressive disorder (MDD),
three a subthreshold MDD, and seven subjects had a
history of obsessive– compulsive disorder (OCD). One
subject in the REC AN group had a history of a panic
disorder. None of the REC AN women had a history of
any psychotic disorder.
ROI-Based Analysis of 5-HT2A Receptor Binding
The REC AN subjects had a significant reduction of
5-HT2A receptor binding in mesial temporal cortex, preand subgenual cingulate (Table 2) and a trend toward a
reduction in the sensorimotor cortex. The REC AN and
CW women had similar binding in the prefrontal cortex,
medial, and lateral orbital frontal cortex and the lateral
900
G.K. Frank et al
BIOL PSYCHIATRY
2002;52:896 –906
Table 2. Regional 5-HT2A Receptor Binding between Groups
CW (n ⫽ 23)
DVROI/DVCer
REC AN (n ⫽ 16)
DVROI/DVCer
Region of interest
Mean
SD
Mean
SD
U
Exact Sig.
Prefrontal cortex
Lateral orbital frontal cortex
Medial orbital frontal cortex
Supragenual cingulate
Subgenual cingulate
Pregenual cingulate
Lateral temporal cortex
Mesial temporal cortex
Parietal cortex
Sensorimotor cortex
2.42
2.39
2.58
2.45
2.69
2.58
2.63
1.68
2.6
2.28
0.25
0.25
0.28
0.31
0.27
0.28
0.22
0.19
0.28
0.28
2.41
2.4
2.51
2.29
2.47
2.4
2.65
1.52
2.49
2.13
0.26
0.26
0.32
0.25
0.27
0.24
0.29
0.17
0.32
0.27
183
170
155
129
110
113
179
86
127
124
.9
.7
.4
.1
.035
.04
.9
.004
.2
.09
Group comparison by Mann–Whitney U test. DVROI/DVCER is the distribution volume of regional serotonin 2A (5-HT2A)
receptor binding in relation to cerebellar value.
CW, healthy comparison women; REC AN, recovered anorexic women; Sig., significance.
temporal cortex. Ten ROIs were assessed. After correction
for multiple comparisons, REC AN women continued to
have reduced binding in the mesial temporal cortex (p ⫽
.04).
Because the CW women were studied on two scanners,
a comparison was done between CW (n ⫽ 11) and REC
AN (n ⫽ 16) women who were scanned on the same
scanner (ECAT HR⫹). Both groups were of similar ages
and BMI. The REC AN subjects continued to show
significantly reduced binding in the mesial temporal cortex (p ⫽ .008) and anterior medial cingulate (p ⫽ .02) and
a trend toward reduced binding in the supragenual (p ⫽
.08) and subgenual (p ⫽ .05) cingulate, as well as the
lateral orbital frontal (p ⫽ .1), parietal (p ⫽ .06), and
sensorimotor cortex (p ⫽ .09).
The cerebellar 5HT2A DV between CW (1.36 ⫾ 0.18)
and REC AN (1.23 ⫾ 0.37) was similar (U ⫽ 118, p ⫽ .1).
In addition, we compared the percentage of unmetabolized
[18F]altanserin (parent) in plasma between control and
anorexic subjects five times throughout the study (2, 10,
30, 60, and 90 min) using a repeated measures ANOVA.
Data between CW and REC AN were similar (F ⫽ 0.6,
p ⫽ .7).
SPM-Based Analysis of 5-HT2A Receptor Binding
This analysis revealed significant clusters of reduced
5-HT2A receptor binding in REC AN compared with CW
after correction for multiple comparisons. In the left
hemisphere, these regions were located in the mesial
temporal cortex, middle temporal gyrus, and subcortical
parietal lobe (Table 3 and Figure 1). In the right hemisphere, these regions were located in the middle temporal
gyrus, amygdaloid complex, and subiculum– hippocampus.
Analysis of Structural Images Using VBM/SPM
There was no significant difference between groups on a
voxel level. In particular, no mesial temporal or cingulate
related alterations were found.
Table 3. Cluster Sizes, p values, and Z Scores for Areas of Most Prominent 5-HT2A Binding
Alterations for Right (r) and Left (l) Hemispheres for Statistical Parametric Mapping–Based
Analysis
Cluster
Size
Coordinates (mm)
p (corrected)
4478
.001
7446
⬍.001
Z score
x
y
z
Brain Region
4.31
3.80
3.43
3.77
3.42
3.25
⫺50
⫺30
⫺38
32
26
56
⫺44
⫺28
⫺52
4
⫺12
⫺40
⫺14
⫺22
26
⫺36
⫺30
⫺16
Middle temporal gyrus (l)
Mesial temporal cortex (l)
Subcortical parietal lobe (l)
Amygdaloid complex (r)
Subiculum/hippocamps (r)
Middle temporal gyrus (r)
Subjects scanned on the HR⫹ scanner (CW n ⫽ 11; REC AN n ⫽ 16).
CW, control women; REC AN, recovered anorexic women.
Serotonin Receptor Activity in Anorexia
BIOL PSYCHIATRY
2002;52:896 –906
901
reduced 5HT2A receptor binding compared with CW for
the mesial temporal cortex (1.4 ⫾ 0.05 vs. 1.7 ⫾ 0.2, p ⫽
.001; p ⫽ .01 after correction for multiple comparisons)
and a tendency toward reduced binding (p ⬍ .1) in
sensorimotor, parietal, subgenual cingulate cortex, and
basal ganglia (data not shown). Neither the CW nor the
REC AN women had significant relationships between
measures of behavior and 5-HT2A binding. There was no
difference between groups in terms of the relationship
between 5HT2A receptor binding and seasonality (X ⫽
2.5, df ⫽ 1, p ⫽ .2).
Discussion
Figure 1. Clusters of significantly reduced 5HT2A binding in
recovered anorexic women (REC AN, n ⫽ 16) compared with
healthy comparison women (CW, n ⫽ 11) with all subjects
scanned on the HR⫹ scanner. p ⬍ .05 for each voxel between
groups, df ⫽ 1,25 based on the t-statistic; all clusters shown are
significant after correction for multiple comparisons (p ⱕ .001).
The upper image row shows significant clusters in a standard
grid system. The lower row overlays significant clusters on a
normalized reference MRI.
Relationships of Demographic Values and
Comorbidity with 5HT2A Receptor Binding
The CW and REC AN groups each showed significantly
negative relationships between age and 5-HT2A receptor
binding for most cortical regions (Table 4). A comparison
of slopes shows similarities for all regions for REC AN
and CW. Neither group had significant relationships between 5-HT2A receptor binding and current BMI, plasma
BHBA, or E2. Subgroups of REC AN subjects had similar
regional binding when compared as to whether they had a
lifetime history of MDD or OCD. The REC AN without a
history of MDD (n ⫽ 5) continued to show significantly
Table 4. Regional 5-HT2A Receptor Binding and Correlation
with Age
CW
(n ⫽ 23)
Prefrontal cortex
Lateral orbital frontal cortex
Medial orbital frontal cortex
Supragenual cingulate
Subgenual cingulate
Pregenual cingulate
Lateral temporal cortex
Mesial temporal cortex
Parietal cortex
Sensorimotor cortex
REC AN
(n ⫽ 16)
rho
p
rho
p
⫺.5
⫺.3
⫺.5
⫺.5
⫺.5
⫺.5
⫺.5
⫺.3
⫺.5
⫺.5
.01
.23
.03
.01
.03
.02
.03
.20
.01
.01
⫺.4
⫺.6
⫺.6
⫺.6
⫺.4
⫺.6
⫺.5
⫺.3
⫺.5
⫺.6
.13
.01
.01
.02
.10
.02
.04
.35
.56
.02
CW, healthy control women; REC AN, recovered anorexic women; rho,
Spearman correlation coefficient.
These data confirm that a disturbance of brain 5-HT
neuronal function persists after recovery from AN. Directed ROI and whole brain SPM analyses suggested that
the most substantial reduction in 5-HT2A receptor binding
occurred in the mesial temporal cortex, including the
amygdala and hippocampus.
Recovered AN women have increased CSF 5-HIAA
raising the possibility that they have increased brain 5-HT
activity (Kaye et al 1991). One possible explanation for
the findings in this study is that reduced 5-HT2A binding
is a compensatory response for increased extracellular
levels of 5-HT. Studies in animals confirm that reduced
5-HT2A receptor density occurs in response to increased
intra synaptic 5-HT (Rioux et al 1999; Saucier et al 1998)
or 5HT agonists (Eison and Mullins 1996). In addition,
paroxetine treatment for depression reduces 5-HT2A receptors in the brain, presumably due to increased intrasynaptic 5-HT (Meyer et al 2001). Some, but not all, studies
raise the question of whether an increased frequency of a
variant of the 2A receptor is present in AN (Hinney et al
2000); however, it is unknown if this receptor variant has
functional significance. It is also important to note that
these PET imaging studies do not permit a determination
of whether there is an alteration in affinity or number of
the 5-HT2A receptor.
We are not aware of any previous in vivo neuroreceptor
studies in ill or recovered AN women; however, 5-HT2, or
more specifically 5-HT2A receptor binding, has been
assessed in depressed subjects. Some studies of MDD
have found reduced 5-HT2A receptor binding in frontal,
temporal, parietal, and occipital cortical regions before or
after treatment (Attar-Levy et al 1999; Biver et al 1997;
Yatham et al 2000). Other studies in depressed subjects
(Meltzer and Reynolds 1999; Meyer et al 1999) did not
find such changes. To our knowledge, no such studies
have been done in anxiety disorders or OCD.
Other types of brain imaging studies in AN have
reported structural or functional alterations. Subjects with
active AN have enlarged ventricles and sulci widening
902
BIOL PSYCHIATRY
2002;52:896 –906
(see review Ellison and Fong 1998). A 1H-MR scan
revealed reduced lipid signals in the frontal white matter
and occipital gray matter and was associated with decreased BMI (Roser et al 1999). These alterations have
been thought to be reversible after recovery but recent data
raise the question of persistent changes after recovery
(Katzman et al 1997; Lambe et al 1997). A number of
studies using single photon computed tomography
(SPECT) or PET with 2-deoxy-glucose, have shown
temporal alterations and less frequently frontal or cingulate changes. Gordon et al (1997) using SPECT found ill
AN patients had unilateral temporal lobe hypoperfusion
that persisted in subjects studied after weight restoration.
Ellison et al (1998) using functional MR imaging, found
that ill AN patients, when viewing pictures of high-caloric
drinks, had increased signal changes in the left insular,
cingulate gyrus, and left amygdala-hippocampus region
and increased anxiety. Rauch et al (2000) using PET O-15
and pictures of high-calorie food, found ill AN patients
had elevated regional cerebral blood flow in bilateral
mesial temporal lobes and increased anxiety. Taken together, these studies suggest that temporal cortex alterations occur in AN.
Similarly, our study found that the most pronounced
change in 5-HT2A binding in REC AN women was in the
mesial temporal cortex regions, including hippocampus
and amygdala regions. The amygdala is thought to play a
central role in the “interpretation of fear” (Charney and
Deuth 1996; Davis 1992) and anxiety disorders (Benkelfat
et al 1995; Reiman et al 1984; Van der Linden et al 2000).
The mesial temporal cortex may also play a role in
depressive symptoms (Byrum et al 1999; Kennedy et al
1997), OCD (Breiter and Rauch 1996; Zald et al 1996),
memory processing (Marrazzi et al 1990), and aversive
conditioning (Breiter and Rosen 1999; Buchel et al 1999;
Schneider et al 1999; Zalla et al 2000). Thus, these data
support the possibility, raised by recent neuroimaging
studies, that alterations of the hippocampus–amygdala
region may play a more general role in psychopathology
(Fujita et al 2000). In a preliminary analysis, 5HT2A
binding changes in our study were generally bilateral and
not lateralized (data not shown); however, due to the
relatively small sample size and increased variability when
assessing lateralized binding, we cannot exclude a lataralization of altered binding in a larger group of subjects.
Consistent with earlier studies (Srinivasagam et al
1995), REC AN women had increased depression, anxiety,
and perfectionism. In fact, such symptoms, obsessions
(Kaye 1997), and cognitive alterations (Bradley et al 1997;
Strupp et al 1986) occur when people with AN are ill and
persist after recovery. Theoretically, disturbed 5-HT neuronal transmission in the mesial temporal cortex areas in
people with AN could be related to such symptoms.
G.K. Frank et al
This study raises the possibility that REC AN women
have altered 5HT2A binding in cingulate regions as well
as occipitoparietal and sensorimotor cortex. The anterior
cingulate receives afferents from the amygdala and has
direct projections to the premotor frontal cortex and other
limbic regions. The anterior cingulate has been characterized as “executive” in function and contributes to attention
by monitoring the motivational significance of stimuli
(Devinsky et al 1995; Tucker et al 1995). Overall, the
anterior cingulate cortex has a role in affect as well as
visuospatial and memory functions and appears to play a
crucial role in initiation, motivation, and goal-directed
behaviors. The primary sensory and association cortices
have input into the limbic system (Charney and Deuth
1996), and the parietal cortex may be involved in the
circuitry of depression, anxiety (Davidson et al 1999), and
memory consolidation (Izquierdo and Medina 1997).
In another study, our group reported (Kaye et al 2001)
that nine REC BN women, who never had AN, had a
significant downregulation of 5-HT2A receptors in the
orbital frontal cortex and a trend toward a reduction in the
lateral orbital frontal cortex and the sensorimotor cortex.
In addition, the CW showed a well-known negative
relationship between age and 5-HT2A binding in most
cortical regions (data on 12 of the CW in this study were
reported in our previous study). Importantly, a relationship
between age and 5HT2A binding was not found in the
REC BN sample in regions of interest. Although AN and
BN are related disorders because they are cross-transmitted in families, a number of factors distinguish the
subgroups, such as extremes of eating behavior and
impulse control. These data raise the possibility that
regional differences in [18F]altanserin binding or relationships of [18F]altanserin binding to age may distinguish
eating disorder subgroups after recovery. That is, REC BN
women had a substantial reduction of [18F]altanserin
5HT2A receptor binding localized to the orbital frontal
cortex (Kaye et al 2001). In contrast, REC AN show
diminished [18F]altanserin in temporal as well as cingulate, parietal, and sensorimotor binding in this study. The
disturbance of orbital frontal 5HT circuits in BN may
contribute to a vulnerability for imprecise and poorly
modulated self-control, whereas temporocingulate alterations in AN may contribute to impaired motivation and
integration of cognition and mood.
In terms of limitations, we studied a relatively small
number of AN subjects; however, a power analysis using
the data for the mesial temporal cortex showed a power of
0.85 for detection of two-group differences for the sample
size in this study. Still, it is possible that we did not detect
more subtle 5-HT2A receptor alterations because of the
small sample size. The REC AN women had a reduction of
current BMI compared with CW; however, all subjects’
Serotonin Receptor Activity in Anorexia
weights were in a normal weight range, and there was less
than 1 unit of BMI difference between groups. An additional regression analysis using group and BMI as regressors showed a significant effect for group (t ⫽ ⫺2.5, p ⫽
.02) but no effect for BMI (t ⫽ ⫺0.1, p ⫽ .9). Moreover,
no previous study demonstrated a relation of BMI and
brain 5-HT2A receptor binding, and there was no relation
of current BMI and receptor binding in either one of the
groups of this study. Thus, there is no evidence that
differences in weight account for the findings. The use of
self-assessments for the evaluation of recovery may be a
limitation, and different eating patterns between groups
could theoretically alter 5HT2A receptor activity; however, plasma BHBA was similar between groups, suggesting a similar nutritional status. Similar plasma E2 values
further supported normal menstrual function and status of
recovery.
Beside [18F]altanserin, other radioligands have been
used for assessment of 5HT2A receptor imaging (Staley et
al 1998); however, [18F]altanserin binds highly specific to
5HT2A receptors. It shows a high affinity (Ki ⫽ 0.51
nmol/mL) and high selectivity (90- to 400-fold less potent
at ␣1 and 5HT2C receptor) for 5HT2A receptors and is
superior compared with other 5HT2A ligands (Price et al
2001). The use of [18F]altanserin has been validated in the
past (Smith et al 1998). A disadvantage of [18F]altanserin
is its rapid metabolization that may increase nonspecific
binding. [18F]altanserin cerebellar DV values were similar
between groups in this study, however, supporting the
assumption that nonspecific binding was similar between
groups. In addition, the percentage of unmetabolized
[18F]altanserin in plasma was similar between control and
anorexic subjects. This suggested that altered 5HT2A
binding between groups was not driven by different
metabolism of [18F]altanserin. Recent studies have shown
that the cerebellum is not totally devoid of 5HT2A
receptors (Dwivedi and Pandey 1998; Staley et al 2001),
and altered cerebellar 5HT2A binding could contribute to
the study outcome. Because 5HT2A cerebellar data were
similar between groups, however, ROI-specific binding in
CW was not driven by reduced 5HT2A DV values in the
reference region (i.e., cerebellum). When studies performed on different scanners are combined, different
sensitivity or signal to noise ratio could contribute to
altered findings; however, all PET scans were performed
in 2D mode. More important, the analysis procedure used
was a relative measure, thus accounting for eventual
systematically increased or decreased binding detection. In
addition, the binding values between the CW groups from
the two scanners were similar and did not suggest any
systematic errors. The comparison of groups with subjects
BIOL PSYCHIATRY
2002;52:896 –906
903
studied on the HR⫹ scanner only (both by ROI- and
SPM-based analyses), further supports the findings in the
combined group.
It is possible that structural alterations in the REC AN
group might have contributed to this finding (Katzman et
al 1997), but in our investigational analysis of gray matter
volumes between groups, no structural alterations were
found.
In conclusion, this study supports previous findings of
altered 5-HT neuronal transmission after recovery from
AN. It is problematic to identify women with AN before
they develop the disorder. Studying women after longterm recovery may be the best available approximation to
identifying factors that might be involved in the development of AN. Although a scarring effects from the illness
cannot be excluded, reduced 5-HT2A receptor binding in
AN thus could be an indication of a trait related 5-HT
disturbance or, alternatively, a secondary phenomenon in
response to increased central 5HT transmission in this
group.
Supported in part by National Institute of Mental Health Grant No. R01
MH46001-07A1 and Children’s Hospital Clinical Research Center,
Pittsburgh PA (#5 M01RR00084).
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