Psychopharmacology
DOI 10.1007/s00213-007-0896-7
ORIGINAL INVESTIGATION
Serotonin transporter binding after recovery
from eating disorders
Ursula F. Bailer & Guido K. Frank & Shannan E. Henry &
Julie C. Price & Carolyn C. Meltzer & Carl Becker &
Scott K. Ziolko & Chester A. Mathis & Angela Wagner &
Nicole C. Barbarich-Marsteller & Karen Putnam &
Walter H. Kaye
Received: 29 March 2007 / Accepted: 5 July 2007
# Springer-Verlag 2007
Abstract
Rationale Several lines of evidence suggest that altered
serotonin (5-HT) function persists after recovery from
anorexia nervosa (AN) and bulimia nervosa (BN).
Objectives We compared 11 subjects who recovered (>1
year normal weight, regular menstrual cycles, no bingeing
or purging) from restricting-type AN (REC RAN), 7 who
recovered from bulimia-type AN (REC BAN), 9 who
Parts of the manuscript were presented at the 44th American College
of Neuropsychopharmacology (ACNP) Annual Meeting, December
11–15, 2005, Waikoloa, Hawaii.
U. F. Bailer : G. K. Frank : S. E. Henry : C. C. Meltzer :
A. Wagner : W. H. Kaye (*)
Western Psychiatric Institute and Clinic, University of Pittsburgh,
Iroquois Building, Suite 600, 3811 O’Hara Street,
Pittsburgh, PA 15213, USA
e-mail: kayewh@upmc.edu
W. H. Kaye
Psychiatry, University of California San Diego,
8950 Villa La Jolla Drive, Suite C207,
La Jolla, CA 92037, USA
U. F. Bailer
Department of Biological Psychiatry,
University Hospital of Psychiatry, Medical University of Vienna,
Vienna, Austria
J. C. Price : C. C. Meltzer : C. Becker : S. K. Ziolko :
C. A. Mathis
Department of Radiology, Presbyterian University Hospital,
School of Medicine, University of Pittsburgh,
Pittsburgh, PA, USA
C. C. Meltzer
Departments of Radiology and Neurology,
Emory School of Medicine,
Atlanta, GA, USA
recovered from BN (REC BN), and 10 healthy control
women (CW).
Materials and methods Positron emission tomography
(PET) imaging with [11C]McN5652 was used to assess
the 5-HT transporter (5-HTT). For [11C]McN5652, distribution volume (DV) values were determined using a twocompartment, three-parameter tracer kinetic model, and
specific binding was assessed using the binding potential
(BP, BP=DVregion of interest/DVcerebellum −1).
Results After correction for multiple comparisons, the four
groups showed significant (p<0.05) differences for [11C]
C. C. Meltzer : W. H. Kaye
School of Medicine, University of Pittsburgh,
Pittsburgh, PA, USA
G. K. Frank
Laboratory for Developmental Brain Research,
University of Colorado at Denver and Health Sciences Center,
The Children’s Hospital,
1056 E. 19th Avenue,
Denver, CO 80218, USA
A. Wagner
Department of Child and Adolescent Psychiatry,
J.W. Goethe University of Frankfurt/Main,
Frankfurt/Main, Germany
N. C. Barbarich-Marsteller
New York State Psychiatric Institute, Department of Psychiatry,
College of Physicians and Surgeons,
Columbia University Medical Center,
New York, NY, USA
K. Putnam
Department of Environmental Health,
Division of Epidemiology and Biostatistics,
University of Cincinnati School of Medicine,
Cincinnati, OH, USA
Psychopharmacology
McN5652 BP values for the dorsal raphe and antero-ventral
striatum (AVS). Post-hoc analysis revealed that REC RAN
had significantly increased [11C]McN5652 BP compared to
REC BAN in these regions.
Conclusions Divergent 5-HTT activity in subtypes of
eating disorder subjects may provide important insights as
to why these groups have differences in affective regulation
and impulse control.
Keywords Anorexia nervosa . Bulimia nervosa .
Serotonin transporter . Positron emission tomography .
Serotonin . 5-HTTLPR
Introduction
Anorexia nervosa (AN) and bulimia nervosa (BN) are
disorders of unknown etiology that most commonly have
their onset during adolescence in females. These disorders
are characterized by the relentless pursuit of thinness,
obsessive fears of being fat, and aberrant eating behaviors,
such as restrictive eating and episodes of purging and/or
binge eating (American Psychiatric Association 1994).
Physiologic and pharmacologic studies show that disturbances of serotonin (5-HT) activity occur in people who
are ill with eating disorders (EDs; Brewerton and Jimerson
1996; Walsh and Devlin 1998; Wolfe et al. 1997). Such 5HT disturbances may contribute to appetite dysregulation
(Blundell 1984; Leibowitz and Shor-Posner 1986), anxious
and obsessional behaviors and extremes of impulse control
(Cloninger 1987; Higley and Linnoila 1997; Lucki 1998;
Mann 1999; Soubrie 1986). Importantly, disturbances in 5HT measures appear to persist after individuals recover
from AN and BN. It has been demonstrated that individuals
who recovered from AN and BN have elevated cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic
acid (5-HIAA; Kaye et al. 1991a), reduced 5-HT2A receptor
levels (Bailer et al. 2004; Frank et al. 2002; Kaye et al.
2001a), and increased 5-HT1A receptor levels (Bailer et al.
2005). Moreover, those recovered from AN and BN show
altered behavioral responses to 5-HT challenges (Frank
et al. 2001; Kaye et al. 2003; Smith et al. 1999; Ward et al.
1998). Recent imaging studies, using single photon
emission computed tomography (SPECT) with [123I]betaCIT found reduced 5-HTT binding in people who are ill
with bulimic-type EDs (Kuikka et al. 2001; Tauscher et al.
2001). Steiger found that individuals who recovered from
BN had reduced platelet binding of paroxetine (Steiger
et al. 2005b); however, recent studies have shown that
peripheral measures of 5-HT receptor levels (5-HT2A and 5HTT) do not correlate with central measures in healthy
controls. (Cho et al. 1999; Uebelhack et al. 2006; Yatham
et al. 2000).
To date, no studies have explored whether central 5-HTT
abnormalities continue after individuals with EDs have
recovered. The aim of this study was to use positron
emission tomography (PET) imaging with [11C]McN5652
to determine if alterations of 5-HTT persist after recovery
from AN and BN. Persistence of these abnormalities into
recovery may indicate a “trait” phenomenon, possibly
linked to the pathogenesis of the illness. In contrast,
normalization of the 5-HTT alterations upon recovery
would suggest a “state” phenomenon.
The boundaries between subtypes of eating disorders are
poorly understood and somewhat controversial. Reasons for
subdividing recovered restricting-type anorexia nervosa
(REC RAN) and recovered bulimia-type anorexia nervosa
(REC BAN) is that they have differences in affective
modulation and perhaps response to selective serotonin
reuptake inhibitor (SSRI) medication. In addition, other
studies from our group show that they are different in terms
of binding of the 5-HT1A receptor (Bailer et al. 2005).
Finally, this is reasonably consistent with the Diagnostic
and Statistical Manual of Mental Disorders (DSM IV;
American Psychiatric Association 1994) practice of categorizing subgroups as AN, AN-BN, and BN.
A secondary, exploratory aim of this study was to
examine the possible effects of the functional polymorphism in the promoter region of the 5-HTT gene (5HTTLPR) on in vivo expression of 5-HTT in healthy
women and those who recovered from EDs. Some, but not
all, genetic studies find altered frequency of a short allele
polymorphism in the 5-HTTLPR in people with AN and
BN (Di Bella et al. 2000; Gorwood 2004; Lauzurica et al.
2003; Matsushita et al. 2004; Monteleone et al. 2005;
Steiger et al. 2005a). The correlation of genotypes with
imaging findings can be problematic, given the fact that the
sample size is small. Thus, we report exploratory findings.
Materials and methods
Twenty-seven women who recovered from EDs [7 women
recovered from bulimic-type anorexia nervosa (REC BAN),
11 women who recovered from restricting-type anorexia
nervosa (REC RAN), 9 women who recovered from
bulimia nervosa (REC BN)] were recruited as previously
described (Bailer et al. 2005; Wagner et al. 2006) All
individuals underwent four levels of screening: (1) a brief
phone screening, (2) an intensive screening assessing
psychiatric history, lifetime weight, binge eating and
methods of weight loss/control, and menstrual cycle history
as well as eating pattern for the past 12 months, (3) a
comprehensive assessment using structured and semistructured psychiatric interviews conducted by phone or in
person, and (4) a face- to-face interview and physical
Psychopharmacology
examination with a psychiatrist. To be considered “recovered,” subjects had to (1) maintain a weight above 85%
average body weight (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. Restrictive eating pattern was
defined as regularly occurring behaviors, such as restricting
food intake, restricting high-caloric food, counting calories,
and dieting. 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. Ten healthy control women (CW) were
recruited through local advertisements and had no history
of an ED, psychiatric or neurologic disorder, or serious
medical illness. This study was conducted according to the
institutional review board regulations of the University of
Pittsburgh, and all subjects gave written informed consent.
Blood was drawn for assessment of β-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. The ED diagnosis was made by a modified
version of module H of the SCID I. Current psychopathology was assessed with a battery of standardized instruments
including the Beck Depression Inventory (BDI; Beck et al.
1961), the Spielberger–Trait Anxiety Inventory (STAI;
Spielberger et al. 1970), the Frost Multidimensional
Perfectionism Scale (MPS; Frost et al. 1990), the Eating
Disorders Inventory (EDI-2; Garner 1990)), the Yale–
Brown Obsessive Compulsive Scale (Y-BOCS; Goodman
et al. 1989a,b), the Yale–Brown–Cornell Eating Disorder
Scale (YBC-EDS; Mazure et al. 1994; Sunday et al. 1995),
the Barratt Impulsiveness Scale (BIS; Barratt and Patton
1983), and the Temperament and Character Inventory (TCI;
Cloninger et al. 1994) for assessment of harm avoidance,
novelty seeking, and reward dependence.
All subjects were scanned on the ECAT HR+PET
scanner (CTI PET systems, Knoxville, TN) in threedimensional (3D) imaging mode during the first 10 days
of the follicular phase of the menstrual cycle. Details of
PET and magnetic resonance imaging (MRI) acquisition
and co-registration are described elsewhere (Lopresti et al.
2001). Immediately after slow bolus intravenous injection
of 13.8±1.8 mCi [11C]McN5652, dynamic emission scanning with arterial blood sampling (input function) was
performed over 90 min. A scanning time of 90 min was
used to achieve time stable measurements of distribution
volume (DV) across regions for [11C]McN5652 (Frankle
et al. 2004). The following regions of interest (ROI) were
hand drawn on the coregistered MR images by technicians
blind to subject diagnosis and applied to the dynamic PET
data to generate time–activity curves: subgenual cingulate,
thalamus, antero-ventral striatum, dorsal caudate, and
cerebellum (as a reference region; Bailer et al. 2005;
Drevets et al. 2001; Frank et al. 2005). For the dorsal
raphe nucleus, due to the lack of identifiable anatomic
boundaries on the MR, the ROI was placed directly on the
PET image in the following manner. Based on the
coregistered MRs, the brain stem was subdivided into a
rostral (midbrain/upper pons) and caudal region (medulla/
pons) to approximate the dorsal and median raphe nuclei,
respectively. A dorsal midbrain raphe nucleus was drawn
on the dynamic PET image, using circular fixed 6 mm
radius ROIs placed over the area of highest radioactivity.
The dorsal raphe was drawn over three contiguous planes,
and the data from those three planes were sampled. The
inferior border of the dorsal raphe nucleus was identified by
the interpeduncular cistern on the MR. Previous imaging
studies of our group in EDs (Bailer et al. 2004, 2005, 2007;
Frank et al. 2005) have found alterations in these ROIs and
therefore guided our choice of brain regions to investigate
in our subjects in this study. Figure 1 shows examples of
MR and PET image data acquired at the level of the dorsal
raphe.
For the kinetic analyses, regional [11C]McN5652 DV
values were determined using a two-compartment, threeparameter tracer kinetic model (Lopresti et al. 2001).
Specific 5-HTT binding was assessed using binding
potential (BP), where BP was derived as the difference
between the ROI DV value and the cerebellar DV value,
normalized to the cerebellar DV [BP=(DVROI −DVCER)/
DVCER] (Parsey et al. 2000).
An MR-based partial volume effect correction method
was applied to correct the PET data for the dilutional effect
of expanded CSF spaces accompanying normal aging and
disease-related cerebral atrophy (Meltzer et al. 1996, 1999).
For the genotyping data, S and L alleles were determined
using DNA amplification (polymerase chain reaction, PCR)
and established flanking primers. Amplification products
were resolved by electrophoresis and visualized with
ethidium bromide staining and UV transillumination,
according to Edenberg and Reynolds (1998). Genotyping
was performed blind to diagnosis and imaging results.
Global BP differences were estimated by multivariate
analysis of variance (MANOVA) to explore if mean
differences among the three ED groups and controls were
likely to occur by chance. A new linear combination
consisting of all the dependent ROI’s variables (subgenual
cingulate, antero-ventral striatum, thalamus, dorsal caudate,
and dorsal raphe) controlled the experiment-wise error rate
before evaluating specific regions and allowed overall
assessment of global BP patterns. Multiple comparisons
Psychopharmacology
Fig. 1 This figure is representative of a recovered anorexic women,
restricting type (REC RAN). The image is an SUV normalization of a
late sum (30 to 90 min) [ 11 C] McN5652 positron emission
tomography (PET) scan (left) and the subject’s associated coregistered
SPGR magnetic resonance (MR) image (right). The SUV image was
created from the late sum by division (of each pixel) by the subject’s
injected dose in mCi and multiplying by the subject’s weight in kg.
Also shown are examples of the regions-of-interest that were used to
generate the PET time-activity data. DRP Dorsal raphe nucleus; CER
cerebellum
using the Tukey–Kramer method identified the significant
group pairs for statistically significant ANOVAs. Correlations were examined with Pearson correlation coefficients.
A repeated measures analysis of variance (ANOVAR) was
applied to examine potential group differences in radiolabeled metabolites of [11C]McN5652. Values are expressed
as mean±standard deviation (SD). Standard statistical
software packages (SAS Version 9.1) were used.
time course (data not shown). The regional [11C]McN5652
BP values followed the rank order of 5-HTT binding
(Parsey et al. 2000) as shown in Table 2.
MANOVA results for global BP differences were
significant at the 5% level. Follow-up univariate ANOVA
significantly distinguished the groups apart for [11C]
McN5652 BP values in the regions of antero-ventral
striatum (F3,35 =5.19, p=0.004) and dorsal raphe (F3,35 =
4.64, p=0.008; Table 2). Post-hoc analysis revealed that the
REC RAN had significantly increased [11C]McN5652 BP
compared to REC BAN in these regions. REC BAN had
significantly lower [11C]McN5652 BP in the antero-ventral
striatum compared to REC BN. Illustrative scatterplots for
the dorsal raphe and antero-ventral striatum are shown in
Fig. 2.
[11C]McN5652 BP was not related to lifetime history of
major depressive disorder (n=16; 5 REC RAN, 4 REC
BAN, and 7 REC BN), obsessive–compulsive disorder (n=
18), alcohol abuse (n=3) or alcohol dependence (n=1), any
anxiety disorder (n=11), use of birth control pills (n=14),
levels of plasma β-hydroxybuteric acid (BHBA), length of
recovery, age, or current or low body mass index (BMI) in
REC ED (all REC subgroups together) subjects. There was
no relationship between [11C]McN5652 BP and measures
of anxiety, depression, obsessionality, or impulse control at
the time of the study.
Genotyping data were available in 24 REC ED subjects
and 10 CW. ED subjects showed allele frequencies of 58%
for the L and 42% for the S allele and a genotype
distribution of 29.2% LL (n=7), 58.3% SL (n=14), and
12.5% SS (n=3). CW had frequencies of 60% for the L and
40% for the S allele and genotype frequencies of 40% LL
(n=4), 40% SL (n=4) and 20% SS (n=2). This small
number of subjects showed no significant differences in
allele or genotype frequencies between REC ED and CW.
Because of the small sample, all subjects were considered
together (REC ED and CW) when compared to [11C]
McN5652 BP. The subjects with SS alleles had lower [11C]
McN5652 BP than subjects with LL alleles for the dorsal
caudate (SS, 0.43±0.06; LL, 0.60±0.12; p=0.01), but not
other brain regions (Fig. 3). Findings were similar for the
dorsal caudate when only the REC ED subjects were
considered (SS, 0.44±0.08; LL, 0.63±0.09; p=0.03).
Discussion
Results
Demographic data and behavioral assessment data are
shown in Table 1. The repeated measures analysis of the
unmetabolized fraction of [11C]McN5652 (5 time points)
indicated no differences between the four groups over the
This study has several major findings. First, REC RAN had
elevated [11C]McN5652 BP in the dorsal raphe and anteroventral striatum in comparison to REC BAN. Furthermore,
REC BAN had decreased [11C]McN5652 BP in the anteroventral striatum in comparison to REC BN. These findings
suggest that subtypes of ED have differences in 5-HT
Psychopharmacology
Table 1 Demographic values between groups
CW (n=10) REC RAN
(n=11)
REC BAN
(n=7)
REC BN
(n=9)
SD
Mean
SD
Mean
SD
Sig.
24.74
20.74
13.33 (9)
15.91
43.36
43.10 42.33 19.56 (9)
0.83 0.31 0.52 (9)
15.00 4.67 13.78 (9)
0.30 0.67 18.60 (10)
5.48
2.44
2.25
3.21
49.52
26.68
0.31
3.87
4.09
23.66
21.75
15.14
15.83 (6)
12.00 (6)
25.2 (5)
0.52 (4)
16 (5)
18.57
4.17
2.27
1.53
1.94
13.56
25.37
0.21
2.45
3.36
24.44
23.24
18.59
17.38 (8)
17.13 (8)
90.56
1.25 (8)
16.11
19.78
5.27
2.76
1.76
4.69
10.16
99.65
1.46
6.17
1.39
0.396
0.119
<0.001 2, 3<1, 4
0.622
0.143
0.083
0.215
0.729
<0.001 1<2, 3, 4
53.80
20.90
8.40
28.70
80.90
0.00
12.26
4.98
4.22
5.14
21.14
0.00
111.82
15.27
18.00
45.00
72.27
4.64
17.10
7.42
6.26
12.81
21.64
6.39
113.43
21.71
12.86
38.71
88.71
8.00 (6)
20.32
8.50
10.78
12.35
22.22
8.99
99.11
20.32
19.88
47.33
98.33
11.63 (8)
22.03
8.28
6.28
9.80
25.92
10.46
<0.001
0.210
0.004
0.002
0.092
0.013
0.30
0.95
6.18
6.62
6.67 (6)
5.79
5.88 (8)
5.06
0.034
1.50
2.27
8.36
6.82
6.00
4.97
9.11
9.84
0.063
Mean SD
Age (years)
Current BMI (kg/m2)
Low BMI (lifetime) (kg/m2)
Age of Onset (years of age)
Length of Recovery (months)
Estradiol (pg/mL)
β-hydroxybuteric Acid (mg/dL)
Cortisol (mcg/dl)
EDI 2 –Drive for Thinness (“worst ever”)
(Garner 1990)
Perfectionism (MPS) (Frost et al. 1990)
Novelty Seeking (TCI (Cloninger 1987))
Harm Avoidance (TCI)
Trait Anxiety (STAI) (Spielberger et al. 1970)
Self Control (BIS (Barratt and Patton 1983))
Yale-Brown Obsessive-Compulsive Scale (YBOCS)
(Goodman et al. 1989a,b)
Yale-Brown-Cornell Eating Disorders Scale
(YBC-EDS) (Mazure et al. 1994; Sunday et al. 1995)
Depression (BDI) (Beck et al. 1961)
Mean
27.93 6.89
22.66 2.02
20.37 1.60
ANOVA
Group Diff.
1<2, 3, 4
1<2, 4
1<2, 4
1<4
Group comparisons by ANOVA
Sig. Significance; CW healthy control women; REC RAN recovered anorexic women, restricting type; REC BAN recovered anorexic women,
bulimic-type; REC BN recovered bulimic women; BDI Beck Depression Inventory; TCI Temperament and Character Inventory; BIS Barratt
Impulsiveness Scale; STAI State Trait Anxiety Inventory; MPS Multidimensional Perfectionism Scale
function, which may provide important insights into why
these groups have differences in affective regulation and
impulse control.
To our knowledge, imaging studies of 5-HTT have not
been done in individuals with RAN, whether ill or
recovered. Other imaging studies have found reduced 5HTT levels in symptomatic BN subjects. Tauscher et al.
(2001) found reduced [123I]beta-CIT binding in ten individuals who were ill with BN. Two of those individuals had
a history of AN, but specific imaging data for those two
individuals were not identified. Kuikka et al. (2001) found
reduced [123I]beta-CIT binding values in subjects ill with
binge eating disorder. In addition, Steiger et al. (2005b)
showed that individuals remitted from BN have reduced
platelet [3H]paroxetine binding. We found that reduced
[11C]McN5652 BP appeared to occur mainly in the remitted
BAN, not the REC BN subjects. New studies, seeking to
replicate these findings with [11C]DASB, a more specific
Table 2 Regional [11C]McN5652 binding potential (BP) between groups
Dorsal raphe
Antero-ventral striatum
Thalamus
Dorsal caudate
Subgenual cingulate
CW (n=10)
REC RAN
(n=11)
REC BAN
(n=7)
REC BN
(n=9)
ANOVA
Mean
SD
Mean
SD
Mean
SD
Mean
SD
df
F
1.169
0.743
0.693
0.526
0.239
0.337
0.129
0.221
0.129
0.052
1.316
0.835
0.744
0.553
0.237
0.288
0.117
0.201
0.137
0.105
0.749
0.549
0.519
0.575
0.236
0.332
0.236
0.085
0.180
0.066
1.027
0.767
0.722
0.565
0.224
0.348
0.133
0.327
0.155
0.086
3.35
3.35
3.35
3.35
3.35
4.65
5.19
1.54
0.19
0.06
Uncorrected
p value
Tukey-Kramer
Multiple
Comparison
0.008
0.004
0.073
0.882
0.752
2>3
2>3; 3<4
Group comparisons by ANOVA. The cerebellar DV values were similar between groups (CW, 21.23±5.07; REC RAN, 20.56±5.62; REC BAN,
20.58±4.75; REC BN, 22.30±3.54; p=.860).
CW healthy comparison women; REC RAN recovered anorexic women, restricting type; REC BAN recovered anorexic women, bulimic-type; REC
BN recovered bulimic women
Psychopharmacology
2.0
1.2
1.8
1.0
[11C]McN 5652 BP
1.6
[11C]McN 5652 BP
Fig. 2 Scatterplots of the [11C]
McN5652 binding potential
(BP) values in the dorsal raphe
(left plot) and antero-ventral
striatum (right plot). CW
Healthy control women; REC
RAN recovered anorexic
women, restricting type; REC
BAN recovered anorexic
women, bulimic-type; REC BN
recovered bulimic women
1.4
1.2
1.0
0.8
0.6
0.8
0.6
0.4
0.4
0.2
CW
R
REC
AN
B
REC
AN
radiotracer for a reliable quantification of 5-HTT parameters in regions of moderate 5-HTT density, including the
limbic regions (Frankle et al. 2004), are in progress.
Still, this finding raises the possibility that these data can
be used to understand who might respond to medication.
The eating disorders are thought to share a common
vulnerability, as crossover between subtypes is common
(Herzog et al. 1996) and subtypes are cross-transmitted in
families (Kendler et al. 1995; Lilenfeld et al. 1998; Strober
et al. 2000). However, other factors appear to differentiate
subtypes of AN and BN, including degree of weight loss,
affect regulation, self-control, and perhaps response to
SSRI medication (Kaye et al. 2004). It should be noted
that we only studied recovered individuals with “pure”
subtypes. For example, RAN individuals had never engaged in bulimic behaviors.
While BN individuals show a response to higher doses
of fluoxetine (Fluoxetine Bulimia Nervosa Collaborative
Study Group 1992), the efficacy of such medication has
been questioned, as relatively few individuals abstain from
binge and purge behaviors, and relapse during treatment is
common (Walsh 1991). It remains controversial whether
BN
0.2
CW
REC
RAN
REC
BAN
REC
0.8
p = .03
p = .01
0.7
0.7
0.6
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
SS
LL
Genotype
BN
SSRIs are effective in RAN individuals (Kaye et al. 2001b;
Walsh et al. 2006). Our clinical experience (Kaye et al.
1991b) suggests that individuals with RAN respond better
to fluoxetine than those with BAN did and that some
individuals with BN can be relatively insensitive to high
doses of SSRIs. There is little data determining whether
BAN and BN individuals have differential responses to
SSRIs. While highly speculative, our findings raise the
provocative possibility that decreased 5-HTT function may
be related to poor response to SSRI medication, whereas
individuals with increased 5-HTT activity may respond to
higher SSRI doses. Thus, PET and radioligand studies may
be a useful tool for investigating and managing medication
response in treatment resistant individuals.
In general, the REC RAN individuals had elevated 5HTT binding, suggesting they have relatively greater 5-HT
uptake and reduced extracellular 5-HT compared to REC
BAN and BN. In support of this possibility, the REC BAN
and BN individuals tend to have higher binding of 5-HT1A
post-synaptic receptors and autoreceptors (Bailer et al.
2005; Kaye et al., unpublished data), which may be a
compensatory means of downregulating raphe activity
0.8
[11C]McN 5652 BP dorsal caudate
Fig. 3 Scatterplot of [ 11 C]
McN5652 binding potential (BP)
in the dorsal caudate in the CW
and REC eating disorder sample
(left graph) and REC eating disorder only (right graph) by
5-HTLPR genotype (SS and
LL only)
REC
SS
LL
Genotype
Psychopharmacology
(Cooper 1996; Hajos et al. 2003). Moreover, reduced 5HTT activity, in terms of genotypes (Steiger et al. 2005a),
has been associated with affect dysregulation, which tends
to be more common in the bulimic subgroups. Furthermore,
in people with impulsive aggressivity, reduced 5-HTT
binding was found in the anterior cingulate cortex, a region
involved in affect regulation (Frankle et al. 2005). Imaging
studies (using SPECT or PET) in other psychiatric disorders
with altered affect regulation have revealed inconsistent
results. In obsessive–compulsive disorder, increased
(Pogarell et al. 2003), unaltered (Simpson et al. 2003), or
decreased 5-HTT binding (Hesse et al. 2005; StenglerWenzke et al. 2004; Zitterl et al. 2007) was found. Results
remain contradictory in depression as well (see Hesse et al.
2004 for review).
The functional polymorphism in the promoter region of
the human 5-HTT gene (SLC6A4) has been implicated in
the modulation of mood and antidepressant response
(Murphy et al. 2004). We included data on possible
relationships between 5-HTTLPR and [11C]McN5652 BP,
despite our concerns that the sample was small, because of
the interest in this topic. Several lines of evidence show that
the genotype with two copies of the long (L, 528 bp) allele
leads to greater 5-HT reuptake compared to genotypes
having either one or two copies of the short (S, 484 bp)
allele (Lesch et al. 1996). As 5-HTT regulates 5-HT
concentrations in the synaptic cleft by recycling released
5-HT, individuals with the S allele are likely to have higher
extracellular 5-HT due to decreased 5-HT reuptake (Lesch
et al. 1996; Sundaramurthy et al. 2000). In other disorders,
relationships between 5-HTTLPR genotypes and imaging
measures of the transporter measures have been reported to
occur (Heinz et al. 2000; Little et al. 1998) or not (Parsey
et al. 2006; Shioe et al. 2003; Willeit et al. 2001). Some, but
not all studies, have found increased S allele frequency in
BN and AN (Di Bella et al. 2000; Fumeron et al. 2001;
Hinney et al. 1997; Lauzurica et al. 2003; Matsushita et al.
2004; Sundaramurthy et al. 2000). The data in our study
suggest that SS homozygous individuals have reduced 5HTT binding in the dorsal caudate. In individuals with BN,
the S allele has been associated with poor response to SSRI
therapy (Monteleone et al. 2005) and outpatient multimodal
group therapy (K. Bruce, personal communication), as well
as greater affective instability and impulsivity (Steiger et al.
2005a). Together, these data further support the possibility
that there is a group of individuals with ED who have
decreased 5-HTT function, and these individuals may
respond poorly to treatment. The subjects in our study
were all white women, 18 to 45 years old, studied in their
early follicular menstrual phase. Other studies have been
less homogenous, which may obscure potential findings.
In terms of limitations, the sample size is small, and
replication of these findings in larger samples is clearly
needed. The major limitation of the radioligand used in this
study is the high nonspecific binding, precluding reliable
measurement of 5-HTT in the human neocortex; we
therefore restricted our ROI analysis to regions for which
the derivation of [11C]McN5652 BP has been found reliable
(Parsey et al. 2000) and in which we previously found
alterations. Persistent alterations in monoamine activity
after recovery raise the question of whether this is a
premorbid vulnerability for developing ED symptoms.
Alternatively, it is possible that chronic disturbances of
nutrition during the ill state might contribute to a persistent
“scar” in recovered individuals, caused by chronic malnutrition and emaciation. Patients were off medication (e.g.,
SSRIs) for greater than 3 months, so it is unlikely that
persistent effects of 5-HT active medication accounted for
the results. Fourteen ED subjects (3 REC RAN, 5 REC
BAN, and 6 REC BN) were on SSRIs in the past. There
was no difference in [11C]McN BP across ROIs between
subjects who were or were not on SSRIs in the past within
each group and within the entire group of REC ED
subjects.
In summary, these data support and extend studies
suggesting that a disturbance of 5-HTT neuronal function
persists after normalization of weight and nutritional status
in people who have had eating disorders.
Acknowledgements The authors are indebted to the participating
individuals for their contribution of time and effort in support of this
study. We would like to thank W. Gordon Frankle for review of this
manuscript, Eva Gerardi and Katherine Plotnicov for editorial
assistance, and the University of Pittsburgh Medical Center PET
Facility staff for their invaluable contribution to this study. This study
was supported by grants from National Institute of Mental Health
(NIMH) MH46001, MH42984, K05-MD01894, NIMH Training
Grant T32-MH18399, and the Price Foundation. U.F.B. was funded
by an Erwin-Schrödinger-Fellowship of the Austrian Science Fund
(nos. J 2188 and J 2359-B02).
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