Serotonin Transporter Binding After Recovery from Eating Disorders

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 recovered from BN (REC BN), and 10 healthy control Rationale Several lines of evidence suggest that altered women (CW). serotonin (5-HT) function persists after recovery from Materials and methods Positron emission tomography anorexia nervosa (AN) and bulimia nervosa (BN). (PET) imaging with [11C]McN5652 was used to assess Objectives We compared 11 subjects who recovered (>1 the 5-HT transporter (5-HTT). For [11C]McN5652, distri- year normal weight, regular menstrual cycles, no bingeing bution volume (DV) values were determined using a two- or purging) from restricting-type AN (REC RAN), 7 who compartment, three-parameter tracer kinetic model, and recovered from bulimia-type AN (REC BAN), 9 who specific binding was assessed using the binding potential

(BP, BP=DVregion of interest/DVcerebellum−1). Results After correction for multiple comparisons, the four Parts of the manuscript were presented at the 44th American College 11 of Neuropsychopharmacology (ACNP) Annual Meeting, December groups showed significant (p<0.05) differences for [ C] 11–15, 2005, Waikoloa, Hawaii. U. F. Bailer : G. K. Frank : S. E. Henry : C. C. Meltzer : C. C. Meltzer : W. H. Kaye A. Wagner : W. H. Kaye (*) School of Medicine, University of Pittsburgh, Western Psychiatric Institute and Clinic, University of Pittsburgh, Pittsburgh, PA, USA Iroquois Building, Suite 600, 3811 O’Hara Street, Pittsburgh, PA 15213, USA G. K. Frank e-mail: [email protected] Laboratory for Developmental Brain Research, University of Colorado at Denver and Health Sciences Center, W. H. Kaye The Children’s Hospital, Psychiatry, University of California San Diego, 1056 E. 19th Avenue, 8950 Villa La Jolla Drive, Suite C207, Denver, CO 80218, USA La Jolla, CA 92037, USA A. Wagner U. F. Bailer Department of Child and Adolescent Psychiatry, Department of Biological Psychiatry, J.W. Goethe University of Frankfurt/Main, University Hospital of Psychiatry, Medical University of Vienna, Frankfurt/Main, Germany Vienna, Austria N. C. Barbarich-Marsteller J. C. Price : C. C. Meltzer : C. Becker : S. K. Ziolko : New York State Psychiatric Institute, Department of Psychiatry, C. A. Mathis College of Physicians and Surgeons, Department of Radiology, Presbyterian University Hospital, Columbia University Medical Center, School of Medicine, University of Pittsburgh, New York, NY, USA Pittsburgh, PA, USA K. Putnam C. C. Meltzer Department of Environmental Health, Departments of Radiology and Neurology, Division of Epidemiology and Biostatistics, Emory School of Medicine, University of Cincinnati School of Medicine, Atlanta, GA, USA Cincinnati, OH, USA Psychopharmacology

McN5652 BP values for the dorsal raphe and antero-ventral To date, no studies have explored whether central 5-HTT striatum (AVS). Post-hoc analysis revealed that REC RAN abnormalities continue after individuals with EDs have had significantly increased [11C]McN5652 BP compared to recovered. The aim of this study was to use positron REC BAN in these regions. emission tomography (PET) imaging with [11C]McN5652 Conclusions Divergent 5-HTT activity in subtypes of to determine if alterations of 5-HTT persist after recovery eating disorder subjects may provide important insights as from AN and BN. Persistence of these abnormalities into to why these groups have differences in affective regulation recovery may indicate a “trait” phenomenon, possibly and impulse control. linked to the pathogenesis of the illness. In contrast, normalization of the 5-HTT alterations upon recovery Keywords Anorexia nervosa . Bulimia nervosa . would suggest a “state” phenomenon. Serotonin transporter . Positron emission tomography. The boundaries between subtypes of eating disorders are Serotonin . 5-HTTLPR poorly understood and somewhat controversial. Reasons for subdividing recovered restricting-type anorexia nervosa (REC RAN) and recovered bulimia-type anorexia nervosa Introduction (REC BAN) is that they have differences in affective modulation and perhaps response to selective serotonin Anorexia nervosa (AN) and bulimia nervosa (BN) are reuptake inhibitor (SSRI) medication. In addition, other disorders of unknown etiology that most commonly have studies from our group show that they are different in terms their onset during adolescence in females. These disorders of binding of the 5-HT1A receptor (Bailer et al. 2005). are characterized by the relentless pursuit of thinness, Finally, this is reasonably consistent with the Diagnostic obsessive fears of being fat, and aberrant eating behaviors, and Statistical Manual of Mental Disorders (DSM IV; such as restrictive eating and episodes of purging and/or American Psychiatric Association 1994) practice of cate- binge eating (American Psychiatric Association 1994). gorizing subgroups as AN, AN-BN, and BN. Physiologic and pharmacologic studies show that dis- A secondary, exploratory aim of this study was to turbances of serotonin (5-HT) activity occur in people who examine the possible effects of the functional polymor- are ill with eating disorders (EDs; Brewerton and Jimerson phism in the promoter region of the 5-HTT gene (5- 1996; Walsh and Devlin 1998; Wolfe et al. 1997). Such 5- HTTLPR) on in vivo expression of 5-HTT in healthy HT disturbances may contribute to appetite dysregulation women and those who recovered from EDs. Some, but not (Blundell 1984; Leibowitz and Shor-Posner 1986), anxious all, genetic studies find altered frequency of a short allele and obsessional behaviors and extremes of impulse control polymorphism in the 5-HTTLPR in people with AN and (Cloninger 1987; Higley and Linnoila 1997; Lucki 1998; BN (Di Bella et al. 2000; Gorwood 2004; Lauzurica et al. Mann 1999; Soubrie 1986). Importantly, disturbances in 5- 2003; Matsushita et al. 2004; Monteleone et al. 2005; HT measures appear to persist after individuals recover Steiger et al. 2005a). The correlation of genotypes with from AN and BN. It has been demonstrated that individuals imaging findings can be problematic, given the fact that the who recovered from AN and BN have elevated cerebrospi- sample size is small. Thus, we report exploratory findings. nal 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. Materials and methods

2001a), and increased 5-HT1A receptor levels (Bailer et al. 2005). Moreover, those recovered from AN and BN show Twenty-seven women who recovered from EDs [7 women altered behavioral responses to 5-HT challenges (Frank recovered from bulimic-type anorexia nervosa (REC BAN), et al. 2001; Kaye et al. 2003; Smith et al. 1999; Ward et al. 11 women who recovered from restricting-type anorexia 1998). Recent imaging studies, using single photon nervosa (REC RAN), 9 women who recovered from emission computed tomography (SPECT) with [123I]beta- bulimia nervosa (REC BN)] were recruited as previously CIT found reduced 5-HTT binding in people who are ill described (Bailer et al. 2005; Wagner et al. 2006) All with bulimic-type EDs (Kuikka et al. 2001; Tauscher et al. individuals underwent four levels of screening: (1) a brief 2001). Steiger found that individuals who recovered from phone screening, (2) an intensive screening assessing BN had reduced platelet binding of paroxetine (Steiger psychiatric history, lifetime weight, binge eating and et al. 2005b); however, recent studies have shown that methods of weight loss/control, and menstrual cycle history peripheral measures of 5-HT receptor levels (5-HT2A and 5- as well as eating pattern for the past 12 months, (3) a HTT) do not correlate with central measures in healthy comprehensive assessment using structured and semi- controls. (Cho et al. 1999; Uebelhack et al. 2006; Yatham structured psychiatric interviews conducted by phone or in et al. 2000). person, and (4) a face- to-face interview and physical Psychopharmacology examination with a psychiatrist. To be considered “recov- hand drawn on the coregistered MR images by technicians ered,” subjects had to (1) maintain a weight above 85% blind to subject diagnosis and applied to the dynamic PET average body weight (Company 1959), (2) have regular data to generate time–activity curves: subgenual cingulate, menstrual cycles, and (3) have not binged, purged, or thalamus, antero-ventral striatum, dorsal caudate, and engaged in significant restrictive eating patterns for at least cerebellum (as a reference region; Bailer et al. 2005; 1 year before the study. Restrictive eating pattern was Drevets et al. 2001; Frank et al. 2005). For the dorsal defined as regularly occurring behaviors, such as restricting raphe nucleus, due to the lack of identifiable anatomic food intake, restricting high-caloric food, counting calories, boundaries on the MR, the ROI was placed directly on the and dieting. Additionally, subjects must not have used PET image in the following manner. Based on the psychoactive medication such as antidepressants or met coregistered MRs, the brain stem was subdivided into a criteria for alcohol or drug abuse or dependence, major rostral (midbrain/upper pons) and caudal region (medulla/ depressive disorder, or severe anxiety disorder within 3 pons) to approximate the dorsal and median raphe nuclei, months of the study. Ten healthy control women (CW) were respectively. A dorsal midbrain raphe nucleus was drawn recruited through local advertisements and had no history on the dynamic PET image, using circular fixed 6 mm of an ED, psychiatric or neurologic disorder, or serious radius ROIs placed over the area of highest radioactivity. medical illness. This study was conducted according to the The dorsal raphe was drawn over three contiguous planes, institutional review board regulations of the University of and the data from those three planes were sampled. The Pittsburgh, and all subjects gave written informed consent. inferior border of the dorsal raphe nucleus was identified by Blood was drawn for assessment of β-hydroxybutyrate the interpeduncular cistern on the MR. Previous imaging (BHBA), a plasma ketone body that is relatively sensitive studies of our group in EDs (Bailer et al. 2004, 2005, 2007; to reflecting the presence of starvation (Fichter et al. 1990), Frank et al. 2005) have found alterations in these ROIs and as well as for evaluation of gonadal hormone levels therefore guided our choice of brain regions to investigate (estradiol, E2). The Structured Clinical Interview for in our subjects in this study. Figure 1 shows examples of DSM-IV Axis I Disorders (First et al. 1996) was used to MR and PET image data acquired at the level of the dorsal assess the lifetime prevalence of Axis I psychiatric raphe. disorders. The ED diagnosis was made by a modified For the kinetic analyses, regional [11C]McN5652 DV version of module H of the SCID I. Current psychopathol- values were determined using a two-compartment, three- ogy was assessed with a battery of standardized instruments parameter tracer kinetic model (Lopresti et al. 2001). including the Beck Depression Inventory (BDI; Beck et al. Specific 5-HTT binding was assessed using binding 1961), the Spielberger–Trait Anxiety Inventory (STAI; potential (BP), where BP was derived as the difference Spielberger et al. 1970), the Frost Multidimensional between the ROI DV value and the cerebellar DV value,

Perfectionism Scale (MPS; Frost et al. 1990), the Eating normalized to the cerebellar DV [BP=(DVROI−DVCER)/ Disorders Inventory (EDI-2; Garner 1990)), the Yale– DVCER] (Parsey et al. 2000). Brown Obsessive Compulsive Scale (Y-BOCS; Goodman An MR-based partial volume effect correction method et al. 1989a,b), the Yale–Brown–Cornell Eating Disorder was applied to correct the PET data for the dilutional effect Scale (YBC-EDS; Mazure et al. 1994; Sunday et al. 1995), of expanded CSF spaces accompanying normal aging and the Barratt Impulsiveness Scale (BIS; Barratt and Patton disease-related cerebral atrophy (Meltzer et al. 1996, 1999). 1983), and the Temperament and Character Inventory (TCI; For the genotyping data, S and L alleles were determined Cloninger et al. 1994) for assessment of harm avoidance, using DNA amplification (polymerase chain reaction, PCR) novelty seeking, and reward dependence. and established flanking primers. Amplification products All subjects were scanned on the ECAT HR+PET were resolved by electrophoresis and visualized with scanner (CTI PET systems, Knoxville, TN) in three- ethidium bromide staining and UV transillumination, dimensional (3D) imaging mode during the first 10 days according to Edenberg and Reynolds (1998). Genotyping of the follicular phase of the menstrual cycle. Details of was performed blind to diagnosis and imaging results. PET and magnetic resonance imaging (MRI) acquisition Global BP differences were estimated by multivariate and co-registration are described elsewhere (Lopresti et al. analysis of variance (MANOVA) to explore if mean 2001). Immediately after slow bolus intravenous injection differences among the three ED groups and controls were of 13.8±1.8 mCi [11C]McN5652, dynamic emission scan- likely to occur by chance. A new linear combination ning with arterial blood sampling (input function) was consisting of all the dependent ROI’s variables (subgenual performed over 90 min. A scanning time of 90 min was cingulate, antero-ventral striatum, thalamus, dorsal caudate, used to achieve time stable measurements of distribution and dorsal raphe) controlled the experiment-wise error rate volume (DV) across regions for [11C]McN5652 (Frankle before evaluating specific regions and allowed overall et al. 2004). The following regions of interest (ROI) were assessment of global BP patterns. Multiple comparisons Psychopharmacology

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% Fig. 1 This figure is representative of a recovered anorexic women, for the L and 42% for the S allele and a genotype restricting type (REC RAN). The image is an SUV normalization of a late sum (30 to 90 min) [11C] McN5652 positron emission distribution of 29.2% LL (n=7), 58.3% SL (n=14), and tomography (PET) scan (left) and the subject’s associated coregistered 12.5% SS (n=3). CW had frequencies of 60% for the L and SPGR magnetic resonance (MR) image (right). The SUV image was 40% for the S allele and genotype frequencies of 40% LL ’ created from the late sum by division (of each pixel) by the subject s (n=4), 40% SL (n=4) and 20% SS (n=2). This small 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 number of subjects showed no significant differences in generate the PET time-activity data. DRP Dorsal raphe nucleus; CER allele or genotype frequencies between REC ED and CW. cerebellum Because of the small sample, all subjects were considered together (REC ED and CW) when compared to [11C] using the Tukey–Kramer method identified the significant McN5652 BP. The subjects with SS alleles had lower [11C] group pairs for statistically significant ANOVAs. Correla- McN5652 BP than subjects with LL alleles for the dorsal tions were examined with Pearson correlation coefficients. caudate (SS, 0.43±0.06; LL, 0.60±0.12; p=0.01), but not A repeated measures analysis of variance (ANOVAR) was other brain regions (Fig. 3). Findings were similar for the applied to examine potential group differences in radio- dorsal caudate when only the REC ED subjects were labeled metabolites of [11C]McN5652. Values are expressed considered (SS, 0.44±0.08; LL, 0.63±0.09; p=0.03). as mean±standard deviation (SD). Standard statistical software packages (SAS Version 9.1) were used. Discussion

Results This study has several major findings. First, REC RAN had elevated [11C]McN5652 BP in the dorsal raphe and antero- Demographic data and behavioral assessment data are ventral striatum in comparison to REC BAN. Furthermore, shown in Table 1. The repeated measures analysis of the REC BAN had decreased [11C]McN5652 BP in the antero- unmetabolized fraction of [11C]McN5652 (5 time points) ventral striatum in comparison to REC BN. These findings indicated no differences between the four groups over the suggest that subtypes of ED have differences in 5-HT Psychopharmacology

Table 1 Demographic values between groups

CW (n=10) REC RAN REC BAN REC BN ANOVA (n=11) (n=7) (n=9)

Mean SD Mean SD Mean SD Mean SD Sig. Group Diff.

Age (years) 27.93 6.89 24.74 5.48 23.66 4.17 24.44 5.27 0.396 Current BMI (kg/m2) 22.66 2.02 20.74 2.44 21.75 2.27 23.24 2.76 0.119 Low BMI (lifetime) (kg/m2) 20.37 1.60 13.33 (9) 2.25 15.14 1.53 18.59 1.76 <0.001 2, 3<1, 4 Age of Onset (years of age) 15.91 3.21 15.83 (6) 1.94 17.38 (8) 4.69 0.622 Length of Recovery (months) 43.36 49.52 12.00 (6) 13.56 17.13 (8) 10.16 0.143 Estradiol (pg/mL) 43.10 42.33 19.56 (9) 26.68 25.2 (5) 25.37 90.56 99.65 0.083 β-hydroxybuteric Acid (mg/dL) 0.83 0.31 0.52 (9) 0.31 0.52 (4) 0.21 1.25 (8) 1.46 0.215 Cortisol (mcg/dl) 15.00 4.67 13.78 (9) 3.87 16 (5) 2.45 16.11 6.17 0.729 EDI 2 –Drive for Thinness (“worst ever”) 0.30 0.67 18.60 (10) 4.09 18.57 3.36 19.78 1.39 <0.001 1<2, 3, 4 (Garner 1990) Perfectionism (MPS) (Frost et al. 1990) 53.80 12.26 111.82 17.10 113.43 20.32 99.11 22.03 <0.001 1<2, 3, 4 Novelty Seeking (TCI (Cloninger 1987)) 20.90 4.98 15.27 7.42 21.71 8.50 20.32 8.28 0.210 Harm Avoidance (TCI) 8.40 4.22 18.00 6.26 12.86 10.78 19.88 6.28 0.004 1<2, 4 Trait Anxiety (STAI) (Spielberger et al. 1970) 28.70 5.14 45.00 12.81 38.71 12.35 47.33 9.80 0.002 1<2, 4 Self Control (BIS (Barratt and Patton 1983)) 80.90 21.14 72.27 21.64 88.71 22.22 98.33 25.92 0.092 Yale-Brown Obsessive-Compulsive Scale (YBOCS) 0.00 0.00 4.64 6.39 8.00 (6) 8.99 11.63 (8) 10.46 0.013 1<4 (Goodman et al. 1989a,b) Yale-Brown-Cornell Eating Disorders Scale 0.30 0.95 6.18 6.62 6.67 (6) 5.79 5.88 (8) 5.06 0.034 (YBC-EDS) (Mazure et al. 1994; Sunday et al. 1995) Depression (BDI) (Beck et al. 1961) 1.50 2.27 8.36 6.82 6.00 4.97 9.11 9.84 0.063

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 a history of AN, but specific imaging data for those two these groups have differences in affective regulation and individuals were not identified. Kuikka et al. (2001) found impulse control. reduced [123I]beta-CIT binding values in subjects ill with To our knowledge, imaging studies of 5-HTT have not binge eating disorder. In addition, Steiger et al. (2005b) been done in individuals with RAN, whether ill or showed that individuals remitted from BN have reduced recovered. Other imaging studies have found reduced 5- platelet [3H]paroxetine binding. We found that reduced HTT levels in symptomatic BN subjects. Tauscher et al. [11C]McN5652 BP appeared to occur mainly in the remitted (2001) found reduced [123I]beta-CIT binding in ten indi- BAN, not the REC BN subjects. New studies, seeking to viduals who were ill with BN. Two of those individuals had replicate these findings with [11C]DASB, a more specific

Table 2 Regional [11C]McN5652 binding potential (BP) between groups

CW (n=10) REC RAN REC BAN REC BN ANOVA Uncorrected Tukey-Kramer (n=11) (n=7) (n=9) p value Multiple Comparison Mean SD Mean SD Mean SD Mean SD df F

Dorsal raphe 1.169 0.337 1.316 0.288 0.749 0.332 1.027 0.348 3.35 4.65 0.008 2>3 Antero-ventral striatum 0.743 0.129 0.835 0.117 0.549 0.236 0.767 0.133 3.35 5.19 0.004 2>3; 3<4 Thalamus 0.693 0.221 0.744 0.201 0.519 0.085 0.722 0.327 3.35 1.54 0.073 Dorsal caudate 0.526 0.129 0.553 0.137 0.575 0.180 0.565 0.155 3.35 0.19 0.882 Subgenual cingulate 0.239 0.052 0.237 0.105 0.236 0.066 0.224 0.086 3.35 0.06 0.752

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

Fig. 2 Scatterplots of the [11C] 2.0 1.2 McN5652 binding potential (BP) values in the dorsal raphe 1.8 (left plot) and antero-ventral 1.6 1.0 striatum (right plot). CW Healthy control women; REC 1.4 RAN recovered anorexic 0.8 women, restricting type; REC 1.2 BAN recovered anorexic 1.0 women, bulimic-type; REC BN 0.6 recovered bulimic women 0.8 [11C]McN 5652 BP [11C]McN 5652 BP 0.6 0.4 0.4

0.2 0.2 CW BN CW C RAN C BAN RAN C BAN RE RE REC REC RE REC BN radiotracer for a reliable quantification of 5-HTT parame- SSRIs are effective in RAN individuals (Kaye et al. 2001b; ters in regions of moderate 5-HTT density, including the Walsh et al. 2006). Our clinical experience (Kaye et al. limbic regions (Frankle et al. 2004), are in progress. 1991b) suggests that individuals with RAN respond better Still, this finding raises the possibility that these data can to fluoxetine than those with BAN did and that some be used to understand who might respond to medication. individuals with BN can be relatively insensitive to high The eating disorders are thought to share a common doses of SSRIs. There is little data determining whether vulnerability, as crossover between subtypes is common BAN and BN individuals have differential responses to (Herzog et al. 1996) and subtypes are cross-transmitted in SSRIs. While highly speculative, our findings raise the families (Kendler et al. 1995; Lilenfeld et al. 1998; Strober provocative possibility that decreased 5-HTT function may et al. 2000). However, other factors appear to differentiate be related to poor response to SSRI medication, whereas subtypes of AN and BN, including degree of weight loss, individuals with increased 5-HTT activity may respond to affect regulation, self-control, and perhaps response to higher SSRI doses. Thus, PET and radioligand studies may SSRI medication (Kaye et al. 2004). It should be noted be a useful tool for investigating and managing medication that we only studied recovered individuals with “pure” response in treatment resistant individuals. subtypes. For example, RAN individuals had never en- In general, the REC RAN individuals had elevated 5- gaged in bulimic behaviors. HTT binding, suggesting they have relatively greater 5-HT While BN individuals show a response to higher doses uptake and reduced extracellular 5-HT compared to REC of fluoxetine (Fluoxetine Bulimia Nervosa Collaborative BAN and BN. In support of this possibility, the REC BAN

Study Group 1992), the efficacy of such medication has and BN individuals tend to have higher binding of 5-HT1A been questioned, as relatively few individuals abstain from post-synaptic receptors and autoreceptors (Bailer et al. binge and purge behaviors, and relapse during treatment is 2005; Kaye et al., unpublished data), which may be a common (Walsh 1991). It remains controversial whether compensatory means of downregulating raphe activity

11 Fig. 3 Scatterplot of [ C] 0.8 0.8 McN5652 binding potential (BP) p = .01 p = .03 in the dorsal caudate in the CW and REC eating disorder sample 0.7 0.7 (left graph) and REC eating disorder only (right graph)by 0.6 0.6 5-HTLPR genotype (SS and LL only) 0.5 0.5

0.4 0.4

0.3 0.3 [11C]McN 5652 BP dorsal caudate 0.2 0.2 SS LL SS LL Genotype Genotype Psychopharmacology

(Cooper 1996; Hajos et al. 2003). Moreover, reduced 5- needed. The major limitation of the radioligand used in this HTT activity, in terms of genotypes (Steiger et al. 2005a), study is the high nonspecific binding, precluding reliable has been associated with affect dysregulation, which tends measurement of 5-HTT in the human neocortex; we to be more common in the bulimic subgroups. Furthermore, therefore restricted our ROI analysis to regions for which in people with impulsive aggressivity, reduced 5-HTT the derivation of [11C]McN5652 BP has been found reliable binding was found in the anterior cingulate cortex, a region (Parsey et al. 2000) and in which we previously found involved in affect regulation (Frankle et al. 2005). Imaging alterations. Persistent alterations in monoamine activity studies (using SPECT or PET) in other psychiatric disorders after recovery raise the question of whether this is a with altered affect regulation have revealed inconsistent premorbid vulnerability for developing ED symptoms. results. In obsessive–compulsive disorder, increased Alternatively, it is possible that chronic disturbances of (Pogarell et al. 2003), unaltered (Simpson et al. 2003), or nutrition during the ill state might contribute to a persistent decreased 5-HTT binding (Hesse et al. 2005; Stengler- “scar” in recovered individuals, caused by chronic malnu- Wenzke et al. 2004; Zitterl et al. 2007) was found. Results trition and emaciation. Patients were off medication (e.g., remain contradictory in depression as well (see Hesse et al. SSRIs) for greater than 3 months, so it is unlikely that 2004 for review). persistent effects of 5-HT active medication accounted for The functional polymorphism in the promoter region of the results. Fourteen ED subjects (3 REC RAN, 5 REC the human 5-HTT gene (SLC6A4) has been implicated in BAN, and 6 REC BN) were on SSRIs in the past. There the modulation of mood and antidepressant response was no difference in [11C]McN BP across ROIs between (Murphy et al. 2004). We included data on possible subjects who were or were not on SSRIs in the past within relationships between 5-HTTLPR and [11C]McN5652 BP, each group and within the entire group of REC ED despite our concerns that the sample was small, because of subjects. the interest in this topic. Several lines of evidence show that In summary, these data support and extend studies the genotype with two copies of the long (L, 528 bp) allele suggesting that a disturbance of 5-HTT neuronal function leads to greater 5-HT reuptake compared to genotypes persists after normalization of weight and nutritional status having either one or two copies of the short (S, 484 bp) in people who have had eating disorders. allele (Lesch et al. 1996). As 5-HTT regulates 5-HT concentrations in the synaptic cleft by recycling released Acknowledgements The authors are indebted to the participating individuals for their contribution of time and effort in support of this 5-HT, individuals with the S allele are likely to have higher study. We would like to thank W. Gordon Frankle for review of this extracellular 5-HT due to decreased 5-HT reuptake (Lesch manuscript, Eva Gerardi and Katherine Plotnicov for editorial et al. 1996; Sundaramurthy et al. 2000). In other disorders, assistance, and the University of Pittsburgh Medical Center PET relationships between 5-HTTLPR genotypes and imaging Facility staff for their invaluable contribution to this study. This study was supported by grants from National Institute of Mental Health measures of the transporter measures have been reported to (NIMH) MH46001, MH42984, K05-MD01894, NIMH Training occur (Heinz et al. 2000; Little et al. 1998) or not (Parsey Grant T32-MH18399, and the Price Foundation. U.F.B. was funded et al. 2006; Shioe et al. 2003; Willeit et al. 2001). Some, but by an Erwin-Schrödinger-Fellowship of the Austrian Science Fund not all studies, have found increased S allele frequency in (nos. J 2188 and J 2359-B02). BN and AN (Di Bella et al. 2000; Fumeron et al. 2001; Hinney et al. 1997; Lauzurica et al. 2003; Matsushita et al. References 2004; Sundaramurthy et al. 2000). The data in our study suggest that SS homozygous individuals have reduced 5- American Psychiatric Association (1994) Diagnostic and statistical HTT binding in the dorsal caudate. In individuals with BN, manual of mental disorders, 4 edn. American Psychiatric the S allele has been associated with poor response to SSRI Association therapy (Monteleone et al. 2005) and outpatient multimodal Bailer UF, Price JC, Meltzer CC, Mathis CA, Frank GK, Weissfeld L, group therapy (K. Bruce, personal communication), as well McConaha CW, Henry SE, Brooks-Achenbach S, Barbarich NC, Kaye WH (2004) Altered 5-HT2A receptor binding after recovery as greater affective instability and impulsivity (Steiger et al. from bulimia-type anorexia nervosa: relationships to harm 2005a). Together, these data further support the possibility avoidance and drive for thinness. Neuropsychopharmacology that there is a group of individuals with ED who have 29:1143–1155 decreased 5-HTT function, and these individuals may Bailer UF, Frank GK, Henry SE, Price JC, Meltzer CC, Weissfeld L, Mathis CA, Drevets WC, Wagner A, Hoge J, Ziolko SK, respond poorly to treatment. The subjects in our study McConana CW, Kaye WH (2005) Altered brain serotonin 5- were all white women, 18 to 45 years old, studied in their HT1A receptor binding after recovery from anorexia nervosa early follicular menstrual phase. Other studies have been measured by positron emission tomography and [11C] less homogenous, which may obscure potential findings. WAY100635. Arch Gen Psychiatry 62:1032 Bailer UF, Frank G, Henry S, Price J, Meltzer C, Mathis C, Wagner A, In terms of limitations, the sample size is small, and Thornton L, Hoge J, Ziolko SK, Becker C, McConaha C, Kaye replication of these findings in larger samples is clearly WH (2007) Exaggerated 5-HT1A but normal 5-HT2A receptor Psychopharmacology

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