Scientific Correspondence 7.0
6.0
6.0
5.0 4.0 3.0 2.0 1.0 0.0
p =.04 LL
LS , SS
3.0 (11C)WAY 100635 BP dorsal raphe
7.0 (11C)WAY 100635 BP pregenual cingulate
(11C)WAY 100635 BP subgenual cingulate
716
5.0 4.0 3.0 2.0 1.0 0.0
2.0
1.0
p =.05 LL
p =.94 0.0
LS , SS
LL
LS , SS
11
Figure 1 Scatter histograms with mean and standard deviation of the [ C]WAY100635 BP values for LL and LS/SS genotypes in the subgenual cingulate (left graph), the pregenual cingulate (middle graph), and the dorsal raphe (right graph) of HW. Group comparisons by Wilcoxon’s rank-sum test with Exact Sig. presented.
availability. Experimental paradigms, which involve massive manipulations of a homeostatic system in animals, have different findings. 5-HTT knockout mice show reduced density of 5-HT1A receptors in the raphe, and some nuclei of the hypothalamus, amygdala, and septum.13 Rodents chronically treated with SRIs14,15 have desensitization of 5-HT1A receptors in the raphe and hypothalamus, but not the hippocampus or cortex. Together, these data suggest that 5-HT1A receptor response is region specific and may also be influenced by gender.13,16 5-HT1A receptors and the 5-HTT are part of a complex 5-HT neuronal pathway involving many other receptors, intracellular cascades, enzymes, and other components. It is likely that different paradigms have different functional effects on these many elements that contribute to neuronal activity. Finally, in support of these findings, others have found that individuals with SS or LS genotypes exhibit greater amygdala neuronal activity in response to salient stimuli, in comparison to individuals with LL genotype.17 It is possible that an increase in 5-HT1A receptor density associated with SS/LS genotype may inhibit function of the anterior cingulate, a region that normally serves to inhibit amygdala reactivity,18 thus contributing to heightened amygdale response.
Acknowledgements This work was supported by grants from NIMH MH46001, MH42984, and K05-MD01894. UFB was funded by an Erwin–Schro¨dinger Fellowship of the Austrian Science Fund (Nos. J 2188 and J 2359-B02). M Lee1, UF Bailer2,3, GK Frank2,4, SE Henry2, CC Meltzer2,5,6, JC Price5, CA Mathis5, KT Putnam7, RE Ferrell1, AR Hariri2 and WH Kaye2 1 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; 2Department of Psychiatry, Western Psychiatric Institute and Clinic, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 3Department of General Psychiatry, Medical University of Vienna, University Hospital of Psychiatry, Vienna, Austria; 4Department of Child and Adolescent Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA; Molecular Psychiatry
5 Department of Radiology, School of Medicine, University of Pittsburgh, Presbyterian University Hospital, Pittsburgh, PA, USA; 6Department of Neurology, School of Medicine, University of Pittsburgh, Presbyterian University Hospital, Pittsburgh, PA, USA; 7Department of Environmental Health, Division of Epidemiology and Biostatistics, University of Cincinnati, Cincinnati, OH, USA
Correspondence should be addressed to WH Kaye, MD, University of Pittsburgh, School of Medicine, Department of Psychiatry, Western Psychiatric Institute and Clinic, Iroquois Building, Suite 600, 3811 O’Hara Street, Pittsburgh, PA 15213, USA. E-Mail:
[email protected]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Murphy D et al. Mol Interv 2004; 4: 109–123. Lesch K et al. Science 1996; 274: 1527–1531. Blier P, de Montigny C. Biol Psychiatry 1998; 44: 313–323. Bailer UF et al. Neuropsychopharmacology 2004; 29: 1143–1155. Meltzer CC et al. Neuropsychopharmacology 2004; 12: 2258–2265. Logan J et al. J Cereb Blood Flow Metab 2001; 21: 307–320. Parsey RV et al. J Cereb Blood Flow Metab 2000; 20: 1111–1133. Edenberg H, Reynolds J. Psychiatric Genet 1998; 8: 193–195. Gelernter J et al. Hum Genet 1997; 101: 243–246. Adell A et al. Brain Res Brain Res Rev 2002; 39: 154–180. Hajos M et al. Neuropharmacology 2003; 45: 72–81. Rumajogee P et al. Eur J Neurosci 2004; 19: 937–944. Li Q et al. J Neurosci 2000; 20: 7888–7895. Le Poul E et al. Neuropharmacology 2000; 39: 110–122. Raap DK et al. J Pharm Exp Ther 1999; 288: 561–567. Van de Kar LD et al. Neuropharmacology 2002; 43: 45–54. Hariri A et al. Science 2002; 297: 400–403. Allman J et al. Ann NY Acad Sci 2001; 935: 107–117.
Serotonin transporter polymorphism and potential response to SSRIs in bulimia nervosa Molecular Psychiatry (2005) 10, 716–718. doi:10.1038/sj.mp.4001683; published online 3 May 2005 Sir—Selective serotonin reuptake inhibitors (SSRIs), alone or in combination with different psychothera-
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pies and/or nutritional counselling, have been proved to reduce binge eating and vomiting frequencies in patients with bulimia nervosa (BN). However, percent reductions in bingeing and purging range from 18 to 87%.1 It has been suggested that the initial capacity, affinity or genotype of proteins involved in the regulation of SSRI action could account for differences in treatment outcome.2 The 5-HT transporter (5-HTT) represents the prime target of SSRIs, and a long (L) and a short (S) variant of the promoter region of the 5-HTT gene, with different transcriptional efficiencies, have been identified.3 The S allele of the 5-HTT gene-linked polymorphic region (5-HTTLPR) has been associated with poorer SSRI response in major depression.2,4–7 To test the hypothesis that the 5-HTTLPR is associated to SSRI response also in BN, we performed the screening of the 5-HTTLPR in 47 bulimic outpatients undergoing a 12-week treatment with SSRIs plus nutritional counselling in a naturalistic setting (30 patients received fluoxetine, six paroxetine, five sertraline, three fluvoxamine, two citalopram and one escitalopram). All patients were Caucasian women who met the DSM-IV criteria for BN, were older than age 18 years, were on no antidepressant medication and had not failed to respond to previous SSRI treatments. At baseline, they underwent a comprehensive clinical assessment encompassing the Structured Clinical Interviews for DSM-IV Axis I and II disorders, the Eating Disorder Inventory-2, the Bulimia Investigation Test Edinburgh, the Montgomery Asberg Depression Rating Scale, and an ad hoc structured interview collecting historical and clinical data about bulimic symptomatology. Genomic DNA was extracted from whole blood and 5-HTTLPR was analyzed by PCR amplification as previously described.8 At the end of the 12-week treatment, 32 patients (68%) had a 450% decrease in the frequency of binge–purging and were considered as responders; 21 of them (44.6%) showed a complete absence of binge– purging. One-way analysis of variance (ANOVA) showed no significant difference between responders and nonresponders in the mean daily doses of SSRIs expressed as fluoxetine equivalents (39.679.6 vs 44.6711.2 mg/day). A total of 10 patients had the SS genotype, 16 had the SL genotype and 21 had the LL genotype. Genotype frequencies were in Hardy– Weinberg equilibrium (w2 ¼ 3.68; df ¼ 1, P ¼ NS). In all, 80% of the SS subjects were nonresponders vs 37.5% of the SL patients and 0.4% of the LL subjects (w2 ¼ 17.99, df ¼ 2, P ¼ 0.0001). When, according to Lesch et al,3 we considered the S allele as dominant, nonresponders were significantly more frequent among patients carrying at least one S allele than in LL subjects (Table 1). Similarly, remission rates significantly differed among the three genotype groups (w2 ¼ 11.05, df ¼ 2, P ¼ 0.004), and the number of remitted patients was significantly higher in LL subjects than in those carrying at least one S allele (Table 1).
A total of 20 patients had at least one comorbid Axis I disorder and 27 had at least one comorbid Axis II disorder. No significant differences emerged in the frequency of comorbid Axis I (w2 ¼ 3.97, df ¼ 2, P ¼ 0.13) and Axis II disorders (w2 ¼ 3.28, df ¼ 2, P ¼ 0.19) as well as in the frequency of a past history of anorexia nervosa (w2 ¼ 1.52, df ¼ 2, P ¼ 0.46) among genotypes. The distribution of subjects with comorbid Axis I or II disorders between responders and nonresponders was statistically significant (53.1 vs 20%, w2 ¼ 4.58, df ¼ 1, P ¼ 0.03, and 68.7 vs 30%, w2 ¼ 5.24, df ¼ 1, P ¼ 002, respectively), whereas no significant differences were found in baseline nutritional, demographic and psychopathological characteristics except for the mean BMI that was significantly lower in nonresponders (22.073.8 vs 19.971.18 kg/m2; F1,45 ¼ 4.34, P ¼ 0.04). A stepwise multiple regression analysis, with response as dependent variable, and genotype, baseline BMI, past history of anorexia nervosa and comorbid Axis I or II disorders, as independent variables, showed that genotype was the only variable that significantly affected clinical outcome (MR ¼ 0.61; F1,45 ¼ 27.64, Po0.00001; R2 ¼ 0.38). This is the first study reporting that the short form of the 5-HTTLPR is significantly associated with a poorer outcome of SSRI therapy in bulimic women undergoing a naturalistic treatment. Indeed, bulimic subjects carrying at least one copy of the S allele had a 23.33-fold reduced probability to get response. Furthermore, the homozygosity for the long form of the 5-HTTLPR seems to be associated to a higher chance of remission, since patients with LL genotype had a 10.66-fold increase in the probability to get remission. These associations do not appear to be the result of pretreatment clinical or nutritional differences among patients, since neither psychiatric comorbidity, including the past history of anorexia nervosa, nor the patients’ BMI affected treatment outcome; only genotype was able to explain 38% of
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Table 1 Distribution of responder/nonresponder and remitted/nonremitted patients among 5-HTTLPR genotype groups 5-HTTLPR genotype SS/SL
LL
Total
Nonresponder patients Responder patients Total
14 12 26
1 20 21
15 32 47
Nonremitted patients Remitted patients Total
20 6 26
5 16 21
25 22 47
Responder/nonresponder patients: Fisher exact P ¼ 0.0003, odds ratio ¼ 23.33, 95% confidence interval ¼ 2.59–209.76; remitted/nonremitted patients: Fisher exact P ¼ 0.0003, odds ratio ¼ 10.66, 95% confidence interval ¼ 2.66–42.39. Molecular Psychiatry
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the variance in the patients’ response to SSRIs. The simplest explanation for such an association could be that, since subjects carrying the S allele likely have a reduced expression of the transporter protein, the decreased availability of 5-HTT at brain serotonergic synapses does not allow the SSRIs to fully express their therapeutic potential. Consistent with our results, an association between the S allele and a poorer SSRI response has been repeatedly reported in subjects with major depression.2,4–7 It is intriguing that the same 5-HTTLPR genotype is associated to a poorer SSRI response in both BN and major depression, independent of their cooccurrence. This should prompt similar studies in other psychiatric syndromes, such as panic disorder and obsessive-compulsive disorder, where SSRIs are currently used as first-line treatments, in order to investigate whether this genotype may represent a common biological background for SSRI response. Finally, because of some limitations of this study (small number of patients, assessment of clinical response on the basis of only the percent reduction in binge/vomiting frequency, lack of a placebo control group), our results need to be confirmed in future studies. If replicated, these findings could allow the
Molecular Psychiatry
clinicians to select bulimic patients who would more clearly benefit from SSRI treatment. P Monteleone1, P Santonastaso2, A Tortorella1, A Favaro2, M Fabrazzo1, E Castaldo1, L Caregaro3, A Fuschino1 and M Maj1 1 Department of Psychiatry, University of Naples SUN, Naples, Italy; 2Department of Neurosciences, University of Padua, Padua, Italy; 3Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy Correspondence should be addressed to P Monteleone, MD, Department of Psychiatry, University of Naples SUN, Largo Madonna delle Grazie, 80138 Naples, Italy. E-mail:
[email protected]
1 de Zwaan M, Roerig J. In: Maj M, Halmi K, Lopez-Ibor JJ, Sartorius N (eds). Eating Disorders. John Wiley & Son Ltd: Chichester, 2003, pp 223–285. 2 Rausch JL et al. Biol Psychiatry 2002; 51: 723–732. 3 Lesch KP et al. Science 1996; 274: 1527–1531. 4 Smeraldi E et al. Mol Psychiatry 1998; 3: 508–511. 5 Pollock BG et al. Neuropsychopharmacology 2000; 23: 587–590. 6 Zanardi R et al. J Clin Psychopharmacol 2000; 20: 105–107. 7 Arias B et al. World J Biol Psychiatry 2001; 2: 9S. 8 Deckert J et al. Psychiatr Gen 1997; 2: 45–48.
