SEARCH

SEARCH BY CITATION

Keywords:

  • 5-HTTLPR;
  • depression;
  • bulimia;
  • binging;
  • adolescents

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Earn CE credit for this article!
  9. References

Objective

Depression and bulimia both are associated with low serotonin levels. We examined whether the serotonin transporter gene (5-HTTLPR) moderates the relation between depressive and bulimic symptoms over time.

Method

Fifty adolescent girls with no current or past Axis I disorder were genotyped for the 5-HTTLPR gene. Twice, 6 months apart, participants completed self-report measures of depressive symptoms and bulimic symptoms.

Results

The association between change in depressive symptoms and change in bulimic symptoms over time was significantly stronger in girls who are homozygous for the short 5-HTTLPR allele than for girls with at least one long allele.

Discussion

This finding is consistent with previous studies documenting a relation between depressive and bulimic symptoms in adolescents. Few studies, however, considered the possible role of serotonin linking both disorders. Gaining a better understanding of developmental effects of low serotonin could help to identify high-risk individuals and provide effective prevention and intervention. © 2010 by Wiley Periodicals, Inc. Int J Eat Disord 2011


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Earn CE credit for this article!
  9. References

Depressive symptoms in adolescence have been shown to predict eating disorders, such as binge eating1 and bulimia.2, 3 Importantly, investigators have demonstrated that serotonin, a monoamine neurotransmitter, plays a critical role in both depression and bulimia. For example, studies showed decreased serotonin transporter binding in the midbrain in both obese women with binge eating disorder4 and suicide victims with major depression.5 Moreover, several investigators have documented anomalous serotonin activity in patients with eating disorders (e.g., Refs. 6, 7 for reviews), mirroring the low levels of serotonin that have been found to be associated with depression.8, 9 In fact, acute perturbation of serotonergic tone by dietary depletion of tryptophan, an amino acid that synthesizes serotonin (5-HT), has been linked to increased food intake and mood irritability in individuals with bulimia nervosa.6 Finally, treatments that decrease serotonin activity have been found to increase the likelihood of binge eating in both animals10 and humans (e.g., Refs. 11, 12), whereas medications that increase serotonin activity, such as selective serotonin uptake inhibitors have been demonstrated to be effective in the treatment of both bulimia13 and depression.14

Both expression of the serotonin transporter (5-HTT) and serotonin uptake are reduced in individuals who carry a short (s) allele of the serotonin transporter gene (5-HTTLPR), compared to long-allele homozygotes (l/l; Ref. 15). The 5-HTTLPR s allele has been associated both with bulimia symptoms and disorder16, 17 (although see also Ref. 18) and with depression symptoms and disorder (Refs. 19, 20 for a review, but see Ref. 21 for a recent meta-analysis, and, Ref. 22 for a commentary). Perhaps not surprisingly, therefore, a number of investigators have documented significant comorbidity between depression and bulimia (e.g., Refs. 23, 24); fewer studies, however, have attempted to examine mechanisms that may underlie this association.

The present study was designed to gain a better understanding of the role of 5-HTTLPR in both depressive and bulimic symptoms by examining their association over time. Using a longitudinal design, we assessed the temporal dynamics between symptoms of depression and symptoms of bulimia and examined the moderating influence of the 5-HTTLPR gene. We assessed adolescent girls because adolescence is a critical developmental period that is associated with the onset of a number of psychiatric disorders, including depression and bulimia. Approximately twice as many females as males experience depression,25 and the ratio for eating disorders is even more extreme: adolescent girls are 30 times more likely than are boys to develop bulimia.26 To ensure that the obtained results were not confounded by a history of either clinically significant depression or bulimia, we included in this study only girls who, on structured interview, were free of current or past diagnosable psychopathology. We examined whether change in depressive symptoms is associated with change in bulimic symptoms, and whether this association is stronger in girls who carry a 5-HTTLPR s allele than it is in their homozygous l-allele counterparts. We predicted that a greater increase in depressive symptoms would be associated with a greater increase in bulimic symptoms for girls with one or two s alleles than for girls who are homozygous for the l allele.

Method

  1. Top of page
  2. Abstract
  3. Introduction
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Earn CE credit for this article!
  9. References

Participants were 50 girls between 10 and 16 years (M = 13.9, SD = 1.9) with no current or past history of Axis I disorder. Thirty-five of the girls self-identified as Caucasian, four as Hispanic, seven as Asian American, and four as bi-racial. They were recruited (through their mothers) using advertisements in newspapers and via the internet, and were paid for participating. The mean body mass index (BMI; kg/m2) for the 20 daughters who gave their height and weight was in the normal range (M = 19.5, SD = 2.9); eight of the girls had a BMI lower than 18.5 and, therefore, would be considered underweight, and one girl had a BMI over 25 (BMI = 26.3) and would be considered overweight.

The Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL)27 was used to confirm that girls had no current or lifetime diagnosable psychopathology. In addition, depressive symptoms were assessed with the 10-item version of the Children's Depression Inventory (CDI-S).28 For 10 groups of 3 statements each (e.g., “I am sad once in a while,” “I am sad many times,” “I am sad all the time”), participants are asked to mark the statement that describes them best. Bulimic symptoms were measured at the same times as the CDI-S with the Eating Disorders Inventory for children and adolescents (EDI-C),29 using the items of the factor overeating based on the validated factor structure for this instrument.30 The overeating factor correlates highly (r = .96) with the bulimia scale of the Eating Disorders Inventory for adults30; therefore, we refer to the construct it measures as “bulimic symptoms” throughout the manuscript. The eight items on this factor assess thoughts of engaging in bouts of uncontrollable eating or vomiting (e.g., “I have gone on eating binges where I have felt that I could not stop,” “I have the thought of trying to vomit in order to lose weight”). Both the CDI-S and the EDI-C were administered twice, 6 months apart, using the software dynQuest.31 Cronbach's α for the CDI-S at the first measurement point was α = 0.61 and α = 0.75 at the second measurement occasion; reliability for the EDI-C subscale at the first assessment was α = 0.77 and α = 0.84 at the second assessment.

Participants were genotyped from saliva collected using the Oragene Kit32 an all-in-one system for the collection, preservation, transportation, and purification of DNA from saliva. Oligonucleotide primers flanking the 5-HTT-linked polymorphic region33 and corresponding to the nucleotide positions −1416 to −1397 (stpr5, 5′-GGC GTT GCC GCT CTG AAT GC) and −910 to −888 (stpr3, 5′-GAG GGA CTG AGC TGG ACA ACC AC) of the 5-HTT gene 5′-flanking regulatory region were used to generate 484-bp or 528-bp fragments. The polymerase chain reaction products were electrophoresed through 5% polyacrylamide gel (Acrylamide/bis-Acrylamide ratio 19:1) at 60 V for 60 min. Fourteen of the 50 girls were homozygous for the l allele (l/l genotype), 14 were homozygous for the s allele (s/s genotype), and 22 were heterozygous (s/l genotype). The allele frequencies of 5-HTTLPR were in the Hardy–Weinberg equilibrium, χ2(2,50) = 0.50, p = .78a.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Earn CE credit for this article!
  9. References

For the full sample, CDI-S scores ranged from 0 to 7 (M = 1.20, SD = 1.59) at the first assessment and from 0 to 10 (M = 1.84, SD = 2.17) at the second assessment. The mean CDI-S score at both time points was well below a score of 10, the recommended cut-off for possible depression.28 Twenty girls had higher CDI-S scores at the second assessment than at the first assessment (difference range = 1–7; M = 2.40, SD = 1.73), 22 girls had the same CDI-S score at both assessments, and eight girls had lower scores at the second assessment (difference range = 1–4; M = 2.0, SD = 1.20).

The scores for the bulimic symptoms ranged from 1 to 4 (M = 1.77, SD = 0.66) on a 6-point scale from 1 = never to 6 = always at the first assessment and from 1 to 4.5 (M = 1.84, SD = 0.73) at the second measurement point, indicating that, on average, the girls have low bulimic symptoms. Twenty-six girls had higher scores at the second assessment than they did at the first assessment (difference range = 0.13 to 1.38; M = 0.43, SD = 0.33), seven girls did not change, and 17 girls had lower scores at the second assessment (difference range = 0.13 to 1.00; M = 0.44, SD = 0.29). Change scores for both CDI-S and EDI-C were calculated as the standardized residual from regressing T2 scores on T1 scores. This procedure is preferable to using difference scores, which often lead to overcorrection of the postscore by the prescore.34

The three 5-HTTLPR genotype groups did not differ in age, change in depressive symptoms, or change in bulimic symptoms (see Table1 for means and standard deviations). To examine whether the 5-HTTLPR polymorphism moderated the relation between change in depressive symptoms and change in bulimic symptoms, we conducted an analysis of variance (ANOVA) on change in bulimic symptoms with 5-HTTLPR genotype group (s/s, s/l, l/l) and change in depressive symptoms as predictor variables. Throughout the analyses, change in depressive symptoms was used as a continuous variable. Neither genotype group, F(2,44) = 1.76, p = .19, nor change in depressive symptoms, F(1,44) = 3.23, p = .08, individually predicted change in bulimic symptoms. The interaction of these two variables, however, significantly predicted change in bulimic symptoms, F(2,44) = 4.15, p = .02, indicating that change in depressive symptoms had differential effects on change in bulimic symptoms as a function of genotype group.

Table 1. Means and standard deviations in age, change in depressive symptoms, and change in bulimic symptoms for the three 5-HTTLPR genotype groups (l/l, s/l, s/s)
 l/ls/ls/sResults of ANOVA
  1. Notes: T1, time 1 assessment; T2, time 2 assessment; change between T1 and T2 was calculated as the standardized residual from regressing T2 scores on T1 scores.

Age at T1 in years, Mean (SD)13.6 (2.06)14.1 (1.98)13.9 (1.56)F(2, 47) = 0.30, p = .74
Change in depressive symptoms T1-T2, Mean (SD)−0.18 (0.77)0.06 (0.89)0.06 (1.15)F(2, 47) = 0.35, p = .71
Change in bulimic symptoms T1-T2, Mean (SD)−0.36 (1.00)0.07 (0.62)0.25 (1.36)F(2, 47) = 1.46, p = .24

To examine which of the genotype groups differed from the others in its association with the relation between change in bulimic symptoms and change in depressive symptoms, we conducted three pairwise group comparisons, again conducting ANOVAs with change in bulimic symptoms as the dependent variable and 5-HTTLPR group, change in depressive symptoms, and their interaction as independent variables. The results of these analyses indicated that girls who are homozygous for the s allele differed significantly from girls in the other two genotype groups with respect to the interaction of 5-HTTLPR genotype and change in depressive symptoms (heterozygous girls: F(1,32) = 5.22, p = .03; homozygous l-allele girls: F(1,24) = 4.87, p = .04); the heterozygous girls did not differ significantly from the homozygous l-allele girls, F(1,32)=1.12, p = .30. Neither of the main effects of genotype group or the change in depressive symptoms was significant in any of the three ANOVAs.

These analyses indicate that the association between change in depression and change in bulimic symptoms is different for girls who are homozygous for the s allele than it is for girls with at least one l allele. Computing the strength of the association between these two variables in the three groups of girls yielded correlations of r = .68, p = .01, for s-allele homozygotes, r = .25, p = .26, for heterozygous girls, and r = −.15, p = .61, for girls homozygous for the l allele (see Fig.1). Thus, girls with two s alleles experienced a stronger relation between depressive symptoms and bulimic symptoms than did girls with at least one l allele.

thumbnail image

Figure 1. Change in depressive symptoms (standardized residuals) and change in bulimic symptoms (standardized residuals) between the first (T1) and second (T2) assessment by 5-HTTLPR polymorphism.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Earn CE credit for this article!
  9. References

This study was designed to examine whether the 5-HTTLPR genotype moderates the relation between change in depressive and bulimic symptoms. Consistent with our hypothesis, we found that an increase in depressive symptoms over time was more strongly associated with an increase in bulimic symptoms for girls who have two 5-HTTLPR s alleles than it was for girls who have at least one l allele. It is noteworthy that although girls with s/l and l/l genotypes had a weaker association between change in depressive symptoms and bulimic symptoms than did homozygous s-allele carriers, their magnitude of association did not differ significantly from each other. Although this finding could be due to low power associated with the relatively small sample size, it is also possible that s/l carriers are less vulnerable to life stressors that might initiate or exacerbate depressive symptoms and bulimic symptoms. Indeed, this formulation is consistent with Kendler et al.'s35 finding that individuals with two copies of the s allele were more likely than were their counterparts with two l alleles to become depressed in response to “common low-threat events,” and with Gotlib et al.'s36 finding that girls who were homozygous for the s allele produced higher and more prolonged levels of cortisol in response to a laboratory stressor than did girls with either one or two l alleles.

Our finding of an association between depressive and bulimic symptoms over time is consistent with the results of a number of studies that have documented a relation between depressive and bulimic symptoms in adolescents, both cross-sectionally and longitudinally (e.g., Refs. 23, 37). Few investigators, however, have considered the possible role of serotonin linking both disorders. By examining the serotonin transporter gene polymorphism, we were able to identify a group of individuals that appears to be particularly vulnerable to experiencing comorbidity of bulimia and depression. It is noteworthy that we found that 5-HTTLPR moderates the association between depressive and bulimic symptoms over time in adolescents who had no clinically significant symptoms of either disorder. The significantly stronger link between symptoms of these two disorders in adolescents with two s alleles and, thus, the lowest serotonin uptake, is especially important in attempting to gain a better understanding of the development of this comorbidity, for example, by considering reduced serotonin as a plausible common underlying mechanism.

We were not able in this study to examine statistically the issue of directionality of symptom change, that is, whether depressive symptoms lead to symptoms of bulimia or vice versa. Studies examining this issue have yielded inconsistent findings. Whereas some studies have found that adolescent girls with bulimic symptoms are more likely than are girls without bulimic symptoms to develop depression 4 years later,38, 39 the results of other investigations indicate that depressive symptoms or negative affect can precede bulimic pathology40, 41 and an increase in bulimic symptoms,2, 3 and still other studies have reported a reciprocal relation between symptoms of depression and bulimic symptoms.42 Given the finding in the present study that the relation between change in depressive symptoms and change in bulimic symptoms over a 6-month period is moderated by the 5-HTTLPR gene, it will be important in future research to examine longitudinally the role of serotonin and the serotonin transporter gene in the development, and comorbidity of depression and bulimia. Moreover, given the current debate about the reliability of the interaction of 5-HTTLPR and life stress in predicting depression (e.g., Refs. 21, 43), it will also be important in future research to replicate the present findings concerning the role of the 5-HTTLPR gene in moderating the interaction of changes in depressive and bulimic symptoms.

In this study we examined individuals at high risk for both depression and bulimia—adolescent girls. Our results suggest that serotonin is relevant in understanding the co-occurrence of these disorders. It is particularly noteworthy that the effects of the 5-HTTLPR s/s genotype on the strength of association between bulimic and depressive symptoms over time were evident at subclinical symptom levels in participants without past or current diagnosable psychopathology. Given, however, that subsyndromal depressive symptoms have been found to be associated with impaired psychosocial functioning (e.g., Ref. 44) and to predict the subsequent onset of Major Depressive Disorder (e.g., Ref. 45), it is likely that our findings obtained with individuals experiencing subsyndromal levels of symptoms are relevant for clinical populations as well. Elucidating the developmental effects of lower serotonin on depressive symptoms and risk factors for bulimia nervosa, such as binge eating, will be important in the early identification of groups at risk for these disorders, and in providing effective treatment for affected individuals.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Earn CE credit for this article!
  9. References

The authors thank Kirsten Gilbert, Yamanda Wright, Jutta Joormann, Ewart Thomas, Susanne Scheibe, Rui Mata, and Joachim Hallmayer for their help with this study.

Earn CE credit for this article!

  1. Top of page
  2. Abstract
  3. Introduction
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Earn CE credit for this article!
  9. References

Visit: http://www.ce-credit.com for additional information. There may be a delay in the posting of the article, so continue to check back and look for the section on Eating Disorders. Additional information about the program is available at www.aedweb.org

  1. 1

    Recently, investigators have suggested that a polymorphism (rs25531) modulates the functionality of 5-HTTLPR, leading to a recoding of the 5-HTTLPR long alleles into LA and LG. The LG variant and the s-allele have similar levels of 5-HTT mRNA expression, and both are lower than that of LA (Wendland et al., 2006). It is not known, however, whether the in vitro differences in 5-HTT expression are also responsible for the differences in the gene-environment interaction encountered at the population level; thus, it is unclear whether the recoding of the 5-HTTLPR is warranted (for a review, see Uher and McGuffin, 2008). Forty-six of the girls in our study were genotyped for these subtypes of the long allele (LA and LG); seven girls were homozygous for the high-expressing LA allele, 22 girls had either one copy of the s-allele or the low-expressing LG allele and one copy of the LA allele, and 17 girls had two s-alleles, one s-allele and one LG allele, or two LG alleles. Given the small number of girls in the homozygous LA group and the resultant low statistical power, it is difficult to obtain reliable group differences. Nevertheless, graphing the relations in these three groups between the change in depressive symptoms and change in bulimic symptoms over 6 months yields a figure identical to that presented in Figure 1.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Earn CE credit for this article!
  9. References
  • 1
    Stice E,Presnell K,Spangler D. Risk factors for binge eating onset in adolescent girls: A 2-year prospective investigation. Health Psychol 2002; 21: 131138.
  • 2
    Cooley E,Toray T. Body image and personality predictors of eating disorder symptoms during the college years. Int J Eat Disord 2001; 30: 2836.
  • 3
    Stice E. A prospective test of the dual-pathway model of bulimic pathology: Mediating effects of dieting and negative affect. J Abnorm Psychol 2001; 110: 124135.
  • 4
    Kuikka JT,Tammela L,Karhunen L,Rissanen A, Bergström KA, Naukkarinen H, et al. Reduced serotonin transporter binding in binge eating women. Psychopharmacology 2001; 155: 310314.
  • 5
    Stockmeier CA,Shapiro LA,Dilley GE,Kolli TN,Friedman L,Rajkowska G. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression—Postmortem evidence for decreased serotonin activity. J Neurosci 1998; 18: 73947401.
  • 6
    Kaye WH,Frank GK,Bailer UF,Henry SE, Meltzer CC, Price JC, et al. Serotonin alterations, in anorexia and bulimia nervosa: New insights from imaging studies. Physiol Behav 2005; 85: 7381.
  • 7
    Steiger H. Eating disorders and the serotonin connection: State, trait and developmental effects. J Psychiatry Neurosci 2004; 29: 2029.
  • 8
    Meltzer H. Serotonergic dysfunction in depression. Br J Psychiatry 1989; 8 ( Suppl): 2531.
  • 9
    Placidi GPA,Oquendo MA,Malone KM,Huang YY,Ellis SP,Mann JJ. Aggressivity, suicide attempts, and depression: Relationship to cerebrospinal fluid monoamine metabolite levels. Biol Psychiatry 2001; 50: 783791.
  • 10
    Blundell JE. Serotonin manipulations and the structure of feeding behaviour. Appetite 1986; 7: 3956.
  • 11
    Leibowitz SF,Alexander JT. Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Biol Psychiatry 1998; 44: 851864.
  • 12
    Silverstone T,Goodall E. Serotoninergic mechanisms in human feeding: The pharmacological evidence. Appetite 1986; 7: 8597.
  • 13
    Kaye W,Strober M,Jimerson D. The neurobiology of eating disorders. In: CharneyDS,NestlerEJ, editors. The Neurobiology of Mental Illness. New York: Oxford Press, 2004, pp. 11121128.
  • 14
    Thase ME. Are SNRIs more effective than SSRIs? A review of the current state of the controversy. Psychopharmacol Bull 2008; 41: 5885.
  • 15
    Lesch KP,Bengel D,Heils A,Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 15271531.
  • 16
    Di Bella D,Catalano M,Cavallini MC,Riboldi C,Bellodi L. Serotonin transporter linked polymorphic region in anorexia nervosa and bulimia nervosa. Mol Psychiatry 2000; 5: 233234.
  • 17
    Steiger H,Joober R,Israël M,Young SN,Ng Ying Kin NMK,Gauvin L, et al. The 5HTTLPR polymorphism, psychopathologic symptoms, and platelet [3H-] paroxetine binding in bulimic syndromes. Int J Eat Disord 2005; 37: 5760.
  • 18
    Lee Y,Lin P-Y. Association between serotonin transporter gene polymorphism and eating disorders: A meta-analytic study. Int J Eat Disord 2009 Aug 25; [Epub ahead of print (DOI: 10.1002/eat.20732)].
  • 19
    Caspi A,Sugden K,Moffitt TE,Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 2003; 301: 386389.
  • 20
    Uher R,McGuffin P. The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: Review and methodological analysis. Mol Psychiatry 2008; 13: 131146.
  • 21
    Risch N,Herrell R,Lehner T,Liang KY, Eaves L, Hoh J, et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression a meta-analysis. JAMA 2009; 301: 24622471.
  • 22
    Rutter M,Thapar A,Pickles A. Gene-environment interactions: Biologically valid pathway or artifact? Arch Gen Psychiatry 2009; 66: 12871289.
  • 23
    Lewinsohn PM,Striegel-Moore RH,Seeley JR. Epidemiology and natural course of eating disorders in young women from adolescence to young adulthood. J Am Acad Child Adolesc Psychiatry 2000; 39: 12841292.
  • 24
    Santos M,Richards CS,Bleckley MK. Comorbidity between depression and disordered eating in adolescents. Eat Behav 2007; 8: 440449.
  • 25
    Kessler RC,Wang PS. The epidemiology of depression. In: GotlibIH,HammenCL, editors. Handbook of Depression,2nd ed. New York: Guilford Press, 2009, pp. 522.
  • 26
    Nicholls D,Viner R. Eating disorders and weight problems. BMJ 2005; 330: 950953.
  • 27
    Kaufman J,Birmaher B,Brent DA,Ryan ND,Rao U. K-Sads-Pl. J Am Acad Child Adolesc Psychiatry 2000; 39: 1208.
  • 28
    Kovacs M. The Children's Depression Inventory (CDI). Psychopharmacol Bull 1985; 21: 9951124.
  • 29
    Garner DM. Eating Disorders Inventory-C. Lutz,FL: Psychological Assessment Resources, 1991.
  • 30
    Eklund K,Paavonen EJ,Almqvist F. Factor structure of the Eating Disorder Inventory-C. Int J Eat Disord 2005; 37: 330341.
  • 31
    Rademacher JDM,Lippke S. Dynamic online surveys and experiments with the free open-source software dynQuest. Behav Res Methods 2007; 39: 415426.
  • 32
    DNA Genotek Inc.: Ontario, Canada.
  • 33
    Heils A,Teufel A,Petri S,Stöber G, Riederer P, Bengel D, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66: 26212624.
  • 34
    Cohen J,Cohen P,West SG,Aiken LS. Applied Multiple Regression/Correlation Analysis for the Behavioral Sciences, 3rd ed. Mahwah, NJ: Lawrence Erlbaum Associates, 2003.
  • 35
    Kendler KS,Kuhn JW,Vittum J,Prescott CA,Riley B. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression. Arch Gen Psychiatry 2005; 62: 529535.
  • 36
    Gotlib IH,Joormann J,Minor KL,Hallmayer J. HPA axis reactivity: A mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol Psychiatry 2008; 63: 847851.
  • 37
    Zaider TI,Johnson JG,Cockell SJ. Psychiatric comorbidity associated with eating disorder symptomatology among adolescents in the community. Int J Eat Disord 2000; 28: 5867.
  • 38
    Stice E,Hayward C,Cameron RP,Killen JD,Taylor CB. Body-image and eating disturbances predict onset of depression among female adolescents: A longitudinal study. J Abnorm Psychol 2000; 109: 438444.
  • 39
    Seeley JR,Stice E,Rohde P. Screening for depression prevention: Identifying adolescent girls at high risk for future depression. J Abnorm Psychol 2009; 118: 161170.
  • 40
    Killen JD,Taylor CB,Hayward C,Haydel KF,Wilson DM,Hammer L, et al. Weight concerns influence the development of eating disorders: A 4-year prospective study. J Consult Clin Psychol 1996; 64: 936940.
  • 41
    Stice E,Agras WS. Predicting onset and cessation of bulimic behaviors during adolescence: A longitudinal grouping analysis. Behav Ther 1998; 29: 257276.
  • 42
    Stice E,Burton EM,Shaw H. Prospective relations between bulimic pathology, depression, and substance abuse: Unpacking comorbidity in adolescent girls. J Consult Clin Psychol 2004; 72: 6271.
  • 43
    Caspi A,Hariri AR,Holmes A,Uhre R,Moffitt TE. Genetic sensitivity to the environment: The case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 2010; AiA: 119.
  • 44
    Judd LL,Paulus MP,Wells KB,Rapaport MH. Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population. Am J Psychiatry 1996; 153: 14111417.
  • 45
    Cuijpers P,Smit F. Subthreshold depression as a risk indicator for major depressive disorder: A systematic review of prospective studies. Acta Psychiatr Scand 2004; 109: 325331.
  • 46
    Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL. Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry 2006; 11: 224226.