Depressive disorders have become a widespread health concern throughout the world. The Global Burden of Disease project ranked depressive disorders fourth in terms of global burden (30). In the United States, the National Institute of Mental Health estimated the costs associated with depressive disorders at $26 billion annually. Even in individuals that do not meet the diagnostic criteria for major depression, depressive symptoms have adverse effects. Minor depression and subsyndromal depression have been associated with an increased risk of major depression, function impairment (24,41), higher rates of disability (4), and increased social dysfunction (16,17).
In addition to the escalating costs associated with treatment of depressive disorders, the accessibility and effectiveness of these treatments limit their impact. Only 55% of people afflicted with a depressive disorder are receiving treatment, whereas alleviation of depressive symptoms is seen in only 32% of those receiving treatment (1). Randomized trials have shown the effectiveness of three classes of treatment to be effective in alleviating depressive symptoms: antidepressants, psychotherapy, and electroconvulsive therapy (31). Despite the empirical evidence demonstrating the effectiveness of these treatments, response rates for antidepressants (37,46,47), psychotherapy (9), and ECT (35) indicate that a large number of individuals do not respond to these treatments. These statistics indicate the need for more cost-effective, accessible, and alternative treatments for depressive disorders. Exercise is one potential treatment that has been supported through research.
Several meta-analyses have been conducted to examine the effects of exercise on depressive symptoms (6,33). The effect sizes of these meta-analyses ranged from 0.53 to 0.88, indicating a moderate to large effect. Despite the moderate to large effect sizes, these studies can be criticized for including studies of poor methodological integrity, such as quasi-experimental trials and cross-sectional studies. Three recent meta-analyses have addressed this criticism by including only randomized controlled trials (28,36,43). With effect sizes ranging from 1.05 to 1.39 within clinical populations, these meta-analyses provide support for the use of exercise in the treatment of depression. Within the general population, an observed effect size of 0.66 (36) indicates that exercise results in a moderate decrease in depressive symptoms in nonclinical populations.
A recent trend in research has been to identify individual differences in response to treatments. One area of examination has been the difference in treatment effects across genetic polymorphisms of the serotonin transporter gene. The serotonin transporter polymorphic region (5-HTTLPR) is characterized by two alleles, long (l) and short (s) (22), and has been associated with several potential physiological mechanisms that may influence the serotonergic system. The s allele is associated with a lower transcription rate of the serotonin transporter (5-HTT) (13), a decrease in 5-HT metabolism (48), and a lower 5-HT1A receptor density and receptor binding potentials (7). These alterations within the serotonergic system could potentially increase the likelihood of depression (34). Furthermore, the s allele has been associated with a blunted response to selective serotonin reuptake inhibitors (SSRI) (39). It has been suggested that the lower transcription rates (13,22) and the decreased 5-HT binding sites (32) associated with the s allele may be responsible for this blunted response to SSRI treatment (21).
SSRI act on the serotonergic system by inhibiting 5-HTT and thus decreasing the reuptake of 5-HT from the synaptic cleft (8). SSRI treatment has been associated with decreases in platelet, plasma, serum, and whole-blood serotonin levels (10,14,18,28,29). Likewise, exercise results in a decrease in serum 5-HT (49). In addition, decreases in 5-HT2A receptors have been observed following both SSRI treatment (27) and exercise (44). Considering these similarities, it is plausible that the effect of exercise on depressive symptoms across 5-HTTLPR genotypes will be similar to that of SSRI.
The purpose of the current research was to examine the antidepressant effects of exercise across 5-HTTLPR polymorphisms. It is hypothesized that the exercise intervention will result in a decrease in depressive symptoms compared with a no-treatment control group. Considering the similar effects of SSRI and exercise on the serotonergic system, it is hypothesized that exercise will have effects similar to SSRI on depressive symptoms across 5-HTTLPR genotypes. It is therefore hypothesized that exercise will result in a greater decrease in depression scores in individuals with at least one l allele.
Participants were recruited in January 2008 from undergraduate kinesiology classes and received extra credit at their instructor's discretion for their participation. Both men and women, ages 18-23 yr, were included in the study. Before participation in the study, participants completed an informed consent form, which was approved by the university's institutional review board, and a health history questionnaire. To be eligible for participation, individuals were required to be physically able to exercise, determined by a health history questionnaire. Potential participants were excluded from the study if they were currently being treated for a psychiatric condition. To assess the effectiveness of the exercise intervention on depressive symptoms, a power analysis revealed that 60 participants are needed to achieve a power of 0.80 on the basis of an effect size d = 0.66. The effect size in the power analysis was based on a meta-analysis that estimated an effect size of d = 0.66 for an exercise intervention on depressive symptoms in a healthy population (36). However, a larger sample was recruited to guard against participant attrition and to detect the difference in effect across 5-HTTLPR genotypes. Participants received extra credit at their instructors' discretion for their participation in the study.
At pretest, participants completed the Beck Depression Inventory (BDI) (3), the Life Experiences Survey (LES) (38), and the Multidimensional Scale of Perceived Social Support (MSPSS) (51). For DNA analysis, a saliva sample was collected using the Oragene DNA Self-Collection kits (2-mL collection tubes) (DNA Genotek). A 0.5-mL aliquot was removed from each vial for isolation of genomic DNA following the manufacturer's protocol. Before amplification, purified genomic DNA was analyzed by spectroscopy and agarose gel electrophoresis to determine concentration and overall quality. Using previously described methods (11), primers for the promoter region of 5-HTT were used in a polymerase chain reaction that amplified either the long, l allele, which yields a 419-bp product (16 repeats), or the short, s allele, which yields a 375-bp product (14 repeats). Reaction conditions were as follows: 1× Pfx Amplification Buffer (Invitrogen, Carlsbad, CA), 1× PCRx Enhancer Solution (Invitrogen) 1.5 mM of MgS04, 0.3 mM of dNTPs, 0.1 μM of each primer, 50 ng of genomic DNA, and 1 U of Pfx DNA Polymerase (Invitrogen). Polymerase chain reaction was performed on a PTC-225 DNA Engine (MJ Research, Waltham, MA) after an initial denaturation step of 15 min at 95°C using 35 cycles of the following: denaturation at 94°C for 30 s, annealing at 60°C for 30 s, extension at 68°C for 40 s, followed by a final extension at 68°C for 15 min. Polymerase chain reaction products were analyzed by agarose gel electrophoresis.
After the initial data collection, individuals were randomly assigned by the lead author using a random numbers table to either an exercise intervention or a no-treatment control group. Participants selected for the exercise intervention group were required to attend three exercise sessions per week for 5 wk. Each exercise session consisted of 30 min of cycling on a stationary bicycle at 60%-70% of the age-based theoretical maximum heart rate (HRmax = 220 − age). Heart rate was monitored using 810i Polar heart rate monitors (Kempele, Finland). The exercise dose used was based on the findings of Rethorst et al. (36), who demonstrated that the greatest effect on depressive symptoms was associated with moderate intensity exercise of 30-45 min, three times per week. After the completion of the 5-wk exercise intervention, participants from both the exercise and the control groups were asked to once again complete the BDI, the MSPSS, and the LES.
After the exercise intervention, an effect size, Cohen's d, was calculated to quantify the posttest difference in BDI score between the exercise and the control groups. Cohen (5) provides criteria for categorization of effect size classifying an effect size of 0.20 as small, 0.50 as moderate, and 0.80 as large. Finally, a series of ANOVAs were conducted to examine the effects of exercise on depression within the entire population, across 5-HTTLPR genotype, and across gender. A mixed 2 × 2 (group × time) ANOVA was used to analyze the effect of the exercise intervention on depressive symptoms. A mixed 3 × 2 × 2 (genotype × exercise group × time) ANOVA was used to analyze the effect of the exercise intervention across 5-HTT genotypes. An additional 2 × 2 × 2 ANOVA was conducted with the only two genotype groups (ll/ls vs ss). After the identification of a significant three-way interaction in this analysis, a 2 × 2 (genotype × time) ANOVA was run separately for each treatment group to examine differences in treatment response across genotypes.
One hundred seventy-one participants were assessed before the intervention. The genotype frequencies were not significantly different from the Hardy-Weinberg equilibrium (χ2 = 0.058, P > 0.05), which tests for expected genotype distribution. After the preintervention assessment, 70 participants were assigned to the exercise intervention, while the remaining 101 participants were assigned to the no-treatment control group. One hundred twenty-nine participants completed the intervention phase, 64 in the control group and 65 in the exercise group. Within the exercise group, 67 of the 70 (95.7%) participants completed the exercise program; three participants did not complete the exercise program (two due to illness and one discontinued exercise without giving a reason). Furthermore, two participants that completed the exercise program failed to complete the postintervention questionnaires. Among those who completed the exercise program, participants attended an average of 11.8 exercise sessions. Of those 101 participants assigned to the no-treatment control group, 64 responded to e-mail requests for measurement at posttest (Fig. 1). There was no difference in pretest measurements between those who completed postintervention and those that did not, F(1, 100) = 1.198, P = 0.276.
Effect of exercise intervention on depression score.
Descriptive statistics for preintervention measures of depression, negative life stress events, and social support can be found Table 1. Posttest descriptive statistics are included in Table 1. Mixed 2 × 2 (group × time) ANOVAs revealed nonsignificant group × time interactions for negative life stress, F(1, 127) = 0.004, P > 0.05, and social support, F(1, 127) = 2.253, P > 0.05. The main effect for time was also nonsignificant for both negative life stress, F(1, 127) = 0.212, P > 0.05, and social support, F(1, 127) = 2.998, P > 0.05.
The two groups did not differ significantly in depression score at pretest, t(127) = 0.966, P > 0.05. The 2 × 2 (group × time) ANOVA revealed a significant interaction, F(1, 127) = 16.816, P < 0.01, indicating that the exercise group experienced a significant reduction in depression score compared with the no-treatment control group (Fig. 2). The effect size for reduction in depression (Cohen's d) was −0.62, indicating a moderate to large effect of exercise compared with the no-treatment control.
Effect of exercise on depression across 5-HTTLPR genotypes.
Descriptive statistics by genotype are included in Table 2. A mixed 3 × 2 × 2 (genotype × exercise group × time) was used to analyze the effect of the exercise intervention across 5-HTT genotypes. The three-way interaction approached significance, F(1, 124) = 2.758, P = 0.067. However, the distribution of genotypes was not consistent across the treatment groups, putting the analysis at risk because of multicollinearity. To address this concern, the ls and ll genotypes were grouped together (Table 3) because of their similar response to exercise, and an additional 2 × 2 × 2 ANOVA was conducted.
Results of the 2 × 2 × 2 ANOVA revealed a significant three-way interaction, F(1, 125) = 4.836, P = 0.030, indicating that the effect of exercise varied across genotype. To follow-up on the significant three-way interaction, a 2 × 2 (genotype × time) ANOVA was run separately for each treatment group. Within the exercise group, the ANOVA revealed a significant genotype × time interaction, F(1, 63) = 4.375, P = 0.041, indicating a significant reduction in depression symptoms in the ll/ls group compared with the ss group (partial η2 = 0.065) (Fig. 3). Within the control group, the genotype × time interaction, F(1, 62) = 1.610, P > 0.05, and the time main effect, F(1, 62) = 0.303, P > 0.05, were not significant.
As hypothesized, the exercise intervention was effective in decreasing depressive symptoms compared with a no-treatment control. The effect size of 0.62 is nearly identical with the effect size (0.66) found within the general population of a previous meta-analysis (36). Furthermore, a significant difference in the effect of the exercise intervention across 5-HTTLPR genotypes was observed, by which individuals with at least one l allele showed significant decreases in depression scores after the exercise intervention compared with the ss homozygotes.
The effect of exercise on depressive symptoms across 5-HTTLPR genotypes is similar to the effect of SSRI, in which the ss genotype has been associated with a blunted response (39). The results of the current study, along with previous research, suggest that one potential interpretation of this finding is that the physiological mechanisms responsible alleviation of depressive symptoms may be similar for exercise and SSRI treatment. Previous research has demonstrated that serum, platelet, whole blood, and plasma 5-HT is decreased after SSRI treatment (10,14,18,28,29) and an exercise intervention (47). Furthermore, both exercise (44) and SSRI (27) have been associated with decreases 5-HT2A receptors. In addition to these findings in humans, animal models further suggest similar actions of exercise and SSRI on the serotonergic system. Chronic wheel running in mice results in decreased levels of 5-HTT mRNA levels in the dorsal and medial raphe nuclei and a decrease in dorsal raphe nuclei 5-HT1B mRNA (12). Similarly, SSRI treatment is associated with a decrease in raphe 5-HTT mRNA (20,23,45) and 5-HT1B mRNA in the dorsal raphe nuclei (2,32).
Zanardi et al. (50) and Smeraldi et al. (42) have hypothesized that the blunted response to SSRI observed in the ss genotype may be due to the decreased 5-HTT expression associated with the s allele. A decrease in 5-HTT expression would lead to an increase in extracellular 5-HT, triggering self-inhibition of the 5-HT1A receptors. A similar self-inhibitory action may occur after exercise. Animal models have demonstrated an increase in 5-HT release after exercise (15). In individuals with the s allele, this increased release of 5-HT may result in a level of extracellular 5-HT that triggers self-inhibition of 5-HT1A receptors.
However, these results should be interpreted with caution considering the limitations of the present study. First, the sample size needed to detect genetic influence is often quite large. Although the sample size of the current study was sufficient to detect a significant difference across genotype groups, future studies must carefully consider sample size. Second, because of differences in genotype distribution across treatment groups, the ll and the ls genotypes were collapsed into one group for the analysis. Ideally, the analysis would be conducted using all three genotype groups leading to a better understanding of the effect of 5-HTTLPR genotype on response to exercise. In addition, care should be taken in drawing conclusions from the data on the basis of the comparatively low depression scores observed in the ss genotype in both the treatment and the control groups. Although the pretest BDI scores were not significantly different across genotypes, the relatively low depression scores in the ss genotype may result in a floor effect when examining the effect of treatment. Future research should examine the effect of exercise across 5-HTTLPR genotypes in participants with higher levels of depressive symptoms to avoid the potential influence of a floor effect. Furthermore, there is a need for research that aims to better understand the cellular mechanisms underlying the influence of 5-HTTLPR genotype on the antidepressant effects of exercise. Finally, in previous studies, attempts have been made to control for social interaction as a result of the exercise intervention (24,26,40). Although no such attempts were made in this study, the fact that posttest scores for social support were not significantly different from the pretest scores suggests that the decrease in depressive symptoms seen in the exercise group was not the result of social interaction.
Despite these limitations, the significant results of this study suggest the need for future research in the area that may result in significant implications for the treatment of depression. If the difference in response to exercise treatment across 5-HTTLPR genotypes can be replicated within a clinical population, it would support the conclusion that the mechanisms responsible for the exercise-induced alleviation of depressive symptoms are the same mechanisms responsible for decreases in depressive symptoms seen with SSRI treatment. This finding would strengthen the argument that exercise is a legitimate treatment for depressive disorders. Also, this finding would suggest that 5-HTTLPR genotype should be a factor in determining the proper line of treatment for depression, with ll and ls genotype individuals receiving exercise or antidepressant medications, whereas ss individuals would be less likely to benefit from these treatments and may be better served through psychotherapy or other alternative treatments.
This study was partially funded by a North American Society for the Psychology of Sport and Physical Activity Graduate Student Research Grant and the State of Arizona. Chad Rethorst was supported by the National Institute of Mental Health grant No. T32MH073452 during preparation of the manuscript.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
1. Andrews G, Sanderson K, Corry J, Lapsley HM. Using epidemiological data to model efficiency in reducing the burden of depression. J Ment Health Policy Econ
2. Anthony J, Sexton T, Neumaier J. Articles-antidepressant-induced regulation of 5-HT1B mRNA in rat dorsal raphe nucleus reverses rapidly after drug discontinuation. J Neurosci Res
3. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry
4. Broadhead W, Blazer D, George L, Tse C. Depression, disability days, and days lost from work in a prospective epidemiologic survey. JAMA
5. Cohen J. Statistical Power Analysis for the Behavioral Sciences
. Hillsdale (NJ): Lawrence Erlbaum.
6. Craft LL, Landers DM, Jackson SA, et al. The effect of exercise on clinical depression and depression resulting from mental illness: a meta-analysis. J Sport Exerc Psychol
7. David SP, Murthy NV, Rabiner EA, et al. A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci
8. Dechant KL, Clissold SP. Paroxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness. Drugs
9. Elkin I, Shea MT, Watkins JT, et al. National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments. Arch Gen Psychiatry
. 1989;46(11):971-82; discussion 983.
10. Figueras G, Pérez V, San Martino O, Alvarez E, Artigas F. Pretreatment platelet 5-HT concentration predicts the short-term response to paroxetine in major depression. Biol Psychiatry
11. Gelernter J, Kranzler H, Cubells JF. Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects. Hum Genet
12. Greenwood BN, Foley TE, Day HEW, et al. Wheel running alters serotonin (5-HT) transporter, 5-HT1A, 5-HT1B, and alpha1b-adrenergic receptor mRNA in the rat raphe nuclei. Biol Psychiatry
13. Heils A, Teufel A, Petri S, et al. Allelic variation of the human serotonin transporter gene expression. J Neurochem
14. Hughes CW, Petty F, Sheikha S, Kramer GL. Whole-blood serotonin in children and adolescents with mood and behavior disorders. Psychiatry Res
15. Jacobs BL. Serotonin, motor activity and depression-related disorders. Am Sci
16. Judd LL, Paulus MP. Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population. Am J Psychiatry
17. Judd LL, Rapaport MH, Paulus MP, Brown JL. Subsyndromal symptomatic depression: a new mood disorder? J Clin Psychiatry
18. Karege F, Widmer J, Bovier P, Gaillard JM. Platelet serotonin and plasma tryptophan in depressed patients: effect of drug treatment and clinical outcome. Neuropsychopharmacology
19. Lawlor DA, Hopker SW. The effectiveness of exercise as an intervention in the management of depression: systematic review and meta-regression analysis of randomised controlled trials. Br Med J
20. Le Poul E, Boni C, Hanoun N, et al. Differential adaptation of brain 5-HT1A and 5-HT1B receptors and 5-HT transporter in rats treated chronically with fluoxetine. Neuropharmacology
21. Lesch KP. Serotonergic gene expression and depression: implications for developing novel antidepressants. J Affect Disord
22. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science
23. Lesch KP, Aulakh CS, Wolozin BL, Tolliver TJ, Hill JL, Murphy DL. Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants. Brain Res Mol Brain Res
24. Lyness JM, Kim JH, Tang W, et al. The clinical significance of subsyndromal depression in older primary care patients. Am J Geriatr Psychiatry
25. McCann IL, Holmes DS. Influence of aerobic exercise on depression. J Pers Soc Psychol
26. McNeil JK, LeBlanc EM, Joyner M. The effect of exercise on depressive symptoms in the moderately depressed elderly. Psychol Aging
27. Meyer JH, Kapur S, Eisfeld B, et al. The effect of paroxetine on 5-HT2A receptors in depression: an [18F] setoperone PET imaging study. Am J Psychiatry
28. Moreno J, Campos MG, Lara C, et al. Tryptophan and serotonin in blood and platelets of depressed patients. Effect of an antidepressant treatment. Salud Ment
29. Muck-Seler D, Jakovljevic M, Deanovic Z. Effect of antidepressant treatment on platelet 5-HT content and relation to therapeutic outcome in unipolar depressive patients. J Affect Disord
30. Murray CJL, Lopez AD. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. In: Global Burden of Disease and Injury Series (Vol. 1)
. Boston: Harvard University Press; 1996. p. 1-900.
31. Nathan PE, Gorman JM. A Guide to Treatments that Work
. New York: Oxford University Press; 2007. 271-308.
32. Neumaier JF, Root DC, Hamblin MW. Chronic fluoxetine reduces serotonin transporter mRNA and 5-HT1B mRNA in a sequential manner in the rat dorsal raphe nucleus. Neuropsychopharmacology
33. North TC, McCullagh P, Tran ZVU. Effect of exercise on depression. Exerc Sport Sci Rev
34. Owens M, Nemeroff C. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem
35. Pagnin D, de Queiroz V, Pini S, Cassano GB. Efficacy of ECT in depression: a meta-analytic review. Focus
36. Rethorst CD, Wipfli BM, Landers DM. The antidepressive effects of exercise: a meta-analysis of randomized trials. Sports Med
37. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med
38. Sarason IG, Johnson JH, Siegel JM. Assessing the impact of life changes: development of the Life Experiences Survey. J Consult Clin Psychol
39. Serretti A, Kato M, De Ronchi D, Kinoshita T. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry
40. Singh N, Clements K, Fiatarone M. A randomized controlled trial of progressive resistance training in depressed elders. J Gerontol A Biol Med Sci
41. Skodol A, Schwartz S, Dohrenwend B, Levav I, Shrout P. Minor depression in a cohort of young adults in Israel. Arch Gen Psychiatry
42. Smeraldi E, Zanardi R, Benedetti F, Bella DD, Perez J, Catalano M. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry
43. Stathopoulou G, Powers MB, Berry AC, Smits JAJ, Otto MW. Exercise interventions for mental health: a quantitative and qualitative review. Clin Psychol
44. Struder HK, Hollman W, Platen P, Wostmann R, Weicker H, Molderings GH. Effect of acute and chronic exercise on plasma amino acids and prolactin concentrations and on [3H] ketanserin binding to 5-HT2A receptors on human platelets. Eur J Appl Physiol
45. Swan MC, Rahman NA, Bennett JP. Expression of serotonin transporter mRNA in rat brain: Presence in neuronal and non-neuronal cells and effect of paroxetine. J Chem Neuroanat
46. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med
47. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry
48. Williams RB, Marchuk DA, Gadde KM, et al. Central nervous system serotonin function and cardiovascular response to stress. Psychosom Med
49. Wipfli B, Landers D. An examination of serotonin and psychological variables in the relationship between exercise and mental health. Scand J Med Sci Sports
. in press.
50. Zanardi R, Benedetti F, Daniela Di Bella MD, Catalano M, Smeraldi E. Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol
51. Zimet GD, Dahlem NW, Zimet SG, Farley GK. The Multidimensional Scale of Perceived Social Support. J Pers Assess
Keywords:©2010The American College of Sports Medicine
PHYSICAL ACTIVITY; DEPRESSION; SEROTONIN TRANSPORTER GENE; NEGATIVE LIFE STRESS