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Original Article |

A Prospective Cohort Study Investigating Factors Associated With Depression During Medical Internship FREE

Srijan Sen, MD, PhD; Henry R. Kranzler, MD; John H. Krystal, MD; Heather Speller, MD; Grace Chan, PhD; Joel Gelernter, MD; Constance Guille, MD
[+] Author Affiliations

Author Affiliations: Department of Psychiatry, University of Michigan, Ann Arbor (Dr Sen); Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (Drs Sen, Krystal, Speller, Gelernter, and Guille); Departments of Psychiatry and Genetics and Developmental Biology, University of Connecticut School of Medicine, Farmington (Drs Kranzler and Chan); and Department of Psychiatry, Medical University of South Carolina, Charleston (Dr Guille).


Arch Gen Psychiatry. 2010;67(6):557-565. doi:10.1001/archgenpsychiatry.2010.41.
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Published online

Context  Although the prevalence of depression among medical interns substantially exceeds that of the general population, the specific factors responsible are not well understood. Recent reports of a moderating effect of a genetic polymorphism (5-HTTLPR) in the serotonin transporter protein gene on the likelihood that life stress will precipitate depression may help to understand the development of mood symptoms in medical interns.

Objectives  To identify psychological, demographic, and residency program factors that are associated with depression among interns and to use medical internship as a model to study the moderating effects of this polymorphism.

Design  A prospective cohort study.

Setting  Thirteen US hospitals.

Participants  Seven hundred forty interns entering participating residency programs.

Main Outcome Measures  Subjects were assessed for depressive symptoms using the 9-item Patient Health Questionnaire (PHQ-9), a series of psychological traits, and the 5-HTTLPR genotype prior to internship and then assessed for depressive symptoms and potential stressors at 3-month intervals during internship.

Results  The PHQ-9 depression score increased from 2.4 prior to internship to a mean of 6.4 during internship (P < .001). The proportion of participants who met PHQ-9 criteria for depression increased from 3.9% prior to internship to a mean of 25.7% during internship (P < .001). A series of factors measured prior to internship (female sex, US medical education, difficult early family environment, history of major depression, lower baseline depressive symptom score, and higher neuroticism) and during internship (increased work hours, perceived medical errors, and stressful life events) was associated with a greater increase in depressive symptoms during internship. In addition, subjects with at least 1 copy of a less-transcribed 5-HTTLPR allele reported a greater increase in depressive symptoms under the stress of internship (P = .002).

Conclusions  There is a marked increase in depressive symptoms during medical internship. Specific individual, internship, and genetic factors are associated with the increase in depressive symptoms.Published online April 5, 2010 (doi:10.1001/archgenpsychiatry.2010.41).

Figures in this Article

Internship is known to be a time of high stress.1,2 New physicians are faced with long work hours, sleep deprivation, loss of autonomy, and extreme emotional situations.3 A series of cross-sectional studies has examined the prevalence of significant depressive symptoms among interns. Although the proportion of interns who screen positive for major depression varied markedly across these studies (7%-49%), most studies found rates of major depression among interns to be higher than the rates found in the general population (4%-5%).2,414

Prospective, longitudinal studies are necessary to understand the factors underlying the development of depression among interns. Prospective studies of depression during internship to date have yielded inconsistent findings; some studies reported that factors such as female sex, neuroticism, and medical errors were associated with increased depression, but other studies failed to replicate these results.12,1522 A review of these studies concluded that it is difficult to draw firm conclusions because each of the studies had significant limitations.23 Most notably, the studies enrolled relatively small samples that were restricted to individual residency programs or institutions and suffered from high attrition rates and short follow-up periods.23 Furthermore, many potentially important factors, such as work hours and social support, have not been well explored in internship depression. We report herein on the largest longitudinal study to date of a sample of interns drawn from multiple institutions and specialties over a 14-month period. It aims to identify factors associated with the development of depression during internship.

Genetic epidemiological studies indicate that in addition to life stressors, genetic factors play a major role in the etiology of depression.24 The gene most extensively investigated in depression is SLC6A4, which encodes the serotonin transporter protein. The serotonin transporter is a transmembrane protein located on the presynaptic membrane of serotonergic neurons. It is a major target of many common antidepressant medications, such as selective serotonin reuptake inhibitors and tricyclic antidepressants.

Caspi and colleagues25 reported an interaction between a functional promoter polymorphism at this locus (5-HTTLPR) and life stress in the development of depression. They found that among subjects who experienced no life stressors, 5-HTTLPR was not associated with depressive symptoms. As the number of stressful life events reported by subjects increased, however, subjects with at least 1 copy of the less transcriptionally active (low-functioning) 5-HTTLPR short (S) allele reported significantly more depressive symptoms than subjects with 2 copies of the high-functioning 5-HTTLPR long (L) allele. To date, there have been (at least) 37 follow-up studies, with some studies supporting the presence of an interaction and others not.

Two recent meta-analyses have assessed a subset of these studies and concluded that there is no evidence supporting the presence of the interaction.26,27 It is important to note, however, that these meta-analyses have important limitations. First, in contrast to traditional genetic association studies, there is marked variation in study design among studies examining this interaction. Both meta-analyses were heavily weighted toward large studies in which stressful events were not well assessed, while discounting studies with more comprehensive assessments of stress that necessarily used smaller samples. Furthermore, even the larger of the 2 meta-analyses was able to include only 14 of the 38 published studies that examined the association between 5-HTTLPR, stress, and depression. The vast majority of the studies excluded by the meta-analysis reported that the presence of the 5-HTTLPR S allele increased the risk of depression under stress, suggesting that it is premature to draw definitive conclusions about the presence or absence of this interaction from these meta-analyses.2847

The inconsistency among studies to date may be due in part to methodological limitations of some of these studies.48 First, most of the studies assessed stressful life events and depressive symptoms retrospectively and concurrently. For some studies, subjects were asked to recall stressors and putative depressive episodes that occurred many years before the interview.49,50 This is problematic because the induction of depressed mood significantly increases the recall of stressful life events.51 Furthermore, individuals with a history of depression experience perceived more stressful life events than healthy individuals.52 As a result, many of the studies to date do not adequately disentangle the cause and effect relationship between depression and reports of life stress. Additionally, most previous studies assessed a set of life stressors that were highly variable in character and intensity. Combining quantitatively and qualitatively disparate stressors may act to increase the “noise” of a study, reducing its statistical power to detect interaction effects.

Some studies have attempted to avoid the problems of impaired recall and variable stressors by focusing on specific populations that have experienced a substantial, uniform stressor, such as stroke or myocardial infarction.3746 However, because these specific stressor studies assess subjects only after the onset of the stressor, they cannot determine whether the depression was present before the onset of the stressor or whether the depression played a role in precipitating the stressor. Although one could study this question prospectively, with depression measured in the same subjects before and after the onset of a uniform stressor, it is generally not possible to predict the occurrence of a stressor. Medical internship provides a rare instance in which the onset of a major stressor can be predicted for a defined population. The present study seeks to identify the factors important in the development of depression during medical internship and to use internship as a stress model to study subjects before and after the onset of a major stressor and assess the moderating effect of 5-HTTLPR on the development of depression.

PARTICIPANTS

One thousand three hundred ninety-four interns entering traditional and primary care internal medicine, general surgery, pediatrics, obstetrics/gynecology, and psychiatry residency programs during the 2007-2008 and 2008-2009 academic years were sent an e-mail 2 months prior to commencing internship and invited to participate in the study. For 123 subjects, our e-mail invitations were returned as undeliverable and we were unable to obtain a valid e-mail address. Seven hundred forty (n = 1271 [58%]) of the remaining invited subjects agreed to participate in the study. The institutional review board at Yale University and the participating hospitals approved the study. Participating subjects provided electronic informed consent. Subjects were given $30 (2007-2008 cohort) or $40 (2008-2009 cohort) gift certificates.

DATA COLLECTION

All surveys were conducted through a secure Web site designed to maintain confidentiality, with subjects identified only by numbers. No links between the identification number and the subjects' identities were maintained.

Depressive symptoms were measured using the depression module of the 9-item Patient Health Questionnaire (PHQ-9).53 The PHQ-9 is a self-report component of the Primary Care Evaluation of Mental Disorders inventory, which is designed to screen for depressive symptoms. For each of the 9 depressive symptoms, interns indicated whether, during the previous 2 weeks, the symptom had bothered them “not at all,” “several days,” “more than half the days,” or “nearly every day.” Each item yields a score of 0 to 3, so that the PHQ-9 total score ranges from 0 to 27; PHQ-9 scores of 10 to 14, 15 to 19, and 20 or greater correspond to moderate, moderately severe, and severe depression, respectively.54 A score of 10 or greater on the PHQ-9 has a sensitivity of 93% and a specificity of 88% for the diagnosis of major depressive disorder.54 Diagnostic validity of the PHQ-9 is comparable with clinician-administered assessments.53

Initial Assessment

Subjects completed a baseline survey 1 to 2 months prior to commencing internship. The survey assessed general demographic factors (age, sex, and marital status), medical education factors (American or foreign medical school and medical specialty), personal factors (baseline PHQ-9 depressive symptoms and self-reported history of depression) and the following psychological measures: (1) neuroticism (NEO-Five Factor Inventory55), (2) resilience (Connor-Davidson Resilience Scale56), (3) perceived stress (Perceived Stress Scale57), (4) social supports (Sarason Social Support Questionnaire58), (5) early family environment (Risky Families Questionnaire59), and (6) cognitive styles (modified Sociotropy-Autonomy Scale60). Subjects also self-reported their ethnicity from a set of options that the investigator provided.

Within-Internship Assessments

Participants were contacted via e-mail at months 3, 6, 9, and 12 of their internship year and asked to complete the PHQ-9. They were also queried regarding their rotation setting, perceived medical errors, work hours, and sleep during the past week and the occurrence of a series of noninternship life stresses (serious illness; death or serious illness in a close family member or friend; financial problems; end of a serious relationship; and becoming a victim of crime or domestic violence) during the past 3 months.

DNA COLLECTION

Subjects choosing to take part in the study were given the option to submit a saliva sample for DNA extraction. We used the Oragene salivary DNA self-collection kit,61 which allows subjects to submit a salivary sample by mail without direct contact with study personnel.

SEROTONIN TRANSPORTER GENOTYPING

The serotonin transporter 5-HTTLPR variant was genotyped using previously described polymerase chain reaction conditions and primers.62 An A→G single-nucleotide polymorphism has been identified within the 5-HTTLPR repeat region (rs25531).63 Functional studies have shown that promoter regions with the 16-repeat variant and the G allele (LG) were functionally equivalent to the low-functioning 14-repeat variant (S allele). To genotype the additional single-nucleotide polymorphism that occurs in the variable-number-tandem-repeat region of the SLC6A4 promoter,63 we used a restriction enzyme assay that was described previously.64

STATISTICAL ANALYSIS

All analyses were performed using SPSS, version 16.0 (SPSS Inc, Chicago, Illinois). The point prevalence of depressive symptoms and a positive screen for depression during internship were determined through analysis of PHQ-9 depressive symptom scores at the 3-, 6-, 9-, and 12-month assessments. To investigate whether there was a significant change in depressive symptoms during the internship year, we compared baseline PHQ-9 depressive symptoms and depressive symptoms at the 3-, 6-, 9-, and 12-month assessments through a series of paired t tests.

Baseline Factors

The association between variables measured at baseline and the development of depressive symptoms during internship was assessed through a 2-step process. Using Pearson correlations for continuous measures and χ2 analyses for nominal measures, we identified baseline demographic variables that were associated with the mean change in depressive symptoms from baseline to the quarterly assessments during internship (change in PHQ-9 score = mean PHQ-9 depressive symptoms at 3-, 6-, 9- and 12-month assessments – PHQ-9 depressive symptoms at baseline). Significant variables were subsequently entered into a stepwise linear regression model to identify significant predictors while accounting for colinearity among variables.

Within-Internship Factors

The association between variables measured through recurring assessments during internship (within-internship variables) and change in depressive symptoms were assessed through a generalized estimating equation analysis to account for correlated repeated measures within subjects. Internship variables (work hours, occurrence of medical errors, hours of sleep, and noninternship stressful life events) were incorporated as predictor variables, and associated baseline factors were used as covariates. We used concurrently measured depressive symptoms as the outcome variable (ie, 3-month depressive symptoms were indexed to the 3-month within-internship variable, 6-month depressive symptoms were indexed to 6-month medical errors, etc).

Next, to gain insight into the direction of causality between associated within-internship factors and depressive symptoms, we assessed whether the depressive symptom score prior to internship predicted increased levels of the associated within-internship variables at 3 months. For this analysis, we used a general linear model, with the associated within-internship measure as the dependent variable and baseline depressive symptom score as the independent variable. Baseline factors associated with increased depressive symptoms were included as covariates. Finally, for the variables for which baseline depressive symptom score predicted increased levels of the associated within-internship variables at 3 months, we tested whether the 3-month depressive symptom score was associated with the relevant within-internship factor after controlling for baseline depressive symptoms. Thus, 3-month depressive symptom scores were reintroduced into the general linear model as an independent variable in the analysis.

Serotonin Transporter Polymorphism

Because there are substantial racial/ethnic differences in 5-HTTLPR allele frequencies (S allele frequency: Caucasian, 0.44; African, 0.11; and Chinese, 0.70),62 we performed separate analyses for individual racial/ethnic groups to minimize the chance of false association due to the presence of population stratification.65 To explore the effects of 5-HTTLPR and stress on the emergence of depressive symptoms, we performed a generalized estimating equation analysis with the presence of a 5-HTTLPR low-functioning allele (S or LG) as the grouping variable and change in depressive symptoms as the outcome variable. To gain insight into the specific factors that moderate a potential genotype effect on depressive symptoms, we introduced the baseline and within-internship factors that had significant main effects on this outcome measure in the previous analysis and the corresponding genotype × factor interaction terms as predictor variables into the generalized estimating equation analysis.

Individuals who chose to take part in the study were younger (27.9 vs 28.4 years; P < .001) and more likely to be female (54.4% vs 52.5%; P < .001) than individuals who chose not to participate (Table 1) (eTable 1, eTable 2, eTable 3, and eTable 4). Six hundred fifty-one (n = 740 [88%]) subjects completed at least 1 follow-up survey, with a mean of 69% of subjects responding to each of the 4 follow-up surveys.

Table Graphic Jump LocationTable 1. Sample Demographic Characteristics
PREVALENCE OF DEPRESSIVE SYMPTOMS

The mean PHQ-9 depressive symptom score reported by subjects increased significantly from baseline (2.38 [SD, 2.99]) to 3 months (6.70 [SD, 5.37]; P < .001), 6 months (6.33 [SD, 4.98]; P < .001), 9 months (6.48 [SD, 4.98]; P < .001), and 12 months (6.26 [SD, 5.10]; P < .001) of internship. Using the criteria for major depression developed by Kroenke et al54 (PHQ-9 score ≥10), we found that the percentage of subjects meeting this diagnosis increased from 3.9% at baseline to 27.1%, 23.3%, 25.7%, and 26.6% at the 3-, 6-, 9-, and 12-month points of internship, respectively (Figure 1). We found that 41.8% of subjects met criteria for major depression at 1 or more quarterly assessments. On sensitivity analysis, assuming that all nonresponders did not experience a depressive episode during internship, the prevalence of a depressive episode during internship would be 19.5% (272 of 1394). The percentage of subjects meeting criteria for moderately severe depression (PHQ-9 score >15) increased from 0.7% at baseline to 6.6%, 6.2%, 7.8%, and 7.6% at the 3-, 6-, 9-, and 12-month points of the internship, respectively. Similarly, the percentage of subjects who met criteria for severe depression (PHQ-9 score >20) increased from 0% at baseline to 2.3%, 1.6%, 1.8%, and 0.8% at 3, 6, 9, and 12 months of internship, respectively.

Place holder to copy figure label and caption
Figure 1.

The proportion of interns who met the 9-item Patient Health Questionnaire (PHQ-9) criteria for depression52 prior to internship and at 3-month intervals through the internship year.

Graphic Jump Location

To determine whether the increase in overall PHQ-9 score was due to an increase in all depressive symptoms or only a subset, we assessed the change from baseline to mean internship level individually for each of the PHQ-9 symptoms. Subjects reported a significant increase (P < .001) for all 9 items. The increase in mean symptom score ranged from 70% (difficulty sleeping) to 370% (thoughts of death).

BASELINE FACTORS

Among 15 baseline variables tested, 9 were significantly correlated with a change in depressive symptoms from the baseline assessment to the mean of the 4 internship assessments (female sex, r = 0.147, P < .001; European American ethnicity, r = 0.084, P = .04; history of depression, r = 0.206, P < .001; lower baseline depressive symptoms, r = 0.126, P = .002; US medical education, r = 0.115, P = .004; higher neuroticism, r = 0.115, P < .001; difficult early family environment, r = 0.108, P < .001; higher perceived stress, r = 0.094, P = .02; and higher sociotropy, r = 0.116, P = .004). When these 9 variables were entered into the stepwise linear regression to account for colinearity between variables, 6 variables remained significant (neuroticism, β = 0.24, P < .001; personal history of depression, β = 0.17, P < .001; lower baseline depressive symptoms, β = 0.38, P < .001; female sex, β = 0.08, P = .03; US medical education, β = 0.10, P = .005; and difficult early family environment, β = 0.08, P = .04).

WITHIN-INTERNSHIP FACTORS

We used a generalized estimating equation analysis to assess factors during internship that were associated with a change in depressive symptoms while controlling for repeated measurements. Three within-internship variables were associated with an increase in depressive symptoms (work hours, Wald χ299 = 2.8 × 1011, P < .001; reported medical errors, Wald χ21 = 16.2, P < .001; and noninternship stressful life events, Wald χ25 = 71.6, P < .001). There were no significant sex interactions for any of the associated baseline or within-internship factors (data not shown) (Table 2).

Table Graphic Jump LocationTable 2. Predictors of Increased Depressive Symptoms

To gain insight into the direction of the association of within-internship factors and depression, we assessed whether baseline depressive symptoms predicted an increased level of the within-internship factor at the 3-month internship assessment. Baseline depressive symptom score predicted reported medical errors at 3 months (F21 = 2.201, P = .002), but not work hours (F21 = 1.116, P = .22) or noninternship stressful life events (F21 = 1.029, P = .45) at 3 months. For the reported medical errors analysis, reintroduction of the 3-month depressive symptom score showed it to be a significant predictor of medical errors at 3 months even in the presence of baseline depressive symptoms (F27 = 1.676, P = .004).

SEROTONIN TRANSPORTER GENOTYPE

A total of 409 of 652 (63%) eligible subjects provided saliva samples. There were no significant differences on sex, age, or ethnicity between subjects who provided a sample and those who did not. For both major racial/ethnic groups in our sample (European American and Asian), allele frequencies were consistent with previous reports and Hardy-Weinberg equilibrium (data not shown). Among European Americans, subjects with at least 1 low-functioning 5-HTTLPR (S or LG) allele reported a significantly greater increase in depressive symptoms than subjects with 2 high-functioning 5-HTTLPR (LA) alleles (Wald χ21 = 8.2, P = .004) (Figure 2). The percentage of European American subjects with at least 1 low-functioning 5-HTTLPR allele who met criteria for depression increased from 2.4% before internship to 42.5% at its highest during internship, while the percentage of European American subjects with 2 high-functioning 5-HTTLPR alleles who met criteria for depression increased from 5.1% before internship to 36.2% at its highest during internship (Table 3).

Place holder to copy figure label and caption
Figure 2.

Nine-item Patient Health Questionnaire (PHQ-9) depression scores in white subjects stratified by the presence of at least 1 copy of a 5-HTTLPR low-functioning allele. Error bars indicate standard error of the mean.

Graphic Jump Location
Table Graphic Jump LocationTable 3. Serotonin Transporter Functional Genotype and Change in Depressive Symptoms During Medical Internship

To identify variables that moderate the association between 5-HTTLPR and depressive symptoms, we introduced the main effect and interaction terms, consisting of genotype and each of the baseline and within-internship variables that were significantly associated with an increase in depressive symptoms into the 5-HTTLPR generalized estimating equation analysis. Among baseline variables, there was a significant interaction of 5-HTTLPR with neuroticism (Wald χ219 = 30.6, P = .045), but the interactions of 5-HTTLPR with the other 5 baseline variables were not significant. Among within-internship variables, there was a significant interaction of 5-HTTLPR with work hours (Wald χ261 = 5757.3, P < .001), but the interactions of 5-HTTLPR with noninternship stressful life events and reported medical errors were not significant. Among Asian subjects, there was no difference in the change in depressive symptoms between genotype groups (t = 1.06; P = .40).

In this study, we found that the rate of depression increased dramatically during the internship year, from 3.9% of subjects meeting PHQ-9 criteria for depression before internship to an average of 25.3% of subjects meeting criteria at quarterly assessments during the internship year. Most subjects who met criteria for depression were classified as moderately depressed, with few subjects meeting PHQ-9 criteria for moderately severe or severe depression. Because the development of major depression has been linked to a higher risk of future depressive episodes and greater long-term morbidity risk,66,67 future studies should examine how the rate of depression changes as training physicians progress through their careers beyond internship and the possible effects of depression on the general health of physicians.

Beyond assessing depression prevalence, we also identified a series of factors associated with the development of depressive symptoms during internship. The baseline factors that were associated with the development of depression in this study include some that have been implicated in prior residency studies (female sex, difficult early family environment, neuroticism, and a prior history of depression) and other factors not previously identified (US medical education and lower baseline depressive symptoms). It is also interesting to note that a number of factors, such as medical specialty and age, were not associated with the development of depression. With effective interventions to help prevent the onset of depression now available, the predictive factors identified herein could allow at-risk interns to take steps before the onset of symptoms to lower their chances of developing depression.68

As with baseline factors, we identified within-internship factors that were previously implicated as well as novel factors associated with the development of depression. Our finding that medical errors are associated with depression supports the findings of 2 recent studies.69,70 Herein, we extend the association identified in prior studies by demonstrating that depressive symptoms that are present before internship predicted reported errors during internship, indicating that depression results in increased medical errors. Controlling for the baseline level of depressive symptoms, a strong correlation between errors and depression persisted, indicating that errors may also cause depression and that the association between depression and reported medical errors is bidirectional.

In addition to building on previous work exploring the relationship between medical errors and depression, this is the first study to demonstrate a direct association between the number of hours worked and risk of depression in medical interns. In contrast to our finding with medical errors, we found no evidence that depressive symptom score before internship predicted one's work hours during internship. These findings suggest that increased work hours lead to increased depressive symptoms during internship. Future studies could explore whether systemic changes designed to improve patient safety, such as additional safeguards against medical errors and further resident work hours' restrictions, reduce the development of depression among interns.

There are a number of limitations to our findings related to depressive symptoms and internship. First, our finding that the association between depressive symptoms and reported medical errors persisted when controlling for preexisting depressive symptoms does not definitively prove that errors led to depression. It is possible that some third factor differentially promoted depression in a subset of the sample and also led to an increase in the reported within-internship factor in that group of residents. Although no variable that we measured (sex, age, specialty, or institution) appeared to account for this effect, it is possible that an unmeasured variable could have caused it.

Second, only 58% of invited individuals chose to participate in the study. Although there were only modest differences in age and sex between those who chose to take part in the study and those who did not, our results should be extrapolated with caution.

Third, although multiple studies have demonstrated the validity, sensitivity, and specificity of the PHQ-9 inventory, it is important to note that we assessed depression through a self-report inventory rather than a diagnostic interview.

Fourth, we assessed medical errors through self-report rather than through objective measurement, leading to the possibility that we did not accurately capture the occurrence of medical errors. For instance, the established tendency of depressed individuals toward enhanced memory of emotionally negative events may have resulted in depressed residents recalling more errors rather than actually committing more errors.24 Previous studies, however, have demonstrated that resident self-report of errors can act as a reasonable proxy for errors assessed through medical record review and that self-report was actually more effective in detecting preventable errors.71,72

Finally, our study was restricted to interns and thus our results may not hold for advanced residents or physicians who have completed their training. In addition, although we did not find significant differences in results among hospitals or specialties, the interns and programs included here may not represent the country in general.

SEROTONIN TRANSPORTER, STRESS, AND DEPRESSIVE SYMPTOMS

In addition to identifying factors associated with the development of depression during internship, we also used internship as a model to explore the relationship between a serotonin transporter promoter polymorphism and stress in the development of depression. We found evidence that this variant moderates the response to stress in European American subjects, with subjects carrying at least 1 low-functioning 5-HTTLPR allele reporting a 43% greater increase in depressive symptoms than subjects with 2 high-functioning alleles. Consistent with an earlier study exploring the 5-HTTLPR × stress interaction in the context of personality traits, we found that the association between 5-HTTLPR and the development of depressive symptoms under stress was moderated by neuroticism.32 Furthermore, in exploring the type of stress for which 5-HTTLPR affects sensitivity, we found evidence supporting an interaction of 5-HTTLPR with work hours, but not with medical errors or stressful life events. This finding supports the results of a prior study in which the 5-HTTLPR × stress interaction effect on depressive symptoms was the result of increased sensitivity to common, mild stressors among individuals carrying the low-functioning allele, rather than an increased sensitivity to rare and severe life events.31 The association between 5-HTTLPR, stress, and depression has not been well studied in Asian populations. In our sample, there was no evidence that 5-HTTLPR genotype influenced the change in depression score among subjects of Asian ethnicity.

The results of our study support the original study that demonstrated an association between 5-HTTLPR, stress, and depression risk,25 but they conflict with the results of some other studies and 2 recent meta-analyses. It is possible that no actual interaction exists and the results of our study, along with the other studies reporting a significant interaction, are false-positives. However, because the approaches used in studies exploring the interaction vary substantially, an alternate explanation for our findings is that a true, but modest gene × environment interaction effect exists, but that certain study design features are necessary to detect the effect.73 Our study illustrates a number of features that may be important to maximize the power to detect gene × environment interaction effects. First, we used a stressor that has a substantial direct effect on depression. This is in contrast to many of the negative studies exploring this interaction that assessed a set of life stressors that were highly variable in character and intensity. Second, by using a prospective design, we minimized the biases inherent in the retrospective and concurrent assessment of stress and depressive symptoms present in other studies.

It is interesting to note that 8 of the 10 previous studies that avoided the problems of impaired recall and variable stressors by using a specific stressor approach have reported an association between the 5-HTTLPR S allele and increased depression under stress.3746 Herein, we extend the results of that specific stressor group of studies by assessing the same subjects before and after the onset of the stressor. This allowed us to avoid the confounding attributable to differences between subjects that are inherent in case-control studies and demonstrate that the association between genotype and depressive symptoms was not present before the onset of the stressor. Last, we maximized the genetic information obtained from the locus of interest by genotyping the functional single-nucleotide polymorphism within the 5-HTTLPR locus and functionally classifying the low-functioning LG allele with the low-functioning S allele. The functional misclassification of alleles in some previous studies may also have reduced the power to detect interaction effects.

OVERALL SIGNIFICANCE

In summary, we conducted the largest prospective study to date of depression during medical internship. We identified a high level of depressive symptoms among interns and a series of baseline and within-internship factors that are associated with increased depressive symptoms in this population. Subsequent studies that more fully explore the consequences of depression among interns both on patients and the physicians in training themselves are needed. In this study, we also used internship to model the relationship between 5-HTTLPR, stress, and depression and found that the 5-HTTLPR low-functioning allele was associated with a significantly greater increase in depressive symptoms under stress. Our study highlights the striking variation in experimental design among studies of this interaction and the impact on the findings of these different designs. In the future, meta-analyses exploring the relationship between 5-HTTLPR, stress, and depression should account for this variation in study design and systematically assess whether heterogeneity of study design predicts the estimated overall effect.

Correspondence: Srijan Sen, MD, PhD, Department of Psychiatry, University of Michigan, 5061 Biomedical Sciences Research Bldg, 109 Zina Pitcher Place, Ann Arbor, MI 48109 (srijan@umich.edu).

Submitted for Publication: August 12, 2009; final revision received November 30, 2009; accepted December 15, 2009.

Published Online: April 5, 2010 (doi:10.1001/archgenpsychiatry.2010.41). This article was corrected on April 29, 2010.

Author Contributions: Dr Sen had full access to all of the data in the study and conducted the statistical analyses. He takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: Dr Kranzler reports consulting arrangements with Alkermes Inc, Ortho-McNeil Pharmaceuticals, Elbion Pharmaceuticals, Solvay Pharmaceuticals, and Sanofi-Aventis Pharmaceuticals and has received research support from Merck and Merck Company, Bristol-Myers Squibb Company, and Ortho-McNeil Pharmaceuticals. Dr Krystal reports consulting arrangements with Abbott Laboratories, Astra-Zeneca, Atlas Venture, Bristol-Meyers Squibb, Cypress Bioscience Inc, Eli Lilly and Co, Fidelity Biosciences, Forest Laboratories, Glaxo-SmithKline, Houston Pharma, Lohocla Research Corporation, Merz Pharmaceuticals, Organon Pharmaceuticals, Pfizer Pharmaceuticals, Schering Plough Research Institute, Shire Pharmaceuticals, Sumitomo Pharmaceuticals America Ltd, Takeda Industries, Transcept Pharmaceutical, UCB Pharma, US Micron, and Tetragenex Pharmaceuticals (compensation in exercisable warrant options until March 21, 2012; value less than $10 000), and he is a cosponsor on pending patents related to glutamatergic agents for psychiatric disorders (depression and obsessive-compulsive disorder) and antidepressant effects of oral ketamine.

Funding/Support: This work was supported by a Donaghue Foundation Clinical and Community Grant, an American Psychiatric Association Substance Abuse and Mental Health Services Administration grant, a Veterans Administration Research Enhancement Award Program award, and an American Foundation for Suicide Prevention Young Investigator Grant.

Role of the Sponsor: The funding sources played no role in the design or conduct of the study; collection management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

Additional Contributions: The authors thank Sobia Sarmast, BA, and Michelle Streckenbach, BA, for technical support and the participating residents and program directors for the time that they invested in this study. They also thank the American Medical Association for providing demographic information about participating residency programs.

Duffy  TP Glory days: what price glory? Pharos Alpha Omega Alpha Honor Med Soc 2005;68 (4) 22- 30
PubMed
Butterfield  PS The stress of residency: a review of the literature. Arch Intern Med 1988;148 (6) 1428- 1435
PubMed Link to Article
Shanafelt  THabermann  T Medical residents' emotional well-being. JAMA 2002;288 (15) 1846- 1847
PubMed Link to Article
Kash  KMHolland  JCBreitbart  WBerenson  SDougherty  JOuellette-Kobasa  SLesko  L Stress and burnout in oncology. Oncology (Williston Park) 2000;14 (11) 1621- 1633
PubMed
Murphy  JMLaird  NMMonson  RRSobol  AMLeighton  AH A 40-year perspective on the prevalence of depression: the Stirling County Study. Arch Gen Psychiatry 2000;57 (3) 209- 215
PubMed Link to Article
Hsu  KMarshall  V Prevalence of depression and distress in a large sample of Canadian residents, interns, and fellows. Am J Psychiatry 1987;144 (12) 1561- 1566
PubMed
Bellini  LMBaime  MShea  JA Variation of mood and empathy during internship. JAMA 2002;287 (23) 3143- 3146
PubMed Link to Article
Schneider  SEPhillips  WM Depression and anxiety in medical, surgical, and pediatric interns. Psychol Rep 1993;72 (3, pt 2) 1145- 1146
PubMed Link to Article
Kirsling  RAKochar  MSChan  CH An evaluation of mood states among first-year residents. Psychol Rep 1989;65 (2) 355- 366
PubMed Link to Article
Archer  LRKeever  RRGordon  RAArcher  RP The relationship between residents' characteristics, their stress experiences, and their psychosocial adjustment at one medical school. Acad Med 1991;66 (5) 301- 303
PubMed Link to Article
Hendrie  HCClair  DKBrittain  HMFadul  PE A study of anxiety/depressive symptoms of medical students, house staff, and their spouses/partners. J Nerv Ment Dis 1990;178 (3) 204- 207
PubMed Link to Article
Reuben  DB Depressive symptoms in medical house officers: effects of level of training and work rotation. Arch Intern Med 1985;145 (2) 286- 288
PubMed Link to Article
Shanafelt  TDBradley  KAWipf  JEBack  AL Burnout and self-reported patient care in an internal medicine residency program. Ann Intern Med 2002;136 (5) 358- 367
PubMed Link to Article
Michels  PJProbst  JCGodenick  MTPalesch  Y Anxiety and anger among family practice residents: a South Carolina family practice research consortium study. Acad Med 2003;78 (1) 69- 79
PubMed Link to Article
Clark  DCSalazar-Grueso  EGrabler  PFawcett  J Predictors of depression during the first 6 months of internship. Am J Psychiatry 1984;141 (9) 1095- 1098
PubMed
Girard  DEElliot  DLHickam  DHSparr  LClarke  NGWarren  LKoski  J The internship: a prospective investigation of emotions and attitudes. West J Med 1986;144 (1) 93- 98
PubMed
Firth-Cozens  J Emotional distress in junior house officers. Br Med J (Clin Res Ed) 1987;295 (6597) 533- 536
PubMed Link to Article
Baldwin  PJDodd  MWrate  RM Young doctors' health–II: health and health behaviour. Soc Sci Med 1997;45 (1) 41- 44
PubMed Link to Article
Williams  SDale  JGlucksman  EWellesley  A Senior house officers' work related stressors, psychological distress, and confidence in performing clinical tasks in accident and emergency: a questionnaire study. BMJ 1997;314 (7082) 713- 718
PubMed Link to Article
Hainer  BLPalesch  Y Symptoms of depression in residents: a South Carolina Family Practice Research Consortium study. Acad Med 1998;73 (12) 1305- 1310
PubMed Link to Article
Tyssen  RVaglum  PGronvold  NTEkeberg  O The impact of job stress and working conditions on mental health problems among junior house officers: a nationwide Norwegian prospective cohort study. Med Educ 2000;34 (5) 374- 384
PubMed Link to Article
Tyssen  RVaglum  PGronvold  NTEkeberg  O Factors in medical school that predict postgraduate mental health problems in need of treatment: a nationwide and longitudinal study. Med Educ 2001;35 (2) 110- 120
PubMed Link to Article
Tyssen  RVaglum  P Mental health problems among young doctors: an updated review of prospective studies. Harv Rev Psychiatry 2002;10 (3) 154- 165
PubMed Link to Article
Kendler  KSNeale  MCKessler  RCHeath  ACEaves  LJ A longitudinal twin study of personality and major depression in women. Arch Gen Psychiatry 1993;50 (11) 853- 862
PubMed Link to Article
Caspi  ASugden  KMoffitt  TETaylor  ACraig  IWHarrington  H McClay  JMill  JMartin  JBraithwaite  APoulton  R Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301 (5631) 386- 389
PubMed Link to Article
Munafò  MRDurrant  CLewis  GFlint  J Gene × environment interactions at the serotonin transporter locus. Biol Psychiatry 2009;65 (3) 211- 219
PubMed Link to Article
Risch  NHerrell  RLehner  TLiang  KYEaves  LHoh  JGriem  AKovacs  MOtt  JMerikangas  KR Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 2009;301 (23) 2462- 2471
PubMed Link to Article
Scheid  JMHolzman  CBJones  NFriderici  KHNummy  KASymonds  LLSikorskii  ARegier  MKFisher  R Depressive symptoms in mid-pregnancy, lifetime stressors and the 5-HTTLPR genotype. Genes Brain Behav 2007;6 (5) 453- 464
PubMed Link to Article
Kaufman  JYang  BZDouglas-Palumberi  HHoushyar  SLipschitz  DKrystal  JHGelernter  J Social supports and serotonin transporter gene moderate depression in maltreated children. Proc Natl Acad Sci U S A 2004;101 (49) 17316- 17321
PubMed Link to Article
Kaufman  JYang  BZDouglas-Palumberi  HGrasso  DLipschitz  DHoushyar  SKrystal  JHGelernter  J Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry 2006;59 (8) 673- 680
PubMed Link to Article
Kendler  KSKuhn  JWVittum  JPrescott  CARiley  B The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry 2005;62 (5) 529- 535
PubMed Link to Article
Jacobs  NKenis  GPeeters  FDerom  CVlietinck  Rvan Os  J Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression. Arch Gen Psychiatry 2006;63 (9) 989- 996
PubMed Link to Article
Sjöberg  RLNilsson  KWNordquist  NOhrvik  JLeppert  JLindström  LOreland  L Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol 2006;9 (4) 443- 449
PubMed Link to Article
Cicchetti  DRogosch  FASturge-Apple  ML Interactions of child maltreatment and serotonin transporter and monoamine oxidase A polymorphisms: depressive symptomatology among adolescents from low socioeconomic status backgrounds. Dev Psychopathol 2007;19 (4) 1161- 1180
PubMed
Aguilera  MArias  BWichers  MBarrantes-Vidal  NMoya  JVilla  Hvan Os  JIbáñez  MIRuipérez  MAOrtet  GFañanás  L Early adversity and 5-HTT/BDNF genes: new evidence of gene-environment interactions on depressive symptoms in a general population. Psychol Med 2009;39 (9) 1425- 1432
PubMed Link to Article
Stein  MBSchork  NJGelernter  J Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology 2008;33 (2) 312- 319
PubMed Link to Article
Kim  JMStewart  RKim  SWYang  SJShin  ISYoon  JS Modification by two genes of associations between general somatic health and incident depressive syndrome in older people. Psychosom Med 2009;71 (3) 286- 291
PubMed Link to Article
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Lenze  EJMunin  MCFerrell  REPollock  BGSkidmore  ELotrich  FRogers  JCQuear  THouck  PReynolds  CF  III Association of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) genotype with depression in elderly persons after hip fracture. Am J Geriatr Psychiatry 2005;13 (5) 428- 432
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Nakatani  DSato  HSakata  YShiotani  IKinjo  KMizuno  HShimizu  MIto  HKoretsune  YHirayama  AHori  MOsaka Acute Coronary Insufficiency Study Group, Influence of serotonin transporter gene polymorphism on depressive symptoms and new cardiac events after acute myocardial infarction. Am Heart J 2005;150 (4) 652- 658
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Otte  C McCaffery  JAli  SWhooley  MA Association of a serotonin transporter polymorphism (5-HTTLPR) with depression, perceived stress, and norepinephrine in patients with coronary disease: the Heart and Soul Study. Am J Psychiatry 2007;164 (9) 1379- 1384
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Ramasubbu  RTobias  RBuchan  AMBech-Hansen  NT Serotonin transporter gene promoter region polymorphism associated with poststroke major depression. J Neuropsychiatry Clin Neurosci 2006;18 (1) 96- 99
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Mössner  RRiederer  P Allelic variation of a functional promoter polymorphism of the serotonin transporter and depression in Parkinson's disease. Parkinsonism Relat Disord 2007;13 (1) 62
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Phillips-Bute  BMathew  JPBlumenthal  JAMorris  RWPodgoreanu  MVSmith  MStafford-Smith  MGrocott  HPSchwinn  DANewman  MFPerioperative Genetics and Safety Outcomes Investigative Team, Relationship of genetic variability and depressive symptoms to adverse events after coronary artery bypass graft surgery. Psychosom Med 2008;70 (9) 953- 959
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Lotrich  FEFerrell  RERabinovitz  MPollock  BG Risk for depression during interferon-alpha treatment is affected by the serotonin transporter polymorphism. Biol Psychiatry 2009;65 (4) 344- 348
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PubMed Link to Article
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PubMed
Glassman  AHShapiro  PA Depression and the course of coronary artery disease. Am J Psychiatry 1998;155 (1) 4- 11
PubMed
Paykel  ES Cognitive therapy in relapse prevention in depression. Int J Neuropsychopharmacol 2007;10 (1) 131- 136
PubMed Link to Article
Fahrenkopf  AMSectish  TCBarger  LKSharek  PJLewin  DChiang  VWEdwards  SWiedermann  BLLandrigan  CP Rates of medication errors among depressed and burnt out residents: prospective cohort study. BMJ 2008;336 (7642) 488- 491
PubMed Link to Article
West  CPHuschka  MMNovotny  PJSloan  JAKolars  JCHabermann  TMShanafelt  TD Association of perceived medical errors with resident distress and empathy: a prospective longitudinal study. JAMA 2006;296 (9) 1071- 1078
PubMed Link to Article
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PubMed Link to Article
Weingart  SNCallanan  LDShip  ANAronson  MD A physician-based voluntary reporting system for adverse events and medical errors. J Gen Intern Med 2001;16 (12) 809- 814
PubMed Link to Article
Moffitt  TECaspi  ARutter  M Strategy for investigating interactions between measured genes and measured environments. Arch Gen Psychiatry 2005;62 (5) 473- 481
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

The proportion of interns who met the 9-item Patient Health Questionnaire (PHQ-9) criteria for depression52 prior to internship and at 3-month intervals through the internship year.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Nine-item Patient Health Questionnaire (PHQ-9) depression scores in white subjects stratified by the presence of at least 1 copy of a 5-HTTLPR low-functioning allele. Error bars indicate standard error of the mean.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Sample Demographic Characteristics
Table Graphic Jump LocationTable 2. Predictors of Increased Depressive Symptoms
Table Graphic Jump LocationTable 3. Serotonin Transporter Functional Genotype and Change in Depressive Symptoms During Medical Internship

References

Duffy  TP Glory days: what price glory? Pharos Alpha Omega Alpha Honor Med Soc 2005;68 (4) 22- 30
PubMed
Butterfield  PS The stress of residency: a review of the literature. Arch Intern Med 1988;148 (6) 1428- 1435
PubMed Link to Article
Shanafelt  THabermann  T Medical residents' emotional well-being. JAMA 2002;288 (15) 1846- 1847
PubMed Link to Article
Kash  KMHolland  JCBreitbart  WBerenson  SDougherty  JOuellette-Kobasa  SLesko  L Stress and burnout in oncology. Oncology (Williston Park) 2000;14 (11) 1621- 1633
PubMed
Murphy  JMLaird  NMMonson  RRSobol  AMLeighton  AH A 40-year perspective on the prevalence of depression: the Stirling County Study. Arch Gen Psychiatry 2000;57 (3) 209- 215
PubMed Link to Article
Hsu  KMarshall  V Prevalence of depression and distress in a large sample of Canadian residents, interns, and fellows. Am J Psychiatry 1987;144 (12) 1561- 1566
PubMed
Bellini  LMBaime  MShea  JA Variation of mood and empathy during internship. JAMA 2002;287 (23) 3143- 3146
PubMed Link to Article
Schneider  SEPhillips  WM Depression and anxiety in medical, surgical, and pediatric interns. Psychol Rep 1993;72 (3, pt 2) 1145- 1146
PubMed Link to Article
Kirsling  RAKochar  MSChan  CH An evaluation of mood states among first-year residents. Psychol Rep 1989;65 (2) 355- 366
PubMed Link to Article
Archer  LRKeever  RRGordon  RAArcher  RP The relationship between residents' characteristics, their stress experiences, and their psychosocial adjustment at one medical school. Acad Med 1991;66 (5) 301- 303
PubMed Link to Article
Hendrie  HCClair  DKBrittain  HMFadul  PE A study of anxiety/depressive symptoms of medical students, house staff, and their spouses/partners. J Nerv Ment Dis 1990;178 (3) 204- 207
PubMed Link to Article
Reuben  DB Depressive symptoms in medical house officers: effects of level of training and work rotation. Arch Intern Med 1985;145 (2) 286- 288
PubMed Link to Article
Shanafelt  TDBradley  KAWipf  JEBack  AL Burnout and self-reported patient care in an internal medicine residency program. Ann Intern Med 2002;136 (5) 358- 367
PubMed Link to Article
Michels  PJProbst  JCGodenick  MTPalesch  Y Anxiety and anger among family practice residents: a South Carolina family practice research consortium study. Acad Med 2003;78 (1) 69- 79
PubMed Link to Article
Clark  DCSalazar-Grueso  EGrabler  PFawcett  J Predictors of depression during the first 6 months of internship. Am J Psychiatry 1984;141 (9) 1095- 1098
PubMed
Girard  DEElliot  DLHickam  DHSparr  LClarke  NGWarren  LKoski  J The internship: a prospective investigation of emotions and attitudes. West J Med 1986;144 (1) 93- 98
PubMed
Firth-Cozens  J Emotional distress in junior house officers. Br Med J (Clin Res Ed) 1987;295 (6597) 533- 536
PubMed Link to Article
Baldwin  PJDodd  MWrate  RM Young doctors' health–II: health and health behaviour. Soc Sci Med 1997;45 (1) 41- 44
PubMed Link to Article
Williams  SDale  JGlucksman  EWellesley  A Senior house officers' work related stressors, psychological distress, and confidence in performing clinical tasks in accident and emergency: a questionnaire study. BMJ 1997;314 (7082) 713- 718
PubMed Link to Article
Hainer  BLPalesch  Y Symptoms of depression in residents: a South Carolina Family Practice Research Consortium study. Acad Med 1998;73 (12) 1305- 1310
PubMed Link to Article
Tyssen  RVaglum  PGronvold  NTEkeberg  O The impact of job stress and working conditions on mental health problems among junior house officers: a nationwide Norwegian prospective cohort study. Med Educ 2000;34 (5) 374- 384
PubMed Link to Article
Tyssen  RVaglum  PGronvold  NTEkeberg  O Factors in medical school that predict postgraduate mental health problems in need of treatment: a nationwide and longitudinal study. Med Educ 2001;35 (2) 110- 120
PubMed Link to Article
Tyssen  RVaglum  P Mental health problems among young doctors: an updated review of prospective studies. Harv Rev Psychiatry 2002;10 (3) 154- 165
PubMed Link to Article
Kendler  KSNeale  MCKessler  RCHeath  ACEaves  LJ A longitudinal twin study of personality and major depression in women. Arch Gen Psychiatry 1993;50 (11) 853- 862
PubMed Link to Article
Caspi  ASugden  KMoffitt  TETaylor  ACraig  IWHarrington  H McClay  JMill  JMartin  JBraithwaite  APoulton  R Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301 (5631) 386- 389
PubMed Link to Article
Munafò  MRDurrant  CLewis  GFlint  J Gene × environment interactions at the serotonin transporter locus. Biol Psychiatry 2009;65 (3) 211- 219
PubMed Link to Article
Risch  NHerrell  RLehner  TLiang  KYEaves  LHoh  JGriem  AKovacs  MOtt  JMerikangas  KR Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 2009;301 (23) 2462- 2471
PubMed Link to Article
Scheid  JMHolzman  CBJones  NFriderici  KHNummy  KASymonds  LLSikorskii  ARegier  MKFisher  R Depressive symptoms in mid-pregnancy, lifetime stressors and the 5-HTTLPR genotype. Genes Brain Behav 2007;6 (5) 453- 464
PubMed Link to Article
Kaufman  JYang  BZDouglas-Palumberi  HHoushyar  SLipschitz  DKrystal  JHGelernter  J Social supports and serotonin transporter gene moderate depression in maltreated children. Proc Natl Acad Sci U S A 2004;101 (49) 17316- 17321
PubMed Link to Article
Kaufman  JYang  BZDouglas-Palumberi  HGrasso  DLipschitz  DHoushyar  SKrystal  JHGelernter  J Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry 2006;59 (8) 673- 680
PubMed Link to Article
Kendler  KSKuhn  JWVittum  JPrescott  CARiley  B The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry 2005;62 (5) 529- 535
PubMed Link to Article
Jacobs  NKenis  GPeeters  FDerom  CVlietinck  Rvan Os  J Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression. Arch Gen Psychiatry 2006;63 (9) 989- 996
PubMed Link to Article
Sjöberg  RLNilsson  KWNordquist  NOhrvik  JLeppert  JLindström  LOreland  L Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol 2006;9 (4) 443- 449
PubMed Link to Article
Cicchetti  DRogosch  FASturge-Apple  ML Interactions of child maltreatment and serotonin transporter and monoamine oxidase A polymorphisms: depressive symptomatology among adolescents from low socioeconomic status backgrounds. Dev Psychopathol 2007;19 (4) 1161- 1180
PubMed
Aguilera  MArias  BWichers  MBarrantes-Vidal  NMoya  JVilla  Hvan Os  JIbáñez  MIRuipérez  MAOrtet  GFañanás  L Early adversity and 5-HTT/BDNF genes: new evidence of gene-environment interactions on depressive symptoms in a general population. Psychol Med 2009;39 (9) 1425- 1432
PubMed Link to Article
Stein  MBSchork  NJGelernter  J Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology 2008;33 (2) 312- 319
PubMed Link to Article
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Factors associated with depression during medical internship
Posted on June 21, 2010
Debasish Basu, M.D.
Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, India
Conflict of Interest: None Declared
Srijan Sen and colleagues(1) have shown that the internship year can be a major stressor for medical students and that it can be used as a predictable stress model to prospectively study depression and various biopsychosocial factors associated with it. They have demonstrated the relationship between certain personality traits, pre-internship and within-internship factors, stressful life events, genetic polymorphisms of the serotonin transporter gene and development of depressive symptoms. Given the substantive importance of this work, both for providing a heuristic model and for generating significant data, we would like to comment upon two areas which, we believe, merit some discussion to enhance the interpretation, meaningfulness and impact of this work. The first comment concerns the primary outcome measure adopted by the authors: change in depressive symptoms from baseline to internship, rather than a diagnostic threshold of depression per se. They used the depression module of 9-item Patient Health Questionnaire (PHQ-9)(2) to score self- reported depressive symptoms at baseline, and at 3-, 6-, 9- and 12-months of internship. They derived their primary outcome measure as "the mean change in depressive symptoms from baseline to the quarterly assessments during internship (change in PHQ-9 score = mean PHQ-9 depressive symptoms at 3-, 6-, 9- and 12-month assessments - PHQ-9 depressive symptoms at baseline)."(1), (p.E3) [It is to be noted that although the authors did not specifically use the term "primary outcome measure", they did use the change score as the dependent variable in all their major associational analysis as depicted in their Tables 2 and 3.] We have a number of issues with adopting this measure as the main outcome variable.
First, in their analysis, the authors have used "baseline depressive symptoms (PHQ-9 baseline score)" as an independent variable. But this variable is itself a computational part of their "dependent" variable (change score), and, hence, is not an "independent" variable after all. Accordingly, this analysis is flawed. Being a part of the dependent variable itself, it is not surprising that the "independent" variable of baseline depressive symptoms would be strongly (but spuriously) associated with the "dependent" variable; indeed, that is what was found, baseline depressive symptoms tautologically "predicting" maximum variance (ß = - 0.38) in the change-in-depression score (authors' Table 2). This could also perhaps explain the rather paradoxical finding that a lower baseline depressive symptom score would predict a greater change in depression scores during internship. The authors have not commented on this counterintuitive direction of the association.
Second, because there is a validated way to convert the PHQ-9 scores into clinically diagnosable major depression (PHQ-9 score = 10),(3) and because an appreciable proportion of the interns met this threshold at 3-, 6-, 9- and 12-months (27.1%, 23.3%, 25.7%, and 26.6% respectively, with a large proportion - 41.8% - having met the criteria during at least one quarterly assessment), we wonder if that could be a more clinically meaningful and statistically sound way of looking for who becomes clinically depressed. For example, a subject with a baseline score of 2 but a maximum within-internship score of 9 would generate a large change score but would still not have major clinical depression, while contributing heavily to the variance in the analysis conducted by the authors. On the other hand, another subject with a baseline score of 8 and within-internship score of 12 would still be clinically depressed (and perhaps need intervention) despite a much smaller magnitude of change. After all, a clinical diagnosis which meets criteria for major depression should be clinically a more meaningful outcome than a symptom change score. The authors did acknowledge the limitation of not using a diagnostic interview. Perhaps this way of handling the data could have partly offset this limitation and would be more meaningful and useful to the clinicians and administrators alike.
Thus, to us, it appears that there are issues with the current data analysis, and it may be worthwhile to (a) define the primary outcome as "number or proportion of subjects who developed major depression (PHQ-9 score = 10) during internship", (b) use this as a binary dependent variable (depressed vs. not depressed) in a multivariate logistic regression model, (c) explore significant associations between baseline, within-internship and genetic variables with this dependent variable, and finally (d) enter the significant variables from step (c) into step (b) to find important predictors of who become depressed versus who do not. Similarly, the gene x environment (GxE) interactions could also be explored within this framework.
Our second comment concerns the interpretation of the genetic data. The authors have stated that in European American subjects there was an association between at least one low-functioning variant of the serotonin transporter gene and an increase in depressive symptoms. There was, however, no such association found in Asian or other subjects, and the authors have not discussed this issue (lack of genetic association) further.
If we look at their Table 3 closely, however, a very interesting finding strikes us. In European American subjects there is a gradient of increasing depression scores along the gradient of functionality of the serotonin transporter gene, with the lowest increase in depressive symptoms in the high-high functional genotype, intermediate increase in the high-low group and the highest increase in the low-low group, which makes sense if we believe that the high-functioning variants of the gene somehow protects against depression (or against the depressogenic effect of stress). However, a different picture emerges when we look at the Asian data. Not only is there no such association as above, but also, actually, the high-high functioning genotype shows the maximum increase in depression scores during internship! This is obviously contrary to the hypothesis just mentioned above. Rather than simply glossing over this apparently paradoxical finding, we are reminded of a number of pharmacogenetic studies from Korea, Japan and other Asian Countries(4-7) that demonstrates that the low-functioning genotype of the serotonin transporter gene is actually associated with a better outcome with several antidepressants. This is again in contrast to the vast majority of studies from Caucasians that show a better or faster antidepressant response in those carrying the high-functioning variants.(8)
If we extrapolate these pharmacogenetic findings to the present data as mentioned above, it appears that the same counterintuitive findings are applicable to the Asian population as well, but this time related to the genesis of depression in a stressful environment rather than antidepressant response. Taken together, this could provide a further confirmation of the association of alleles of opposite functional effect (in this case, high- vs. low-functioning alleles of serotonin transporter gene) with the same phenotype (in this case, depression) in different race/ethnicities (Asian vs. European American, respectively). This "genetic flip-flop phenomenon"(9) can be due to several factors, including different patterns of linkage disequilibrium of the identified marker with other unidentified but causally important genes in different populations. This has also to be seen in the perspective that the prevalence of the low -functioning allele of the serotonin transporter gene itself varies widely between different geographic and ethnic populations, being much higher in Asian populations. It has recently been postulated that the higher prevalence of this allele in the Asian populations is associated with a higher collectivistic value (encouraging social harmony, norms and mutual support), and with a lower prevalence of mood and anxiety disorders, in these populations.(10) We suggest that rather than ignoring the apparently paradoxical finding in Sen et al.'s study(1), it can be taken on board as providing an important, if preliminary, input for further study in this new and exciting area of GxE research.
References
1. Sen S, Kranzler HR, Crystal JH, Speller H, Chan G, Gelernter J, Guille C. A prospective cohort study investigating factors associated with depression during medical internship. Arch Gen Psychiatry. 2010; 67(6): 557-565 (doi:10.1001/archgenpsychiatry.2010.41)
2. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self- report version of PRIME-MD: the PHQ primary care study, Primary Care Evaluation of Mental Disorders, Patient Health Questionnaire. JAMA. 1999; 282(18):1737-1744.
3. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001; 16(9):606-613.
4. Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG, Carroll BJ. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport. 2000; 11(1): 215-219.
5. Yoshida K, Ito K, Sato K, Takahashi H, Kamata M, Higuchi H, Shimizu T, Itoh K, Inoue K, Tezuka T, Suzuki T, Ohkubo T, Sugawara K, Otani K. Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry. 2002; 26: 383-386.
6. Kim H, Lim S-W, Kim S, Kim J-W, Chang YH, Carroll BJ, Kim DK. Monoamine transporter gene polymorphisms and antidepressant response in Koreans with late-life depression. JAMA. 2006; 296:1609-1618.
7. Kang RH, Wong ML, Choi MJ, Paik JW, Lee MS. Association study of the serotonin transporter promoter polymorphism and mirtazapine antidepressant response in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31:1317-1321.
8. Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry. 2010; 15(5): 473-500.
9. Lin P-I, Vance J-M, Pericak-Vance MA, Martin ER. No gene is an island: the flip-flop phenomenon. Am J Hum Genet. 2007; 80: 531-538. 10. Chiao JY, Blizinsky KD. Culture-gene coevolution of individualism- collectivism and the serotonin transporter gene. Proc R Soc B. 2010; 277: 529-537.
Debasish Basu, M.D. Munish Aggarwal, M.D. Department of Psychiatry, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India
No relevant conflicts of interest declared by authors.
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