Retrospective studies have established a strong correlation between reports of life stress and depression. Investigators have begun to further explore this relationship by examining the role of gene x stress interactions in the pathogenesis of depression. In a recent landmark study, Caspi and colleagues (2003) reported an interaction between a serotonin transporter promoter polymorphism and life stress in the development of depression. This finding has been replicated in some but not all follow up studies. Despite the initial promise of these results, the ability to draw definitive conclusions is compromised by significant study design limitations: 1) retrospective design 2) a focus on acute rather than chronic stress 3) substantial variation in the character and intensity of stress between subjects. Medical internship is a period filled with predictable and high levels of chronic uncontrolled stress. Rates of depression among interns are elevated compared to the general population. In this study, we aim to utilize the predictable and consistent stress of internship to investigate the relationship between stress, genes and depression with a prospective study design that bypasses some of the pitfalls of previous studies.

Specific Aims Retrospective studies have established a strong correlation between reports of life stress and depression. Investigators have begun to further explore this relationship by examining the role of gene x stress interactions in the pathogenesis of depression. In a recent landmark study, Caspi and colleagues (2003) reported an interaction between a serotonin transporter promoter polymorphism and life stress in the development of depression. This finding has been replicated in some but not all follow up studies. Despite the initial promise of these results, the ability to draw definitive conclusions is compromised by significant study design limitations: 1) retrospective design 2) a focus on acute rather than chronic stress 3) substantial variation in the character and intensity of stress between subjects. Medical internship is a period filled with predictable and high levels of chronic uncontrolled stress. Rates of depression among interns are elevated compared to the general population. In this study, we aim to utilize the predictable and consistent stress of internship to investigate the relationship between stress, genes and depression with a prospective study design that bypasses some of the pitfalls of previous studies.

Goal 1) Assess the prevalence and development of depression among medical interns

Although small studies have assessed the point prevalence of depression among medical residents, no study has prospectively followed the development of depressive symptoms through residency. We will collect baseline psychological profiles of incoming interns prior to the commencement of residency duties and subsequently assess for depressive symptoms at 3-month intervals throughout internship. This data will allow us to:

1. Assess the point prevalence of depression among interns in a large sample.
2. Determine the change in depressive symptoms through the course of the intern year
3. Evaluate stable psychological factors that associate with the development of depression in the face of life stress.

Goal 2) Evaluate the presence of genotype x stress interaction among this sample

1. There is conflicting evidence concerning the presence of an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and life stress in the development of depression. We will assess the presence and strength of this interaction in the sample of medical interns using a study design that avoids many of the pitfalls affecting previous studies.
2. We will explore novel putative interactions between stress and genetic variants in additional genes including BDNF, CRH, COMT, serotonin 1A and serotonin 2A receptor variants in the development of depression.

Goal 3) Evaluate the relationship between serum endothelial and immune factors and the development of depressive symptoms under stress.

The identification biomarkers that predict the onset of depression can facilitate more timely and accurate identification of individuals at high risk for the disorder. Unfortunately appropriate studies are lacking, largely because it is difficult to know exactly when a depressive episode will occur. Medical internship represents a rare situation where we can prospectively predict when a cohort of individuals shift will shift from a low stress environment to a high stress environment and thus predict when this cohort will experience a dramatic increase in depressive symptoms.

Goal 4) Examine the temporal relationship between hair cortisol levels, stress exposure and development of depressive symptoms.A novel technique allows us to assess chronic HPA axis activity by measuring cortisol in the growing hair, providing an integrated measure of total cortisol secretion over extended periods of time (1-3 months).

By incorporating this novel method into an established longitudinal study of a chronic stressor that dramatically increases rates of depression, we have a unique opportunity to determine a) whether cortisol levels prior to stress exposure predict risk of depression in response to the stressor (b) whether cortisol rise in response to stress exposure precedes and perhaps contributes to development of depressive symptoms or whether cortisol elevations in depression develop after symptom onset and perhaps reflect a consequence of depression.

Inclusion Criteria:

• Subjects for our study will be drawn from incoming interns in the traditional and primary care internal medicine, general surgery, pediatrics, obstetrics/gynecology, neurology and psychiatry residency programs at participating University and Community residency programs, as well as fourth year medical students at participating medical schools.

Exclusion Criteria:

• None.

Medical internship is an attractive model to bypass some limitations of previous studies. Internship is well chronicled as a time of high stress (Butterfield 1988; Addison et al 2004). Interns are faced with long work hours, sleep deprivation, loss of autonomy and extreme emotional situations (Shanafelt & Habermann 2002). Many physicians recall internship as among the most stressful years of their lives (Duffy 2005). The stress of internship is often uncontrollable, unpredictable and chronic; features that are particularly linked to the development of depression (Kendler et al 2003; Cryan et al 2004). Several studies have estimated the point prevalence of depression among interns at 28%-37% (Valko & Clayton 1975; Reuben 1985; Cohen et al 2006), in contrast to a point prevalence of 5% in general population (Murphy et al 2000). There is also evidence that physicians have underlying personality traits that predispose to depression (McDonough 1990; Hojat et al 1999).