Vol. 22, No. 4 / November 2010

Major depressive disorder and other medical illness: A two-way street

•INTRODUCTION
•MDD: EFFECT ON CONCURRENT MEDICAL ILLNESS
•MDD AND CVD
•COMORBID MEDICAL ILLNESS: EFFECT ON MDD OUTCOMES
•PATHOPHYSIOLOGY OF MDD AND CHRONIC MEDICAL ILLNESS
•PREFRONTAL CORTEX AND MDD
•EMOTIONAL STRESS, MDD, AND MEDICAL ILLNESS
•TREATMENT OF MDD: IMPROVED CHRONIC MEDICAL CONDITION OUTCOMES
•CONCLUSION
Philip R. Muskin, MD 

Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons; Chief, Consultation-Liaison Psychiatry, Columbia University Medical Center; Faculty Psychoanalyst, Columbia University Psychoanalytic Center 

Dr Muskin participates in speakers bureaus on behalf of AstraZeneca, Bristol-Myers Squibb, and Jazz Pharmaceuticals and is a retained consultant for Otsuka America Pharmaceutical, Inc.

Table of Contents

Switch or augment? Lessons from STAR*D

Switching, combination, and augmentation strategies for major depressive disorder

Major depressive disorder and other medical illness: A two-way street

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INTRODUCTION

Major depressive disorder (MDD) is exceedingly common, with a lifetime prevalence of over 15% in the United States.1 Patients with chronic medical conditions are at increased risk for developing MDD at some point during their lifetimes; in fact, 10% to 30% of patients with chronic medical illnesses have concurrent MDD.1,2 Additionally, many patients with MDD have ≥1 chronic medical illnesses. In clinical practice, this means many psychiatrists will encounter patients with MDD who have coexistent chronic medical conditions.3 Therefore, psychiatrists need to have an understanding of the pathophysiologic connections between MDD and chronic medical illnesses, and to coordinate the care of these patients with primary care physicians and other medical specialists.

A growing body of evidence describes the relationship between medical illness and MDD as bidirectional. MDD increases a patient’s risk for developing a medical illness and worsens the prognosis of comorbid medical illnesses, while having a medical illness puts patients at increased risk for developing MDD.3 This phenomenon has been most extensively studied in cardiovascular disease (CVD), and recent evidence points to a bidirectional relationship between MDD and diabetes and obesity.3-5

Potential biologic mechanisms that link MDD to chronic medical illnesses have been proposed but have yet to be fully elucidated. Besides attempting to answer the question of mechanism and causation, studies have also been addressing whether interventions aimed at modifying factors associated with one illness will positively affect comorbid illnesses as well.3

MDD: EFFECT ON CONCURRENT MEDICAL ILLNESS

The presence of MDD in patients with chronic medical illness has been shown to negatively affect symptom burden, functional impairment, adherence to self-care regimens, and cost of health care services.2 Additionally, MDD has been shown to be associated with poor prognosis and higher mortality rates in patients who have concurrent medical illnesses, even when controlling for the severity of illness6-9 (TABLE).10-17 Ludman et al demonstrated that the overall number of diabetic symptoms a patient reported was related to the number of depressive symptoms he or she experienced (FIGURE 1).18 Von Korff et al found that health-related quality of life for patients with MDD was strongly related to the presence and severity of depressive symptoms and only weakly related to the number of diabetes complications or the presence of other medical comorbidities (FIGURE 2).19 One study demonstrated that a diagnosis or history of MDD independently predicted the odds of mortality for inpatients who were hospitalized for a medical condition (FIGURE 3).9


TABLE 1
Impact of depression on cardiovascular disease

Cardiovascular illness

Impact

Citation

Diabetes

2x increased risk of type 2 diabetes

Golden et al, 200410

Hypertension

Up to 3x increased risk of morbidity

Jonas et al, 199711

Stable coronary artery disease

3x increased risk of MACE

Frasure-Smith et al, 200812

Ischemic cardiac events (fatal or nonfatal MI,
angina pectoris)

3x increased risk of first ischemic event

Bremmer et al, 200613

Unstable angina

3x increased risk of cardiac death,
6x increased risk of nonfatal MI

Lespérance et al, 200014

Cerebrovascular accident (CVA)

3x increased risk of CVA

Larson et al, 200115

Post—myocardial infarction

2x-3x increased risk of mortality

Carney et al, 200916

Congestive heart failure

8x increased risk of mortality

Jünger et al, 200517

MACE, major adverse cardiac event (cardiac death, MI, cardiac arrest, nonelective revascularization); MI, myocardial infarction.

FIGURE 1 Depression and severity of physical symptoms

Reproduced with permission from Ludman et al. Gen Hosp Psychiatry. 2004;26(6):430-436.

The number of diabetes symptoms correlated strongly with the number of symptoms of depression and only weakly with diabetes severity. N=4168 patients with diabetes. Major depressive disorder (MDD) symptoms were assessed using the Patient Health Questionnaire. Diabetes symptoms included numbness in hands or feet, cold extremities, pain in hands or feet, polyuria, blurred vision, feeling faint, and daytime sleepiness.

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FIGURE 2 Depression and health-related quality of life

Adapted from Von Korff et al. Psychosom Med. 2005;67(2):233-240.

A poor health-related quality of life (HRQoL) correlated strongly with symptoms of depression and only weakly with diabetes complications or other medical comorbidity. N=4357 patients with diabetes. Major depressive disorder (MDD) symptoms were assessed using the Patient Health Questionnaire. Major depression is defined as the presence of at least 5 of 9 MDD symptom criteria more than half the days in the past 2 weeks, and 1 of the symptoms is depressed mood or anhedonia.

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FIGURE 3 Depression and mortality in medically ill patients9

A diagnosis of major depressive disorder (MDD) based on criteria modified for patients with medical illness better predicted in-hospital mortality than a diagnosis based on inclusive criteria or a past history of MDD.9

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MDD AND CVD

Numerous studies have investigated the effect of MDD on patients with CVD. Post–myocardial infarction (MI) depression has been found to be an independent predictor of increased mortality, even after controlling for the effects of established post-MI predictors of morbidity and mortality, such as left ventricular ejection fraction.20 Patients with MDD after an acute MI have been shown to have a much greater mortality rate than similar patients who are not depressed.21 MDD is associated with a 3- to 4-fold increase in cardiac mortality over the first 18 months post-MI.7 The Montreal Heart Study found that long-term survival after MI decreased as depressive symptoms during hospitalization increased, as measured by the Beck Depression Inventory (BDI). This study also demonstrated that the level of depressive symptoms measured by the BDI at the time of admission for MI was related to long-term survival independent of other established prognostic factors. An increased risk of cardiac mortality was demonstrated with BDI scores below the usual cutoff for mild depression (FIGURE 4). The study found that using the BDI to measure depressive symptoms 2 days post-MI was more predictive of cardiac mortality than measuring them 1 month or 1 year post-MI.22

Post-MI depression is common; approximately 1 out of 6 patients experiences MDD post-MI.21 Patients who experience depressive symptoms while hospitalized during the days after MI should be thoroughly evaluated and closely followed. If these patients’ depressive symptoms persist, they should be prescribed antidepressant therapy by their psychiatrists, internists, or cardiologists. In addition to having an increased risk of death, depressed patients are less likely to adhere to medical regimens, exercise, or eat healthful diets. Thus, treating MDD post-MI has many potential benefits.21

FIGURE 4 Single greatest predictor of cardiac death over 5 years is depression score in hospital after heart attack22

Long-term survival (days post-discharge) after myocardial infarction (MI) in relation to Beck Depression Inventory (BDI) score during hospitalization.22

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COMORBID MEDICAL ILLNESS: EFFECT ON MDD OUTCOMES

The presence of comorbid illness significantly affects the course of MDD. Patients who have a medical illness in addition to MDD have worse depression outcomes, including more chronic depression, incomplete recovery, and more relapses.23,24 They also require more time to recover from depressive episodes.25 One recent meta-analysis suggested that obesity (body mass index ≥30) increased the risk of onset of depression by 55%; in the same analysis, depression increased the risk of developing obesity by 58%, highlighting the reciprocal nature of MDD and medical illness.4 The presence of multiple comorbid disorders can exacerbate these issues for psychiatrists; Rush et al found that as the number of concurrent medical conditions increased, the odds of achieving remission from MDD decreased (FIGURE 5).26

FIGURE 5 Number of concurrent medical conditions predicts decreased chance of remission26

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PATHOPHYSIOLOGY OF MDD AND CHRONIC MEDICAL ILLNESS

Studies on the biology of depression have revealed that multiple neurochemical, neuroendocrine, and neuroanatomical alterations exist in MDD (FIGURE 6).27,28 Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis results in hypersecretion of corticotropin-releasing factor and increased synthesis and release of corticotropin (ACTH), ß-endorphin, and other pro-opiomelanocortin products from the anterior pituitary gland. Additionally, dysregulation of the sympathoadrenal system in patients with MDD can lead to hypersecretion of catecholamines, including norepinephrine, from the adrenal medulla.27 Increases in cortisol and norepinephrine have been associated with increased visceral fat, insulin resistance, increased inflammation, enhanced blood coagulation, deficient fibrinolysis, decreased bone formation, and increased bone resorption. Consequently, depression can affect comorbid medical conditions, including coronary artery disease, diabetes, and osteoporosis.28

Documented responses to dysregulation of the sympathoadrenal system include diminished heart rate variability, ventricular instability, myocardial ischemia in response to emotional stress, and alterations in platelet receptors and reactivity. Some of these pathophysiologic alterations can lead to vulnerability to CVD.27 Cellular adhesion molecules of the selectin family and immunoglobulin group, including intercellular adhesion molecule-1 (ICAM-1), mediate the attachment of monocytes and lymphocytes to endothelial cells. The inflammation process in the vessel wall is reflected by levels of soluble adhesion molecules and predicts cardiovascular events in healthy populations. Hopelessness seems to function independently of depression as a negative risk factor in CVD, and has been shown to correlate with levels of soluble ICAM-1, a marker for endothelial dysfunction.29

This type of research may provide a link to how psyche translates to soma. On a cellular level, increases in norepinephrine can lead to increased levels of nuclear factor-κB (NF-κB), which has been shown to be a marker for cellular oxidative stress.30 NF-κB plays an important role in the regulation of genes that relate to the development of chronic illnesses such as CVD and diabetes.31 There is also evidence that MDD is associated with the increased expression of proinflammatory cytokines, including tumor necrosis factor (TNF) α, interleukin (IL)-6, and IL-1.5,28 Additionally, an association between MDD and increased levels of the inflammatory marker C-reactive protein (CRP) has been noted.28 High-sensitivity CRP has been shown to be associated with an increased risk of CVD and cardiovascular mortality.32 Future studies on how activation of inflammatory pathways in depression and chronic diseases like CVD are related will help clarify the link between MDD and chronic medical conditions.

FIGURE 6 Pathophysiology of psychosocial stressors or MDD in chronic medical illness

Adapted from Musselman et al. Arch Gen Psychiatry.1998;55:580-592; and Gold PW, Charney DS. Am J Psychiatry. 2002;159:1826.

ACTH, corticotropin; Epi, epinephrine; MDD, major depressive disorder; NE, norepinephrine.

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PREFRONTAL CORTEX AND MDD

Another possible mechanism by which MDD affects the pathophysiology of many systems may be its effects on the prefrontal cortex.28 There is evidence that patients with MDD have a loss of cells in the prefrontal cortex. The prefrontal cortex exerts control over many regions, including the amygdala through regulation of the HPA axis and the sympathetic nervous system. The amygdala performs the primary role in processing and memory of emotional reactions.28 One study demonstrated that patients with MDD treated with antidepressants who responded to treatment had decreased prefrontal cortical activity, while patients who improved with placebo had increased prefrontal cortical activity. Nonresponders in both treatment arms, however, had the same amount of prefrontal cortical activity.33 Studying involvement of the prefrontal cortex and its effect on biochemical pathways may shed further light on the connections between emotional stressors, including MDD and chronic medical illnesses.28

EMOTIONAL STRESS, MDD, AND MEDICAL ILLNESS

A study of almost 25,000 people from around the world found that stress was associated with an increased risk of MI. MDD was found to be one of the stressors that predicted MI in these patients.34 Multiple studies have investigated potentially harmful pathophysiologic effects of emotional stress and have shown that emotional stress can have a significant negative effect on cardiovascular health.35 Two studies followed patients with implantable cardioverter defibrillators (ICDs) before and after the September 2001 World Trade Center attacks. The frequency of ventricular arrhythmias significantly increased after the attacks in patients in both New York City and Gainesville, Florida, thus demonstrating that even patients outside the immediate location of the attacks had changes in cardiovascular functioning. These changes possibly resulted from the effects of increased levels of emotional stress.36,37

Chronic stress has been shown to lead to abnormally elevated concentrations of cortisol. Glucocorticoids inhibit the HPA axis in the short term, yet the chronic action of glucocorticoids can stimulate the brain, leading, for example, to a heightened importance of pleasurable activities, such as the ingestion of “comfort foods” during emotional stress.38 Consumption of comfort foods can lead to abdominal obesity, which increases the risk of developing diabetes, which in turn may increase the risk of developing MDD. Overeating often can be a sign of MDD. This further demonstrates the complex cyclical or bidirectional relationship between emotional stressors such as MDD and medical illnesses such as CVD and diabetes.38

TREATMENT OF MDD: IMPROVED CHRONIC MEDICAL CONDITION OUTCOMES

Treating MDD in patients with chronic medical conditions raises a number of questions. One is whether treating MDD has an effect on prognosis and outcome of coexisting medical illnesses.

A recent Cochrane review compared antidepressant therapy with placebo in a large number of patients with coexistent MDD and medical illnesses. Review of 44 studies that included 3372 patients demonstrated that antidepressants were superior to placebo for treating MDD in patients with chronic illness.39 The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial demonstrated that citalopram was superior to placebo in patients with MDD and coronary artery disease.40 The Sertraline Antidepressant Heart Attack Trial (SADHART) demonstrated that sertraline was safe and effective for the treatment of depression in the setting of recent MI or unstable angina. Overall response rates were not statistically different for sertraline compared with placebo in terms of left ventricular ejection fraction, the primary outcome measure, suggesting that medication neither improved nor worsened cardiac function. Statistically significant improvement was demonstrated for the secondary outcome measures of improvement in depression in more severely depressed patients and in patients with prior depressive episodes for sertraline compared to placebo.8 Nelson et al demonstrated that patients with MDD and ischemic heart disease had significant improvement of depression post-MI with both nortriptyline and paroxetine.41 A study of the use of sertraline in patients with diabetes mellitus showed that maintenance therapy with sertraline prolonged depression-free intervals following remission of MDD. Finally, a study by Lustman of patients with MDD and diabetes demonstrated that achieving sustained remission with or without treatment was associated with improved glycosylated hemoglobin levels for at least 1 year.42

Adding pharmacologic treatment for MDD to what are often complex treatment regimens for chronic medical disease increases the chances of drug-drug interaction. In addition, some agents used to treat MDD may have specific properties or adverse effects that could negatively impact certain chronic comorbid conditions.43 For example, some antidepressants and antipsychotics approved for use in MDD may lead to increased risk of weight gain, limiting their use in patients who are overweight or obese.44

Treatment of MDD in patients with chronic medical conditions should take into account the potential adverse effects of adding antidepressant medications. When medication choices are carefully considered, however, treating MDD in the presence of comorbid medical illnesses can be safe and effective.

CONCLUSION

The existence of MDD and/or emotional stress affects the course of chronic comorbid illnesses, and, conversely, chronic illnesses can lead to MDD. There is evidence that this is a bidirectional phenomenon and that biochemical and anatomic alterations, including increased levels of cortisol and norepinephrine and the loss of prefrontal cortical cells, may be markers for underlying pathophysiologic abnormalities that link MDD with chronic illnesses. Treating MDD that occurs in the presence of chronic medical illness may improve the course of both the depression and the medical illness. Psychiatrists should work together with internists and appropriate medical specialists to decide on best management strategies for MDD and chronic medical conditions when they coexist. MDD, emotional stress, and chronic illness are related in a complex manner, with many pathophysiologic underpinnings yet to be fully described. Interventions that decrease emotional stress and those that treat MDD may improve patients’ psychological and physical well-being.

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