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The Interaction of Major Depression and Medical Illness

Authors: Paul J. Perry, PhDFaculty and Disclosures



Depression presenting in the medically ill may represent 1 of these conditions:

  1. A major depressive episode independent of the medical condition;

  2. An adjustment disorder with depressed mood, precipitated by the stress of the medical illness;

  3. A secondary depression, where the medical illness precedes the depression and is felt to have an etiologic (pathophysiologic) relationship to the depression;

  4. Substance-induced depression in which alcohol, drug, or a prescription medication produces a depressed mood; or

  5. Depressive symptoms that are a normal response to being severely ill.

This symposium reviewed the interaction between major depression and the medical variables of stress, cardiovascular illness, adult-onset diabetes, stroke, and chronic pain.

Stress and Depression

Charles Raison, MD,[1] Assistant Professor of Psychiatry at Emory University in Atlanta, reviewed the mechanisms in the immune-stress system interactions to shed some insight on issues regarding diagnosis and treatment of depression in the context of medical illness. For some patients, precipitating stressors that occur early in life might lead to a diagnosis of adjustment disorder with depressed mood. This diagnosis is reversible on removal of the stressor and thus does not require a therapeutic intervention. However, the patient's subsequent exposure to multiple stressors may result in a hyperactive hypothalamic-adrenal-pituitary axis, taking a far greater toll on the patient because of the increased probability of being diagnosed with lifelong chronic depression.

A study by Musselman and colleagues[2] helps to illustrate this. Depression often complicates treatment with the cytokine interferon alfa-2b. However, animal models of antidepressant pretreatment of depression demonstrate less severe depression-like symptoms after the administration of a cytokine. This antidepressant treatment strategy was challenged in a randomized control trial of paroxetine vs placebo in 40 patients with malignant melanoma who were being treated with high-dose interferon alfa therapy. The antidepressant treatment was begun 2 weeks before the initiation of interferon alfa and continued for the first 12 weeks of therapy. During the first 12 weeks, the diagnosis of major depressive episode occurred less often in the paroxetine-pretreated patients. Two of 18 patients in the paroxetine group and 9 of 20 patients in the placebo group were diagnosed with major depression.

An item analysis by Capuron and Miller[3] of the depressive symptom changes in the Musselman study over the treatment period concluded that mood and/or cognitive symptoms of depressed mood, anxiety, and cognitive dysfunction improved while the neurovegetative symptoms of psychomotor retardation, fatigue, sleep disturbance, and anorexia did not. The improvement in the mood/cognitive symptoms was a function of increased central nervous system (CNS) serotonin levels, but improving the neurovegetative symptoms required an increase in CNS catecholamine levels. The clinical insight from these observations is that the dual receptor agonists of serotonin and norepinephrine, such as venlafaxine and duloxetine, would be preferable as antidepressants in the treatment of patients diagnosed with secondary major depression with comorbid medical illnesses.

Cardiovascular Disease and Depression

Frasure-Smith and colleagues[4] studied 222 consecutively admitted patients with acute myocardial infarction (MI). Individuals were interviewed and screened for major depressive disorder within 10 days of their MI. Major depressive disorder criteria were met by 35 of the 222 patients (16%), suggesting an interaction between major depressive disorder and cardiovascular disease. Further, patients with a diagnosis of major depressive disorder were 3.5 times more likely to have died at 6 months than nondepressed patients.

However, it is unknown from the study design whether major depression put patients at risk for an MI, or whether the MI led to the development of depression. The relationship was maintained after controlling for underlying cardiovascular disease severity, eliminating the chance that depression was showing up simply as a marker for severity of cardiovascular illness.

The Frasure-Smith study illustrates some of the different hypotheses and relationships between major depression and illness. The first hypothesis is, of course, the null hypothesis that there is no relationship. There are certainly disease states for which this is true. However, among cardiovascular patients and those with other diseases, including cancer, there appears to be a relationship. The question becomes, What is the nature of the relationship?

One hypothesis is that depression occurs as a reaction to being medically ill. This may be either an emotional or physical reaction to the medical illness. The Frasure-Smith data potentially support this hypothesis in that having an MI placed patients at risk for becoming depressed. Patrick R. Finley, PharmD,[5] Professor of Clinical Pharmacy, University of California at San Francisco, tried to indirectly answer the most clinically relevant question about the prophylactic use of antidepressants in patients with cardiovascular disease: Does prophylactic treatment with an SSRI antidepressant decrease the morbidity and mortality following an MI?

Finley proposed that recently available data from Taylor and colleagues[6] provide a suggestive but not a definitive answer to this question. The Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial randomized 2481 depressed and/or socially isolated patients from 1996 to 1999. A posthoc secondary analysis was conducted on the 1834 patients enrolled with depression (849 women and 985 men) who either received or did not receive antidepressant treatment. The investigators tried to determine whether exposure to antidepressants reduced subsequent morbidity and mortality.

During a mean follow-up of 29 months, 457 cardiovascular events occurred. The risk of death or recurrent MI was significantly lower in patients taking selective serotonin reuptake inhibitor (SSRI) antidepressants, as were the risk of all-cause mortality and recurrent MI, compared with patients who did not use SSRIs; the above risks were similar for patients taking non-SSRI antidepressants and nonusers. The authors concluded that use of an SSRI in depressed patients who experience an acute MI might reduce subsequent cardiovascular morbidity and mortality, although a controlled trial is still needed to examine this important issue.

Stroke and Depression

Michelle Y. Splinter, PharmD,[7] Clinical Associate Professor of Clinical Pharmacy, University of Oklahoma, reviewed the current evidence-based data on whether antidepressant treatment of depression in patients suffering strokes was beneficial. Another hypothesis about depression and medical illness is that depression occurs through the same biological mechanisms as the underlying disease. Vascular depression is an example. This hypothesis originates from the observation that major depressive disorder is commonly associated with hypertension, diabetes, coronary artery disease, and stroke. The hypothesis revolves around the impression that the vascular lesions occurring in the peripheral system associated with vascular medical illnesses also occur in the brain. These vascular lesions lead to the production of depressive symptoms.

The hypothesis has several important implications for medical treatment. First, it is unknown whether aggressive screening for and treatment of medical illnesses with antihypertensive agents, cholesterol-lowering agents, or antiplatelet drugs will also prevent or reduce the risk of vascular depression. Second, if depressive symptoms can stem from central vascular lesions, a mechanism that probably differs in patients with lifelong depressions, can we expect traditional antidepressant treatment to produce an equivalent clinical response for vascular depression?

An example of this important treatment implication is in post-stroke depression (major depression or minor depression and a baseline Hamilton Depression [HAMD] score ≥ 12).[8] In this randomized controlled trial, the investigators treated 104 depressed (DSM-IV) and nondepressed acute stroke patients with either nortriptyline up to 100 mg per day, fluoxetine 40 mg per day, or placebo. Nondepressed patients were included in this study to determine whether administering an antidepressant to nondepressed post-stroke patients would improve outcomes and recovery.

Among the nortriptyline-treated depressed patients, the HAMD scores were reduced from 22.5 at baseline to a mean of 9.0 at endpoint. By contrast, patients treated with fluoxetine went from a baseline HAMD score of 20.4 to an endpoint of 18.5, suggesting very little therapeutic impact. The placebo patients' scores decreased from a baseline of 17.5 to an endpoint of 12.2. Therefore, it was concluded that nortriptyline was more effective than either fluoxetine or placebo in the treatment of post-stroke depression. The results of this study reinforce the important implication that patients with late-onset depression, in this case post-stroke, may have a differential response to traditional antidepressants.

Diabetes and Depression

The prevalence of depression among individuals with diabetes ranges from 8.5% to 27.3%. Severity of depression correlates strongly with many diabetic symptoms.[9] The hydrazine monoamine oxidase inhibitor (MAOI), phenelzine, exacerbates hypoglycemia due to its hydrazine structure affecting glucogenesis. However, MAOI increase in dopamine and norepinephrine may result in hyperglycemia. Additionally, serotonergic agonist drugs such as SSRI antidepressants lower blood glucose. Clinically, they may cause as much as a 30% decrease in fasting plasma glucose and have an anorectic effect (causing weight loss of about 2 pounds), while possibly improving alertness.

The evidence from randomized clinical trials supporting the use of serotonin agonist drugs specifically in the treatment of depression in diabetic patients is minimal. A small 10-week randomized controlled trial found paroxetine 20 mg per day similar to placebo in the treatment of 15 mildly depressed women with non-optimally controlled type 2 diabetes.[10] However, there was a trend for superior efficacy of paroxetine in clinician-rated anxiety and depression.

Despite these findings, paroxetine was approved by the FDA for the treatment of acute major depressive disorder (for adults only). Thus, one must surmise that a significant amount of unpublished positive data was made available to the FDA to support the indication. A larger randomized controlled trial of 60 insulin-dependent diabetics with significant depressive symptoms and diabetic neuropathies found that a 10-week course of the tricyclic antidepressants imipramine or amitriptyline 100 mg/day was effective in reversing both disorders.[11] Both of these tricylics inhibit both norepinephrine and serotonin reuptake. Thus, from a theoretical frame of reference, because depression is frequent among diabetic patients and impairs diabetic management, to maximize response of both depression and diabetic disorder, one should consider the SSRIs over the tricyclic antidepressants.

Neuropathic Pain and Depression

Lori Reisner, PharmD,[12] Professor of Clinical Pharmacy, University of California at San Francisco, reviewed the association between pain and depression. She specifically addressed her comments to neuropathic pain (pain resulting from a lesion or dysfunction in the nervous system) rather than nociceptive pain (pain in response to tissue damage).

To illustrate the importance of the association of chronic pain and depression, the work of Currie and Wang[13] was cited as an example. The investigators estimated the prevalence and correlates of major depression in persons with chronic back pain using data from a sample of 118,533 household residents. The prevalence of chronic back pain was estimated at 9% in persons 12 years and older. Rates of major depression were estimated at 5.9% for pain-free individuals and 19.8% for persons with chronic back pain.

The rate of major depression increased in a linear fashion with greater pain severity. Back pain emerged as the strongest predictor of major depression after adjusting for possible confounding factors such as demographics and medical comorbidity. The combination of chronic back pain and major depression was associated with greater disability than either condition alone, although pain severity was found to be the strongest overall predictor of disability.

Reisner pointed out that an examination of the mechanism of analgesic action for the treatment of neuropathic pain revealed that tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors such as venlafaxine and duloxetine were the only analgesics effective at the levels of the autonomic nervous system, spinal cord, and CNS. The strength of the analgesic effect was apparent in that the number needed to treat to see a difference between these effective drugs and no effective drugs was only 3.

Clinical trial evidence suggests that the tricyclics are likely effective in the treatment of diabetic neuropathies, postherpetic neuralgia, fibromyalgia, back pain, and migraine. There is less overall supporting evidence for venlafaxine and duloxetine. However, because the mechanism of action on serotonin and norepinephrine for these 2 latter drugs is the same as that for the tricyclics, it is reasonable to assume they ought to be similarly effective in these disorders. When the neuropathic pain is accompanied by a diagnosis of major depression, the use of these drugs can help the clinician avoid the hazards of polypharmacy in treating these dual conditions.


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  2. Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961-966.
  3. Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry. 2004;56:819-824.
  4. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA. 1993;270:1819-1825.
  5. Finley P. Depression and cardiovascular disease. Program and abstracts of the American College of Clinical Pharmacy 2005 Annual Meeting; October 22-26, 2005; San Francisco, California.
  6. Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry. 2005;62:711-712.
  7. Splinter M. Depression and stroke. Program and abstracts of the American College of Clinical Pharmacy 2005 Annual Meeting; October 22-26, 2005; San Francisco, California.
  8. Robinson RG, Schultz SK, Castillo C, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Am J Psychiatry. 2000;157:351-359.
  9. Goodnick PJ, Henry JH, Buki VM. Treatment of depression in patients with diabetes mellitus. J Clin Psychiatry. 1995;56:128-136.
  10. Paile-Hyvarinen M, Wahlbeck K, Eriksson JG. Quality of life and metabolic status in mildly depressed women with type 2 diabetes treated with paroxetine: a single-blind randomised placebo controlled trial. BMC Fam Prac. 2003;4:7.
  11. Turkington RW. Depression masquerading as diabetic neuropathy. JAMA. 1980;243:1147-1150.
  12. Reisner L. Depression and Pain. Program and abstracts of the American College of Clinical Pharmacy 2005 Annual Meeting; October 22-26, 2005; San Francisco, California.
  13. Currie SR, Wang J. Chronic back pain and major depression in the general Canadian population. Pain. 2004;107:54-60.
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