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EDITORIAL

Mood Disorders and Medical Illness: A Major PublicHealth Problem

Despite efficacious and widely available antidepressantsand psychotherapeutic interventions, the psychosocial andmedical burden of depression is increasing. In fact, theWorld Health Organization projects that depression willcontinue to be prevalent, and by the year 2 020, will remaina leading cause o f disability, second on ly to cardiovasculardisease (Michaud et al 2001). Although we do not knowwith certainty why rates and disability associated withdepression are increasing, it is likely that this mooddisorder continues to be remarkably under-recognized andunder-treated. Depression frequently occurs in the context

of chron ic medical illness, and it is only relatively recentlythat the research community has turned its attention to therelationship between depression and chronic medical con-ditions. However, there is much work yet to be done. Therecently released Institute of Medicine report (2003) ac-knowledged dep ression as one of a number of chronicconditions that requires priority action, but did not addressthe importance of com orbid depression and medical ill-ness.

The relationship between depression and medical ill-nesses is complex. A chronically ill patient who also isclinically depressed may experience enhanced morbidity,a poorer prognosis, and even increased mortality from themedical diagnosis. Simply put, depression makes every-thing worse. But the association with depression goesbeyond the effects of comorbidity on the course andoutcome of a medical illness. A burgeoning body ofevidence has now demonstrated that the relationship be-tween depression and certain medical illnesses may indeedbe bidirectional in nature. Depression may be both a causeand a consequence of some medical illnesses, such ascardiovascular disease, stroke, HIV/AID S, cancer, andepilepsy.

In recognition of the need to increase awareness aboutthis topic and improve the quality of life for persons with

depression, the Depression and B ipolar Support Alliance,the w orld's largest patient advocacy organization, con-vened a two-day, multidisciplinary consensus conferenceon November 12, 20 02 in W ashington, DC. Nearly 50experts in the fields of psychiatry, cardiology, immunol-ogy, oncology, neurology, endocrinology, internal medi-cine, family medicine, federal health care agency p olicyand research, and patient advocacy participated in thisprocess. Formal presentations centered around the per-spectives and goals of the National Institutes of Health andthe Food and Drug Administration, the personal and

societal burden of depression and medical illness, and thepidemiology, mechanisms, diagnosis, treatment, andprognosis of depression in the context of cardiovasculardisease, cancer, HIV/AIDS , stroke, neurologic diseases,diabetes, osteoporosis, obesity, and chronic pain. Work-groups met to discuss specific issues related to these topicand on the second day, work group leaders presented theirfindings and facilitated open discussions from the group.

Burden of Mood Disorders and Medical

Illness

The fun ctional impairment associated with depressioncontributes significantly to the economic burden ofchronic medical illness. Depression also is becomingrecognized as a cause of increased morbidity and mortalitin chronic medical illness. As reviewed by Katon (2003)medical costs for patients with major depression areapproximately 50% higher than the costs of chronicmedical illness alone. In addition, Katon (20 03) und erscores the equally important, but often less appreciated,effects of depression on adverse h ealth behaviors, such asmoking, unhealthy diet, sedentary lifestyle, and poor

adherence to medical regimens (e.g., cardiac rehabilitation). The findings from a number of studies have estab-lished that major dep ression is associated w ith significanfunctional impairment, lost work produ ctivity, occupa-tional disability, and increased h ealth care resource utilization, and that effective treatment restores functioning.Simon (2003) reviews these data in the context of evi-dence from recent cross-sectional, longitudinal, and treatment studies of depressed patients with and withoutarthritis, chronic obstructive pulmonary disease, diabetesor heart disease. This emerging body of evidence de monstrates that depression significantly increases the burden o

functional impairment in medical illness, and that treatment reduces disability and health service costs. The effecof other mood d isorders, such as dysthym ia or bipolardisorder, on the burden of chronic medical illness isremarkably understudied.

Cardiovascular Disease

It is now recognized that m ajor depression and bipolardisorder are associated with increased rates of death from

2003 Society of Biological Psychiatry 006-3223/03/$30.00doi:10.1016/S0006-3223(03)00639-5


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coronary heart disease (CHD), and that major depressionor depressive symptoms increase the risk of incident CHD(Musselman et al 1998). As reviewed by Rudisch andNemeroff (2003), as many as 27% of patients with CH D

have m ajor depression, but a substantially larger numberof cardiac patients have subsyndromal depressive symp-toms. Depression is a particularly lethal development forpatients with acute myocardial infarction (MI). In theUnited States, there are approximately 150,000 deaths inthe first year after an initial MI, and Carney an d Freedland(2003) estimate that at least 90,000 of these deaths may berelated to post-MI depression. The cum ulative body ofevidence in support of an association between dep ressionand cardiovascular disease is large and impressive; Carneyand Freedland (2003) evaluate this literature and outlinefuture directions for research, including studies that will

better elucidate the role of depression in the developm entand progression of atherosclerosis, ischemia, and arrh yth-mias.

One particularly diverse and robust field of research isdedicated to better understanding the mechanism s thatunderlie the relationship between depression and cardio-vascular disease. In their paper, Joynt and colleagues(2003) overview seven probable mechanisms associatedwith depression that may be related to cardiovasculardisease: noncompliance w ith cardiac rehabilitation andmedical regimens; risk factor clustering (e.g., smo king,hypertension, diabetes, hy percholesterolemia, obesity);

hypothalamic-pituitary-adrenal (HPA) axis hyperactivityand cortisol elevation; decreased heart rate variability;elevated plasma levels of pro-inflammatory cytokinesleading to atherosclerosis; platelet activation and h yperco-agulability; and psychological stress.

The demonstrated adverse effect of depression on therisk of new and progression of established CHD hasspurred the nex t emergent area of clinical study in thisfield: the conseq uences of depression treatment on cardio-vascular morbidity and survival. As noted in the paper byRoose (200 3), findings from the few o pen-label or ran-domized, controlled clinical trials suggest that the selec-

tive serotonin reuptake inhibitors (SSRIs), bupropion, andcertain psychotherapeutic interventions are safe and effec-tive treatment of depression in patients with CH D. Th etricyclic antidepressants (TCAs) increase heart rate, causeorthostatic hypotension and conduction delays, have beenshown to increase the risk of cardiac mortality, and shouldbe avoided in this patient population. There is one pub -lished placebo-controlled trial, which suggests that SSRItreatment of depressed post-MI patients may improveoutcome and increase survival, but this study was notadequately powered to find significant changes in thesecardiac disease outcomes. Thus, it is still not known

wheth er treatment of depression enhances the outcom e othe cardiac disease. Further study is clearly needed.

Cancer

As with cardiovascular disease, there is a large andgrowing body of evidence in support of a relationshipbetween depression and cancer. Research efforts havefocused on depression as a risk factor for cancer, depres-sion as a consequence of cancer, and the dynamics ofcomorbid depression and cancer. Large population studiessuggest that depressed mood or stressful life events mayincrease the risk of cancer. Although it is acknowledgedthat these observations of increased risk may be due in pato earlier, undetected malignancies or factors other thandepression (Lillberg et al 200 3; Penninx et al 199 8), thefindings are compelling and further study is warranted.

Depression also is a common occurrence in patientswith a wide range of different malignancies and oftenprevents patients from complying with treatment regimensand other h ealth-promoting behaviors, thus worsening thprognosis. A diagnosis of cancer represents a significanlife stressor, which in vulnerable persons can precipitatan episode of depression. In addition, patients with cancemay develop "sickness behavior" or depressive syndromedue to proinflamm atory cytokine activation that is theresult of tumor cell burden , tissue destruction, radiationtreatments, and chemotherapy. The papers by Raison andMiller (2003) and Spiegel and Giese-Davis (2003) revi

the relationships between depression and cancer and offeinsight into disease progression and treatment. Of imme-diate clinical utility are th e findings of stud ies show inthat pretreatment with serotonergic antidepressants canprevent neurotoxicity and clinical depression in patienttreated with interferon-alpha.

HIV/AIDSMood disorders, including depression and mania, areprevalent in persons with human immunodeficiency viru(HIV) disease and may be associated with impaired

quality of life, neurocognitive and functional impairmentand poor ad herence to antiretroviral therapy. In additionemerging data suggest that dep ression is associated witdeclining CD4 cell counts, accelerated disease p rogression, and increased mortality. In their paper, Cruess andcolleagues (2003) discuss the negative impact of moodisorders on HIV/AIDS and review evidence for safetyand efficacy of antidepressants, mood stabilizers, andnovel pharmaco therapies in this population (Evans et a200 2a). Leserman (2003) also reviews this topic, but wia focus on the biological mechanisms underlying therelationship between m ood disorders and HIV d iseas


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and the immune effects that result from this comorbid-ity (Leserman et al 1997; Evans et al 2002b). Patientswith HIV/AIDS and comorbid depression are a signif-icantly underserved and understudied population. Fur-ther epidemiologic, biological, and therapeutic studiesare urgently needed to better understand the nature ofthis comorbidity, increase case-finding, and developeffective treatment strategies.

Neurologic DiseaseThis special issue also includes papers devoted to thetopics of depression and comorbid neurologic disorders,such as stroke, Parkinson's disease, Alzheimer's disease,and epilepsy. Of these neurologic disorders, the relation-ship between mood disorders and cerebrovascular acci-dents is particularly well-studied. As reviewed by Robin-son (200 3), depression is comm on in poststroke patients,with reported prevalence rates of approximately 20%;bipolar disorder is less common. There is no standardizeddiagnostic approach for poststroke depression, and thecontroversies surrounding various approaches are summa-rized by Robinson (2003). The findings of treatmentstudies showing efficacy of antidepressants, electrocon-vulsive therapy, psychostimulants, and cognitive behav-ioral therapy in patients with p oststroke depression are ofconsiderable clinical importance. Importantly, treatmentof depression improves measures of function and cogni-tion and may result in improved survival. Evidence that

antidepressants may prevent poststroke depression offershope.As with m any other medical comorbidities, depres-sion may increase the risk of stroke, and the findings oftwo large epidemiologic studies support the role of depres-sion as a risk factor for stroke. These findings furtherunderscore the importance of identifying the underlyingbiological mechanisms associated with depression comor-bidity.

Depression occurs in roughly half of patients withParkinson's disease and is associated with significantimpairment, including reduction in fine motor skills andcognitive function. In their paper, McDonald and col-

leagues (2003) review th e distinct presentation of depres-sion in this population, discuss the challenges associatedwith diagnosis, and highlight the need for more sensitivescreening and d iagnostic tools.

Depression in this population may not be due simply tothe disability and added life stressors associated withParkinson's disease. Rather, emerging evidence suggeststhat depression in th ese patients may be a consequence ofneurodegeneration. Treatment of depression in Parkin-son's disease is complicated by variable responses, sensi-tivity to adverse effects, and drug interactions. Random-ized, placebo-controlled trials, particularly of the SSRIs

and dopamine agents, are needed. The findings of func-tional neuroimaging studies are presented, which mayeventually lead to the improved understanding of theneurocircuitry of depression in Parkinson's disease.

Even though depression occurs in as many as 50% ofpatients with Alzheimer's disease, contributing to accel-erated functional and cognitive decline, impaired qualityof life, care-giver depression, and earlier institutionaliza-tion, surprisingly little evidence-base d data are available tinform diagnosis and treatment. The diagnosis of depres-sion in this cohort is particularly challenging becausesymptoms, such as psychomotor retardation, insomnia,and emotional liability, which occur in nondepressedpatients with Alzheimer's disease may be difficult todifferentiate from a true depressive episode. Moreover,symptoms of dementia may mask an underlying depres-sive disorder. In an effort to guide research and better

inform clinical care, the National Institute of MentalHealth has undertaken the task of developing diagnosticcriteria for depression in Alzheimer's disease. Lee andLyketsos (2003) review these developm ents and describan ongoing longitudinal study of depression and otherneuropsychiatric comorbidities in new cases of Alzhei-mer's disease, which will provide valuable information othe epidemiology, natural course, and diagnosis of depression in this population.

Epilepsy is another neurologic disorder that often iscomplicated by como rbid depression. As many as 50% oepileptic patients seen in tertiary treatment centers may

have depression, and suicidality among depressed epileptics have been reported to be as h igh as 10 times the ratethan in the general population. Kanner (20 03) reviews thchallenges related to diagnosing depression in epilepsy:patients often present with atypical depressive symptom(e.g., anxiety, irritability, hypomania, pain); the peri-ictalperiod often is associated with a recurrent and short-livedysphoria that is clinically significant but does not con-form to standard diagnostic criteria; and antiepilepticdrugs and su rgical intervention can be iatrogenic cause s odepression. Clearly, epilepsy is a risk factor for depres-sion; however, recent evidence suggests that depressionmay increase the risk for epilepsy by 4- to 6-fold. Furthestudies are needed to better characterize this complexrelationship.

Call for Action

The con tributions made by this conference and th e paperspublished in this special issue of Biological Psychiatryshould not simply be measured by th e quality and quantitof the data, wh ich are impressive. Rather, the strength othis publication also lies in the fact that the views ofexperts from widely divergent fields of clinical and scie


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tific endeavor resonate along 4 basic themes: 1) Depres-sion is very common in chronic medical illness; 2)Comorbidity with depression inevitably hinders recoveryand worsens prognosis; 3) Medical illness is a risk factorfor depression because of psychosocial stressors, func-tional impairment, and oth er biological mechanisms (e.g.,Parkinson's disease); and 4) Depression may figure prom-inently as an etiologic factor in the onset and course ofmedical illness, particularly cardiovascular disease, stroke,HIV/ AIDS, cancer, and epilepsy. The latter observation istruly remarkable. Much more research is needed to betterunderstand this bidirectional relationship and identifypossible common pathogenic, mechanistic pathways thatlink depression and serious medical illness.

These are pow erful messages that must no t be ignored.The w eight of evidence is so persuasive that there shou ldnever again be a valid reason for not aggressively seekingout and treating depression in medically ill patients.Increasing aw areness, reducing stigma, and maintaining ahigh level of vigilance for depression in medically illpatients must beco me a p riority for clinicians. In addition,the efforts of the research comm unities must continue tobetter elucidate the prevalence, risk profile, diagnosticcriteria, treatment, and biological underpinnings of thecomorbid relationship between depression and medicalillness. Only by furthering research efforts and aggres-sively diagnosing and treating depression, will we be ableto achieve substantive gains in health care and in ourpatients' quality of life.

Dwight L. Evans

Department of PsychiatryUniversity of Pennsylvania School of Medicine3 Blockley Hall423 G uardian DrivePhiladelphia, PA 19104-6021

Dennis S. Charney

Mood and Anxiety Disorders Research ProgramNational Institute of Mental HealthBethesda, Maryland

We acknowledge Sally K. Laden for editorial support.

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