Depressive Disorders in the Medically Ill

Depressive Disorders in the Medically III An Overview EDWIN

H.

CASSEM,

M.D.

Depressive disorders are far more serious than most people realize, and depressive disorders are disabling affected persons progressively earlier in life. Heavy utilization of medical services, extensive disability and morbidity, and high suicide risk exact a staggering economic toll in the United States annually. Depressive illness is, like pneumonia and septic shock, a dread complication of major medical illness, and depressive illness appears more frequently as the medical illness worsens; diseases affecting the brain may have the highest rates of depressive symptoms. Correctly diagnosing a depressive disorder in a medically ill patient is a clinical challenge that requires systematic, persistent clinical scrutiny. Compassion demands that depressive disorders, when diagnosed, be treated aggressively. (Psychosomatics 1995; 36:S2-S 10)

N

early one in every five Americans will be afflicted with a mood disorder during their lifetime. In what are likely the most accurate epidemiologic statistics ever gathered so far, the National Comorbidity Survey I documents that the prevalence of psychiatric disorders in the United States is greater than previously thought, with at least 48% of Americans having had at least one lifetime disorder. The lifetime and 12-month prevalences of mood disorders are shown in Table 1. 2 The significant correlates for primary major depression found in this study included the following: being female; having a lower level of education; being separated, widowed, divorced, or never married; being employed as homemaker or "other"; being between the ages of 15 and 24 years; being Dr. Cassem is chief. Depanmenl of Psychiatry. Massachusetts General Hospital. Address reprint requests to Dr. Cassem, Chief. Depanment of Psychiatry. Massachusetts General Hospilal. Bullfinch. Third noor. Fruit Street, Boslon. MA 02114. Copyright © 1995 The Academy of Psychosomatic Medicine.

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Hispanic; earning less than $20,000 per year; and living with a person other than a spouse. The National Comorbidity Survey included only persons under age 55, so there remains some controversy as to rates of major depression among individuals over age 55. Although the Epidemiologic Catchment Area (ECA) study suggests that rates of depressive disorders in older individuals are generally lower than in younger individuals,3 a study by Burke et al. 4 suggests a dramatic rise in the onset of major unipolar depression in persons over age 84. This surge possibly is due to the high likelihood that medical illness complicates these later years. Dysthymia, much less thoroughly studied than major depression, may have more in common with major depression than previously thought. Ravindram et al. 5 reported significantly lower tritiated serotonin levels in dysthymic patients than in normal control subjects. In the only published randomized, controlled trial of antidepressant treatment in dysthymia, Hellerstein et al. 6 demonstrated in an 8-week, double-blind, randomized study of fluoxetine PSYCHOSOMATICS

Cassem

vs. placebo that f1uoxetine produced significantly greater improvement in Hamilton Rating Scale for Depression and Clinical Global Impressions scores, but no significant improvement in Symptoms Checklist-58 or Cornell Dysthymia Scale scores. Marin et al./ in an open 8-week trial of 42 patients with dysthymia and 33 patients with "double" depression, showed that desipramine produced complete or partial remission in 70% of patients with dysthymia and 52% of patients with double depression. In another recent study, Markowitz8 reported promising results using interpersonal psychotherapy to treat patients with dysthymia. Primary major depression has several distinctive characteristics. First, it is a chronic condition whose nature is to recur. If a patient has a first episode, there is a 50% chance that a second episode will occur; after a second episode, the chances of a third episode rise to between 80% and 90%.9 Second, the rates of major depression are changing with each successive decade, that is, earlier onset and higher rates at younger ages (Figure 1).10 For example, a medical student in the 1945-1954 birth cohort had twice as great a risk for major depression as did a student the same age a decade earlier. This rate change has been found essentially worldwide. One subculture in which increasing rates of major depression have not occurred is among

the old-order Amish in Pennsylvania. II Third, the lethality of major depression has remained high, with 15% of patients with major depression at risk for suicide. 12 Finally, the rates of major depression rise when serious medical illness is present. 13 DEPRESSIVE DISORDERS IN THE MEDICALLY ILL In a unique study using data from 2,554 subjects from the National Institute of Mental Health (NIMH) ECA program in the Los Angeles area, Wells et al. 14 compared 841 subjects with one or more chronic medical illnesses with 1,711 subjects who had no medical illness, hypothesizing that DSM-III depressive and anxiety disorders would be more prevalent among people with any of the chronic medical illnesses. The sex- and age-adjusted 6-month prevalence was 24.7%; the lifetime prevalence was 42.2% for those with medical illness, compared with 17.5% (6-month prevalence) and 33% (lifetime prevalence) for those with no medical illness. In other words, medical illness was associated with about a 41 % higher adjusted prevalence rate of recent psychiatric disorders and a 28% higher prevalence rate of lifetime psychiatric disorders. Substance use disorder was the most FIGURE I.

TABLE I.

Changing rate of major depression

Lifetime and 12-month prevalence of mood disorders, % US ECA (5 sites). N=18.244

Men

Women

Total 0.10

Major depression Lifetime 12-month Manic episode Lifetime 12-month Dysthymia Lifetime 12-month Any mood disorder Lifetime 12-month

13

21

17

8

13

10

1.6 1.4

1.7

1.6

1.3

1.3

5 2

8 3

6

15

24 14

19 II

IS ::; a:'"

8

Kessler RC. et al: Arch Gen Psychiatry 1994; 51:819; Copyright 1994. American Medical Association. 2

VOLUME 36 • NUMBER 2 • MARCH - APRIL 1995

1925·1934

.~ 0.04 10

. . 1915-1924

0;

§

2.5

0.08

'0 ~ 0,06

1905·1914

0.02

U

-

-<1905

0 .......~~J--~~....;...--,----, o 5 15 25 35 45 55 65 75 Age of Onset (years)

Adapted from Cross-National Collaborative Group: JAMA 1992; 268:3098-3105; Copyright 1992. American Medical Association. 10

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Overview

prevalent, followed by anxiety and affective disorders. Lifetime prevalences for the three categories were the following: substance use, 26.2%; anxiety, 18.2%; and affective disorders, 12.9%. Recent prevalence rates were the following: substance use, 8.5%; anxiety, 11.9%; and affective disorders, 9.4%. Within the anxiety category, phobias were the most common (12.1%, lifetime), with panic and obsessive-compulsive disorders occurring much less frequently (1.5% and 2.4%, respectively). No data were given for differences in these diagnoses between medically ill and well samples. The lifetime prevalence for major depression and dysthymia was 7% and 4.5%, respectively. Again. no differentiation was made between the two samples. According to the National Comorbidity Survey, 1 the overall 30-day prevalence of major depression in the United States is 4.9%. This statistic can be used as a reference when reviewing studies that used DSM-III or DSM-III-R criteria to detect the presence of major depression in medically ill patients. (All studies except that of Lansky et al. 1S used DSM-III or DSMIII-R criteria to diagnose the presence of major depression.) Table 2 shows the prevalence of major depression in seriously ill medical outpatients. 15- 19 These rates of major depression do not appear to be significantly different from those found in the general population. Table 3 shows the prevalence of major depression in samples of hospitalized medically ill patients. '8 .2()"26 These rates clearly are substantially higher than the rates found in medical outpatients. Carney et a1. 20 found major depression in 18% of patients with angiographically proven coronary artery disease. In hospitalized patients with cancer, Bukberg et al. 22 found the incidence of nonbipolar depression to be 42% (24%, severe; 18%, moderately severe). In patients with gynecologic cancer, Evans and colleagues24 found that 23% met DSM-III criteria for major depression. Of great interest is the comparison of patients with stomach cancer vs. patients with pancreatic cancer by Holland et al. 23 Depressive disorders were significantly more severe in paS4

tients with pancreatic carcinoma, but no DSMIII prevalence figures for gastric cancer were cited. Joffe et al.,25 however, studied consecutively admitted patients with pancreatic cancer and found that 4 of 12 met the criteria for major depression, compared with 0 of 9 patients with stomach cancer. Many regard depression associated with pancreatic cancer to be the result of humoral factors, that is, paraneoplastic syndrome. 25 A survey of consecutively admitted patients with chronic pain by Katon et al. 26 showed a current major depression prevalence of 32%. DISEASES AFFECfING THE CENTRAL NERVOUS SYSTEM Whenever the CNS is a target of medical illness, depression may be found more frequently in TABLE 2.

Prevalence of major depression In serl·

ously III medical outpatients Percent

Cancer Derogatis et ai, (1983)16 Lansky el ai, (l98S) 15 Renal dialysis Craven et aI. (1987)17 Hongel aI. (1987)18 Hinrichsen el ai, (1989) 19

TABLE 3.

6.0

S.3 8.1

S.O 6.S

Prevalence of major depression In hospltaUzed medical patients Percent

Coronary artery disease (Carney et aI. 1987)20 Acule myocardial infarction (Schleifer el aI. 19891 1 Major depression Minor depression Cancer Inpatients (Bukberg el aI. 1984)22 GI (Holland el aI. 1986)23 Gynecologic (Evans el aI. 1986)24 Pancreas (Joffe el aI. 1986)25 End-stage renal disease (Hong el aI. 1987)18 Chronic pain (Katon el aI. 1985)26

18

18

27 42 20

23 33 30

32

PSYCHOSOMATICS

Cassem

these patients than in those with other systemic medical illnesses (Table 4).27-37 Even in Alzheimer's disease-in which depression is found less frequently than it is in subcortical dementias-Greenwald et aI.27 found a prevalence rate of II %, a rate which is roughly double that found in the general population. The prevalence figures for epilepsy,29 multiple sclerosis,30 Parkinson's disease,31 Cushing's disease,32 and stroke 33 .34 are sufficiently large to suggest that basic neuronal changes have occurred. It is particularly important to note that Robinson's group33.34 used the old Research Diagnostic Criteria for minor depression in stroke victims so that the degrees of severity and distinct diagnoses could be retained. In their studies, the outcomes of patients with major and minor depression were distinctively different. Patients who met the full criteria for major depression spontaneously remitted between I and 2 years after the stroke, whereas patients who met two of eight or three of nine criteria had not recovered at 2-year follow-up. It is also striking to find in studies of human immunodeficiency virus (HIV)-positive patients without acquired immunodeficiency syndrome (AIDS) that rates of major depression can either be equal to those in the normal population or two to three times higher. 35 In the World Health Organization study reported by TABLE 4.

Prevalence of major depression in diseases of the central nervous system Percent

Alzheimer's (Greenwald et al. 1989)27 II Huntington's (Folstein et al. 1983)28 41 Epilepsy (Mendez et ai, 1986)29 55 Multiple sclerosis (Minden and Schiffer. 1990)30 6-57 Parkinson's (Sanoet al. 1989)31 51 Cushing's (Haskett. 1985)32 83 Stroke (Robinson et ai, 1984. 1987)33.34 Major depression 27 Minor depression 20 HIV+ (w/o AIDS) (Maj et al. 1994 [WHOJ)35 4-18.4 (Brown et al. 1992 [USAFJ)36 5.6-12.2 Traumatic brain injury (Jorge et ai, 1993)37 26 Adapted from Cassem EH: Psychiatr Clin North Am 1990; 13:597--{j I 2. 13

VOLUME 36· NUMBER 2 • MARCH - APRIL 1995

Maj et aI.,35 the highest rates (18.4%) were found in HIV-positive intravenous drug abusers in Thailand. Studies by Brown and colleagues36 of HIV-positive U.S. Air Force personnel showed rates of depression that varied between 5.6% and 12.2%. Notably, Jorge et aI. 37 found a 26% prevalence rate of major depression in patients with traumatic brain injury. These studies were not restricted to hospitalized patients. It is still premature to say that having a disease of the CNS automatically raises the risk for major depression. THE IMPACT OF DEPRESSIVE DISORDERS ON MEDICAL SERVICES UTILIZAnON During the 1994 annual meeting of the American Psychiatric Association, Judd et aI. 38 showed that major depression, alone or in combination with anxiety disorders, increases the utilization rates of medical services. In their study of lifetime utilization of medical services by patients with psychiatric diagnoses, use of medical outpatient facilities was found to be substantially increased in patients with a diagnosis of major depression (36%) compared with patients with no mental disorder (8%, baseline); the addition of one anxiety disorder to major depression increased the use to 49%, and the addition of two or more anxiety disorders raised outpatient use to 69%. There is an implicit assumption that many of the physical symptoms that bring these patients to the medical outpatient facility are, in fact, the result of psychiatric disorders and not a medical iIIness. 39 Accurate detection of psychiatric disorders could, hopefully, result in proper treatment and a subsequent significant decrease in utilization rates of medical outpatient and emergency services. IMPACT OF DEPRESSIVE DISORDERS ON FUNCTION There is a tendency to interpret the psychiatric literature of depressive disorder studies, which measure success by the measured reduction of depression severity scores, as Hamilton DepresS5

Overview

sion or Beck Depression Inventory scores. An unfortunate interpretation of these successfully reduced scores would be that the patient has completely recovered from the depressive disorder. Studies show that generally recovery is not the case. 40 Mintz and colleagues 40 showed that recovery offunction, as measured by social and occupational measures, lagged considerably behind the reduction in depression severity scores. (A patient whose Beck Depression Inventory score fell to around to still had 60% disability as measured by the functional scales.) In this study, 8-9 months generally were required for full recovery from the debilitating aspects of major depression. In a related study, Wells et al. 41 compared impairment in physical and social functioning in patients with arthritis, diabetes, hypertension, and no chronic illness vs. patients with primary major depression (Figure 2). Not only is the social functioning of patients with major depression significantly more impaired than that found in the three medical illness groups. but the physical functioning of depressed patients is significantly more impaired as well. These results further support the assertion that depression is as physical an illness as arthritis. diabetes, and hypertension-if not more so. Depression certainly carries a greater social and physical disability.

FIGURE 2.

Physical and social functioning in patients with depressive disorders

'00

DepressIve

O,SoQ,{j$,

Hyper1enSI()n

D,abeleS

Anh',l!s

No ChrOl"lIC

Condrllon

•A score of 100 = perfect functioning t p < 0.000 I versus depressive disorder lp < O.OOS versus depressive disorder §p < O.OS versus depressive disorder Adapted from Wells KB. Slewart A. Hays RD. et al: JAMA 19119; 262;914-919. 41

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MAKING A DIAGNOSIS OF DEPRESSIYE DISORDER IN MEDICALLY ILL PATIENTS Before the introduction of DSM_Iy 42 diagnostic criteria, a diagnosis of major depression in a medically ill patient was essentially not permitted in psychiatric nosology. DSM-III and DSMIII-R made no provision for the category of secondary depression, and the category of organic mood disorder remained problematic because the criteria explicitly include, not five of nine symptoms to meet criteria, but only one criterion symptom, mood itself. In DSM-III and DSM-III-R, one of the exclusion criteria for making a diagnosis of major depression was that the depressed mood itself could not be attributed to an organic mental disorder. Thus, there was no place to make a diagnosis of major depression in a medically ill patient. This criterion implied that organic mood disorder could not be major and possibly therefore not severe. Another unfortunate implication was that treatment was not as important in these types of depression as it was in primary depression. DSM-IY is a major advance for the clinician. It delineates four classes of mood disorders. In addition to the bipolar and depressive disorder categories, DSM-IY includes mood disorders "due to a general medical condition" and "substance-induced" mood disorders (Figure 3). The DSM-IY criteria for a major depressive episode are shown in Table 5. These are very familiar to all clinicians who have used DSMIII and DSM-III-R. However, when applied to medically ill patients, at least four of these symptoms have raised repeated doubts in clinicians' minds because they seem to be potentially invalid when applied to a medically ill patient. These four criteria (focused on disturbances of sleep, energy, concentration, and appetite) could all be disordered or disrupted by a medical illness such as cancer. To remedy these potentially confounding diagnostic features. Endicott 4J introduced four potential replacements (Table 6) for the DSM-III symptoms: I) fearful or depressed appearance; 2) social withdrawal or decreased talkativeness; 3) brooding. PSYCHOSOMATICS

Cassem

FIGURE 3.

DSM·IV c1assiftcatlon or mood disorders

Note: BP =bipolar; NOS =not otherwise specified. Adapted from Diagnostic and Statistical Manual of Mental Disorders. 4th Edition. 1994:317-391.42

TABLE S.

DSM·IV diagnostic: criteria ror m~or depression

Five of nine symptoms present during the same 2-week period: Depressed mood most of the day. nearly every day Diminished interest or pleasure in almost all activities Significant weight gain or loss Insomnia or hypersomnia nearly every day Psychomotor agitation or retardation nearly every day Fatigue or loss of energy nearly every day Feelings of worthlessness or guilt Diminished ability to think or concentrate. indecisiveness Recurrent thoughts of death or suicide Diagnostic and Statistical Manual of Mental Disorders. 4th Edition. 1994. p.327. 42

TABLE 6.

Criteria ror

m~or

self-pity, or pessimism; and 4) mood that is not reactive (the patient cannot be cheered up, does not smile, shows no reaction to good news). The use of these symptoms has proved to be both reliable and valid; Chochinov and colleagues44 showed how the use of either the original DSMIII-R criteria or the Endicott-modified criteria can change the diagnostic rates of major depression in a population of cancer patients. The most important lesson from this study is that if a high threshold is used to make the diagnosis, the results are exactly the same, that is, major depression is diagnosed as often by the DSM-III-R criteria as it is by the Endicott modifications. A high threshold requires that the depressed mood be present for most of the time and that the loss of interest covers almost all activities. If these requirements are met, either set of criteria can be used. Some concerns about psychiatric diagnosis are of particular importance when depression is present in serious medical illness. One of the most common, most misleading, and most potentially damaging uses of a major depression diagnosis in serious medical illness is labeling it "appropriate." A physician, for example, might say that, if a young male patient were admitted to the emergency department with a hemorrhaging femoral artery after a knife fight, the shock that follows the hemorrhage is "appropriate." Likewise, for the patient with an indwelling Foley catheter and urinary tract infection, one could say that the septic shock that followed gram-negative sepsis was also

depression (Endicott's substitutions)·

Depressed Mood or Anhedonia At least four: Appetite disturbance Sleep disturbance Psychomotor abnormality Loss of interest Loss of energy Guilt Difficulty concentrating Suicide/preoccupation with death

(Depressed appearance)· (Social withdrawal)·

(Self-pity or pessimism)· (Nonreactive mood)·

Endicott J: Cancer 1984; 53:2243-2248. 43

VOLUME 36· NUMBER 2· MARCH - APRn.. 1995

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Overview

FIGURE 4.

Disability and depressive disorders among high utilizers or health care. Age- and sex-adjusted and standardized Symptom Checklist·90, revised, depression scores (z-scores) at baseline, 6 months, and 12 months by depression severity and improvement status (N = 143)

3.5 3 2.5

Severely depressed Unimproved (n=27) 97%

2

•

1.5 Standard Score

1

92% ..

_------

0.5

Severely depressed 1m roved

a -0.5

Moderately depressed Improved (n=41 )

-1

-1.5

Moderately depressed Unimproved - . (n=48)

Baseline

6 months

Population Percentile

77%

41%

12 months

Adapted from Von Korff M. et al: Arch Oen Psychiatry 1992; 49:91-100; Copyright 1992, American Medical Association. 45

FIGURE S.

Disability and depressive disorders among high utilizers or health care. Disability score at baseline, 6 months, and 12 months by depression severity and improvement status (N = 145)

FIGURE 6.

3

160

25

140

2

Severely depres~ UnImproved

Disability Score 1,5

120

100

Disability Days 80

60 40

05 20

oL - - -6 months - - - -12-months ----Baseline

Disability and depressive disorders among high utilizers or health care. Annualized disability days at baseline, 6 months, and 12 months by depression severity and improvement status (N = 138)

•

~

_.'ely depressed _

UNmpt'OVed

~

Seve'elvdep'.'sed ImprOVed

Moderately depressed I~'oved

0 'Baseline - - - -6 - - -12-months ----months

Adapted from Von Korff M, et al: Arch Oen Psychiatry 1992; 49:91-100; Copyright 1992. American Medical Association. 45

Adapted from Von Korff M, et a1: Arch Oen Psychiatry 1992; 49:91-100; Copyright 1992, American Medical Association. 45

"appropriate." Of course. physicians don't talk that way about shock. Psychiatrists should be staunchly unwilling to allow major depression

to be labeled as appropriate. Rather. it makes far more sense to encourage physicians to say that, like shock, major depression is a dread

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PSYCHOSOMATICS

Cassem

complication of serious medical illness. The word "appropriate" implies that treatment either is not important or will not work and is therefore irrelevant. This is a most unfortunate conclusion. unkind to the patient and unjustified by the data. Unfortunately. there are many psychiatrists who would agree that major depression in patients with advanced cancer is appropriate. Some of these individuals appear to cling to the notion that a depressive disorder is a psychological process rather than a systemic illness that is more debilitating than many. if not most. physical illnesses and physically debilitating as well. Not all patients with terminal cancer have a depressive disorder. It is more accurate to think of a depressive disorder as a form of encephalitis than it is to think of it as normal sadness intensified. Many more studies of major depression in the seriously medically ill will be required before diagnostic and treatment issues have a clarity that approaches that found in patients with major depression alone. Nonetheless. the studies are sufficient to indicate that patients with

depressive disorders are high users of medical resources. There are studies by the University of Washington group45 which indicate that, among the high users of health services who have a depressive disorder, treatment of depression makes a significant impact on symptoms (Figure 4), annual disability scores of the patients (Figure 5). and the number of disability days per year that are lost to depressive illness (Figure 6). CONCLUSION The clinical imperative of a physician is to diagnose suffering and make every reasonable effort to reduce it. Depressed mood in medically ill patients should be thoroughly examined. and when major depression is present. it should be aggressively treated. We look for further studies to guide us in choosing the most effective treatments for medically ill patients who are unfortunate enough to sustain the severe complication of major depression.

References I. Blazer 00. Kessler RC. McGonagle KA. et a1: The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry 1994; 151:979-986 2. Kessler RC. McGonagle KA. Zhao S. et al: Lifetime and 12-month prevalence of OSM-UI-R psychiatric disorders in the United States. Arch Gen Psychiatry 1994; 51:8-19 3. Regier OA, Boyd JH. Burke JD Jr. et a1: One-month prevalence of mental disorders in the United States: based on five Epidemiologic Catclunent Area sites. Arch Gen Psychiatry 1988; 45:977-986 4. Burke KC. Burke JD Jr. Regier OA. et a1: Age at onset of selected mental disorders in five community populations. Arch Gen Psychiatry 1990; 47:511-518 5. Ravindram AV, Chudzik J. Bialik RJ, et a1: Platelet serotonin measures in primary dysthymia. Am J Psychiatry 1994; 151:1369-1371 6. Hellerstein OJ. Yanowitch P, Rosenthal J. et a1: A randomized double-blind study offluoxetine versus placebo in the treatment of dysthymia. Am J Psychiatry 1993; 150:1169-1175 7. Marin OB. Kocsis JH. Frances AJ. et a1: Desipramine for the treatment of "pure" dysthymia versus "double" depression. Am J Psychiatry 1994; 151: 1079-1080

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8. Markowitz JC: Psychotherapy of dysthymia. Am J Psychiatry 1994; 151:1114-1121 9. Kupfer OJ: Long-term treatment of depression. J Oin Psychiatry 1991; 52(suppI5):28-34 10. Cross-National Collaborative Group: The changing rate of major depression. JAMA 1992; 268:3098-3105 I I. Pauls OL. Morton LA. Egeland JA: Risks of affective illness among first-degree relatives of bipolar Iold-order Amish probands. Arch Gen Psychiatry 1992; 49:703708 12. Goodwin FKL. Jamison KR: Manic-Depressive illness. New York. Oxford University Press. 1990 13. Cassem EH: Depression and anxiety secondary to medical illness. Psychiatr Oin North Am 1990; 13:597~12 14. Wells KB. Golding JM. Burnam MA: Psychiatric disorder in a sample of the general population with and without chronic medical conditions. Am J Psychiatry 1988; 145:976-981 15. Lansky SB. List MA. Herrmann CA. et a1: Absence of major depressive disorder in female cancer patients. J Clin Onco11985; 3:1553-1560 16. Derogatis LR. Morrow GR. Fetting J. et a1: The prevalence of psychiatric disorders among cancer patients. JAMA 1983; 249:751-757 17. Craven JL. Rodin GM. Johnson L. et a1: The diagnosis

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Overview

of major depression in renal dialysis patients. Psychosom Med 1987; 49:482-492 18. Hong BA. Smith MD. Robson AM. et al: Depressive symptomatology and treatment in patients with endstage renal disease. Psychol Med 1987; 17:185-190 19. Hinrichsen GA. Lieberman JA. Pollack S. et al: Depression in hemodialysis patients. Psychosomatics 1989; 30:284-289 20. Carney RM. Rich MW. Tevelde A. et al: Major depressive disorder in coronary artery disease. Am J Cardiol 1987;60:1273-1275 21. Schleifer SJ. Macari-Hinson MM. Coyle DA. et al: The nature and course of depression following myocardial infarction. Arch Intern Med 1989; 149:1785-1789 22. Bukberg J. Penman D. Holland JC: Depression in hospitalized cancer patients. Psychosom Med 1984; 46:199212 23. Holland JC, Korzun AH. Tross S. et al: Comparative psychological disturbance in patients with pancreatic and gastric cancer. Am J Psychiatry 1986; 143:982-986 24. Evans DL. McCartney CF. Nemeroff CB. et al: Depression in women treated for gynecological cancer: clinical and neuroendocrine assessment. Am J Psychiatry 1986; 143:447-452 25. Joffe RT. Rubinow DR. Denicoff KD. et al: Depression and carcinoma of the pancreas. Gen Hosp Psychiatry 1986; 8:241-245 26. Katon W. Egan K. Miller D: Chronic pain: lifetime psychiatric diagnoses and family history. Am J Psychiatry 1985; 142:1156--1160 27. Greenwald BS. Kramer-Ginsberg E. Marin DB. et al: Dementia with coexistent major depression. Am J Psychiatry 1989; 146: 1472-1478 28. Folstein SE. Abbotl MH. Chase GA. et al: The association of affective disorder with Huntington's disease in a case series and in families. Psychol Med 1983; 13:537542 29. Mendez MF. Cummings JL. Benson F: Depression in epilepsy: significance and phenomenology. Arch Neurol 1986; 43:766-770 30. Minden SL. Schiffer RB: Affective disorders in multiple sclerosis: review and recommendations for clinical research. Arch Neurol 1990; 47:98-104 31. Sano M. Stern Y. Williams J. et al: Coexisting dementia and depression in Parkinson's disease. Arch Neurol 1989;46:1284-1286

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32. Haskett RF: Diagnostic categorization of psychiatric disturbance in Cushing's syndrome. Am J Psychiatry 1985; 142:911-916 33. Robinson RG. Starr LB. Price TR: A two-year longitudinal study of mood disorders following stroke: prevalence and duration at six months follow-up. Br J Psychiatry 1984; 144:256--262 34. Robinson RG. Bolduc P. Price TR: A two-year longitudinal study of post-stroke depression: diagnosis and outcome at one- and two-year follow-up. Stroke 1987; 18:837-843 35. Maj M. Janssen R. Starace F. et al: WHO neuropsychiatric AIDS study. cross-sectional phase I. Arch Gen Psychiatry 1994; 51:39-49 36. Brown GR. Rundell JR. McManis SE. et al; Prevalence of psychiatric disorders in early states of HIV infection. Psychosom Med 1992; 54:588--601 37. Jorge RE. Robinson RG. Arndt SV. et al: Comparison between acute- and delayed-onset depression following traumatic brain injury. J Neuropsychiatry C1in Neurosci 1993: 5:43-49 38. Judd L: Cited in APA Symposia Highlights on the Treatment of Depressive Disorders. May 21-26. 1994 39. Johnson J. Weissman MM. Klerman GL: Service utilization and social morbidity associated with depressive symptoms in the community. JAMA 1992; 267:14781483 40. Mintz J. Mintz L1. Arruda MJ. Hwang SS: Treatments of depression and the functional capacity to work. Arch Gen Psychiatry 1992: 49:761-768 41. Wells KB. Stewart A. Hays RD. et al: The functioning and well-being of depressed patients. Results from the Medical Outcomes Study. JAMA 1989: 262:914-919 42. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 4th Edition. Washington. DC. American Psychiatric Association. 1994 43. Endicotl J: Measurement of depression in patients with cancer. Cancer 1984; 53(May 15 suppl):2243-2248 44. Chochinov HM. Wilson KG. Enns M. et al: Prevalence of depression in the terminally ill: effects of diagnostic criteria and symptom threshold judgments. Am J Psychiatry 1994; 151 :537-540 45. Von Korff M. Orrnel J. Katon W. et al: Disability and depression among high utilizers of health care. Arch Gen Psychiatry 1992: 49:91-100

PSYCHOSOMATICS