- Email: [email protected]
Chest pain: Relationship of psychiatric illness to coronary arteriographic results
VOLUME 84
The
American
Journal
NUMBER 1
of
A~UARY I98
Medicin CLINICAL STUDIES
Chest Pain: Relationship of Psychiatric Illness to Coronary Arteriographic Results
WAYNE
KATON,
MARGARET JOAN
RUSSO,
LAWRENCE MICHAEL PETER
M.D.
L. HALL,
M.D.
Ph.C. CORMIER,
HOLLIFIELD, P. VITALIANO,
M.D. B.S. Ph.D.
Seattle, Washington BERNARD
D. BEITMAN,
M.D.
Columbia, Missouri
Seventy-four patients with chest pain and no prior history of organic heart disease were interviewed with a structured psychiatric interview immediately after coronary arteriography. The majority of patients with both negative and positive coronary angiographies had undergone previous exercise tolerance tests, but the patients with angiographic coronary artery disease were significantly more likely to have had positive results on a treadmill test. Patients with chest pain and negative coronary arteriograms were significantly younger; more likely to be female; more apt to have a higher number of autonomic symptoms (tachycardia, dyspnea, dizziness, and paresthesias) associated with chest pain, and more likely to describe atypical chest pain. Patients with chest pain and normal coronary arteriographic results also had significantly higher psychologic scores on indices of anxiety and depression and were significantly more likely to meet criteria of the Diagnosfic and Statistical Manual of Mental Disorders, third edition, for panic disorder (43 percent versus 6.5 percent), major depression (36 percent versus 4 percent), and two or more phobias (36 percent versus 15 percent) than were patients with chest pain and a coronary arteriography study demonstrating coronary artery stenosis. There are few affectations which excite more alarm and anxiety in the mind of the patient than this. He fancies himself doomed to become a martyr to organic disease of the heart, of the horrors of which he has an exaggerated idea; it is the more difficult to divest him of this impression because the nervous state which gives rise to his complaint impatts a fanciful gloom and desponding tone to his imagination. J. Hope (1832)
From the Division of Consultation/Liaison Psychiatry and the Department of Medicine, University of Washington Medical School, Seattle, Washington, and the Psychiatry Department, University of Missouri, Columbia, Missouri. Requests for reprints should be addressed to Dr. Wayne Katon, Department of Psychiatry and Behavioral Sciences RP-10, University of Washington Medical School, Seattle, Washington 98195. Manuscript submitted June 22, 1987, and accepted in revised form October 5, 1987.
Studies have demonstrated that 10 to 30 percent of patients with chest pain who undergo coronary arteriography have no arterial abnormalities [l--3]. Follow-up studies of these patients have consistently shown that the risk of subsequent myocardial infarction is low [4-IO], yet 50 to 75 percent have persistent complaints of chest pain and disability after normal coronary arteriograms [6,8]. Both cardiac (Prinzmetal’s angina and mitral valve prolapse) and non-cardiac problems (esophageal spasm, costochondritis, hyperventilation syndrome, and anxiety neurosis) have been implicated as having etiologic significance.
January
1988
The American
Journal
of Medicine
Volume
84
1
CHEST
PAIN
AND
PSYCHIATRIC
ILLNESS-KATON
ET AL
There has been a long historical interest in functional cardiac symptoms (particularly chest pain and tachycardia). In 1832, Hope [ 1 l] discussed the subject of “nervous palpitations” in one of the first English textbooks of cardiology. Terms such as Da Costa’s syndrome, irritable heart, soldier’s heart, effort syndrome, neurocirculatory asthenia, hyperdynamic beta-adrenergic circulatory state, hyperventilation syndrome, and mitral valve prolapse have been used to describe functional cardiac symptoms in patients [ 121. Osler [ 131 recognized the difficulty in differentiating between chest pain caused by coronary artery disease and that attributable to non-cardiac factors when he described two distinct categories of true angina and pseudoangina. In the second category, he found an excess of women in whom episodes of pain were characteristically periodic and nocturnal, lasting one to two hours and accompanied by nervous symptoms and vasomotor disturbances. In more recent years, Mayou [14] reported that in patients attending a cardiology clinic with chest pain, those with no evidence of cardiac disease were characterized as being younger and describing more atypical chest pain and somatic anxiety symptoms than patients with demonstrable cardiac lesions. Waxler et al [7] estimated that 40 percent of 86 women with chest pain, who had normal coronary arteriograms, displayed neurotic and hypochondriacal behavior. Many studies have found that anxiety-induced hyperventilation symptoms and nonspecific electrocardiographic ST- and T-wave changes were common in patients with chest pain and normal coronary arteriograms [ 15-171. Elias and colleagues [ 181 found a negative correlation between the maximum degree of coronary stenosis and measures of neuroticism (anxiety, depression, and somatic complaints) in a sample of 136 men and women awaiting arteriography. The more anxious, depressed, or concerned with somatic complaints the person was, the less coronary artery stenosis was demonstrated. In a group of 83 patients referred to coronary atteriography for chest pain, Costa and colleagues [ 191 demonstrated that neuroticism influenced the quality of the chest pain presentation, and that these symptoms did not predict arteriographic coronary stenosis [ 191. Channer and colleagues [20] assessed anxiety and depression by a short patient self-rating scale in 87 consecutive patients with chest pain before diagnostic treadmill testing. Significantly more patients who had high scores on anxiety or depression had negative test results. Bass and Wade [21] studied 99 patients with chest pain referred to arteriography. Almost two thirds (6 1 percent) of the 46 patients with hemodynamically insignificant disease had a psychiatric diagnosis (most commonly anxiety neurosis) compared with 23 percent of the 53 patients with significant coronary artery disease. Finally, Katon [22] reported that 39 percent of 55 patients referred for psychiatric consultation by primary care physi-
2
January
1988
The American
Journal
of Medicine
Volume
cians who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, third edition, (DSM Ill) [23] for panic disorder presented with chest pain and/or tachycardia. Thus, these studies suggest that persons who score high on neuroticism (anxiety and depression) often present with somatic complaints in the absence of organic pathology and may contribute to the 10 to 30 percent of patients undergoing arteriography who prove to have nondiseased coronary arteries. However, it is unclear whether patients with chest pain and negative coronary atteriograms have a clinical syndrome, i.e., major depression or panic disorder, or simply have higher anxiety and depression-scores on psychologic tests. The purpose of this investigation was to compare the prevalence of psychiatric disorders in patients with chest pain who had a negative coronary arteriographic study with that in those that had atteriographic evidence of coronary artery stenosis. If a clinical study were to observe a high association between specific treatable psychiatric disorders and chest pain with negative coronary atteriography, this information could be used to improve patient care and possibly to influence physicians’ selection of patients with coronary arteriography [24]. PATIENTS AND METHODS Patients. Patients were referred for coronary arteriography to the University of Washington Hospital by cardiologists from three practice settings: the University system, a health maintenance organization, and a large suburban private practice. The sample consisted of 74 consecutive subjects recruited from 78 eligible patients, aged 25 and older, referred for evaluation of chest pain. The cardiac evaluation completed prior to arteriography was carefully reviewed in order to assess if the patient met inclusion and exclusion criteria and to compare the pre-angiographic evaluations of the patients with negative and positive arteriographic results. The fact that the evaluating cardiologist had determined that the patient’s chest pain was sufficiently suspect to warrant coronary arteriography was taken as adequate for study inclusion. There was no difference over time in the frequency of negative arteriography among the three patient referral sources. In an attempt to simulate pertinent aspects of the evaluation of patients with “new chest pain” presenting to the primary care physician or cardiologist, and in order to test our hypothesis, we excluded patients with a history of organic heart disease (valvular or congenital heart disease or previously documented coronary artery disease). To meet exclusion criteria for previously documented coronary artery disease, we required evidence of (1) a definite myocardial infarction on electrocardiogram or enzyme evaluation; (2) definite segmental wall motion abnormality by noninvasive test or left ventriculography; or (3) previous positive coronary arteriogram. Patients were not excluded for a positive or equivocal treadmill test result or resting STsegment or T-wave changes on electrocardiogram. Pa-
84
CHEST
tients with mitral valve prolapse documented by either auscultation or echocardiography were also not excluded. Two hundred patients were screened for the study with 78 meeting inclusion and exclusion criteria. There were four otherwise eligible patients who were excluded because they could not be satisfactorily interviewed due to foreign language (two), severe dementia (one), or deaf and mute (one). Patients who express psychiatric disorder in an idiom of somatic distress are frequently quite defensive about their symptoms being secondary to mental illness. Therefore, to minimize defensiveness about mental disorders, the patients with chest pain were informed that the purpose of the research was to determine the prevalence of a common autonomic nervous system disorder that frequently caused cardiac symptoms such as rapid heart beat or chest pain.
PSYCHIATRIC INSTRUMENTS Psychiatric Diagnosis. A modified version of the structured psychiatric interview, the Diagnostic Interview Schedule (DIS) [25] was administered to each participant by one of two trained interviewers (a senior psychiatric resident and a medical student) immediately after a coronary arteriogram was obtained. The patients had usually been given a preliminary report on their angiogram prior to the interview but were instructed not to report that to the psychiatric interviewer. Thus, the psychiatric interviewer was unaware of the coronary arteriographic results. The DIS specifies questions and probes for the determination of diagnoses according to criteria outlined in the DSM Ill of the American Psychiatric ,Association [23]. Six diagnoses were sought and recorded in this investigations: panic disorder, simple phobic disorder, major depression, dysthymic disorder, alcohol abuse, and alcohol dependence. These diagnoses were selected because epidemiologic studies of medical patients have determined that these six diagnoses encompass more than 90 percent of the psychiatric diseases in this population [26]. The psychiatric diagnoses were considered to be current if the diagnostic criteria were met within the month prior to catheterization. Ten percent of subjects were interviewed by both examiners in order to assess inter-rater reliability. The inter-rater reliability for all psychiatric diagnoses was high (kappa = 0.90, p
PAIN
AND
PSYCHIATRIC
ILLNESS-KATON
ET AL
ic results were classified as coronary artery disease negative [CAD(-)] when there was less than 50 percent stenosis in all coronary vessels [27,28]. A chart review was completed to assess each patient’s coronary artery risk factors (family history of coronary artery disease, hypertension, smoking, obesity, diabetes, hyperlipemia, or increased cholesterol levels), the preliminary cardiac workup that had led to referral for coronary arteriography (exercise treadmill test), and the medications that each patient was taking prior to catheterization. A positive family history of cardiovascular disease included a first-degree family member (mother, father, and siblings) with coronary heart disease or stroke occurring at 60 years of age or less. Hypertension was defined as a documentation in the medical record of a combination of diastolic blood pressure above 90 mm Hg and a systolic blood pressure over 140 mm Hg as well as current treatment with one or more antihypertensive agents. Hyperlipidemia, hypercholesterolemia, obesity, and smoking were listed as present if they were noted in the referring cardiologist’s or the catheterization cardiologist’s summary of cardiac risk factors and thus were dependent on their qualitative judgement. The study cardiologist rated each patient’s chest pain as typical or atypical (unaware of the psychiatric and cardiac diagnoses) based on the following criteria [7]: Typical angina was described as substernal chest pain or pressure brought on predominantly (in more than 75 percent of cases) by exertion and relieved promptly by rest. Atypical angina pectoris was considered present when there was an unusual feature such as location, duration, or quality (pleuritic, jabbing) of pain or consistency to physical exertion or emotional stress described, but at some time the pain had been related to physical or emotional stress. Self-Report Measures. Each participant was asked to fill out three self-report questionnaires after the psychiatric interview was completed: (1) an abridged version of the Hopkins Symptom Checklist (SCL-90) [29]; (2) the Zung Self-Rating Anxiety Scale (SAS) [30]; and (3) the Life Experiences Survey (LES) [31]. The abridged SCL-90 includes 49 current symptoms scored on a 0 to 4 severity scale of somatization, anxiety, phobic-anxiety, depression, and additional subscales. The SAS measures the current severity of 20 anxiety symptoms scored on a 1 to 4 severity scale. The LES is a schedule of 50 life events (marriage, death of spouse, new job) experienced in the past year. It asks patients to rate the events that they have experienced on a negative (0 to -3) to positive (0 to i-3) continuum of the perceived impact that the event had. Negative and positive life events were summated separately. Statistical Methods. Chi-square tests with Yates’ correction were used to evaluate the relationship of coronary artery disease status and demographic variables, coronary risk factors, psychiatric diagnoses, use of medications, and type of chest pain. To evaluate the degree to which gender could be a confounder or effect modifier of these relationship and because of the disparate number of male (51) versus female (23) patients, the phi coefficient (8) was used [32]. The phi coefficient, unlike the chi-square statistic, is
January 1988
The American Journal of Medicine
Volume 84
3
CHEST
PAIN AND
TABLE I
PSYCHIATRIC
ILLNESS-KATON
ET AL
differences in age, number of autonomic symptoms, life events, and the psychologic test scores were evaluated using two-tailed Student t tests.
Demographic Variables among Patients with Negative Versus Positive Coronary Artery Disease Negative Coronary Artery Disease (n-= 28) Number [Percent)
Age (SD)* Male* Married Hollingshead’s social class I, II, Ill (nonmanual) IV, V (manual)
Positive Coronary
ArteryDisease (n-= 46) Number (Percent)
51.2 f (10.6) 13 (46.4) 20 (7 1.4)
59.5 f (10.5) 38 (82.6) 34 (73.9)
11 (37.3) 17 (60.7)
25 (54.3) 21 (45.7)
* p
TABLE ii
Coronary
Risk Factors Smoking Family history Diabetes Obesity* Hyperlipedemia Hypertension Mean number risk factors
of (SD)
Artery
Disease
Risk Factors
CADI-j (n =.26j Number Percent
CAD(+) (n =‘46j Number Percent
12 4 4 9 4 15 1.71
29 16 5 4 15 21 2.04
44.4 14.8 14.8 33.3 14.8 53.6 1.27
63 34.8 10.9 8.7 32.6 45.7 1.15
* p <0.02.
TABLE
iii
Cardiac
Variables Had an ETT (percent yes) Results of ETT” Positivet Nonspecific abnormalitiest Negatives
Testing
Prior to Arteriography
CAD(-) CAD(+) Number Percent Number Percent 19
70.4
37
80.4
2 IO 7
10.5 52.6 36.8
25 5 7
67.6 13.5 18.9
ETT = exercise tolerance test. * p
unbiased by the sample size of the tables, and it gives an indication of the strength of the association (0 = no relationship; +I = perfect association). (The drawback of 8 in the current context is that it cannot reach a maximum value
of -i-1. Hence, the numerical interpretation of the strengths of association in the current analyses are conservative and they are stronger than they appear [32]). Mean group
4
January 1988 The American Journal of Medicine Volume 84
RESULTS
Over a five-month period, 74 patients with chest pain were enrolled in the study. Twenty-eight (38 percent) had negative coronary arteriograms [CAD(-)] and 46 (62 percent) had coronary arteriographic evidence of coronary artery disease [CAD(+)]. Table I describes the demographic characteristics of the patients. Patients with chest pain and a negative coronary arteriographic study were significantly younger (t = 3.2, df = 72, p <0.002) and more likely to be female (X*(l) = 8.8, p <0.003) than patients with chest pain and a positive coronary arteriogram. There were no significant differences in marital status (X*(l) = 0.01) or social class (Hollingshead Index) (X2(1) = 0.92) between the two groups of patients. Table II describes the coronary artery disease risk factors in the patients with CAD(-) and the patients with CAD(+). Overall, there were no differences in the prevalence of any risk factor with the exception of obesity, which was significantly more prevalent in the patients with CAD(-) (X*(l) = 5.47, p <0.02). There was also no difference in the total number of coronary artery disease risk factors in the patients with CAD(-) and CAD(+). Table Ill describes the cardiac evaluations that were completed by the 74 patients with chest pain prior to coronary arteriography. There were no significant differences in the number of patients who had an exercise tolerance test prior to arteriography in the CAD(-) and CAD(+) groups. However, only two of the 19 (10.5 percent) patients who had a negative arteriographic study had a positive treadmill test result compared with 25 of 37 (67.6 percent) patients with coronary artery disease on angiography (X2(2) = 17.26, p
CHEST
at-teriography and psychiatric diagnoses, we examined the association of coronary artery disease status and psychiatric diagnoses both with gender and stratified by gender. Gender was not significantly related to panic disorder (X2(1) = 0.27); however, it was significantly related to major depression (X2(1) = 3.8; p <0.05): 30.4 percent of the women compared with 9.8 percent of the men met DSM III criteria for major depression. These gender effects are not due to age because there was no significant difference between the mean age of female (58.3 years) and male (55.5 years) subjects (t = 1.07, df = 72, p = NS). The strength of association between coronary artery disease status and panic disorder is very similar for male (a, = 0.44; p
TABLE IV
PAIN
AND
PSYCHIATRIC
ILLNESS-KATON
DSM Ill Psychiatric Diagnoses with Negative Versus Positive Artery Disease Negative Coronary
ArteryDisease (n = 28)
Number(Percent) Panic disorder* Simple phobias (2 or more)+ Major depression, current* Lifetime depressiont Lifetime alcohol abuse Lifetime alcohol dependence Alcohol abuse Alcohol dependence No current psychiatric diagnosis*
ET AL
in Patients Coronary
Positive Coronary Artery Disease (n = 46)
Number(Percent)
12 (42.9) IO (35.7)
3 (6.5) 7 (15.2)
10 (35.7)
2 (4.3)
18 (64.3) IO (35.7) 4 (14.3)
11 (23.9) 15 (32.6) 8 (17.4)
3 (10.7) 1 (3.6) 6 (21.4)
3 (6.5) 2 (4.3) 34 (73.9)
p
TABLE V
Description of Pain and Preceding Life Events in Patients with Negative Versus Positive Coronary Artery Disease Negative Coronary Positive Coronary Artery Disease ArteryDisease (n = 28) (n = 46)
Chest Pain* Typical (percent) Atypical (percent) Mean number of autonomic symptoms (SD)+ Mean number of positive life events (SD) Mean number of negative life events (SD)
7 (25.9) 20 (74.1) 5.2 f (2.6)
40 (88.9) 5 (11.1) 3.8 f (2.7)
3.7 f (4.0)
4.5 f (6.5)
7.8 f (6.9)
4.0 f (6.5)
* p
= 0.06). Table VI describes the medications prescribed to pa-
tients with CAD(-) and CAD(+). Patients with CAD(-) were significantly more likely to be taking psychoactive, medication in general (X2(1) = 7.19; p <0.007), antianxiety agents (X*(l) = 5.45; p <0.02), and diuretics (X*(l) = 3.55; p <0.05) than patients with CAD(+). Patients with CAD(+) were significantly more likely to be prescribed an organic nitrate (X*(l) = 4.15, p <0.04). Overall, patients with CAD(-) were taking significantly more medications than were patients with CAD(+) [t(38.5) = 1.97; p <0.05]. The results of the SCL-90 and the SAS can be seen in Table VII. Self-report measures were completed by 63 (85 percent) of the 74 patients. Although patients with CAD(-) had higher scores on every psychologic mea-
sure, only the SCL-90 depression (t = 2.0; df = 61; p <0.05) and SAS anxiety scores (t = 2.2, df = 61; p <0.03) reached statistical significance. COMMENTS
In this study of 74 patients with chest pain referred for coronary arteriography, 37.8 percent had a negative workup, which is a higher percentage than the 10 to 30 percent reported in other studies. This result was expected due to the exclusion of patients with previously documented organic heart disease. The patients with chest pain and CAD(-) were equally likely to have had an exercise tolerance test prior to arteriography, but the patients with CAD(+) were significantly more likely to
January 1998
The
American Journal of Medicine Volume 84
5
CHEST
PAIN AND PSYCHIATRIC
TABLE VI
ILLNESS-KATON
ET AL
coronary arteriographic results and patients with chest pain who had positive coronary arteriographic results. Patients with chest pain and normal coronary arteries were younger; more likely to be female; more apt to have a higher number of autonomic symptoms associated with chest pain; and more likely to present with atypical pain. Patients with chest pain and normal coronary arteries also had higher psychologic scores on indices of anxiety and depression and were significantly more likely to meet DSM-III criteria for panic disorder or major depression as well as to report two or more simple phobias. The fact that there were more female patients with CAD(-) did not confound the relationship between CAD(-) and panic disorder because both men and women with panic disorder had similar high rates of negative coronary arteriograms. However, in the diagnosis of major depression, gender was a confounding factor; major depression was more strongly associated with a negative coronary arteriogram in women than in men. Other studies have documented that patients with chest pain and normal coronary arteries were significantly younger [21] and more likely to be female [7,21]. We did not ask the physicians caring for the patients to rate the likelihood of finding anatomic disease at catheterization; however, in prior studies, the physician’s impression of the pain as atypical had a strong predictive association with a normal coronary arteriographic study [7,2 1,331. In the current study, chest pain evaluations were done by a chart review of the patient’s description of pain by the study cardiologist (MLH), who was unaware of the patient’s age and sex and the results of the atteriography. The accuracy of this measure might have been increased by direct interview. Moreover, the primary cardiologists undoubtedly screened out many patients in their initial evaluation who reported atypical chest pain. For this reason, we believe that the strength of association between psychiatric diagnosis and chest pain determined upon presentation in the cardiologist’s office may be increased over that observed in the current study. The study patients may well represent the more difficult subset of patients with chest pain associated with psychiatric disease. The increased prevalence of psychiatric disorders among patients with chest pain who are found to have negative coronary arteriographic results has long been suspected. Previous studies suggested that patients with chest pain and negative cardiac studies had higher neuroticism scores than did patients with chest pain and coronary artery disease. The suspicion from these studies was that high neuroticism (anxiety, depression, and somatization scores) made patients more apt to complain and amplify minor body symptoms. However, in this study, which is the first to utilize both a structured psychiatric interview (DIS) and operational diagnostic criteria based on DSM III, two specific psychiatric disorders-panic
Medications CAD (-) (n = 28) Percent Number Using
Drua Any psychiatric medication * Antianxiety+ Antidepressant Beta blocker with high lipophilicity+ Beta blocker with low-tomoderate lipophilicity Calcium channel blocker Organic nitrates+ Diuretics+ Other antihypertensives Aspirin Digoxin Diabetic medication Opiate Mean number of medications* (SD)
7
25
6 1 3 14 12 9 14 2 3 3 3 2
CAD (+) (n = 46) Percent Number Using 1
2.2
21.4 3.6 10.7
1 0 12
2.2 0 26.1
50
27
58.7
ia
39.1 56.5 28.3 0 10.9 2.2 2.2 0 1.6
42.9 32.1 50 7.1 10.7 10.7 10.7 7.1 3.4 f 2.7
p
26 13 0 5 1 1 0 2.3 f
l
TABLE
VII
(propranolol) associated
Psychologic Test Scores Negative Versus Positive Disease
SCL-90 * Somatization Depression+ Anxiety Phobia Other SAS+
cross the with central
in Patients with Coronary Artery
Negative Coronary Artery Disease Mean SD
Positive Coronary Artery Disease Mean SD
70.4 68.3 61.2 44.6 1.08 46.9
65.6 62.7 56.8 40.8 20.87 41.9
6.1 9.2 16.2 17.3 0.8 7.7
* SCL-90 raw scores (with the exception scale for which there are no norms) were ized (T-score) norms for non-patients. + p <0.05.
11.4 11.7 14.8 17.1 0.74 9.5
of the additional item converted to standard-
have had a positive outcome on an exercise tolerance test. Cardiac risk factors were equally prevalent in both groups of patients with chest pain with the exception of obesity. The high number of risk factors present in patients with CAD(-) was probably one factor that contributed to the cardiologist’s decision to refer them for arteriography. There were also important differences in demographic variables, pain phenomenology, and psychiatric diagnoses between patients with chest pain who had negative
6
January
1988
The American
Journal
of Medicine
Volume
84
CHEST
PAIN
AND
PSYCHIATRIC
ILLNESS-KATON
ET AL
tendencies. Katon and colleagues [44] demonstrated that patients with panic disorder had a significantly higher total number of symptoms than did control subjects (13 symptoms in patients with panic disorder versus seven in control subjects) on a medical review of symptoms [44]. In another study, 80 percent of 55 primary care patients with panic disorder presented initially with a pain complaint, most commonly chest pain, headache, or epigastric pain [23]. Noyes and colleagues [45] found that prior to treatment, patients with panic disorder scored as high on an index of hypochondriasis, the Illness Behavior Questionnaire (IBQ) [46], as did a group of hypochondriacal psychiatric patients [46]. After treatment, patients with panic disorder had significant reductions in somatic preoccupation, disease phobia, and disease conviction as reviewed by the IBQ. Major depression has been demonstrated in both retrospective and prospective studies to be associated with increased rates of medical utilization [47,48]. In addition, these studies have demonstrated that patients with major depression often present to physicians not only with nonspecific complaints (decreased libido, weight loss, insomnia, fatigue), but often with pain complaints (headache, chest pain, back pain) [47,48]. Two recent studies have demonstrated more specifically that when patients with major depression are compared with nondepressed control subjects on a medical review of systems, depressive patients complain of significantly more symptoms [49,50]. In both of these studies, depressive patients complained of chest pain significantly more than did control patients. One cautionary note is that although our data imply a strong association between panic disorder and major depression and chest pain with negative angiographic evidence of coronary artery disease, the data cannot be necessarily assumed to imply a cause-and-effect relationship. Future studies need to be completed to verify this association in a larger sample and treatment studies need to be initiated to test whether the chest pain improves with treatment of panic disorder and major depression. An additional important methodologic improvement in these future studies would be to interview patients prior to angiogram in order to ensure that patient and interviewer are not biased by arteriographic results. An unanswered question from this study is what proportion of patients with chest pain and normal coronary atteriograms have other medical illnesses associated with episodic chest pain, such as mitral valve prolapse, Prinzmetal’s angina, small coronary artery spasm [51], or esophageal disease. Dart and colleagues [52] studied 98 patients with chest pain and normal coronary arteries and found that esophageal disease was present in 17 patients and coronary spasm was present in one. Ergotamine was given during this study without provoking coronary spasm and there was no evidence that the patients with esopha-
disorder and major depression-were significantly more prevalent in the patients with chest pain who had normal coronary arteriographic studies. More than 70 percent of patients with chest pain and negative coronary arteriographic results had either panic disorder, major depression, or both illnesses compared with about 9 percent of patients with chest pain and positive coronary arteriographic results. The results of the psychiatric interviews are supported by the results of the psychologic tests in which the depression scale of the SCL-90 and the SAS were significantly higher in the patients with CAD(-) compared with the patients with CAD(+). The fact that patients with CAD(-) were prescribed significantly more psychiatric medication in general and antianxiety agents in particular compared with patients with CAD(+) also supports the results of the psychiatric interview. The increase in depression in the CAD(-) patients is not secondary to taking beta blockers that readily cross the blood-brain barrier (lipophilic beta blockers such as propranolol) or other antihypertensive agents since these medications were prescribed equally to both groups of patients. Recent psychiatric literature has suggested that panic disorder is associated with a biophysiologic abnormality as demonstrated by the observed familial predisposition [34], specific pharmacologic treatment responses to tricyclic antidepressants, monoamine oxidase inhibitors, and some specific benzodiazepines [35], and biologic markers including an association with mitral valve prolapse [36] and lactate sensitivity [37]. Two of the core symptoms of panic disorder are chest pain or tightness and tachycardia. Recent evidence points to central dyscontrol of the locus ceruleus and the sympathetic nervous system, and higher than normal peripheral epinephrine levels and resting heart rates in patients with panic disorder [38,39]. Da Costa [40] in his 1871 treatise described the irritable heart syndrome as resulting “from the heart’s overaction and frequent excitement and that a disorder of innervation keeps it so.” Indeed panic disorder seems to result from central dyscontrol of the sympathetic nervous system resulting in an episodic syndrome of rapid heart beat, chest pain, dyspnea, paresthesias, tremulousness, diaphoresis, hot or cold flashes, dizziness, depersonalization, and a fear of impending doom associated with great fear and anxiety. Recent biologic studies have supported the idea that panic disorder and hyperventilation syndrome may be synonymous [41] (patients with panic disorder have been demonstrated to be chronically hyperventilating) and hyperventilation causes direct circulatory effects, i.e., increases in myocardial contractility [42], stroke volume, and cardiac output [43]. These physiologic changes may explain the mechanism by which panic disorder produces cardiac symptoms. Several recent studies have emphasized the association between panic disorder and marked hypochondriacal
January
1988
The American
Journal
of Medicine
Volume
84
7
CHEST
PAIN
AND
PSYCHIATRIC
ILLNESS-KATON
ET AL
geal spasm had spasm of the coronary artery as well. Other studies have found esophageal disease in 17 to 100 percent of patients with chest pain and normal coronary arteries [52,53]. Thus, esophageal spasm is found in a significant number of patients with chest pain and normal coronary arteries; interestingly, a recent study found that 84 percent of 25 patients with esophageal manometric abnormalities met criteria for a psychiatric diagnosis by DSM-III criteria [54]. The most common psychiatric diagnosis in this sample of patients with esophageal abnormalities was (as in our sample of patients with chest pain and normal coronary arteriograms) depression and anxiety. Although the presence of panic disorder or major depression alone cannot be regarded as indicative of normal coronary anatomy, concomitant clinical psychiatric interviewing may obviate the need for further study in some patients and may facilitate appropriate therapy for treatable psychiatric disorders. Since many patients with psy-
chiatric disease and somatic complaints refuse a psychiatric explanation or referral for their complaints, it is important for cardiologists and primary care physicians to be prepared to identify and treat panic disorder and major depression, which can result in high degrees of morbidity, lost productivity, and overutilization of medical resources [21,23,36,48,52]. The importance of accurate diagnosis and treatment is emphasized by follow-up studies of patients with chest pain who have negative arteriograms. Ockene and colleagues [6] have demonstrated that a negative coronary artery study does not necessarily reassure patients with chest pain. After following 57 patients with chest pain (who had negative coronary arteriograms) for an average of 17 months, 44 percent still believed they had heart disease; 51 percent were unable to work because of chest pain; and 47 percent still described their activity as limited by chest pain [6]. Accurate psychiatric diagnosis and treatment may decrease somatization and illness behavior in these patients.
REFERENCES 1.
2.
3.
4.
5.
6.
10.
11.
8
Kemp HG, Vokonas PS, Cohn PF, Gorlin R: The angina1 syndrome associated with normal coronary arteriograms: report of a six-year experience. Am J Med 1973; 54: 73% 742. Marchandise B, Bourrassa MG, Chaitman BR, Lesperance J: Angiographic evaluation of the natural history of normal coronary arteries and mild coronary atherosclerosis. Am J Cardiol 1978; 41: 216-220. Proudfit WL, Shirey EK, Sones FM Jr: Selective cinecoronary arteriography: correlation with clinical findings in 1,000 patients. Circulation 1966; 33: 901-910. Proudfit WL, Bruschke AVG, Sones FM: Clinical course of patients with normal or slightly or moderately abnormal coronary arteriograms: lo-year follow-up of 521 patients. Circulation 1980; 62: 712-717. Day LJ, Sowton E: Clinical features and follow-up of patients with.angina and normal coronary arteries. Lancet 1979; II: 334-337. Ockene IS, Shay MJ, Alpert JS, Weiner BH, Dalen JE: Unexplained chest pain in patients with normal coronary arteriograms: a follow-up study of functional status. N Engl J Med 1980; 303: 1249-1252. Waxler EB, Kimbiris D, Dreifus LS: The fate of women with normal coronary arteriograms and chest pain resembling angina pectoris. Am J Cardiol 1971; 28: 25-32. Lavey EB, Winkle RA: Continuing disability of patients with chest pain and normal coronary arteriograms. J Chronic Dis 1979; 32: 191-196. lsner JM, Salem DN, Banas JS Jr, Levire HS: Long-term clinical course of patients with normal coronary arteriography: follow-up study of 121 patients with normal or nearly normal coronary arteriograms. Am Heart J 1981; 102: 645-653. Kemp HG, Kronmal RA, Vlietstra RE, Frye RL: Seven year survival of patients with normal or near normal coronary arteriograms: a Cass Registry Study. J Am Coil Cardiol 1986; 7: 479-483. Hope J: A treatise on the disease of the heart and great vessels comprising a new view of the physiology of the
January
1988
The American
Journal
of Medicine
Volume
12. 13. 14. 15.
16. 17.
la.
19.
20.
21
22. 23.
24.
84
heart’s action according to which the physical signs are explained. London: Churchill, 1832. Skerret PW: Anxiety and the heart-a historical review. Psycho1 Med 1983; 13: 17-25. Osler W: The principles and practice of medicine. Edinburgh: J Pentland Young, 1892. Mayou R: The patient with angina: symptoms and disability. Postgrad Med J 1973; 49: 250-254. Magarian GJ: Hyperventilation syndromes: infrequently recognized common expression of anxiety and stress. Medicine (Baltimore) 1982; 61: 219-235. Evans DW, Lum LC: Hyperventilation: an important cause of pseudoangina. Lancet 1977; I: 155-158. Lary D, Goldschlager N: Electra cardiogram changes during hyperventilation resembling myocardial ischemia in patients with normal coronary arteriograms. Am Heart J 1974; 87: 383-390. Elias MF, Robbins MA, Blow FC, Rice AP, Edgecomb JL: Symptom reporting, anxiety and depression in arteriographically classified middle-aged chest pain patients. Exp Aging Res 1982; 8: 45-51. Costa PT, Zonderman AB, Engel BT, Baile WF, Brimlow DL, Brinker J: The relation of chest pain symptoms to angiographic findings of coronary artery stenosis and neuroticism. Psychosom Med 1985; 47: 285-293. Channer KS, James MA, Papouchado M, Rees JR: Anxiety and depression in patients with chest pain referred for exercise testing. Lancet 1985; I: 820-823. Bass C, Wade C: Chest pain with normal coronary arteries: a comparafive study of psychiatric and social morbidity. Psycho1 Med 1984; 14: 51-61. Katon W: Panic disorder and somatization: review of 55 cases. Am J Med 1984; 77: 101-106. American Psychiatric Association, Task Force on Nomenclature and Statistics: Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. Washington: American Psychiatric Association, 1980. Harris JN: Coronary angiography and its complication. Arch Intern Med 1984; 144: 337-341.
CHEST
25.
26.
27.
28.
29.
30. 31.
32. 33.
34.
35. 36.
37.
38.
39.
40.
Robins LN, Helzer JE, Croughan J, Ratcliff KS: National Institute of Mental Health Diagnostic interview Schedule: its history, characteristics and validity. Arch Gen Psychiatry 1981; 38: 381-389. Yates WR: The National Institute of Mental Health Epidemiologic Study: implications for family practice. J Fam Pratt 1986; 22: 251-255. Welch CC, Proudfit WL, Sfieldon WC: Coronary arteriographic findings in 1,000 women under age 50. Am J Cardiol 1975; 35: 211-215. Fuster V, Frye RL, Connolly DC, Danielson MA, Elveback LR, Kurland LT: Arteriographic patterns early in the onset of the coronary syndromes. Br Heart J 1975; 37: 12501255. Derogatis LR: SCL-9OR manual. I: Scoring, administration, and procedures for the SCL-9OR. Baltimore: Johns Hopkins University School of Medicine, 1977. Zung WWK: A rating instrument for anxiety disorders. Psychosomatics 1971; 12: 37i-379. Sarason IG, Johnson JH, Siegel JM: Assessing the impact of life changes: development of the life experiences survey. J Consult Clin Psycho1 1978; 46: 932-946. Fleiss JL: Statistical methods for rates and proportions. New Yprk: John Wiley and Sons, 1973. Bruschke AV, Proudfit WB, Sones FM: Clinical course of patients with normal and slightly or moderately abnormal coronary arteriograms. A follow-up study of 500 patients: Circulation 1973; 47: 936-945. Crowe RR: The role of genetics in the etiology of panic disorder. In: Grinspoon L, ed. Psychiatry update, vol 3. Washington: American Psychiatric Association, 1984. Sheehan DV: Panic attacks and phobias. N Engl J Med 1982; 307: 156-158. Pariser S, Pinta E, Jones B: Mitral valve prolapse syndrome and anxiety nerosis/panic disorder. Am J Psychiatry 1978; 135: 240-247. Liebowitz MR, Fyer AJ, Gorman JM, et al: Lactate provocation of panic attacks. I. Clinical and behavioral findings. Arch Gen Psychiatry 1984; 41: 764-770. Nesse RM, Cameron OG, Curtis GC, McCann DS, HuberSmith MJ: Adrenergic function in patients with panic anxiety. Arch Gen Psychiatry 1984; 41: 771-776. Charney DS, Heniger GR, Breir A: Noradrenergic function in panic anxiety. Arch Gen Psychiatry 1984; 41: 751-763. Da Costa JM: On irritable heart. Am J Med Sci 1871; 61: 17-
41.
42.
43.
44.
45.
46.
47.
48.
49. 50.
51.
52.
53.
54.
January
PAIN AND
PSYCHIATRIC
ILLNESS-KATON
ET AL
52. Reiman EM, Raichle ME, Robins E, et al: The application of positron emission tomography to the study of panic disorder. Am J Psychiatry 1986; 4: 469-477. Hurst WJ, King SB, Walter PF, Freisinger GC, Edward JE: Atherosclerotic coronary heart disease: angina pectoris, myocardial infarction and other manifestations of myocardial ischemia. In: Hurst JW, ed. The heart. New York: McGraw-Hill, 1982. Streisand RL, Gourin A, Stuckey JH: Respiratory and metabolic alkalosis and myocardial contractility. J Thoracic Cardiovasc Surg 1971; 62: 431-435. Katon W, Vitalliano PP, Russo J, Cormier L, Jones M, Anderson K: Panic disorder: epidemiology in primary care. J Fam Pratt 1986; 23: 233-239. Noyes R, Reich J, Clancy J, et al: Reduction in hypochondriasis with treatment of panic disorder. Br J Psychiatry 1986; 631-635. Pilowsky I, Spence ND: Manual for the Illness Behavior Questionnaire (IBQ) 2nd ed. Adelaide, South Austria: University of Adelaide, 1983. Katon W, Berg AQ, Robins AJ, Risse S: Depression: medical utilization and somatization. West J Med 1986; 144: 564568. Widmer RB, Cadoret RJ: Depression in primary care: changes in pattern of visits and complaints during a developing depression. J Fam Pratt 1978; 7: 293-302. Mathew RJ, Weinman ML, Mirabi M: Physical symptoms of depression. Br J Psychiatry 1981; 139: 293-296. Waxman HM, McCreary G, Weinrit RM, Carner EA: A comparison of somatic complaints among depressed and nondepressed older persons. Gerontologist 1985; 25: 501507. Cannon RO, Leon MB, Watson R, Rosing DR, Epstein SE: Chest pain and “normal” coronary arteries-role of small coronary arteries. Am J Cardiol 1985; 55: 508-608. Dart AM, Davies AH, Dalal J, et al: “Angina” arid normal coronary arteriograms: a follow-up study. Eur Heart J 1980; 1: 97-100. Brand DL, Martin D, Pope CE: II. Esophageal manometrics in patients with angina-like chest pain. Dig Dis Sci 1977; 22: 300-304. Clouse RE, Lustman PJ: Psychiatric illness and contraction abnormalities of the esophagus. N Engl J Med 1983; 309: 1337-1342.
1988
The American
Journal
of Medicine
Volume
84
9
The
American
Journal
NUMBER 1
of
A~UARY I98
Medicin CLINICAL STUDIES
Chest Pain: Relationship of Psychiatric Illness to Coronary Arteriographic Results
WAYNE
KATON,
MARGARET JOAN
RUSSO,
LAWRENCE MICHAEL PETER
M.D.
L. HALL,
M.D.
Ph.C. CORMIER,
HOLLIFIELD, P. VITALIANO,
M.D. B.S. Ph.D.
Seattle, Washington BERNARD
D. BEITMAN,
M.D.
Columbia, Missouri
Seventy-four patients with chest pain and no prior history of organic heart disease were interviewed with a structured psychiatric interview immediately after coronary arteriography. The majority of patients with both negative and positive coronary angiographies had undergone previous exercise tolerance tests, but the patients with angiographic coronary artery disease were significantly more likely to have had positive results on a treadmill test. Patients with chest pain and negative coronary arteriograms were significantly younger; more likely to be female; more apt to have a higher number of autonomic symptoms (tachycardia, dyspnea, dizziness, and paresthesias) associated with chest pain, and more likely to describe atypical chest pain. Patients with chest pain and normal coronary arteriographic results also had significantly higher psychologic scores on indices of anxiety and depression and were significantly more likely to meet criteria of the Diagnosfic and Statistical Manual of Mental Disorders, third edition, for panic disorder (43 percent versus 6.5 percent), major depression (36 percent versus 4 percent), and two or more phobias (36 percent versus 15 percent) than were patients with chest pain and a coronary arteriography study demonstrating coronary artery stenosis. There are few affectations which excite more alarm and anxiety in the mind of the patient than this. He fancies himself doomed to become a martyr to organic disease of the heart, of the horrors of which he has an exaggerated idea; it is the more difficult to divest him of this impression because the nervous state which gives rise to his complaint impatts a fanciful gloom and desponding tone to his imagination. J. Hope (1832)
From the Division of Consultation/Liaison Psychiatry and the Department of Medicine, University of Washington Medical School, Seattle, Washington, and the Psychiatry Department, University of Missouri, Columbia, Missouri. Requests for reprints should be addressed to Dr. Wayne Katon, Department of Psychiatry and Behavioral Sciences RP-10, University of Washington Medical School, Seattle, Washington 98195. Manuscript submitted June 22, 1987, and accepted in revised form October 5, 1987.
Studies have demonstrated that 10 to 30 percent of patients with chest pain who undergo coronary arteriography have no arterial abnormalities [l--3]. Follow-up studies of these patients have consistently shown that the risk of subsequent myocardial infarction is low [4-IO], yet 50 to 75 percent have persistent complaints of chest pain and disability after normal coronary arteriograms [6,8]. Both cardiac (Prinzmetal’s angina and mitral valve prolapse) and non-cardiac problems (esophageal spasm, costochondritis, hyperventilation syndrome, and anxiety neurosis) have been implicated as having etiologic significance.
January
1988
The American
Journal
of Medicine
Volume
84
1
CHEST
PAIN
AND
PSYCHIATRIC
ILLNESS-KATON
ET AL
There has been a long historical interest in functional cardiac symptoms (particularly chest pain and tachycardia). In 1832, Hope [ 1 l] discussed the subject of “nervous palpitations” in one of the first English textbooks of cardiology. Terms such as Da Costa’s syndrome, irritable heart, soldier’s heart, effort syndrome, neurocirculatory asthenia, hyperdynamic beta-adrenergic circulatory state, hyperventilation syndrome, and mitral valve prolapse have been used to describe functional cardiac symptoms in patients [ 121. Osler [ 131 recognized the difficulty in differentiating between chest pain caused by coronary artery disease and that attributable to non-cardiac factors when he described two distinct categories of true angina and pseudoangina. In the second category, he found an excess of women in whom episodes of pain were characteristically periodic and nocturnal, lasting one to two hours and accompanied by nervous symptoms and vasomotor disturbances. In more recent years, Mayou [14] reported that in patients attending a cardiology clinic with chest pain, those with no evidence of cardiac disease were characterized as being younger and describing more atypical chest pain and somatic anxiety symptoms than patients with demonstrable cardiac lesions. Waxler et al [7] estimated that 40 percent of 86 women with chest pain, who had normal coronary arteriograms, displayed neurotic and hypochondriacal behavior. Many studies have found that anxiety-induced hyperventilation symptoms and nonspecific electrocardiographic ST- and T-wave changes were common in patients with chest pain and normal coronary arteriograms [ 15-171. Elias and colleagues [ 181 found a negative correlation between the maximum degree of coronary stenosis and measures of neuroticism (anxiety, depression, and somatic complaints) in a sample of 136 men and women awaiting arteriography. The more anxious, depressed, or concerned with somatic complaints the person was, the less coronary artery stenosis was demonstrated. In a group of 83 patients referred to coronary atteriography for chest pain, Costa and colleagues [ 191 demonstrated that neuroticism influenced the quality of the chest pain presentation, and that these symptoms did not predict arteriographic coronary stenosis [ 191. Channer and colleagues [20] assessed anxiety and depression by a short patient self-rating scale in 87 consecutive patients with chest pain before diagnostic treadmill testing. Significantly more patients who had high scores on anxiety or depression had negative test results. Bass and Wade [21] studied 99 patients with chest pain referred to arteriography. Almost two thirds (6 1 percent) of the 46 patients with hemodynamically insignificant disease had a psychiatric diagnosis (most commonly anxiety neurosis) compared with 23 percent of the 53 patients with significant coronary artery disease. Finally, Katon [22] reported that 39 percent of 55 patients referred for psychiatric consultation by primary care physi-
2
January
1988
The American
Journal
of Medicine
Volume
cians who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, third edition, (DSM Ill) [23] for panic disorder presented with chest pain and/or tachycardia. Thus, these studies suggest that persons who score high on neuroticism (anxiety and depression) often present with somatic complaints in the absence of organic pathology and may contribute to the 10 to 30 percent of patients undergoing arteriography who prove to have nondiseased coronary arteries. However, it is unclear whether patients with chest pain and negative coronary atteriograms have a clinical syndrome, i.e., major depression or panic disorder, or simply have higher anxiety and depression-scores on psychologic tests. The purpose of this investigation was to compare the prevalence of psychiatric disorders in patients with chest pain who had a negative coronary arteriographic study with that in those that had atteriographic evidence of coronary artery stenosis. If a clinical study were to observe a high association between specific treatable psychiatric disorders and chest pain with negative coronary atteriography, this information could be used to improve patient care and possibly to influence physicians’ selection of patients with coronary arteriography [24]. PATIENTS AND METHODS Patients. Patients were referred for coronary arteriography to the University of Washington Hospital by cardiologists from three practice settings: the University system, a health maintenance organization, and a large suburban private practice. The sample consisted of 74 consecutive subjects recruited from 78 eligible patients, aged 25 and older, referred for evaluation of chest pain. The cardiac evaluation completed prior to arteriography was carefully reviewed in order to assess if the patient met inclusion and exclusion criteria and to compare the pre-angiographic evaluations of the patients with negative and positive arteriographic results. The fact that the evaluating cardiologist had determined that the patient’s chest pain was sufficiently suspect to warrant coronary arteriography was taken as adequate for study inclusion. There was no difference over time in the frequency of negative arteriography among the three patient referral sources. In an attempt to simulate pertinent aspects of the evaluation of patients with “new chest pain” presenting to the primary care physician or cardiologist, and in order to test our hypothesis, we excluded patients with a history of organic heart disease (valvular or congenital heart disease or previously documented coronary artery disease). To meet exclusion criteria for previously documented coronary artery disease, we required evidence of (1) a definite myocardial infarction on electrocardiogram or enzyme evaluation; (2) definite segmental wall motion abnormality by noninvasive test or left ventriculography; or (3) previous positive coronary arteriogram. Patients were not excluded for a positive or equivocal treadmill test result or resting STsegment or T-wave changes on electrocardiogram. Pa-
84
CHEST
tients with mitral valve prolapse documented by either auscultation or echocardiography were also not excluded. Two hundred patients were screened for the study with 78 meeting inclusion and exclusion criteria. There were four otherwise eligible patients who were excluded because they could not be satisfactorily interviewed due to foreign language (two), severe dementia (one), or deaf and mute (one). Patients who express psychiatric disorder in an idiom of somatic distress are frequently quite defensive about their symptoms being secondary to mental illness. Therefore, to minimize defensiveness about mental disorders, the patients with chest pain were informed that the purpose of the research was to determine the prevalence of a common autonomic nervous system disorder that frequently caused cardiac symptoms such as rapid heart beat or chest pain.
PSYCHIATRIC INSTRUMENTS Psychiatric Diagnosis. A modified version of the structured psychiatric interview, the Diagnostic Interview Schedule (DIS) [25] was administered to each participant by one of two trained interviewers (a senior psychiatric resident and a medical student) immediately after a coronary arteriogram was obtained. The patients had usually been given a preliminary report on their angiogram prior to the interview but were instructed not to report that to the psychiatric interviewer. Thus, the psychiatric interviewer was unaware of the coronary arteriographic results. The DIS specifies questions and probes for the determination of diagnoses according to criteria outlined in the DSM Ill of the American Psychiatric ,Association [23]. Six diagnoses were sought and recorded in this investigations: panic disorder, simple phobic disorder, major depression, dysthymic disorder, alcohol abuse, and alcohol dependence. These diagnoses were selected because epidemiologic studies of medical patients have determined that these six diagnoses encompass more than 90 percent of the psychiatric diseases in this population [26]. The psychiatric diagnoses were considered to be current if the diagnostic criteria were met within the month prior to catheterization. Ten percent of subjects were interviewed by both examiners in order to assess inter-rater reliability. The inter-rater reliability for all psychiatric diagnoses was high (kappa = 0.90, p
PAIN
AND
PSYCHIATRIC
ILLNESS-KATON
ET AL
ic results were classified as coronary artery disease negative [CAD(-)] when there was less than 50 percent stenosis in all coronary vessels [27,28]. A chart review was completed to assess each patient’s coronary artery risk factors (family history of coronary artery disease, hypertension, smoking, obesity, diabetes, hyperlipemia, or increased cholesterol levels), the preliminary cardiac workup that had led to referral for coronary arteriography (exercise treadmill test), and the medications that each patient was taking prior to catheterization. A positive family history of cardiovascular disease included a first-degree family member (mother, father, and siblings) with coronary heart disease or stroke occurring at 60 years of age or less. Hypertension was defined as a documentation in the medical record of a combination of diastolic blood pressure above 90 mm Hg and a systolic blood pressure over 140 mm Hg as well as current treatment with one or more antihypertensive agents. Hyperlipidemia, hypercholesterolemia, obesity, and smoking were listed as present if they were noted in the referring cardiologist’s or the catheterization cardiologist’s summary of cardiac risk factors and thus were dependent on their qualitative judgement. The study cardiologist rated each patient’s chest pain as typical or atypical (unaware of the psychiatric and cardiac diagnoses) based on the following criteria [7]: Typical angina was described as substernal chest pain or pressure brought on predominantly (in more than 75 percent of cases) by exertion and relieved promptly by rest. Atypical angina pectoris was considered present when there was an unusual feature such as location, duration, or quality (pleuritic, jabbing) of pain or consistency to physical exertion or emotional stress described, but at some time the pain had been related to physical or emotional stress. Self-Report Measures. Each participant was asked to fill out three self-report questionnaires after the psychiatric interview was completed: (1) an abridged version of the Hopkins Symptom Checklist (SCL-90) [29]; (2) the Zung Self-Rating Anxiety Scale (SAS) [30]; and (3) the Life Experiences Survey (LES) [31]. The abridged SCL-90 includes 49 current symptoms scored on a 0 to 4 severity scale of somatization, anxiety, phobic-anxiety, depression, and additional subscales. The SAS measures the current severity of 20 anxiety symptoms scored on a 1 to 4 severity scale. The LES is a schedule of 50 life events (marriage, death of spouse, new job) experienced in the past year. It asks patients to rate the events that they have experienced on a negative (0 to -3) to positive (0 to i-3) continuum of the perceived impact that the event had. Negative and positive life events were summated separately. Statistical Methods. Chi-square tests with Yates’ correction were used to evaluate the relationship of coronary artery disease status and demographic variables, coronary risk factors, psychiatric diagnoses, use of medications, and type of chest pain. To evaluate the degree to which gender could be a confounder or effect modifier of these relationship and because of the disparate number of male (51) versus female (23) patients, the phi coefficient (8) was used [32]. The phi coefficient, unlike the chi-square statistic, is
January 1988
The American Journal of Medicine
Volume 84
3
CHEST
PAIN AND
TABLE I
PSYCHIATRIC
ILLNESS-KATON
ET AL
differences in age, number of autonomic symptoms, life events, and the psychologic test scores were evaluated using two-tailed Student t tests.
Demographic Variables among Patients with Negative Versus Positive Coronary Artery Disease Negative Coronary Artery Disease (n-= 28) Number [Percent)
Age (SD)* Male* Married Hollingshead’s social class I, II, Ill (nonmanual) IV, V (manual)
Positive Coronary
ArteryDisease (n-= 46) Number (Percent)
51.2 f (10.6) 13 (46.4) 20 (7 1.4)
59.5 f (10.5) 38 (82.6) 34 (73.9)
11 (37.3) 17 (60.7)
25 (54.3) 21 (45.7)
* p
TABLE ii
Coronary
Risk Factors Smoking Family history Diabetes Obesity* Hyperlipedemia Hypertension Mean number risk factors
of (SD)
Artery
Disease
Risk Factors
CADI-j (n =.26j Number Percent
CAD(+) (n =‘46j Number Percent
12 4 4 9 4 15 1.71
29 16 5 4 15 21 2.04
44.4 14.8 14.8 33.3 14.8 53.6 1.27
63 34.8 10.9 8.7 32.6 45.7 1.15
* p <0.02.
TABLE
iii
Cardiac
Variables Had an ETT (percent yes) Results of ETT” Positivet Nonspecific abnormalitiest Negatives
Testing
Prior to Arteriography
CAD(-) CAD(+) Number Percent Number Percent 19
70.4
37
80.4
2 IO 7
10.5 52.6 36.8
25 5 7
67.6 13.5 18.9
ETT = exercise tolerance test. * p
unbiased by the sample size of the tables, and it gives an indication of the strength of the association (0 = no relationship; +I = perfect association). (The drawback of 8 in the current context is that it cannot reach a maximum value
of -i-1. Hence, the numerical interpretation of the strengths of association in the current analyses are conservative and they are stronger than they appear [32]). Mean group
4
January 1988 The American Journal of Medicine Volume 84
RESULTS
Over a five-month period, 74 patients with chest pain were enrolled in the study. Twenty-eight (38 percent) had negative coronary arteriograms [CAD(-)] and 46 (62 percent) had coronary arteriographic evidence of coronary artery disease [CAD(+)]. Table I describes the demographic characteristics of the patients. Patients with chest pain and a negative coronary arteriographic study were significantly younger (t = 3.2, df = 72, p <0.002) and more likely to be female (X*(l) = 8.8, p <0.003) than patients with chest pain and a positive coronary arteriogram. There were no significant differences in marital status (X*(l) = 0.01) or social class (Hollingshead Index) (X2(1) = 0.92) between the two groups of patients. Table II describes the coronary artery disease risk factors in the patients with CAD(-) and the patients with CAD(+). Overall, there were no differences in the prevalence of any risk factor with the exception of obesity, which was significantly more prevalent in the patients with CAD(-) (X*(l) = 5.47, p <0.02). There was also no difference in the total number of coronary artery disease risk factors in the patients with CAD(-) and CAD(+). Table Ill describes the cardiac evaluations that were completed by the 74 patients with chest pain prior to coronary arteriography. There were no significant differences in the number of patients who had an exercise tolerance test prior to arteriography in the CAD(-) and CAD(+) groups. However, only two of the 19 (10.5 percent) patients who had a negative arteriographic study had a positive treadmill test result compared with 25 of 37 (67.6 percent) patients with coronary artery disease on angiography (X2(2) = 17.26, p
CHEST
at-teriography and psychiatric diagnoses, we examined the association of coronary artery disease status and psychiatric diagnoses both with gender and stratified by gender. Gender was not significantly related to panic disorder (X2(1) = 0.27); however, it was significantly related to major depression (X2(1) = 3.8; p <0.05): 30.4 percent of the women compared with 9.8 percent of the men met DSM III criteria for major depression. These gender effects are not due to age because there was no significant difference between the mean age of female (58.3 years) and male (55.5 years) subjects (t = 1.07, df = 72, p = NS). The strength of association between coronary artery disease status and panic disorder is very similar for male (a, = 0.44; p
TABLE IV
PAIN
AND
PSYCHIATRIC
ILLNESS-KATON
DSM Ill Psychiatric Diagnoses with Negative Versus Positive Artery Disease Negative Coronary
ArteryDisease (n = 28)
Number(Percent) Panic disorder* Simple phobias (2 or more)+ Major depression, current* Lifetime depressiont Lifetime alcohol abuse Lifetime alcohol dependence Alcohol abuse Alcohol dependence No current psychiatric diagnosis*
ET AL
in Patients Coronary
Positive Coronary Artery Disease (n = 46)
Number(Percent)
12 (42.9) IO (35.7)
3 (6.5) 7 (15.2)
10 (35.7)
2 (4.3)
18 (64.3) IO (35.7) 4 (14.3)
11 (23.9) 15 (32.6) 8 (17.4)
3 (10.7) 1 (3.6) 6 (21.4)
3 (6.5) 2 (4.3) 34 (73.9)
p
TABLE V
Description of Pain and Preceding Life Events in Patients with Negative Versus Positive Coronary Artery Disease Negative Coronary Positive Coronary Artery Disease ArteryDisease (n = 28) (n = 46)
Chest Pain* Typical (percent) Atypical (percent) Mean number of autonomic symptoms (SD)+ Mean number of positive life events (SD) Mean number of negative life events (SD)
7 (25.9) 20 (74.1) 5.2 f (2.6)
40 (88.9) 5 (11.1) 3.8 f (2.7)
3.7 f (4.0)
4.5 f (6.5)
7.8 f (6.9)
4.0 f (6.5)
* p
= 0.06). Table VI describes the medications prescribed to pa-
tients with CAD(-) and CAD(+). Patients with CAD(-) were significantly more likely to be taking psychoactive, medication in general (X2(1) = 7.19; p <0.007), antianxiety agents (X*(l) = 5.45; p <0.02), and diuretics (X*(l) = 3.55; p <0.05) than patients with CAD(+). Patients with CAD(+) were significantly more likely to be prescribed an organic nitrate (X*(l) = 4.15, p <0.04). Overall, patients with CAD(-) were taking significantly more medications than were patients with CAD(+) [t(38.5) = 1.97; p <0.05]. The results of the SCL-90 and the SAS can be seen in Table VII. Self-report measures were completed by 63 (85 percent) of the 74 patients. Although patients with CAD(-) had higher scores on every psychologic mea-
sure, only the SCL-90 depression (t = 2.0; df = 61; p <0.05) and SAS anxiety scores (t = 2.2, df = 61; p <0.03) reached statistical significance. COMMENTS
In this study of 74 patients with chest pain referred for coronary arteriography, 37.8 percent had a negative workup, which is a higher percentage than the 10 to 30 percent reported in other studies. This result was expected due to the exclusion of patients with previously documented organic heart disease. The patients with chest pain and CAD(-) were equally likely to have had an exercise tolerance test prior to arteriography, but the patients with CAD(+) were significantly more likely to
January 1998
The
American Journal of Medicine Volume 84
5
CHEST
PAIN AND PSYCHIATRIC
TABLE VI
ILLNESS-KATON
ET AL
coronary arteriographic results and patients with chest pain who had positive coronary arteriographic results. Patients with chest pain and normal coronary arteries were younger; more likely to be female; more apt to have a higher number of autonomic symptoms associated with chest pain; and more likely to present with atypical pain. Patients with chest pain and normal coronary arteries also had higher psychologic scores on indices of anxiety and depression and were significantly more likely to meet DSM-III criteria for panic disorder or major depression as well as to report two or more simple phobias. The fact that there were more female patients with CAD(-) did not confound the relationship between CAD(-) and panic disorder because both men and women with panic disorder had similar high rates of negative coronary arteriograms. However, in the diagnosis of major depression, gender was a confounding factor; major depression was more strongly associated with a negative coronary arteriogram in women than in men. Other studies have documented that patients with chest pain and normal coronary arteries were significantly younger [21] and more likely to be female [7,21]. We did not ask the physicians caring for the patients to rate the likelihood of finding anatomic disease at catheterization; however, in prior studies, the physician’s impression of the pain as atypical had a strong predictive association with a normal coronary arteriographic study [7,2 1,331. In the current study, chest pain evaluations were done by a chart review of the patient’s description of pain by the study cardiologist (MLH), who was unaware of the patient’s age and sex and the results of the atteriography. The accuracy of this measure might have been increased by direct interview. Moreover, the primary cardiologists undoubtedly screened out many patients in their initial evaluation who reported atypical chest pain. For this reason, we believe that the strength of association between psychiatric diagnosis and chest pain determined upon presentation in the cardiologist’s office may be increased over that observed in the current study. The study patients may well represent the more difficult subset of patients with chest pain associated with psychiatric disease. The increased prevalence of psychiatric disorders among patients with chest pain who are found to have negative coronary arteriographic results has long been suspected. Previous studies suggested that patients with chest pain and negative cardiac studies had higher neuroticism scores than did patients with chest pain and coronary artery disease. The suspicion from these studies was that high neuroticism (anxiety, depression, and somatization scores) made patients more apt to complain and amplify minor body symptoms. However, in this study, which is the first to utilize both a structured psychiatric interview (DIS) and operational diagnostic criteria based on DSM III, two specific psychiatric disorders-panic
Medications CAD (-) (n = 28) Percent Number Using
Drua Any psychiatric medication * Antianxiety+ Antidepressant Beta blocker with high lipophilicity+ Beta blocker with low-tomoderate lipophilicity Calcium channel blocker Organic nitrates+ Diuretics+ Other antihypertensives Aspirin Digoxin Diabetic medication Opiate Mean number of medications* (SD)
7
25
6 1 3 14 12 9 14 2 3 3 3 2
CAD (+) (n = 46) Percent Number Using 1
2.2
21.4 3.6 10.7
1 0 12
2.2 0 26.1
50
27
58.7
ia
39.1 56.5 28.3 0 10.9 2.2 2.2 0 1.6
42.9 32.1 50 7.1 10.7 10.7 10.7 7.1 3.4 f 2.7
p
26 13 0 5 1 1 0 2.3 f
l
TABLE
VII
(propranolol) associated
Psychologic Test Scores Negative Versus Positive Disease
SCL-90 * Somatization Depression+ Anxiety Phobia Other SAS+
cross the with central
in Patients with Coronary Artery
Negative Coronary Artery Disease Mean SD
Positive Coronary Artery Disease Mean SD
70.4 68.3 61.2 44.6 1.08 46.9
65.6 62.7 56.8 40.8 20.87 41.9
6.1 9.2 16.2 17.3 0.8 7.7
* SCL-90 raw scores (with the exception scale for which there are no norms) were ized (T-score) norms for non-patients. + p <0.05.
11.4 11.7 14.8 17.1 0.74 9.5
of the additional item converted to standard-
have had a positive outcome on an exercise tolerance test. Cardiac risk factors were equally prevalent in both groups of patients with chest pain with the exception of obesity. The high number of risk factors present in patients with CAD(-) was probably one factor that contributed to the cardiologist’s decision to refer them for arteriography. There were also important differences in demographic variables, pain phenomenology, and psychiatric diagnoses between patients with chest pain who had negative
6
January
1988
The American
Journal
of Medicine
Volume
84
CHEST
PAIN
AND
PSYCHIATRIC
ILLNESS-KATON
ET AL
tendencies. Katon and colleagues [44] demonstrated that patients with panic disorder had a significantly higher total number of symptoms than did control subjects (13 symptoms in patients with panic disorder versus seven in control subjects) on a medical review of symptoms [44]. In another study, 80 percent of 55 primary care patients with panic disorder presented initially with a pain complaint, most commonly chest pain, headache, or epigastric pain [23]. Noyes and colleagues [45] found that prior to treatment, patients with panic disorder scored as high on an index of hypochondriasis, the Illness Behavior Questionnaire (IBQ) [46], as did a group of hypochondriacal psychiatric patients [46]. After treatment, patients with panic disorder had significant reductions in somatic preoccupation, disease phobia, and disease conviction as reviewed by the IBQ. Major depression has been demonstrated in both retrospective and prospective studies to be associated with increased rates of medical utilization [47,48]. In addition, these studies have demonstrated that patients with major depression often present to physicians not only with nonspecific complaints (decreased libido, weight loss, insomnia, fatigue), but often with pain complaints (headache, chest pain, back pain) [47,48]. Two recent studies have demonstrated more specifically that when patients with major depression are compared with nondepressed control subjects on a medical review of systems, depressive patients complain of significantly more symptoms [49,50]. In both of these studies, depressive patients complained of chest pain significantly more than did control patients. One cautionary note is that although our data imply a strong association between panic disorder and major depression and chest pain with negative angiographic evidence of coronary artery disease, the data cannot be necessarily assumed to imply a cause-and-effect relationship. Future studies need to be completed to verify this association in a larger sample and treatment studies need to be initiated to test whether the chest pain improves with treatment of panic disorder and major depression. An additional important methodologic improvement in these future studies would be to interview patients prior to angiogram in order to ensure that patient and interviewer are not biased by arteriographic results. An unanswered question from this study is what proportion of patients with chest pain and normal coronary atteriograms have other medical illnesses associated with episodic chest pain, such as mitral valve prolapse, Prinzmetal’s angina, small coronary artery spasm [51], or esophageal disease. Dart and colleagues [52] studied 98 patients with chest pain and normal coronary arteries and found that esophageal disease was present in 17 patients and coronary spasm was present in one. Ergotamine was given during this study without provoking coronary spasm and there was no evidence that the patients with esopha-
disorder and major depression-were significantly more prevalent in the patients with chest pain who had normal coronary arteriographic studies. More than 70 percent of patients with chest pain and negative coronary arteriographic results had either panic disorder, major depression, or both illnesses compared with about 9 percent of patients with chest pain and positive coronary arteriographic results. The results of the psychiatric interviews are supported by the results of the psychologic tests in which the depression scale of the SCL-90 and the SAS were significantly higher in the patients with CAD(-) compared with the patients with CAD(+). The fact that patients with CAD(-) were prescribed significantly more psychiatric medication in general and antianxiety agents in particular compared with patients with CAD(+) also supports the results of the psychiatric interview. The increase in depression in the CAD(-) patients is not secondary to taking beta blockers that readily cross the blood-brain barrier (lipophilic beta blockers such as propranolol) or other antihypertensive agents since these medications were prescribed equally to both groups of patients. Recent psychiatric literature has suggested that panic disorder is associated with a biophysiologic abnormality as demonstrated by the observed familial predisposition [34], specific pharmacologic treatment responses to tricyclic antidepressants, monoamine oxidase inhibitors, and some specific benzodiazepines [35], and biologic markers including an association with mitral valve prolapse [36] and lactate sensitivity [37]. Two of the core symptoms of panic disorder are chest pain or tightness and tachycardia. Recent evidence points to central dyscontrol of the locus ceruleus and the sympathetic nervous system, and higher than normal peripheral epinephrine levels and resting heart rates in patients with panic disorder [38,39]. Da Costa [40] in his 1871 treatise described the irritable heart syndrome as resulting “from the heart’s overaction and frequent excitement and that a disorder of innervation keeps it so.” Indeed panic disorder seems to result from central dyscontrol of the sympathetic nervous system resulting in an episodic syndrome of rapid heart beat, chest pain, dyspnea, paresthesias, tremulousness, diaphoresis, hot or cold flashes, dizziness, depersonalization, and a fear of impending doom associated with great fear and anxiety. Recent biologic studies have supported the idea that panic disorder and hyperventilation syndrome may be synonymous [41] (patients with panic disorder have been demonstrated to be chronically hyperventilating) and hyperventilation causes direct circulatory effects, i.e., increases in myocardial contractility [42], stroke volume, and cardiac output [43]. These physiologic changes may explain the mechanism by which panic disorder produces cardiac symptoms. Several recent studies have emphasized the association between panic disorder and marked hypochondriacal
January
1988
The American
Journal
of Medicine
Volume
84
7
CHEST
PAIN
AND
PSYCHIATRIC
ILLNESS-KATON
ET AL
geal spasm had spasm of the coronary artery as well. Other studies have found esophageal disease in 17 to 100 percent of patients with chest pain and normal coronary arteries [52,53]. Thus, esophageal spasm is found in a significant number of patients with chest pain and normal coronary arteries; interestingly, a recent study found that 84 percent of 25 patients with esophageal manometric abnormalities met criteria for a psychiatric diagnosis by DSM-III criteria [54]. The most common psychiatric diagnosis in this sample of patients with esophageal abnormalities was (as in our sample of patients with chest pain and normal coronary arteriograms) depression and anxiety. Although the presence of panic disorder or major depression alone cannot be regarded as indicative of normal coronary anatomy, concomitant clinical psychiatric interviewing may obviate the need for further study in some patients and may facilitate appropriate therapy for treatable psychiatric disorders. Since many patients with psy-
chiatric disease and somatic complaints refuse a psychiatric explanation or referral for their complaints, it is important for cardiologists and primary care physicians to be prepared to identify and treat panic disorder and major depression, which can result in high degrees of morbidity, lost productivity, and overutilization of medical resources [21,23,36,48,52]. The importance of accurate diagnosis and treatment is emphasized by follow-up studies of patients with chest pain who have negative arteriograms. Ockene and colleagues [6] have demonstrated that a negative coronary artery study does not necessarily reassure patients with chest pain. After following 57 patients with chest pain (who had negative coronary arteriograms) for an average of 17 months, 44 percent still believed they had heart disease; 51 percent were unable to work because of chest pain; and 47 percent still described their activity as limited by chest pain [6]. Accurate psychiatric diagnosis and treatment may decrease somatization and illness behavior in these patients.
REFERENCES 1.
2.
3.
4.
5.
6.
10.
11.
8
Kemp HG, Vokonas PS, Cohn PF, Gorlin R: The angina1 syndrome associated with normal coronary arteriograms: report of a six-year experience. Am J Med 1973; 54: 73% 742. Marchandise B, Bourrassa MG, Chaitman BR, Lesperance J: Angiographic evaluation of the natural history of normal coronary arteries and mild coronary atherosclerosis. Am J Cardiol 1978; 41: 216-220. Proudfit WL, Shirey EK, Sones FM Jr: Selective cinecoronary arteriography: correlation with clinical findings in 1,000 patients. Circulation 1966; 33: 901-910. Proudfit WL, Bruschke AVG, Sones FM: Clinical course of patients with normal or slightly or moderately abnormal coronary arteriograms: lo-year follow-up of 521 patients. Circulation 1980; 62: 712-717. Day LJ, Sowton E: Clinical features and follow-up of patients with.angina and normal coronary arteries. Lancet 1979; II: 334-337. Ockene IS, Shay MJ, Alpert JS, Weiner BH, Dalen JE: Unexplained chest pain in patients with normal coronary arteriograms: a follow-up study of functional status. N Engl J Med 1980; 303: 1249-1252. Waxler EB, Kimbiris D, Dreifus LS: The fate of women with normal coronary arteriograms and chest pain resembling angina pectoris. Am J Cardiol 1971; 28: 25-32. Lavey EB, Winkle RA: Continuing disability of patients with chest pain and normal coronary arteriograms. J Chronic Dis 1979; 32: 191-196. lsner JM, Salem DN, Banas JS Jr, Levire HS: Long-term clinical course of patients with normal coronary arteriography: follow-up study of 121 patients with normal or nearly normal coronary arteriograms. Am Heart J 1981; 102: 645-653. Kemp HG, Kronmal RA, Vlietstra RE, Frye RL: Seven year survival of patients with normal or near normal coronary arteriograms: a Cass Registry Study. J Am Coil Cardiol 1986; 7: 479-483. Hope J: A treatise on the disease of the heart and great vessels comprising a new view of the physiology of the
January
1988
The American
Journal
of Medicine
Volume
12. 13. 14. 15.
16. 17.
la.
19.
20.
21
22. 23.
24.
84
heart’s action according to which the physical signs are explained. London: Churchill, 1832. Skerret PW: Anxiety and the heart-a historical review. Psycho1 Med 1983; 13: 17-25. Osler W: The principles and practice of medicine. Edinburgh: J Pentland Young, 1892. Mayou R: The patient with angina: symptoms and disability. Postgrad Med J 1973; 49: 250-254. Magarian GJ: Hyperventilation syndromes: infrequently recognized common expression of anxiety and stress. Medicine (Baltimore) 1982; 61: 219-235. Evans DW, Lum LC: Hyperventilation: an important cause of pseudoangina. Lancet 1977; I: 155-158. Lary D, Goldschlager N: Electra cardiogram changes during hyperventilation resembling myocardial ischemia in patients with normal coronary arteriograms. Am Heart J 1974; 87: 383-390. Elias MF, Robbins MA, Blow FC, Rice AP, Edgecomb JL: Symptom reporting, anxiety and depression in arteriographically classified middle-aged chest pain patients. Exp Aging Res 1982; 8: 45-51. Costa PT, Zonderman AB, Engel BT, Baile WF, Brimlow DL, Brinker J: The relation of chest pain symptoms to angiographic findings of coronary artery stenosis and neuroticism. Psychosom Med 1985; 47: 285-293. Channer KS, James MA, Papouchado M, Rees JR: Anxiety and depression in patients with chest pain referred for exercise testing. Lancet 1985; I: 820-823. Bass C, Wade C: Chest pain with normal coronary arteries: a comparafive study of psychiatric and social morbidity. Psycho1 Med 1984; 14: 51-61. Katon W: Panic disorder and somatization: review of 55 cases. Am J Med 1984; 77: 101-106. American Psychiatric Association, Task Force on Nomenclature and Statistics: Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. Washington: American Psychiatric Association, 1980. Harris JN: Coronary angiography and its complication. Arch Intern Med 1984; 144: 337-341.
CHEST
25.
26.
27.
28.
29.
30. 31.
32. 33.
34.
35. 36.
37.
38.
39.
40.
Robins LN, Helzer JE, Croughan J, Ratcliff KS: National Institute of Mental Health Diagnostic interview Schedule: its history, characteristics and validity. Arch Gen Psychiatry 1981; 38: 381-389. Yates WR: The National Institute of Mental Health Epidemiologic Study: implications for family practice. J Fam Pratt 1986; 22: 251-255. Welch CC, Proudfit WL, Sfieldon WC: Coronary arteriographic findings in 1,000 women under age 50. Am J Cardiol 1975; 35: 211-215. Fuster V, Frye RL, Connolly DC, Danielson MA, Elveback LR, Kurland LT: Arteriographic patterns early in the onset of the coronary syndromes. Br Heart J 1975; 37: 12501255. Derogatis LR: SCL-9OR manual. I: Scoring, administration, and procedures for the SCL-9OR. Baltimore: Johns Hopkins University School of Medicine, 1977. Zung WWK: A rating instrument for anxiety disorders. Psychosomatics 1971; 12: 37i-379. Sarason IG, Johnson JH, Siegel JM: Assessing the impact of life changes: development of the life experiences survey. J Consult Clin Psycho1 1978; 46: 932-946. Fleiss JL: Statistical methods for rates and proportions. New Yprk: John Wiley and Sons, 1973. Bruschke AV, Proudfit WB, Sones FM: Clinical course of patients with normal and slightly or moderately abnormal coronary arteriograms. A follow-up study of 500 patients: Circulation 1973; 47: 936-945. Crowe RR: The role of genetics in the etiology of panic disorder. In: Grinspoon L, ed. Psychiatry update, vol 3. Washington: American Psychiatric Association, 1984. Sheehan DV: Panic attacks and phobias. N Engl J Med 1982; 307: 156-158. Pariser S, Pinta E, Jones B: Mitral valve prolapse syndrome and anxiety nerosis/panic disorder. Am J Psychiatry 1978; 135: 240-247. Liebowitz MR, Fyer AJ, Gorman JM, et al: Lactate provocation of panic attacks. I. Clinical and behavioral findings. Arch Gen Psychiatry 1984; 41: 764-770. Nesse RM, Cameron OG, Curtis GC, McCann DS, HuberSmith MJ: Adrenergic function in patients with panic anxiety. Arch Gen Psychiatry 1984; 41: 771-776. Charney DS, Heniger GR, Breir A: Noradrenergic function in panic anxiety. Arch Gen Psychiatry 1984; 41: 751-763. Da Costa JM: On irritable heart. Am J Med Sci 1871; 61: 17-
41.
42.
43.
44.
45.
46.
47.
48.
49. 50.
51.
52.
53.
54.
January
PAIN AND
PSYCHIATRIC
ILLNESS-KATON
ET AL
52. Reiman EM, Raichle ME, Robins E, et al: The application of positron emission tomography to the study of panic disorder. Am J Psychiatry 1986; 4: 469-477. Hurst WJ, King SB, Walter PF, Freisinger GC, Edward JE: Atherosclerotic coronary heart disease: angina pectoris, myocardial infarction and other manifestations of myocardial ischemia. In: Hurst JW, ed. The heart. New York: McGraw-Hill, 1982. Streisand RL, Gourin A, Stuckey JH: Respiratory and metabolic alkalosis and myocardial contractility. J Thoracic Cardiovasc Surg 1971; 62: 431-435. Katon W, Vitalliano PP, Russo J, Cormier L, Jones M, Anderson K: Panic disorder: epidemiology in primary care. J Fam Pratt 1986; 23: 233-239. Noyes R, Reich J, Clancy J, et al: Reduction in hypochondriasis with treatment of panic disorder. Br J Psychiatry 1986; 631-635. Pilowsky I, Spence ND: Manual for the Illness Behavior Questionnaire (IBQ) 2nd ed. Adelaide, South Austria: University of Adelaide, 1983. Katon W, Berg AQ, Robins AJ, Risse S: Depression: medical utilization and somatization. West J Med 1986; 144: 564568. Widmer RB, Cadoret RJ: Depression in primary care: changes in pattern of visits and complaints during a developing depression. J Fam Pratt 1978; 7: 293-302. Mathew RJ, Weinman ML, Mirabi M: Physical symptoms of depression. Br J Psychiatry 1981; 139: 293-296. Waxman HM, McCreary G, Weinrit RM, Carner EA: A comparison of somatic complaints among depressed and nondepressed older persons. Gerontologist 1985; 25: 501507. Cannon RO, Leon MB, Watson R, Rosing DR, Epstein SE: Chest pain and “normal” coronary arteries-role of small coronary arteries. Am J Cardiol 1985; 55: 508-608. Dart AM, Davies AH, Dalal J, et al: “Angina” arid normal coronary arteriograms: a follow-up study. Eur Heart J 1980; 1: 97-100. Brand DL, Martin D, Pope CE: II. Esophageal manometrics in patients with angina-like chest pain. Dig Dis Sci 1977; 22: 300-304. Clouse RE, Lustman PJ: Psychiatric illness and contraction abnormalities of the esophagus. N Engl J Med 1983; 309: 1337-1342.
1988
The American
Journal
of Medicine
Volume
84
9