Cortisol measures in primary major depressive disorder with hypersomnia or appetite increase

Journal of Affective Disorders, 15 (1988) 131-140

131

Elsevier J A D 00559

Cortisol measures in primary major depressive disorder with hypersomnia or appetite increase R e g i n a C. C a s p e r , J a m e s K o c s i s , M a u r i c e D y s k e n , P e t e r S t o k e s , Jack Croughan and James Maas Department of Psychiatry, Michael Reese Hospital and Medical Center, Chicago, IL 60616, U.S.A. (Received 28 October 1987) (Accepted 4 March 1988)

Summary Morning plasma cortisol response to the 1 mg dexamethasone suppression test along with cortisol levels in blood, cerebrospinal fluid (CSF), and urine were measured in hospitalized male and female patients with primary major depressive disorder who reported hypersomnia (n = 23), or increase in appetite (n = 22). Comparisons were drawn to cortisol levels in patients with primary major depressive disorder who did not report hypersomnia or appetite increase (n = 23) and to normal controls (n = 23), all age- and sex-matched. Depressives with hypersomnia or increased appetite showed higher than normal 24-h urinary free cortisol concentrations. Depressed patients without hypersomnia or appetite increase had in addition to elevated free urinary cortisol concentrations higher than normal morning plasma cortisol levels before and after dexamethasone administration and a higher incidence of cortisol non-suppression after dexamethasone compared to normal subjects. The findings provide preliminary evidence that HPA activation in depression is diminished in the presence of hypersomnia a n d / o r an increased appetite. Studies of the hypothalamic-pituitary-adrenal axis may be useful for differentiating subtypes of depression characterized by hypersomnia or enhanced appetite.

Key words." Cortisol levels; Major depressive disorder; Hypersomnia; Appetite increase

Introduction Studies in the past several years indicate that the initially reported changes in cortisol release in

Address for correspondence: Regina C. Casper, M.D., Department of Psychiatry, Michael Reese Hospital and Medical Center, Lake Shore Drive at 31st Street, Chicago, IL 60616, U.S.A.

depression, attributed to hypothalamo-pituitaryadrenal (HPA) dysfunction, are not universal to all depressions (Mendlewicz et al., 1982; Stokes et al., 1984; Arana et al., 1985; Carroll, 1985; Rubin et al., 1987). The mechanisms which mediate the activation of the HPA system in depression remain elusive, but there is now substantial evidence that the incidence of hypercortisolism is not the same in different diagnostic subgroups of depression. When Arana et al. (1985) pooled method-

0165-0327/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)

132 ologically comparable studies, the highest rates of dexamethasone (DS) non-suppression, up to 80%, were observed for depressions with psychotic or serious suicidal features. Melancholia, diagnosed on the basis of D S M - I I I criteria, was likewise associated with high D S T suppression rates, followed, in decreasing rate of frequency, by 'endogenous' depressions. In similar order, the familial subtypes of primary unipolar depressive disorder (Winokur, 1979) show the highest percentages of DST non-suppression in familial pure depressive disease, whilst lower rates occur in sporadic depressive disease. Depression spectrum disease, denoting depression in persons who have a first-degree relative with alcoholism a n d / o r an antisocial personality, shows rates of DST non-suppression comparable to normal controls (Schlesser et al., 1980). The present study which subdivides patients with primary depressive disorder according to the presence of hypersomnia or appetite increase (Casper et al., 1985) follows earlier work by Pollitt (1965), Detre et al. (1972), and Paykel (1977), which used specific somatic symptoms as independent variables for studying depression. Currently, little is known about neuroendocrine responses in depressions with atypical somatic features (James et al., 1986), perhaps because patients tend to be younger and are commonly treated outside the hospital (Garvey et al., 1984; Hawkins et al., 1985). Also, patients with 'positive' symptoms such as increased appetite or weight gain were thought to be less physiologically predisposed and hence less likely to show hypothalamic involvement (Pollitt, 1965). This assumption might warrant revision, considering the results of a recent study by Price et al. (1987) which documented a genetic component for depressions with an early onset, before age 30, suggesting some internal disposition for early onset depressions. The aim of the present study was to examine the influence of extended sleep and enhanced appetite upon HPA function by studying cortisol parameters in hospitalized patients whose depression was associated with hypersomnia or appetite increase and by comparing them to sex- and agematched depressed patients without signs of hypersomnia or appetite increase, and to age- and sex-matched normal subjects.

Method

The design and methodology of the N I M H CRB Collaborative Study of the Psychobiology of Depression have been presented in detail in several previous reports (Katz et al., 1969; Maas et al., 1980). The depressed patient and control samples in the present report comprise 90 out of a total of 132 patients hospitalized for participation in the Collaborative Study, all of whom qualified for a diagnosis of primary major depressive disorder. The diagnosis was determined independently by two psychiatrists through evaluation interviews using the Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott et al., 1978) and the Research Diagnostic Criteria ( R D C ) (Spitzer et al., 1978). Age- and sex-matched healthy comparison subjects were screened in a psychiatric interview and, if found suitable, were interviewed by the same procedure for the purpose of ruling out signs of mental illness, medical disorders, and drug or medication use. Female patients and controis on estrogen or progesterone containing preparations were excluded (Streeten et al., 1969). All participating subjects consented in writing after the nature of the study was explained to them and all underwent a physical examination and a battery of laboratory tests including a drug screen. Depressed patients were maintained on placebo during an initial 2-week drug 'wash-out' period prior to the beginning of 4 weeks drug treatment. We used behavior and symptom rating scales with a focus on symptoms including affective, cognitive and perceptual components and secondly on expression, describing activity, appearance and bodily expression (Katz et al., 1984). Characteristics of the two depressed patient groups who reported hypersomnia a n d / o r increased appetite have been reported previously (Casper et al., 1985). Twenty-three patients (or 17.4%) reported hypersomnia, judged present if SADS item 314 was answered in the affirmative as 'frequently sleeps 1 4 h more than usual'. Compared to age- and sex-matched depressed controls who reported no extended sleep or appetite increase, hypersomniac patients reported significantly less sleep disturbance rated as early and late insomnia (SADS-C: Hamilton Depression

133

Rating Scale, 1967; Hopkins Symptom Checklist SCL-90): t = 4.34; d f = 41/41; P < 0.0001. There were 22 depressed patients (or 16.6%) who reported an increase in appetite, considered present if patients endorsed SADS item 320 and said they had ' a mild appetite increase to feeling hungry all the time and ate without restraint'. There was a significant association between increased appetite and weight gain (r = 0.42; P < 0.05) suggesting increased food intake. No subject in this group reported appetite or weight loss. Each group showed a distinct sex distribution with males exceeding females (1.3:1) among patients with hypersomnia and females outnumbering males (1.8:1) in patients with increased appetite. The two groups overlapped; ten patients with hypersomnia reported appetite increase. Therefore depressed controls without signs of hypersomnia, appetite increase, or weight gain were selected for each group separately from the entire sample of hospitalized patients. The characteristics of these patients and the healthy matched control groups are displayed in Table 1.

A subgroup of the appetite increase group composed of 15 depressed patients, who reported both increased appetite and weight gain of 5-25 lbs (SADS item 321) during the episode, was also analyzed. Fifteen healthy age- and sex-matched controls were matched to this group. Cortisol measurements Cortisol levels were determined in plasma, cerebrospinal fluid (CSF), and urine. Blood samples for assaying plasma cortisol levels were taken during baseline on study days 9, 10, and 12 at 8:00 a.m.; the three values were averaged. An evening plasma cortisol level was drawn at 10:00 p.m. on day 12. CSF cortisol was obtained through lumbar puncture after overnight fasting and bed rest with the patient sitting, between 8:00 and 8:30 a.m. on day 11. From day 11 to day 12, 24-h pre-dexamethasone urine specimens were collected for the determination of urinary free cortisol values. At the end of these collections at 10:30 p.m. patients and controls received dexamethasone (1 mg per os in liquid form) under the supervision of

TABL E 1 D I A G N O S T I C G R O U P S WITH AGE, SEX, A N D POLARITY D IS TR IB U TIO N , AS WELL AS H A M I L T O N D E P R E S S I O N SCALE TOTAL SCORES A N D A G E AT ONSET OF P R I M A R Y MA J O R DEPRESSIVE D I S O R D E R n

Depressed with hypersomnia Depressed without hypersomnia or appetite increase Healthy controls Depressed with increased appetite Depressed without hypersomnia or appetite increase Healthy controls Depressed with appetite increase and weight gain Healthy controls

Age (years)

Male/female

Mean

ratio

SD

Unipolar

Bipolar

Hamilton

Age at onset

Depression total score

Mean

SD

Mean

SD

23

34.9

14.3

13/10

12 (6M, 6F)

11 (7M, 4F)

25.6

7.5

25.3

10.1

23 23

37.4 34.5

12.6 14.3

13/10 13/10

11 (4M, 7F) -

12 (9M, 3F)

24.3 2.1

9.7 1.5

26.7 -

9.7

22

36.2

15.0

8/14

11 (2M, 9F)

11 (6M, 5F)

26.7

6.3

28.5

12.1

22 22

40.6 35.5

14.1 15.0

8/14 8/14

11 (2M, 9F) -

11 (6M, 5F) -

27.4 2.1

9.0 1.9

27.0

11.9 -

15 15

34.7 35.0

14.1 14.3

4/11 4/11

8 (IM, 7F) -

7 (3M, 4F) -

25.6 2.5

5.7 2.0

27.9

11.3 -

134 a nurse. Blood samples for plasma cortisol concentrations following dexamethasone administration were obtained on day 13 at 8:30 a.m., 4:00 p.m. and 10:00 p.m. Post-dexamethasone urine free cortisol was determined from 24-h urine collections completed on day 13 at 10:35 p.m. DST non-suppression was defined as a plasma cortisol level equal to or greater than 5 / , g / d l at 8:30 a.m. on day 13. Hypersecretion of urinary tort±sol was defined as day 12 urine free tort±sol (UFC) level above 133.5 p.g/day (mean + 1.28 SD of healthy controls) because 92% of controls fell below that level. A post-dexamethasone urinary free cortisol level of 55 /~g/24 h was chosen for separating DST suppressors from non-suppressors, because after examining the sensitivity and specificity associated with various post-dexamethasone UFC levels, 55 p.g/24 h separated most reliably depressed patients from healthy controls. Cortisol assays The samples obtained were frozen. Cortisol in plasma, CSF, and urine was analyzed from coded duplicate samples in one laboratory by radioimmunoassay procedure which used solid phase rabbit anticortisol antibody. For plasma tort±sol levels the inter-assay coefficients of variation for medium and low plasma pools were ±9.8% and _+21.1 %, respectively, lntra-assay coefficients of variation for medium and low plasma pools were _+6.3% and _+ 15.9%, respectively. For CSF cortisol levels the inter-assay coefficient of variation for the normal pool was _+ 16.5% and the intra-assay coefficient of variation was _+7.2%. For urinary free tort±sol level inter-assay coefficients of variation for high and low pools were +9.4% and _+14.2%, respectively. Intra-assay coefficients of variation were +7% and _+10.4%, respectively Stokes et al., 1984). Statistical analysis If raw data showed significant deviations from a normal distribution, the data were log-transformed for a better fit of the distribution. Only baseline morning cortisol and CSF tort±sol were not transformed to log values, as they did not deviate significantly from a normal distribution. Two-tailed t-tests and analyses of covariance (ANCOVA) covarying for age were used for be-

tween-group comparisons with continuous variables. Chi-square statistics were calculated to compare the distribution of DST suppressor status. Cortisol values are expressed as means ± SEM. Results

The ages, polarity, distribution, and total Hamilton depression scores for all groups are displayed in Table 1. Mean age at onset of the first major depressive episode was below 30 for patients who reported oversleeping and overeating at the time of hospitalization. The patients were on average in their middle 30s. Three patients with hypersomnia were over 50 years old (55, 57, and 58 years), while five patients who noted appetite increase were over 50 years old (57, 59, 59, 66, and 66 years). The Hamilton depression scores indicated moderate to severe depressive symptoms, considering the fact that patients with atypical somatic symptoms scored low on items such as insomnia and appetite or weight loss. Healthy controls had no signs of depression. Given a unipolar/bipolar distribution or nearly 2 : 1 for the entire patient sampie (Katz et al., 1984), a disproportionately higher number of bipolar patients reported hypersomnia or appetite increase, resulting in an about even distribution of unipolar and bipolar patients in either group. Cortisol measures The values and comparisons for tort±sol levels in plasma, CSF. and urine during baseline and following dexamethasone administration for all experimental groups are displayed in Table 2. Table 3 lists the results of the dexamethasone suppression test by diagnostic group. Depression with hvpersomnia Cortisol levels in plasma of depressed patients who reported hypersomnia at baseline - averaged from morning samples obtained on the 9th, 10th, and 12th day following admission on day 12 in the afternoon or evening, or on day 13 after dexamethasone administration, when compared with those of depressed patients who had no hypersomnia and with those of normal controls, were not statistically different. Depressed patients,

135

136 TABLE 3 FREQUENCY OF DEXAMETHASONE(DST) SUPPRESSION OR RESISTANCE TO SUPPRESSION (1 mg DEXAMETHASONE) BY DIAGNOSTIC GROUP Depressed patients Healthy with without controls hypersomnia hypersomnia (n = 23) ( n = 23) or appetite increase (n = 23) DST suppressors 83% DST non-suppressors 17%

61% 39%

91% 9% "

Depressedpatients Healthy with without controls increased increased (n = 22) appetite appetite or ( n = 22) hypersomnia (n = 22)

Depressed Healthy patients controls with appetite (n = 15) increase and weight gain (n = 15)

82%

64%

91'~

80%

87%

18%

36~'

9%

20%

13~

" Chi-square: 6.6: df = 2: P < 0.04.

regardless of classification, had higher u r i n a r y free cortisol levels at baseline ( F = 6.06: dr= 16, 19; P < 0.02; age-corrected F = 5.79; P < 0.02) than n o r m a l controls. Following d e x a m e t h a s o n e adm i n i s t r a t i o n marginally higher u r i n a r y free cortisol levels were f o u n d only in depressed patients without h y p e r s o m n i a ( F = 2.34; df= 18, 20; P < 0.05). In c o m p a r i s o n to healthy controls, depressed patients who reported no signs of oversleeping or overeating showed significantly higher m o r n i n g plasma cortisol c o n c e n t r a t i o n s at baseline (t = 2.3; dr= 41; P < 0.02, no age effect) a n d following d e x a m e t h a s o n e (t = 2.02; df= 40; P < 0.05, no age effect) than healthy controls. A greater n u m ber a m o n g them failed to suppress m o r n i n g plasma cortisol after d e x a m e t h a s o n e a d m i n i s t r a t i o n ( 9 / 2 3 ) than a m o n g depressed patients with hypers o m n i a ( 4 / 2 3 ) or a m o n g n o r m a l controls ( 2 / 2 3 ) (X 2 = 6.6; df= 2; P < 0.04). D S T n o n - s u p p r e s s o r s a m o n g h y p e r s o m n i a patients were 25~ 28, 38, and 57 years old, respectively.

values in plasma or C S F before or after dexam e t h a s o n e a d m i n i s t r a t i o n showed significant differences between the two depressed p a t i e n t groups. Depressed patients regardless of somatic s y m p t o m classification had higher urine free cortisol conc e n t r a t i o n s t h a n h e a l t h y c o n t r o l s in pred e x a m e t h a s o n e ( F = 7.80; df = 2: P < 0.01, no age effect) a n d p o s t - d e x a m e t h a s o n e ( F = 6.2; dr= 2; P < 0 . 0 2 , no age effect) collections. M o r n i n g plasma cortisol levels (t = 2.4: dr= 41, P < 0.02) were higher in depressed patients without hypers o m n i a or increased appetite before and following d e x a m e t h a s o n e (t = 3.00; df= 35: P < 0.01) than in healthy controls. More patients without increased appetite or h y p e r s o m n i a ( 8 / 2 3 ) failed to suppress after d e x a m e t h a s o n e than in the appetite increase group ( 4 / 2 3 ) or a m o n g healthy controls ( 2 / 2 3 ) , but this difference in suppressor status did not reach statistical significance (X 2 : 5.1; dr= 2: P < 0.08). Ages for D S T n o n - s u p p r e s s o r s with appetite increase were 20, 25, 25, a n d 29 years, respectively.

Depression with appetite increase

Depression with appetite increase and weight gain

In patients with an increased appetite, averaged m o r n i n g baseline plasma cortisol c o n c e n t r a t i o n s o b t a i n e d on day 9, 10 a n d 12 were essentially in the same range as plasma cortisol levels in healthy controls, while m o r n i n g plasma cortisol levels in patients without h y p e r s o m n i a or appetite increase were elevated ( F = 3.83; dr= 2; P < 0.05, no significant age effect). N o n e of the other cortisol

The subset of patients with the dual s y m p t o m of appetite and weight gain differed from healthy controls only by higher than n o r m a l urine free cortisol excretion at baseline ( F - 10.17: dr= 1: P < 0 . 0 0 5 , age-corrected F = 9 . 4 2 ; dr= 1: P < 0.007) and marginally higher a f t e r n o o n plasma cortisol level after d e x a m e t h a s o n e ( F - 4.76; df = 1: P < 0 . 0 5 ; age-adjusted F = 4 . 3 6 ; d f = l ; P<

137

0.06). The rate of DST non-suppression among these patients (3/15) was similar to that of normal controls (2/15). Discussion

We found little evidence of HPA hyperactivity among patients, who were hospitalized for primary major depressive disorder and reported either hypersomnia, increased appetite, or increased appetite and weight gain. The only signs were higher than normal urine concentrations of free cortisol at baseline and in patients with appetite increase only, following dexamethasone administration. Age-matched depressed patients who reported no symptoms of oversleeping or overeating had more evidence of hypercortisolism. In addition to higher than normal free urinary cortisol levels before and after dexamethasone, these patients had elevated baseline and post-dexamethasone plasma cortisol levels in comparison to normal controls. Results from the dexamethasone suppression test corresponded by and large to the findings for cortisol levels. Overall, compared to depressed patients with hypersomnia or depressed patients with appetite increase, a higher proportion of depressed patients who had no hypersomnia or appetite increase failed to suppress morning plasma cortisol below the criterion value of 5/~g%. Differences in the severity of depression (Carroll et al., 1981) cannot explain the differences in cortisol levels between the depressed patients with hypersomnia a n d / o r increased appetite and patients who did not have either symptom, since both groups scored about equally depressed judged by the Hamilton depression scale. Also, age, which has been shown to be positively correlated with cortisol levels (Feinberg and Carroll, 1984; Nelson et al., 1984; Fogel and Satel, 1985; Weiner et al., 1987), probably did not influence the findings, since experimental and controls groups were rather closely age-matched and when we took the precaution of covarying for age, probability levels were not appreciably affected. The findings suggest that an increased appetite and perhaps increased caloric intake and hypersomnia may have a mitigating influence upon an otherwise more active HPA axis in depression. In animals, Levine et al. (1979) have shown that

consummatory behavior reduced the pituitaryadrenal response to a normally stressful situation. For humans, only the converse has been demonstrated. Studies in fasting normal volunteers (Fichter and Pirke, 1986; Mullen et al., 1986), in anorexia nervosa (Walsh et al., 1981), and in depressed patients with weight loss (Casper et al., 1987) have shown activation of the H P A axis. In a study examining the influence of extended sleep, Thase et al. (1987) reported DST non-suppression rates comparable to controls among bipolar depressed outpatients who reported hypersomnia, hyperphagia, and weight gain. Philipp et al. (1986) noted a significant association with DST non-suppression only for 'early and intermittent awakening' among 28 diagnostic criteria for endogenous depression in a minor depressive disorder mixed patient sample, suggesting that mechanisms involved in sleep pattern regulation may affect the H P A axis. Of course, we wish to caution that other factors which we did not test, such as bioavailability of dexamethasone, could account for the differences. Also, the present study provides no conclusive evidence that the signs indicating HPA dysfunction in this population can be considered specific for depression. For example, distress and arousal in normals can increase corticosteroid excretion. Rose et al. (1968) reported, for male recruits who underwent combat training, not only a positive relationship between 17-hydroxycorticosteroid excretion and body surface area but also higher corticosteroid values for men in the high-stress group than in the low-stress group. Lundberg and Frankenhaeuser (1980) identified a 'distress' factor associated with higher total cortisol excretion in male and female volunteers subjected to different tasks, which loaded highly on boredom, impatience, tiredness, and irritation. The overall low incidence of hypercortisolemia in our depressed patients is compatible with other studies of young, non-endogenous depressive populations. James et al. (1986) reported a 10% dexamethasone non-suppression rate in patients with seasonal affective disorders, whose mean age was the middle 30s, although their somatic symptoms were not further described. Amsterdam et al. (1982) found no differences in 8:00 a.m. plasma cortisol values or the DST suppression rate be-

138 tween 64 o u t p a t i e n t s with p r i m a r y affective disorder, whose m e a n age was in the mid-30s, a n d 53 h e a l t h y controls, even when a depressed s u b g r o u p was e x a m i n e d for family history of p s y c h i a t r i c illness a c c o r d i n g to W i n o k u r (1979). R a b k i n et al. (1983) noted in p a t i e n t s with major, m i n o r or i n t e r m i t t e n t depressive disorder, whose ages were not r e p o r t e d , similar rates of D S T n o n - s u p p r e s sion for p a t i e n t s categorized as having e n d o g e n o u s (18%) or n o n - e n d o g e n o u s (14%) depressions. K r i s h n a n et al. (1984) r e p o r t e d that D S T n o n - s u p p r e s s o r s a m o n g y o u n g b o r d e r l i n e p a t i e n t s typically were m o r e d e p r e s s e d a n d some showed suicidal behavior. A m o n g 60 o u t p a t i e n t s with p r i m a r y affective d i s o r d e r in a s t u d y b y A v e r y et al. (1985), D S T n o n - s u p p r e s s o r s scored higher on H a m i l t o n items indicative of m e l a n c h o l i a ; nevertheless there were m o r e n o n - s u p p r e s s o r s a m o n g the p a t i e n t s with generalized anxiety d i s o r d e r (23%) whose m e a n age was 35.7 years than a m o n g the slightly o l d e r ( m e a n age 41.5 years) depressed p a t i e n t s (8%). Clearly, further studies will be req u i r e d to d e t e r m i n e to w h a t extent depressed m o o d c o n t r i b u t e s to H P A activation in y o u n g non-end o g e n o u s depressions. In conclusion, the d a t a in the present study i n d i c a t e that e n h a n c e d a p p e t i t e a n d food i n t a k e or e x t e n d e d sleep m a y c o u n t e r a c t a n d thus mask the d e p r e s s i o n - i n d u c e d H P A d y s f u n c t i o n in p a t i e n t s with p r i m a r y depressive disorder. The d a t a also s u p p o r t the n o t i o n that the H P A axis activation in d e p r e s s i o n is not an all or n o t h i n g p h e n o m e n o n b u t rather manifests the i n t e g r a t e d response of a n e u r o e n d o c r i n e system subject to m o d u l a t i o n t h r o u g h different inputs.

Acknowledgements This research was s u p p o r t e d in p a r t b y G r a n t s U01 MH26979, U01 MH26976, U01 MH26977, U01 MH26978, U01 MH26975, U01 MH31921, a n d U01 M H 3 6 2 3 2 f r o m the N a t i o n a l Institute of M e n t a l Health, Rockville, M D . As part of the N a t i o n a l Institute of M e n t a l H e a l t h - C l i n i c a l Research Branch C o l l a b o r a t i v e P r o g r a m on the P s y c h o b i o l o g y of D e p r e s s i o n Biological Studies, this s t u d y was c o m p l e t e d with the c o o p e r a t i o n a n d p a r t i c i p a t i o n of the following

c o l l a b o r a t i v e p r o g r a m investigators: S t e p h e n H. Koslow, P h D (project director), Steven Secunda, M D ( d e p u t y project director), M a r t i n M. Katz, P h D (senior investigator), Israel H a n i n , P h D (consultant), a n d B a r b a r a H a r r i s - L a r k i n ( p r o t o c o l monitor), N a t i o n a l Institute of M e n t a l H e a l t h , Rockville, M D ; J a m e s W. Maas, M D (chairman), San A n t o n i o , TX; D. Eugene R e d m o n d , Jr., M D , A l a n C. Swann, M D , Yale U n i v e r s i t y School of Medicine, N e w Haven, CT. J o h n M. Davis, M D , R e g i n a Casper, M D , Sidney C h a n g , M D , D a v i d Garver, M D , J a v a i d Javaid, PhD, Illinois State Psychiatric Institute, Chicago, IL; J o s e p h M e n d e l s , M D , D a v i d Brunswick, PhD, A l a n Frazer, PhD, T. A l a n R a m s e y , M D , a n d S t e p h e n Stern, Veterans A d m i n i s t r a t i o n M e d i c a l Center, P h i l a d e l p h i a , PA: Peter E. Stokes, M D , a n d J a m e s Kocsis, M D , Cornell University M e d i c a l College, N e w York, N Y ; Eli R o b i n s , M D , and Jack C r o u g h a n , M D , W a s h i n g t o n U n i v e r s i t y School of M e d i c i n e a n d Jewish H o s p i t a l , St. Louis, M O ; a n d C h a r l e s Bowden, M D , a n d R o b e r t S h u l m a n , M D , The U n i v e r s i t y of Texas H e a l t h Science C e n t e r at San A n t o n i o , TX.

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