The CRH stimulation test in bereaved subjects with and without accompanying depression

145

Psychiatry Research. 25, 145-I56 Elsevier

The CRH Stimulation Test in Bereaved Without Accompanying Depression Alec Roy, William Phillip Gold

Gallucci,

Peter

Subjects

Avgerinos,

Markku

With and

Linnoila,

Received July 13, 1987; revised version received December 18, 1987; accepted

January

and

I, 1988.

Abstract. We studied recently bereaved individuals with the corticotropinreleasing hormone (CRH) stimulation test. Subjects with a bereavement complicated by a depressive illness (n q 9) had significantly higher basal plasma cortisol levels and smaller plasma adrenocorticotropic hormone (ACTH) responses to CRH than either subjects with an uncomplicated bereavement (n q 19) or normal controls (n q 34). Subjects with depressed bereavement showed ACTH responses to CRH similar to those of depressed patients (n q 30). Bereaved subjects who had received psychotropic medications in the past (n q 13), compared with those who had not (n q 15), showed significantly smaller plasma ACTH responses to CRH. Significantly more subjects with bereavement complicated by depression, as compared to subjects whose bereavement was uncomplicated, had a past history of treatment for depression. These results suggest that predisposed individuals may respond to the stress of bereavement with a depressive illness accompanied by dysregulation of the hypothalamic-pituitary-adrenal axis. Key Words. Bereavement,

depression,

corticotropin-releasing

hormone.

In 1969, Paykel et al. reported that life events are associated with the onset of depression. Since then, there have been a number of confirmatory studies (Brown and Harris, 1978; Paykel et al., 1980; Benjaminsen, 1981; Fava et al., 1981; Perris, 1984; Roy et al., 1985). It is particularly undesirable life events that are associated with depression (Paykel et al., 1969). However, the great majority of individuals who experience undesirable life events do not become depressed (Klerman, 1979; Paykel, 1979; Lloyd, 1980; Tennant et al., 1981). There is some evidence that individuals with various risk factors for depression are most vulnerable to becoming depressed when they experience adverse life events (Brown and Harris, 1978; reviewed by Hirschfeld and Cross, 1982). One of these risk factors is having a genetic predisposition to an affective disorder (Weissman et al., 1982, 1984; Gershon et al., 1982). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the best documented neurobiological abnormalities in depression. The resulting hypercortisolemia is found in from 40% to 60% of depressed patients (Carroll et al., 1981). Alec Roy, M.B., is Visiting Associate, and Markku Linnoila, M.D., Ph.D., is Chief, Laboratory of Clinical Studies, DICBR, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. William Gallucci, B.S., is Research Associate; Peter Avgerinos, M.D., is Visiting Associate; and Phillip Gold, M.D., is Chief, Section on Neuroendocrinology, Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD. (Reprint requests to Dr. A. Roy, NIAAA, LCS, DICBR, Bldg. 10, Rm. 3819, 9000 Rockville Pike, Bethesda, MD 20892, USA.) 0165-1781/88/SO3.50

@ 1988 Elsevier Scientific

Publishers

Ireland

Ltd.

146 We, and others, have demonstrated that the infusion of corticotropin-releasing hormone (CRH) is associated with a blunted plasma adrenocorticotropic (ACTH) response in depressed patients compared with normal controls (Gold et al., 1984, 1986; Holsboer et al., 1984). This finding suggests that the pituitary corticotroph cell is responding normally to the negative feedback of the raised plasma cortisol levels found in depression and thus responds to the exogenous CRH with an attenuated plasma ACTH response (Gold et al., 1986). A blunted ACTH response to CRH isalso found among both hypercortisolemic patients anorexia nervosa and patients with panic disorder (Kaye et al., 1986; Roy-Byrne et al., 1986). Furthermore, the hypercortisolemia found in depression is probably partly due to a hypersecretion of endogenous CRH from hypothalamic corticotroph cells. In support of this explanation is the recent report by Nemeroff et al. (1984) that depressed patients have elevated cerebrospinal fluid (CSF) levels of CRH and our own report that depressed patients who are nonsuppressors on the dexamethasone suppression test (DST) have significantly higher CSF CRH levels than depressed patients who are DST suppressors (Roy et al., 1987). Activation of the HPA axis is one of the ways that the body responds to stress (Depue et al., 1979). Recent bereavement is a stressful life event whose sequelae have been much studied (Freud, 1957; Parkes 1964, 1970, 1972; Clayton 1971, 1979, 1982; Clayton et al., 1972, 1974; Crisp and Priest, 1972; Priest and Crisp, 1973; Clayton and Darvish, 1979; Pedder, 1982; Raphael, 1982; McFarlane, 1985). It is free of some of the methodological difficulties of other retrospective life event studies in that it can be accurately dated and its emotional impact is generally considered to be undesirable (Brown et al., 1973; Lloyd, 1980; Tennant et al., 1981; Paykel, 1983). We, therefore, decided to study recently bereaved individuals with the CRH infusion test. Our hypotheses were (1) that recently bereaved individuals who responded to their loss with a depressive illness would, like depressed patients, show a blunted plasma ACTH response to an infusion of CRH and (2) that bereaved individuals with a past history of affective disorder would show a blunted plasma ACTH response to CRH when compared with bereaved individuals without such a history.

Methods A series of 28 recently bereaved individuals was obtained from responses to two newspaper articles about bereavement and depression. Inclusion criteria were that the individual had been recently bereaved by the death of a spouse or first degree relative, was without physical illness or prexisting psychiatric disorder, was taking no medications, felt that he or she was still grieving, and had not been depressed in the 6 months before the bereavement. Each bereaved individual was interviewed by a psychiatrist (A. R.) about details of family and past history of psychiatric disorder (treated by a physician or mental health professional) before the bereavement. The 21-item Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960) was completed. Whether the individual met DSM-III criteria (American Psychiatric Association, 1980) for complicated or uncomplicated bereavement was also determined. Complicated bereavement is diagnosed when the individual meets DSM-III criteria for a major depressive episode with in addition morbid preoccupation with worthlessness, prolonged and marked functional impairment, and marked psychomotor retardation. All of these factors were required to qualify a subject as having complicated bereavement. The bereaved individuals completed the Beck Depression Inventory (BDI) (Beck et al., 1961). the Profile of Mood States (POMS) (McNair et al., 1971), and the Texas Inventory of Grief

147 (TIC) (Faschingbauer et al., 1977). The TIC is a brief 7-item scale developed to measure the extent of unresolved grief. (As our subjects were recently bereaved, we omitted item 7 on the TIG which inquires whether the individual gets upset each year at about the same time that the person died.) CRH Stimulation Test and Hormone Assays. Ovine CRH was obtained from Bachem Co. (Torrance, CA) and prepared as previously described (Gold et al., 1984). We administered I pg/ kg of CRH as an i.v. bolus at 2000h, when the HPA axis is normally quiescent. The I-pg/ kg dose was selected because dose-response studies in primates and in man have shown this to be the lowest dose achieving maximal stimulation of cortisol secretion (Schulte et al., 1982; Orth et al., 1983). After insertion of a needle in an antecubital vein at 45 min, blood was drawn at -I 5.0, 5, 15, 30, 60, 90 and 120 min for measurement of ACTH and cortisol, and was processed as previously described (Gold et al., 1986). Plasma ACTH and cortisol were measured by previously described radioimmunoassays (RIAs) (Gold et al., 1986). The detection limit for ACTH ranged from 3 to 5 pg/ ml. Interassay variabilities for ACTH and cortisol were 15% and 8%, and intraassay variabilities were 8% and 5%, respectively. The RIA concentration interpolations were performed by computer-assisted logit log analysis (Rodbard, 1974). The results of the CRH infusion in the two subgroups with complicated and uncomplicated bereavement were compared with results previously reported by us for two other groups: 34 normal controls (20 men, 14 women; mean age 29.4 f SD 5.1 years) and 30 medication-free depressed patients (11 men, 19 women; meanage42.3 f SD 13.1 years)(Gold et al., 1986). These subjects were obtained in a separate study at a different time point, and their assays were thus conducted at a different time (Gold et al., 1986). All subjects were studied in the same way and were in good health and showed no evidence of renal, hepatic, or thyroid disease. Because plasma cortisol and other biological variables correlate positively with age (reviewed in Roy et al., 1986) we also compared complicated bereaved subjects (n = 7) randomly matched with uncomplicated bereaved subjects (n q 7) for age and sex (i 6 years). Statistical Analysis. Responses of ACTH and cortisol were expressed as the area beneath the concentration-time curve during the 2-hour CRH test, minus the area corresponding to the mean of the two basal concentrations. The area under the curve was a computer-generated measurement. Analyses of variance (ANOVAs) were performed between the four groups with the post hoc Bonferronni test set at the p < 0.05 level. Student’s 1 and Fisher’s exact test were also used. All variances are reported using the standard deviation.

Results Nine of the 28 bereaved individuals had a complicated bereavement (depressive illness), and 19 had an uncomplicated bereavement. Subjects with depressed bereavement had significantly higher depression scores on the HRSD @ < O.Ol), BDI @ < 0.05), and POMS (p < 0.02) scales and had been bereaved for a longer period of time (p < 0.01) (Table 1). Significantly more depressed bereaved subjects were female (p< 0.003), had a past history of treatment for depression @ < 0.05), and had a past history of treatment for depression with either antidepressant (n = 4) or minor tranquilizer (n = 3) medication @ < 0.02) (Table 1). There were significant differences between the four groups for basal plasma cortisol levels (F = 9.92, df = 88, p < 0.0001). Complicated bereaved subjects showed significantly higher basal cortisol levels than uncomplicated bereaved subjects (10.2 f 6.5 vs. 7.5 f 4.9 pg/dl,p
148

Table 1. Clinical data and rating scale scores for 28 bereaved subjects (mean k SD) Complicated bereavement (n = 9)

Uncomplicated bereavement (n = 19)

Female

91

12

Male

0

7

47.6 * 14.0

41.5 + 13.7

Married

3

5

Single

I

7

Age (years)

Divorced

or widowed

5

7

Bereaved

by death of spouse

2

5

Bereaved degree

by death of 1st relative

7

14

1st or 2nd degree relative treated for depression

6

7

Past history of treatment for depression

82

9

Past history of treatment of depression by psychotropic medication

73

54

Hamilton

depression

Beck depression

score

score

20.9 ?I 6.15

12.1 It

7.5

25.3 +

16.7 2

9.4

9.76

Profile of Mood States depression-dejection score

36.6 F 14.77

Months

10.2 +

bereaved

Texas Inventory score

24.8 + 13.2

5.6s

5.3 F

4.4

20.2 2

4.2

of Grief 19.7 -c 4.2

1.p
with an anxlolytic

149

Fig. 1. Responses to CRH infusion among subjects with bereavement either complicated or uncomplicated by depression, depressed patients, and normal controls 2( z

,

OGxtrds,N=34 ODepmwdPstbn~.N=3l AUUncanplicatedBBersared.N=lS 0 Ccmpbted Bcsreawd, N = 9

Time (minutes) CRH = corticotropin-releasing hormone. ACTH = adrenocorticotropic hormone. Complicated bereaved subjects showed signifcantly hrgher basal plasma cortisol levels than the other 3 groups (F = 9.92. df = 88, p < 0.0001 1. Complrcated bereaved subjects also showed significantly smaller plasma ACTH responses to CRH than uncomplicated bereaved subjects or controls, but they showed no significant difference from depressed patients cf = 8.71, df = 88, p < 0.0001 1. The depressed control group data were obtained in a different study.

There were significant differences among the four groups for net ACTH responses to CRH (F = 8.71, df = 88, p < 0.0001). Complicated bereaved subjects showed significantly smaller ACTH responses to CRH than either uncomplicated bereaved subjects (725 f 516 vs. 1,354 f 687 pg/ ml per hour,p < 0.05) or controls (725 f 516 vs. 1,603 * 981 pg/ ml per hour, p < 0.05) (Fig. 1). There was no significant difference in ACTH responses to CRH between depressed bereaved subjects and depressed patients (725 + 5 16 vs. 706 f 554 pg/ ml per hour, NS) (Fig. 1). There were significant differences among the four groups for net cortisol responses to CRH (F= 3.10, df = 88,p< 0.003). Complicated bereaved subjects showed significantly greater net cortisol responses to CRH than either uncomplicated bereaved subjects (1,702 It 1,089 vs. 1,3 16 f 437 pg/ dl per hour, p < 0.05), depressed patients (1,702 f 1,089 vs. 1,05 1 + 616 pg/ dl per hour, p< 0.05), or controls (I ,702 f 1,089 vs. 1,163 f 444 erg/ dl per hour, p < 0.05) (Fig. 1).

150

In the sex- and age-matched comparison, complicated bereaved subjects again showed significantly smaller net ACTH responses to CRH than did uncomplicated bereaved subjects (48 1 + 186 vs. 1,846 * 8 13 pg/ ml per hour, t = 4.11, df 6, p < 0.0 1) (Fig. 2). Bereaved subjects who had received psychotropic medication in the past (before the bereavement) (n = 13), compared with those who had not (n= IS), showed significantly smaller plasma ACTH responses to CRH (796 + 447 vs. 1,461+ 734 pg/ ml per hour, t = 2.93, df = 23.5, p < 0.01) (Fig. 3). Bereaved subjects who had received antidepressant medication in the past (before the bereavement) (n = 7), compared with those who had not (n 21), showed significantly smaller plasma ACTH responses to CRH (708 f 465 vs. 1,300 + 703 pg/ ml per hour; I = 2.06, df 26, p < 0.05). Complicated bereaved subjects had a significantly higher cortisol response in relation to ACTH released (ACTH/cortisol ratio) than uncomplicated bereaved subjects (0.50 f 34 vs. 1.07 + 0.46, t = 3.12, df = 26, p < 0.01) as did bereaved subjects who had received past psychotropic medications in comparison with those who had not (0.66 f 0.53 vs. 1.08 + 0.40, I = 2.40, df = 26, p < 0.05). There was no significant correlation between ACTH responses to CRH and severity of depression as indicated q

q

q

Fig. 2. Responses to CRH infusion: age and sex-matched uncomplicated 3oc

Complicated bereaved bereaved subjects

T

T

subjects

vs.

I

0 Compliiewd bereaved. N-7 marched uncomplicated bereaved, N-7

A Age and sex

0

20

40

80

80

TIME Iminutes)

100

120

CRH = corticotropln-releasing hormone. ACTH = adrenocorticotropic hormone. The compkated bereaved subjects in = 7 1were matched to the uncomplicated bereaved subjects ,n = 7 1for age 2 6 years. Comphcated bereaved subjectsshowedasignificantlysmallerplasma ACTH responsetoCRH (1=4.11, dl=6,pc0.01 1. Basal cortisol levels were higher among complicated than uncomplicated bereaved subjects. but this difference was not statistically significant t 10.1 + 7.5 vs. 6.5 i 6.4. t = 0.65, df = 6, NS 8.

151 by the total score on either the HRSD (r = 0.20, n = 28, NS) or the POMS depressiondejection subscale (r = 0.24, N = 28, NS), but there was a trend for a significant correlation with scores on the BDI (r = 0.35, p < 0.1, n = 28). Fig. 3. Responses to CRH infusion: Bereaved subjects who had received psychotropic medication in the past vs. those who had not

0 Received psychotropic medication in past, N-13

I 0

psychotropic madkation. N-15

1 I 1 I L I m 40 60 80 100 12 TIME (minutes)

CRH = cortlcotropin-releasing hormone. ACTH = adrenocorticotropic hormone. Bereaved subjects who had received psychotropic medication in the past (before bereavement) in = 131 showed significantly smaller plasma ACTH responses to CRH it = 2.93, df= 23.5, p< 0.01) than bereaved subjects who had not received such medication in = 15).

Discussion In the present study, individuals who had a bereavement complicated by a depressive illness showed results on the CRH infusion test similar to those seen in depressed patients. Like depressed patients, the depressed bereaved subjects had significantly higher basal cortisol levels and significantly smaller ACTH responses to CRH than normal controls. Furthermore, ACTH responses to CRH were not significantly different between depressed bereaved subjects and depressed patients. Thus, these results indicate that bereaved individuals with a bereavement complicated by depressive illness, like depressed patients, show dysregulation of the HPA axis and hypercortisolemia. The bereaved subjects in the present study were a select group as they responded to

152 two newspaper articles about bereavement and depression. Thus, they included individuals with a bereavement complicated by distressing affective symptoms, which presumably led to their self-referral. However, this allowed us to test our hypotheses that bereavement might precipitate a depression with biological features, particularly in individuals with a past history of affective disorder. In this regard, we did find (1) that the depressed bereaved subgroup showed evidence of HPA dysregulation; (2) that bereaved subjects who had received past psychotropic medications had significantly smaller ACTH responses; and (3) that a significantly higher proportion of the depressed bereaved had both a past history of treatment for depression and treatment with psychotropic medication. That a history of past psychiatric treatment was present significantly more among depressed bereaved subjects is in accord with the study of Clayton and Darvish( 1979). They followed up 149 bereaved individuals and found that 13 months later 16% still had affective symptoms and that a past history of psychiatric disorder was found significantly more often among the depressed bereaved than among the nondepressed bereaved (64% vs. 26% p < 0.001). That significantly more of the depressed bereaved than the uncomplicated bereaved were women is in accord with many other studies that have found that depression is more common in women than in men (reviewed by Weissman and Klerman, 1977). There have been three recent studies of the HPA axis in bereavement using the DST (Das and Berrios, 1984; Kosten et al., 1984; Shuchter et al., 1986). Of the total 53 subjects in these three studies, only three were DST nonsuppressors. However, unlike the complicated bereaved in the present study, who had a mean duration of bereavement of 10.2 months, the subjects in two of these studies had acute grief reactions of only 2-5 weeks’ duration. Interestingly, in the third study (Kosten et al., 1984) where the subjects were elderly and bereaved for 6 months, the four who had either psychomotor retardation or morbid worthlessness showed significantly higher postdexamethasone plasma cortisols than the other nine subjects. Also, in the study of Shuchter et al. (1986), the three acute bereaved subjects who were DST nonsuppressors showed strong trends to have significantly higher depression scores on both the Hamilton and Zung depression scales. The complicated, compared to the uncomplicated bereaved subgroup, showed a proportionally higher cortisol response in relation to the ACTH released during the CRH test. This was reflected in a lower ratio of ACTH responses to cortisol responses. This is the same pattern seen when depressed patients are compared to controls (Gold et al., 1986). These observations are compatible with the development of hyperplasia and hyperresponsiveness of the adrenal cortex in the complicated bereaved subjects. The recent finding that chronically depressed .patients have cortisol responses to exogenous ACTH that are higher than normal supports the concept that the adrenal is hyperresponsive in depression (Amsterdam et al., 1983). In the present study we did not eliminate the possibility of observer bias as the same investigator (A.R.) assessed whether the bereaved individuals had a depressive illness and also determined their past psychiatric history. However, supportive data for the accuracy of the assessments of depression comes from the fact that the depressed bereaved had significantly higher depression scores on both the self-rated BDI and POMS scales which were scored after the clinical interview. Our results are not explicable on the basis that the bereaved

153 group contained individuals with recurrent affective disorder who were already in a depressive episode when they became bereaved. We screened out individuals with such a history; none had had a manic episode or had been diagnosed as having recurrent affective disorder requiring prophylactic medication, and only two subjects had had a psychiatric admission. However, in further studies, careful attention should be given to these methodological points. Our controls did have a different sex ratio than our bereaved population, and this might be a potential source of variance. In support of the results of the present study is the extensive animal literature showing that diverse experimental laboratory stresses cause biological abnormalities in various bodily systems (Hofer, 1981). Of particular interest are studies in primates using the naturalistic life event of separation. Such separation studies have induced depressive-like behavioral changes reversible by imipramine (Suomi et al., 1978), and Suomi (1985) has recently reported that the stress of separation causes chronic elevation of plasma cortisol and ACTH levels, particularly among primates whose biologic relatives have shown similar response to separation. In the past few years, there have been several studies demonstrating that various psychotherapeutic interventions are associated with a therapeutic resolution of the grief process (Ramsey, 1977; Raphael, 1977; Parkes, 1980; Vachon et al., 1980; Mawsonet al., 198 1; Horowitz et al., 1984). One of the clinical implications of the present study is that those individuals in whom bereavement has precipitated depression with accompanying biological abnormality might be considered for a treatment trial with antidepressant medication. In this regard, it is noteworthy that there are some studies suggesting that depressed hypercortisolemic patients, as shown by nonsuppression on the DST, may be more likely to respond to antidepressant medication than DST suppressors (Greden et al., 1980; Brown and Shuey, 1980; Fraser, 1983; Coryell and Turner, 1985; Peselow et al., 1986). In summary, the results of the present study suggest that some predisposed individuals respond to bereavement with a depressive illness and dysregulation of the HPA axis. We speculate that among such individuals the stress of this life event causes dysregulation of biological systems, including hypothalamic CRH neurons, with resulting hypersecretion of endogenous CRH and hypercortisolemia. Our sample of bereaved subjects was small and self-selected. However, the results suggest that further studies on bereaved populations are needed to identify individuals in whom bereavement precipitates depression and persisting central nervous system dysfunction, particularly to investigate whether such individuals may benefit from psychopharmacological intervention. Acknowledgment. Thanks are due Kathy Haley for research assistance Parma for secretarial services.

and to to Dasha

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