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Situational depression and the dexamethasone suppression test
Psychoneuroendocrinology, Vol. 8, No. 4, pp. 441 - 445, 1983.
0 3 0 6 - 4530/83 $3.00 + 0.00 © 1983 Pergamon Press Ltd.
Printed in Great Britain.
SITUATIONAL DEPRESSION AND THE DEXAMETHASONE SUPPRESSION TEST IRA M . LESSER, ROBERT T . RUBIN, ELLEN FINDER, BELLA FORSTER
and RUSSELLE. POLAND Department of Psychiatry and Biobehavioral Sciences, U.C.L.A. School of Medicine, Harbor-U.C.L.A. Medical Center, Torrance, CA 90509, U.S.A.
(Received 22 February 1983; in final form 25 April 1983) SUMMARY Neither baseline integrated 24 hr cortisol concentrations nor cortisol escape from dexamethasone suppression were able to distinguish a group of endogenously depressed patients who experienced precipitating events prior to their depression (situational) from a group of endogenously depressed patients with no discernible precipitating events (non-situational). Symptom severity, features of psychosis, and family history also were similar between the two groups. These results highlight the inadequacy of using the presence or absence of precipitating events for subtyping endogenous depression. INTRODUCTION
THERE is an ongoing controversy about the role of stressful events as precipitants of depressive illness (Paykel et al., 1969; Left et al., 1970; Kendell, 1976; Brown et al., 1979; Paykel, 1982). Until recently, the dichotomy between "reactive" and "endogenous" depression was a widely held basis for the classification of depression (Kendell, 1976). Among the difficulties with this system were the definition of what constituted a precipitating event and what was the necessary time between the event and the onset of illness for a depression to be labeled reactive. These difficulties, along with confusion about the psychotic vs neurotic dimension and illness severity, led to the abandonment of using the presence of precipitating events as a criterion for the classification of depression (Klein, 1974). Among the major diagnostic schemes currently in use, DSM III (American Psychiatric Association, 1980), the Research Diagnostic Criteria (Spitzer & Robins, 1978) and the St. Louis Criteria (Feighner et al., 1972), precipitating events are no longer used for the diagnosis of depression. However, the question remains as to whether patients with precipitating events have different symptom pictures, severity, course, and/or biological correlates compared with patients not experiencing such events. Leff et al. (1970), in a study of environmental factors preceding severe depressions, recorded about equal numbers of stressful events in the months preceding the depression for patients diagnosed as having endogenous and reactive depressions. Further, the number of stresses did not correlate with the intensity or treatment response of the depression. Paykel (1982) noted few differences in the symptom Reprint requests to: Dr. Ira Lesser, Bldg. D-5, Harbor-U.C.L.A. Medical Center, Torrance, CA 90509, U.S.A. 441
442
IRA M. LESSERet al.
pictures of depressions j u d g e d by raters to be precipitated or u n p r e c i p i t a t e d by stressful life events. Hirschfeld (1981) divided patients meeting Research Diagnostic Criteria for m a j o r depressive disorder into a g r o u p of " s i t u a t i o n a l " depressives (their depression almost certainly w o u l d n o t have developed in the absence o f a precipitating event) a n d " n o n s i t u a t i o n a l " depressives (no precipitating event was discernible). A l t h o u g h there were some differences in s y m p t o m p r e s e n t a t i o n , there was n o difference between the two groups in the p r o p o r t i o n o f patients who could be classified as e n d o g e n o u s or n o n e n d o g e n o u s . F u r t h e r m o r e , the overall t r e a t m e n t response did n o t differ between the two groups. Hirschfeld (1981) concluded that, for m a j o r depressive disorder, the presence of a precipitating event is n o t sufficient to define a particular subtype o f depression. A n o t h e r a p p r o a c h which m a y further elucidate whether differences exist between situational a n d n o n - s t i t u a t i o n a l depressives is to study the biological correlates o f their disorder. The h y p o t h a l a m i c - pituitary - a d r e n a l cortical ( H P A ) axis has been extensively examined in depressive illness ( R u b i n & P o l a n d , 1982; Sachar, 1982). M a n y studies suggest that a b o u t 5007o o f patients with e n d o g e n o u s m a j o r depressive disorders have cortisol hypersecretion, which reverts to n o r m a l as their clinical state improves. The d e x a m e t h a s o n e suppression test (DST) has been a m o n g the most reliable a n d replicable tests o f overactivity of the H P A axis (Carroll e t a i . , 1981). A m o n g e n d o g e n o u s l y depressed (melancholic) patients, it has a sensitivity o f a b o u t 40 - 50°70 a n d a specificity of a b o u t 90 - 95070. The present investigation e x a m i n e d H P A axis f u n c t i o n in a g r o u p o f e n d o g e n o u s l y depressed patients who were sub-divided into s i t u a t i o n a l a n d n o n - s i t u a t i o n a l categories. Their clinical presentations, baseline circulating cortisol c o n c e n t r a t i o n s , a n d D S T responses were c o m p a r e d to assess the validity o f separating e n d o g e n o u s depressions o n the basis o f identified external precipitating events. METHODS The subjects were part of an ongoing study of the psychobiology of severe endogenous depression (Rubin et al., 1980; 1981a; 1981b). All subjects were diagnosed as having a primary, definitely endogenous depression by the Schedule for Affective Disorders and Schizophrenia (SADS) (Spitzer & Endicott, 1979) and the Research Diagnostic Criteria (Spitzer & Robins, 1978). Some patients were classified as having bipolar affective disorder and were studied during a depressive episode. The unipolar patients also were sub-typed by family history according to Winokur's (1979) classification. The SADS and all clinical information about each patient were reviewed independently by two psychiatrists to determine whether the depression should be classified as situational or non-situational. The criteria were a modified version of those used by Hirschfeld (1981). Patients were classified as situational depressives if they were judged to have a significant event(s) within six months of the onset of their depression such that, in the opinion of the raters, the depression would not have occurred in the absence of the event(s). Non-situational depressives were judged to have no clear-cut significant precipitating event(s) in the six months preceding the onset of symptoms. After informed consent was obtained, the subjects completed a battery of psychometric tests and were admitted to the Harbor-U.C.L.A. Medical Center Clinical Research Center for 72 hr. Blood samples (7 ml) were taken through an in-dwelling venous catheter every 30 mins from 2100 hr the first night to 2300 hr the second night. At that time, dexamethasone elixir (1.0 mg p.o.) was administered, and blood was drawn at 0700, 1500 and 2300 hr the following day. The blood samples were allowed to clot, centrifuged, and serum was pipetted and frozen until hormone analysis. Serum cortisol was determined by radioimmunoassay with ~'I-cortisol (obtained commercially)as tracer. The cortisol antibody, also obtained commercially, is highly specific for cortisol. Both antibody and ~251-cortisol were obtained from Radioassay Systems Laboratories, Inc., Carson, CA. For the DST, the criterion for escape was a serum cortisol ) 35 ng/ml in any of the three post-dexamethasone samples (Rubin et al., 1981a).
SITUATIONAL DEPRESSIONANDTHE DST
4,*3
RESULTS
O f the 38 endogenously depressed patients, 17 (46°70) were judged to be situational depressions and 20 (54°7o) non-situational. In one case the raters could not agree, and that patient was excluded from the data analysis. In judging the presence or absence of a precipitating event, the raters agreed on 37 o f 38 cases (K = 0.95) (Cohen, 1960). For the situational group, there was less agreement about the certainty as to whether the depression would not have occurred in the absence of the event: the raters agreed on 11 of the 17 cases (K = 0.32) as to whether the depression "almost certainly would not have developed" or " p r o b a b l y would not have developed" in the absence o f the event. The events judged to be significantly related to the onset o f depression and their frequencies were divorce or separation from spouse (5), loss of job (4), death o f parent (3), death of spouse (1), death of friend (1), death of child (1), illness in the family (1), and severe financial loss (1). The one case where the raters did not agree involved a man who had an industrial accident and lost his job. This occurred earlier than six months before the onset o f his depressive symptoms, but his physical disability was an ongoing stressor. As mentioned, this case was not included in the data analysis. TABLE I. CHARACTERISTICSOF SITUATIONALAND NON-SITUATIONALENDOGENOUSLYDEPRESSEDPATIENTS
Age (mean ± S.D.) Male/female Caucasian/black Bipolar/unipolar Non-psychotic/psychotic Familial pure depressive disease Sporadic depressive disease Depression spectrum disease Hamilton Depression Scale (mean ± S.D.) Beck Depression Inventory (mean ± S.D.) Median 24 hr cortisol concentration (range) Median posbDEX cortisol concentrationt (range) Escape from DEX suppression
Situational (n -- 17)
Non-situational (n = 20)
42.7 ± 10.9 7/10 15/2 3/14 16/1 l 5 8 32.4 ± 7.6 36.9 _+ 8.4 95 ng/ml (51 -216 ng/ml) 18 ng/ml ( 8 - 230 ng/ml) 8
38.5 ~- 12.4 7/13 19/1 2/18 16/4 1" 6* 9* 31.3 ± 7.5 33.6 + 10.2 78 ng/ml ( 4 8 - 122 ng/ml) 11.5 ng/ml ( 4 - 96 ng/ml) 5
*Two of the non-situational unipolar depressives were adopted, and no family history was available. tAverage of 0700, 1500 and 2300 hr post-DEX cortisols.
Table I shows the characteristics of the two patient groups. There were no significant differences between the groups on age, sex, race, sub-group of unipolars according to family history, presence of psychosis, or severity of the illness (as measured by Hamilton and Beck Depression Scale scores). The serum cortisol measures were log-distributed across the subjects, so that median values and their ranges are presented in the Table. Parametric statistics were performed on the log-transformed data. There were no significant differences between the groups in baseline integrated 24 hr cortisol concentrations or in the cortisol responses to dexamethasone. Thirteen of the 37 patients (8/17 situational, 5/20 non-situational) showed an escape of cortisol following dexamethasone (1.0 mg elixir p.o.); these ratios were not significantly different (X = 1.91; d f = 1; p < 0.25).
444
IRA M. LESSER et al. DISCUSSION
Several methodological issues should be considered in evaluating our findings. First is the question of whether raters can reliably judge the presence or absence of precipitating events. Paykel (1982) commented upon the difficulties in retrospective rating of precipitating events in depressive illness, noting that the context and technique of data collection are important, as is the period of time from which the data are collected. In our study, not only was the patient interviewed, but family members and other hospital records also were consulted to provide further history. The raters did not have any clinical contact with the patients, so they were not influenced by clinical presentation. The time period studied was only the six months prior to the onset of clinical symptoms. In this context, it was relatively easy for the raters to agree on the presence of precipitating events, but more difficult for them to state with certainty that the patient would not have become depressed in the absence of these events. We were not able to assess the personal meaning the events had for the patients; vulnerability to particular stressful events may be an important factor which could contribute to biological reactivity. Another question concerns the theoretical rationale for using cortisol hypersecretion and escape from dexamethasone suppression as a means of differentiating the two groups. An abnormal DST implies a hyperactivity of the H P A axis, which could be hypothesized to occur in autonomous, non-environmentally responsive, and, therefore, biologically based depressions. Most studies have shown the DST to be positive in 40 to 50°70 of patients who are diagnosed as endogenous/melancholic. Could this group of patients who exhibit cortisol escape have an autonomous, biologically derived illness, while cortisol suppression in the DST would be associated with a depression related to external events? Our data do not support this hypothesis; rather, they indicate that the CNS events leading to increased H P A activity in endogenous depression occur independently of the presence or absence of identifiable precipitating events. Thus, it appears that, in endogenously depressed patients, neither symptom severity nor H P A axis function can be used to differentiate those who have had a precipitating event from those who have not. This supports Hirschfeld's (1981) conclusions regarding the limited usefulness of using precipitating factors as a means of classifying major depression. We do not yet have data to compare course and response to treatment in our two groups of patients. It may be that psychotherapeutic attention to these important precipitating events could affect outcome in endogenous depression, but this remains to be adequately tested (Prusoff et ai., 1980). Our data analysis also assessed whether situational events leading to depression occurred at different rates in those patients who had affective illness in their families. Perris et al. (1982) hypothesized that patients without genetic loading (Winokur's sporadic depression) would require more, or perhaps more severe, environmental stress than those patients with genetic loading and thus a predisposition (Winokur's familial pure depression) but they found no such difference in their patients. Although the number of patients in each category is small, our results also indicate no difference in family history of affective illness between the situational and the non-situational depressives. This confirms the findings of Perris et al. (1982) and lends further weight to the argument against the use of environmental stresses to subtype major depression.
SITUATIONAL DEPRESSIONAND THE DST
445
This work was supported by NIMH Grants MH 28380 and MH 34471, NIMH Research Scientist Award MH 47363 (to R.T.R.), and NIH Clinical Research Center Grant RR 00425. The authors thank Ms. Leslie Lane for technical assistance and Ms. Sharon Kajioka-Hom for secretarial assistance. REFERENCES AMERICAN PSYCHIATRICASSOCIATION(1980) Diagnostic and Statistical Manual of Mental Disorders, 3rd Edn, American Psychiatric Association. BROWN, G. W., NI BHROLCl'IAIN, M. & HARRIS, T. O. (1979) Psychotic and neurotic depressions. Part Ill: aetiological and background factors. J. Affect. Dis. 1, 195 - 21 I. CARROLL, B. J., FEINRERG, M., GREDEN, J. F., TARIKA, J., ALBALA, A. A., HASKETT, R. F., JAMES, N., KRONFOL, Z., LOHR, N., STEINER, M., DEVIGNE, J. P. & YOUNG, E. (1981) A specific laboratory test for the diagnosis of melancholia. Archs gen. Psychiat. 38, 15-22. COHEN, J. (1960) A coefficient of agreement for nominal scales. Educ. psychol. Measur. 20, 37-46. FEIGHNER, J. P., ROBINS, E., GUZE, S., WOODRUFF, R. A., WINOKUR,G. ~,£ MUNOZ, R. (1972) Diagnostic criteria for use in psychiatric research. Archs gen. Psychiat. 26, 57 - 63. HIRSCHFELD, R. i . A. (1981) Situational depression: validity of the concept. Br. J. Psychiat. 139, 297 - 305. KENDELL,R. E. (1976) The classification of depressions: a review of contemporary confusion. Br. J. Psychiat. 129, 15-28. KLEIN, D. F. (1974) Endogenomorphic depression. Archs gen. Psychiat. 31,447-454. LEFE, M. J., ROATCH, J. F. & BUNNEY, W. E., (1970) Environmental factors preceding the onset of severe depressions. Psychiatry 33, 293 - 311. PAYKEL, E. S., MYERS, J. K., DIENELT, M. N., KLERMAN,G. L., LIDENTHAL, J. J. ~. PEPPER, i . P. (1969) Life events and depression: a controlled study. Archs gen. Psychiat. 21, 753 -760. PAYKEL, E. S. (1982) Life events and early environment. In Handbook of Affective Disorders, E. S. Paykel (Ed.), pp. 146- 161. Guilford Press, New York. PERRIS, H., VON KNORRING, L. • PERRIS, C. (1982) Genetic vulnerability for depression and life events. Neuropsychobiology 8, 241 - 247. PRUSOFF, B. A., WEISSMAN, M. M., KLERMAN, G. L. t~ ROUNSAVlLLE, B. J. (1980) Research diagnostic criteria subtypes of depression. Archs gen. Psychiat. 37, 796 - 801. RUBIN, R. T. & POLAND, R. E. (1982) The chronoendocrinology of endogenous depression. In Neuroendocrine Perspectives, E. E. MOller and R. M. MacLeod (Eds.), Vol. 1, pp. 305 - 337. Elsevier, Amsterdam. RUBIN, R. T., POLAND, R. E., BLODGETT, A. L. N., WINSTON, R., FORSTER, B. & CARROLL, B. J. (1980) Cortisol dynamics and dexamethasone pharmacokinetics in primary endogenous depression: preliminary findings. In Progress in Psychoneuroendocrinology, F. Brambilla, G. Racagni and D. De Wied (Eds.), pp. 223- 234. Elsevier, Amsterdam. RUBIN, R. T., POLAND, R. E., BLODGETT,A. L. N., WINSTON,R. A., FORSTER,B. & HART, P. J. (1981a) Endocrine responses to perturbation tests in primary endogenous depression: preliminary findings. In Biological Psychiatry, C. Perris, G. Struwe and B. Jansson (Eds.), pp. 1239- 1243. Elsevier, Amsterdam. RUBIN, R. T., POLAND, R. E., TOWER, B. B., HART, P. J., BLODGETT, A. L. N. & FORSTER, B. (1981b) Hypothalamo-pituitary gonadal function in primary endogenously depressed men: preliminary findings. In Steroid Hormone Regulation of the Brain, K. Fuxe, J.-A. Gustafsson and L. Wetterberg (Eds.), pp. 387- 396. Pergamon Press, Oxford. SACHAg, E. J. (1982) Endocrine abnormalities in depression. In Handbook of Affective Disorders, E. S. Paykel (Ed.), pp. 191 - 201. Guilford Press, New York. SPITZER, R. L. & ENDICOTT, J. (1979) Schedule for Affective Disorders and Schizophrenia (SADS), 3rd Edn. Biometrics Research, New York State Psychiatric Institute, New York. SPITZER,g. L. & ROalNS, E. (1978) Research diagnostic criteria: rationale and reliability. Archs gen. Psychiat. 35, 773 - 782. WINOKUR, G. (1979) Familial (genetic) subtypes of pure depressive disease. Am. J. Psychiat. 136, 911-913.
0 3 0 6 - 4530/83 $3.00 + 0.00 © 1983 Pergamon Press Ltd.
Printed in Great Britain.
SITUATIONAL DEPRESSION AND THE DEXAMETHASONE SUPPRESSION TEST IRA M . LESSER, ROBERT T . RUBIN, ELLEN FINDER, BELLA FORSTER
and RUSSELLE. POLAND Department of Psychiatry and Biobehavioral Sciences, U.C.L.A. School of Medicine, Harbor-U.C.L.A. Medical Center, Torrance, CA 90509, U.S.A.
(Received 22 February 1983; in final form 25 April 1983) SUMMARY Neither baseline integrated 24 hr cortisol concentrations nor cortisol escape from dexamethasone suppression were able to distinguish a group of endogenously depressed patients who experienced precipitating events prior to their depression (situational) from a group of endogenously depressed patients with no discernible precipitating events (non-situational). Symptom severity, features of psychosis, and family history also were similar between the two groups. These results highlight the inadequacy of using the presence or absence of precipitating events for subtyping endogenous depression. INTRODUCTION
THERE is an ongoing controversy about the role of stressful events as precipitants of depressive illness (Paykel et al., 1969; Left et al., 1970; Kendell, 1976; Brown et al., 1979; Paykel, 1982). Until recently, the dichotomy between "reactive" and "endogenous" depression was a widely held basis for the classification of depression (Kendell, 1976). Among the difficulties with this system were the definition of what constituted a precipitating event and what was the necessary time between the event and the onset of illness for a depression to be labeled reactive. These difficulties, along with confusion about the psychotic vs neurotic dimension and illness severity, led to the abandonment of using the presence of precipitating events as a criterion for the classification of depression (Klein, 1974). Among the major diagnostic schemes currently in use, DSM III (American Psychiatric Association, 1980), the Research Diagnostic Criteria (Spitzer & Robins, 1978) and the St. Louis Criteria (Feighner et al., 1972), precipitating events are no longer used for the diagnosis of depression. However, the question remains as to whether patients with precipitating events have different symptom pictures, severity, course, and/or biological correlates compared with patients not experiencing such events. Leff et al. (1970), in a study of environmental factors preceding severe depressions, recorded about equal numbers of stressful events in the months preceding the depression for patients diagnosed as having endogenous and reactive depressions. Further, the number of stresses did not correlate with the intensity or treatment response of the depression. Paykel (1982) noted few differences in the symptom Reprint requests to: Dr. Ira Lesser, Bldg. D-5, Harbor-U.C.L.A. Medical Center, Torrance, CA 90509, U.S.A. 441
442
IRA M. LESSERet al.
pictures of depressions j u d g e d by raters to be precipitated or u n p r e c i p i t a t e d by stressful life events. Hirschfeld (1981) divided patients meeting Research Diagnostic Criteria for m a j o r depressive disorder into a g r o u p of " s i t u a t i o n a l " depressives (their depression almost certainly w o u l d n o t have developed in the absence o f a precipitating event) a n d " n o n s i t u a t i o n a l " depressives (no precipitating event was discernible). A l t h o u g h there were some differences in s y m p t o m p r e s e n t a t i o n , there was n o difference between the two groups in the p r o p o r t i o n o f patients who could be classified as e n d o g e n o u s or n o n e n d o g e n o u s . F u r t h e r m o r e , the overall t r e a t m e n t response did n o t differ between the two groups. Hirschfeld (1981) concluded that, for m a j o r depressive disorder, the presence of a precipitating event is n o t sufficient to define a particular subtype o f depression. A n o t h e r a p p r o a c h which m a y further elucidate whether differences exist between situational a n d n o n - s t i t u a t i o n a l depressives is to study the biological correlates o f their disorder. The h y p o t h a l a m i c - pituitary - a d r e n a l cortical ( H P A ) axis has been extensively examined in depressive illness ( R u b i n & P o l a n d , 1982; Sachar, 1982). M a n y studies suggest that a b o u t 5007o o f patients with e n d o g e n o u s m a j o r depressive disorders have cortisol hypersecretion, which reverts to n o r m a l as their clinical state improves. The d e x a m e t h a s o n e suppression test (DST) has been a m o n g the most reliable a n d replicable tests o f overactivity of the H P A axis (Carroll e t a i . , 1981). A m o n g e n d o g e n o u s l y depressed (melancholic) patients, it has a sensitivity o f a b o u t 40 - 50°70 a n d a specificity of a b o u t 90 - 95070. The present investigation e x a m i n e d H P A axis f u n c t i o n in a g r o u p o f e n d o g e n o u s l y depressed patients who were sub-divided into s i t u a t i o n a l a n d n o n - s i t u a t i o n a l categories. Their clinical presentations, baseline circulating cortisol c o n c e n t r a t i o n s , a n d D S T responses were c o m p a r e d to assess the validity o f separating e n d o g e n o u s depressions o n the basis o f identified external precipitating events. METHODS The subjects were part of an ongoing study of the psychobiology of severe endogenous depression (Rubin et al., 1980; 1981a; 1981b). All subjects were diagnosed as having a primary, definitely endogenous depression by the Schedule for Affective Disorders and Schizophrenia (SADS) (Spitzer & Endicott, 1979) and the Research Diagnostic Criteria (Spitzer & Robins, 1978). Some patients were classified as having bipolar affective disorder and were studied during a depressive episode. The unipolar patients also were sub-typed by family history according to Winokur's (1979) classification. The SADS and all clinical information about each patient were reviewed independently by two psychiatrists to determine whether the depression should be classified as situational or non-situational. The criteria were a modified version of those used by Hirschfeld (1981). Patients were classified as situational depressives if they were judged to have a significant event(s) within six months of the onset of their depression such that, in the opinion of the raters, the depression would not have occurred in the absence of the event(s). Non-situational depressives were judged to have no clear-cut significant precipitating event(s) in the six months preceding the onset of symptoms. After informed consent was obtained, the subjects completed a battery of psychometric tests and were admitted to the Harbor-U.C.L.A. Medical Center Clinical Research Center for 72 hr. Blood samples (7 ml) were taken through an in-dwelling venous catheter every 30 mins from 2100 hr the first night to 2300 hr the second night. At that time, dexamethasone elixir (1.0 mg p.o.) was administered, and blood was drawn at 0700, 1500 and 2300 hr the following day. The blood samples were allowed to clot, centrifuged, and serum was pipetted and frozen until hormone analysis. Serum cortisol was determined by radioimmunoassay with ~'I-cortisol (obtained commercially)as tracer. The cortisol antibody, also obtained commercially, is highly specific for cortisol. Both antibody and ~251-cortisol were obtained from Radioassay Systems Laboratories, Inc., Carson, CA. For the DST, the criterion for escape was a serum cortisol ) 35 ng/ml in any of the three post-dexamethasone samples (Rubin et al., 1981a).
SITUATIONAL DEPRESSIONANDTHE DST
4,*3
RESULTS
O f the 38 endogenously depressed patients, 17 (46°70) were judged to be situational depressions and 20 (54°7o) non-situational. In one case the raters could not agree, and that patient was excluded from the data analysis. In judging the presence or absence of a precipitating event, the raters agreed on 37 o f 38 cases (K = 0.95) (Cohen, 1960). For the situational group, there was less agreement about the certainty as to whether the depression would not have occurred in the absence of the event: the raters agreed on 11 of the 17 cases (K = 0.32) as to whether the depression "almost certainly would not have developed" or " p r o b a b l y would not have developed" in the absence o f the event. The events judged to be significantly related to the onset o f depression and their frequencies were divorce or separation from spouse (5), loss of job (4), death o f parent (3), death of spouse (1), death of friend (1), death of child (1), illness in the family (1), and severe financial loss (1). The one case where the raters did not agree involved a man who had an industrial accident and lost his job. This occurred earlier than six months before the onset o f his depressive symptoms, but his physical disability was an ongoing stressor. As mentioned, this case was not included in the data analysis. TABLE I. CHARACTERISTICSOF SITUATIONALAND NON-SITUATIONALENDOGENOUSLYDEPRESSEDPATIENTS
Age (mean ± S.D.) Male/female Caucasian/black Bipolar/unipolar Non-psychotic/psychotic Familial pure depressive disease Sporadic depressive disease Depression spectrum disease Hamilton Depression Scale (mean ± S.D.) Beck Depression Inventory (mean ± S.D.) Median 24 hr cortisol concentration (range) Median posbDEX cortisol concentrationt (range) Escape from DEX suppression
Situational (n -- 17)
Non-situational (n = 20)
42.7 ± 10.9 7/10 15/2 3/14 16/1 l 5 8 32.4 ± 7.6 36.9 _+ 8.4 95 ng/ml (51 -216 ng/ml) 18 ng/ml ( 8 - 230 ng/ml) 8
38.5 ~- 12.4 7/13 19/1 2/18 16/4 1" 6* 9* 31.3 ± 7.5 33.6 + 10.2 78 ng/ml ( 4 8 - 122 ng/ml) 11.5 ng/ml ( 4 - 96 ng/ml) 5
*Two of the non-situational unipolar depressives were adopted, and no family history was available. tAverage of 0700, 1500 and 2300 hr post-DEX cortisols.
Table I shows the characteristics of the two patient groups. There were no significant differences between the groups on age, sex, race, sub-group of unipolars according to family history, presence of psychosis, or severity of the illness (as measured by Hamilton and Beck Depression Scale scores). The serum cortisol measures were log-distributed across the subjects, so that median values and their ranges are presented in the Table. Parametric statistics were performed on the log-transformed data. There were no significant differences between the groups in baseline integrated 24 hr cortisol concentrations or in the cortisol responses to dexamethasone. Thirteen of the 37 patients (8/17 situational, 5/20 non-situational) showed an escape of cortisol following dexamethasone (1.0 mg elixir p.o.); these ratios were not significantly different (X = 1.91; d f = 1; p < 0.25).
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IRA M. LESSER et al. DISCUSSION
Several methodological issues should be considered in evaluating our findings. First is the question of whether raters can reliably judge the presence or absence of precipitating events. Paykel (1982) commented upon the difficulties in retrospective rating of precipitating events in depressive illness, noting that the context and technique of data collection are important, as is the period of time from which the data are collected. In our study, not only was the patient interviewed, but family members and other hospital records also were consulted to provide further history. The raters did not have any clinical contact with the patients, so they were not influenced by clinical presentation. The time period studied was only the six months prior to the onset of clinical symptoms. In this context, it was relatively easy for the raters to agree on the presence of precipitating events, but more difficult for them to state with certainty that the patient would not have become depressed in the absence of these events. We were not able to assess the personal meaning the events had for the patients; vulnerability to particular stressful events may be an important factor which could contribute to biological reactivity. Another question concerns the theoretical rationale for using cortisol hypersecretion and escape from dexamethasone suppression as a means of differentiating the two groups. An abnormal DST implies a hyperactivity of the H P A axis, which could be hypothesized to occur in autonomous, non-environmentally responsive, and, therefore, biologically based depressions. Most studies have shown the DST to be positive in 40 to 50°70 of patients who are diagnosed as endogenous/melancholic. Could this group of patients who exhibit cortisol escape have an autonomous, biologically derived illness, while cortisol suppression in the DST would be associated with a depression related to external events? Our data do not support this hypothesis; rather, they indicate that the CNS events leading to increased H P A activity in endogenous depression occur independently of the presence or absence of identifiable precipitating events. Thus, it appears that, in endogenously depressed patients, neither symptom severity nor H P A axis function can be used to differentiate those who have had a precipitating event from those who have not. This supports Hirschfeld's (1981) conclusions regarding the limited usefulness of using precipitating factors as a means of classifying major depression. We do not yet have data to compare course and response to treatment in our two groups of patients. It may be that psychotherapeutic attention to these important precipitating events could affect outcome in endogenous depression, but this remains to be adequately tested (Prusoff et ai., 1980). Our data analysis also assessed whether situational events leading to depression occurred at different rates in those patients who had affective illness in their families. Perris et al. (1982) hypothesized that patients without genetic loading (Winokur's sporadic depression) would require more, or perhaps more severe, environmental stress than those patients with genetic loading and thus a predisposition (Winokur's familial pure depression) but they found no such difference in their patients. Although the number of patients in each category is small, our results also indicate no difference in family history of affective illness between the situational and the non-situational depressives. This confirms the findings of Perris et al. (1982) and lends further weight to the argument against the use of environmental stresses to subtype major depression.
SITUATIONAL DEPRESSIONAND THE DST
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This work was supported by NIMH Grants MH 28380 and MH 34471, NIMH Research Scientist Award MH 47363 (to R.T.R.), and NIH Clinical Research Center Grant RR 00425. The authors thank Ms. Leslie Lane for technical assistance and Ms. Sharon Kajioka-Hom for secretarial assistance. REFERENCES AMERICAN PSYCHIATRICASSOCIATION(1980) Diagnostic and Statistical Manual of Mental Disorders, 3rd Edn, American Psychiatric Association. BROWN, G. W., NI BHROLCl'IAIN, M. & HARRIS, T. O. (1979) Psychotic and neurotic depressions. Part Ill: aetiological and background factors. J. Affect. Dis. 1, 195 - 21 I. CARROLL, B. J., FEINRERG, M., GREDEN, J. F., TARIKA, J., ALBALA, A. A., HASKETT, R. F., JAMES, N., KRONFOL, Z., LOHR, N., STEINER, M., DEVIGNE, J. P. & YOUNG, E. (1981) A specific laboratory test for the diagnosis of melancholia. Archs gen. Psychiat. 38, 15-22. COHEN, J. (1960) A coefficient of agreement for nominal scales. Educ. psychol. Measur. 20, 37-46. FEIGHNER, J. P., ROBINS, E., GUZE, S., WOODRUFF, R. A., WINOKUR,G. ~,£ MUNOZ, R. (1972) Diagnostic criteria for use in psychiatric research. Archs gen. Psychiat. 26, 57 - 63. HIRSCHFELD, R. i . A. (1981) Situational depression: validity of the concept. Br. J. Psychiat. 139, 297 - 305. KENDELL,R. E. (1976) The classification of depressions: a review of contemporary confusion. Br. J. Psychiat. 129, 15-28. KLEIN, D. F. (1974) Endogenomorphic depression. Archs gen. Psychiat. 31,447-454. LEFE, M. J., ROATCH, J. F. & BUNNEY, W. E., (1970) Environmental factors preceding the onset of severe depressions. Psychiatry 33, 293 - 311. PAYKEL, E. S., MYERS, J. K., DIENELT, M. N., KLERMAN,G. L., LIDENTHAL, J. J. ~. PEPPER, i . P. (1969) Life events and depression: a controlled study. Archs gen. Psychiat. 21, 753 -760. PAYKEL, E. S. (1982) Life events and early environment. In Handbook of Affective Disorders, E. S. Paykel (Ed.), pp. 146- 161. Guilford Press, New York. PERRIS, H., VON KNORRING, L. • PERRIS, C. (1982) Genetic vulnerability for depression and life events. Neuropsychobiology 8, 241 - 247. PRUSOFF, B. A., WEISSMAN, M. M., KLERMAN, G. L. t~ ROUNSAVlLLE, B. J. (1980) Research diagnostic criteria subtypes of depression. Archs gen. Psychiat. 37, 796 - 801. RUBIN, R. T. & POLAND, R. E. (1982) The chronoendocrinology of endogenous depression. In Neuroendocrine Perspectives, E. E. MOller and R. M. MacLeod (Eds.), Vol. 1, pp. 305 - 337. Elsevier, Amsterdam. RUBIN, R. T., POLAND, R. E., BLODGETT, A. L. N., WINSTON, R., FORSTER, B. & CARROLL, B. J. (1980) Cortisol dynamics and dexamethasone pharmacokinetics in primary endogenous depression: preliminary findings. In Progress in Psychoneuroendocrinology, F. Brambilla, G. Racagni and D. De Wied (Eds.), pp. 223- 234. Elsevier, Amsterdam. RUBIN, R. T., POLAND, R. E., BLODGETT,A. L. N., WINSTON,R. A., FORSTER,B. & HART, P. J. (1981a) Endocrine responses to perturbation tests in primary endogenous depression: preliminary findings. In Biological Psychiatry, C. Perris, G. Struwe and B. Jansson (Eds.), pp. 1239- 1243. Elsevier, Amsterdam. RUBIN, R. T., POLAND, R. E., TOWER, B. B., HART, P. J., BLODGETT, A. L. N. & FORSTER, B. (1981b) Hypothalamo-pituitary gonadal function in primary endogenously depressed men: preliminary findings. In Steroid Hormone Regulation of the Brain, K. Fuxe, J.-A. Gustafsson and L. Wetterberg (Eds.), pp. 387- 396. Pergamon Press, Oxford. SACHAg, E. J. (1982) Endocrine abnormalities in depression. In Handbook of Affective Disorders, E. S. Paykel (Ed.), pp. 191 - 201. Guilford Press, New York. SPITZER, R. L. & ENDICOTT, J. (1979) Schedule for Affective Disorders and Schizophrenia (SADS), 3rd Edn. Biometrics Research, New York State Psychiatric Institute, New York. SPITZER,g. L. & ROalNS, E. (1978) Research diagnostic criteria: rationale and reliability. Archs gen. Psychiat. 35, 773 - 782. WINOKUR, G. (1979) Familial (genetic) subtypes of pure depressive disease. Am. J. Psychiat. 136, 911-913.