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Life events and the dexamethasone suppression test in affective illness
Journal of Affective Disorders, 10 (1986) 203-206 Elsevier
203
JAD 00370
Life Events and the Dexamethasone Suppression Affective Illness J. Mendlewicz, Service de Psychiatric,
F. Charon
Test in
and P. Linkowski
Uniuersiti Libre de Bruxelles, Route de Lennrk 808, B-1070 Brussels (Belgium) (Received 9 January, 1986) (Revised, received 13 February, 1986) (Accepted 25 February, 1986)
Summary Forty patients with primary endogenous major depression were followed up during a 12-month period after recovery, on maintenance therapy. Neither the results of the DST, nor the life events reported could predict the occurrence of affective relapses although bereavement life events tended to be observed more frequently in patients relapsing, regardless of the type of antidepressant treatment.
Key words:
Depression
- Dexamethasone
suppression
Introduction The dexamethasone suppression test (DST) has been proposed as a biological marker of endogenous depression (Carroll et al. 1981; Carroll 1985) but its specificity for the clinical diagnosis of depressive disorders has recently been challenged (Coppen et al. 1983). According to some studies, a relationship exists between clinical remission and normalisation of the DST (Greden et al. 1980). Several authors also suggest that failure to normalize the DST could be a risk factor of early relapses (Holsboer et al. 1980; Targum 1982). If these observations could be confirmed, the DST would be of great clinical and prognostic interest in monitoring acute and long-term antidepressant treatments. Stressful life events (LE) are also considered to be psychosocial risk factors for depressive disorders (Lloyd 1980). Retrospective studies 0165-0327/86/$03.50
test - Life events
show that depressed patients report more stressful life events before the onset of a depressive episode than do normal controls (Paykel 1983). However, there is a controversy regarding the causal role of LE in depressive disorders: methodological problems exist and prospective studies have failed to show a direct effect of LE (Paykel 1983; Tennant 1983) on the onset of depressive illness. ‘Loss’ events and particularly death in the immediate family or among close friends are considered to be important risk factors in the occurrence of a depressive episode (Paykel 1969; Finlay-Jones 1981; Matussek 1981). The present investigation is a 12-month follow-up study of primary endogenous major depressive disorder patients, aimed at exploring the predictive value of the DST performed before and after acute antidepressant treatment in relation to life events.
0 1986 Elsevier Science Publishers B.V. (Biomedical Division)
204 Patients and Methods
Results
We studied patients consecutively hospitalized in the department of psychiatry at Erasme Hospital, Brussels, during the period of November 1981 to October 1983, for a primary endogenous major depressive disorder, unipolar (n = 24) and bipolar (n = 16) type, according to the Research Diagnostic Criteria (RDC) (Spitzer et al. 1978). On admission, a DST was administered, after a drug wash-out period of 2 weeks. 1 mg of dexamethasone was given orally at 11 p.m., and cortisol suppression estimated by determining the cortisol plasma levels at 4 p.m. and 11 p.m. on the following day. Plasma cortisol was measured using a radio-immunoassay kit (Ryner 1978) and an abnormal test, i.e. non-suppression, was defined according to the criteria of Carol1 et al. (1981) on the basis of a plasma cortisol level, at 4 p.m. and/or 11 p.m., equal or greater than 50 pg/l. Patients who were non-suppressors before treatment and showed a clinical remission (improvement of at least 70% from baseline on the Hamilton Rating Scale) (Hamilton 1960) after 8 weeks of treatment were selected for this study (n = 40). Patients with somatic disorders, alcohol or drug addiction were not included. The treatment given was amitriptyline (755225 mg/day; n = 15) or chlorimipramine (loo-250 mg/day; n = 11) and electroconvulsive therapy (n = 14). After eight weeks of treatment, the DST was repeated during clinical remission before patients were discharged. They were then followed up for 12 months in our out-patients clinic with lower maintenance doses of tricyclic antidepressants (50-100 mg amitriptyline or chlorimipramine). Some bipolar (n = 13) and unipolar (n = 14) patients received lithium carbonate in addition to the antidepressive treatment. The lithium doses ranged from 600 to 900 mg with plasma levels between 0.5 and 0.9 mEq/l. A semi-structured clinical interview was used blind to the DST results to ascertain possible depressive or manic relapses, together with the life events interview of Paykel (1983), covering the 12-month follow-up period. Affective relapses were considered only if the patient met the criteria of major depressive disorder, according to the RDC. The results were analyzed using the Fisher exact probability test.
Of the 40 patients studied, 10 had at least one major depressive disorder (MDD) relapse, necessitating treatment changes and/or hospitalisation, and no one had a manic relapse. Table 1 shows the clinical characteristics of the two groups of patients. They were comparable for age but more females showed relapses. There was no difference in the average number of episodes of MDD prior to the current episode in the two groups (2.9 and 2.2). The proportion of unipolar patients was higher in the relapsing group (eight unipolar, two bipolar) than in the non-relapsing group (16 unipolar, 14 bipolar). Among the nine patients whose DST remained abnormal after treatment, two had relapses (22%), and of the 31 patients whose DST was normalized, eight had relapses (25.8%) (Table 2). There was thus no significant difference in the number of patients relapsing after discharge according to the DST (P = 0.29; NS). Table 3 shows that of the 21 patients reporting one or more LE (independent of the pathology and with negative impact), four had affective relapses (19%) and of the 19 patients who reported no life events, six had relapses (31.6%). This difference is not statistically significant (P = 0.30; NS). If only bereavement concerning the immediate family and close friends is considered as a life
TABLE
1
CLINICAL CHARACTERISTICS TIENTS WITH AND WITHOUT
Mean age Female; Males Bipolars Unipolars Average number before current
of M.D.D. episode
a Major depressive
disorder.
OF DEPRESSED RELAPSES Patients with relapses (n = 10)
Patients without relapses (n = 30)
46*12 8 2 2 8
52+ 12 19 11 14 16
a 2.9&2
2.252
PA-
205 TABLE
2
RELAPSE DST a
RATE DURING
DST after acute treatment
ACCORDING
Patients without relapses
Total
2 8
I 23
9 31
10
30
40
Patients with relapses
Abnormal Normal Total
12 MONTHS
TO
Discussion
a Fisher (P = 0.293; NS).
TABLE
3
DISTRIBUTION OF PATIENTS WITH LIFE EVENTS ACCORDING TO RELAPSES a. Patients without relapses (N = 30)
Total
4 6
17 13
21 19
10
30
40
Patients with relapses (N = 30)
Patients Patients
with LE without LE
Total
(LE)
a Fisher (P = 0.30; NS)
event, it can be observed that among the ten patients who relapsed, four reported this type of life events (40%), while among the 30 patients who did not relapse, bereavement was only present in four patients (13%) (Table 4). This difference is still not signficant at the 0.05 level (P = 0.07; NS). Because the type of drug treatment may play a
TABLE
role in the rate of relapses in depressed patients, we examined separately patients who were on maintenance therapy with lithium salts. Of the ten patients who had relapses, four were taking lithium (40%) and of the 30 patients who did not show any relapse, 13 were taking lithium (43.3%). Thus no significant difference could be observed between patients treated with lithium or not in term of relapses.
4
DISTRIBUTION OF BEREAVEMENT ING TO RELAPSES =
EVENTS
ACCORD-
Our results show that the DST has no value for predicting relapses during a 12-month period in a limited sample of 40 unipolar and bipolar depressed patients. Patients in clinical remission with an abnormal DST were not at greater risk of relapse than remitted patients showing a normalisation of the DST. A follow-up of patients on maintenance therapy with tricyclics or lithium for 12 months failed to show any relationship between affective relapses and the presence of life events regardless of the type of treatment or the type of event. Among all life events recorded, bereavement of close relatives and friends was more frequently observed in patients relapsing, suggesting an effect of bereavement on affective relapses, given the small size of our sample. This study shows that ten (25%) out of the 40 affectively ill patients had depressive relapses during a one-year follow-up period on maintenance therapy. Neither the DST nor the recording of life events (except bereavement) could predict the occurrence of affective relapses in this group of patients. Whether bereavement will be shown to have a prognostic value in antidepressant maintenance therapy needs further long-term prospective controlled therapeutic trials in larger samples of affectively ill patients. Acknowledgements
Patients relapses
Patients with bereavement Patients without bereavement Total
with
Patients without relapses
Total
The study was supported C.G.E.R. and the Belgian ment and Labor.
4
4
8
6
26
32
10
30
40
by the F.R.S.M., the Ministry of Employ-
References
a Fisher (P = 0.07; NS).
Carroll, B.J., Dexamethasone contemporary confusion, 13-24.
suppression test; a review of J. Clin. Psychiatry, 46 (1985)
Carroll, B.J., Feinberg, M., Greden. J., Tarika. J., Albala, A., Haskett. R.. James. N., Kronfol, Z., Lohr, N., Steiner, M., de Vigne, J.P. and Young, E., A specific laboratory test for the diagnostics of melancholia: standardisation, validation and clinical utility, Arch. Gen. Psychiatry, 38 (1981) 15-22. Coppen, A., Abou-Saleh, M., Milia, P., Metcalf, M.. Harwood, J. and Baily, J., Dexamethasone suppression test in depression and other psychiatric illness, Br. J. Psychiatry, 142 (1983) 4988504. Finlay-Jones, R. and Brown, G.W., Types of stressful life events and the onset of anxiety and depressive disorders, Psycho]. Med. (London). 11 (1981) 803-815. Greden, J.F., Albala, A.A., Haskett, R.F., James, N., Goodman, L., Steiner, M. and Caroll, J., Normalisation of dexamethasone suppression test: a probable index of recovery among endogenous depressives, Biol. Psychiatry, 15 (1980) 449-458. Hamilton. M., A rating scale for depression, J. Neurol. Neurosurg. Psychiatry, 23 (1960) 56-62. Holsboer, F., Liebl, R. and Hofschuster, E., Repeated dexamethasone suppression test during depressive illness. Normalization of test result compared with clinical improvement, J. Affect. Disord., 4 (1982) 93-101.
Lloyd, C., Life events and depressive disorder - reviewed, Arch. Gen. Psychiatry, 37 (1980) 529-535 and 541-549. Matussek, P. and Neuner, R., Loss events preceding endogenous and neurotic depression, Acta Psychiatr. Stand.. 64 (1981) 340-350. Paykel, ES.. Life events and depression, Arch. Gen. Psychiatry, 21 (1969) 7533760. Paykel. E.S., Methodological aspects of life events research, J. Psychosom. Res., 27 (1983) 341-352. Ryner. J.C., Estimation of plasma cortisol by radio competition or radio-immunoassay. Use of commercial kits, Ann. Radio]. Clin., 36 (1978) 509-514. Spitzer, R.L., Endicott, J. and Robins, E., Research diagnostic criteria: rationale and reliability, Arch. Gen. Psychiatry, 35 (1978) 7733782. Tennant, C.. Life events and psychological morbidity: the evidence from prospective studies, Psycho]. Med. (London), 13 (1983) 483-486. Targum, SD., Persistent neuroendocrine dysregulation in major depressive disorder: a marker for early relapse, Biol. Psychiatry, 19 (1984) 3055317.
203
JAD 00370
Life Events and the Dexamethasone Suppression Affective Illness J. Mendlewicz, Service de Psychiatric,
F. Charon
Test in
and P. Linkowski
Uniuersiti Libre de Bruxelles, Route de Lennrk 808, B-1070 Brussels (Belgium) (Received 9 January, 1986) (Revised, received 13 February, 1986) (Accepted 25 February, 1986)
Summary Forty patients with primary endogenous major depression were followed up during a 12-month period after recovery, on maintenance therapy. Neither the results of the DST, nor the life events reported could predict the occurrence of affective relapses although bereavement life events tended to be observed more frequently in patients relapsing, regardless of the type of antidepressant treatment.
Key words:
Depression
- Dexamethasone
suppression
Introduction The dexamethasone suppression test (DST) has been proposed as a biological marker of endogenous depression (Carroll et al. 1981; Carroll 1985) but its specificity for the clinical diagnosis of depressive disorders has recently been challenged (Coppen et al. 1983). According to some studies, a relationship exists between clinical remission and normalisation of the DST (Greden et al. 1980). Several authors also suggest that failure to normalize the DST could be a risk factor of early relapses (Holsboer et al. 1980; Targum 1982). If these observations could be confirmed, the DST would be of great clinical and prognostic interest in monitoring acute and long-term antidepressant treatments. Stressful life events (LE) are also considered to be psychosocial risk factors for depressive disorders (Lloyd 1980). Retrospective studies 0165-0327/86/$03.50
test - Life events
show that depressed patients report more stressful life events before the onset of a depressive episode than do normal controls (Paykel 1983). However, there is a controversy regarding the causal role of LE in depressive disorders: methodological problems exist and prospective studies have failed to show a direct effect of LE (Paykel 1983; Tennant 1983) on the onset of depressive illness. ‘Loss’ events and particularly death in the immediate family or among close friends are considered to be important risk factors in the occurrence of a depressive episode (Paykel 1969; Finlay-Jones 1981; Matussek 1981). The present investigation is a 12-month follow-up study of primary endogenous major depressive disorder patients, aimed at exploring the predictive value of the DST performed before and after acute antidepressant treatment in relation to life events.
0 1986 Elsevier Science Publishers B.V. (Biomedical Division)
204 Patients and Methods
Results
We studied patients consecutively hospitalized in the department of psychiatry at Erasme Hospital, Brussels, during the period of November 1981 to October 1983, for a primary endogenous major depressive disorder, unipolar (n = 24) and bipolar (n = 16) type, according to the Research Diagnostic Criteria (RDC) (Spitzer et al. 1978). On admission, a DST was administered, after a drug wash-out period of 2 weeks. 1 mg of dexamethasone was given orally at 11 p.m., and cortisol suppression estimated by determining the cortisol plasma levels at 4 p.m. and 11 p.m. on the following day. Plasma cortisol was measured using a radio-immunoassay kit (Ryner 1978) and an abnormal test, i.e. non-suppression, was defined according to the criteria of Carol1 et al. (1981) on the basis of a plasma cortisol level, at 4 p.m. and/or 11 p.m., equal or greater than 50 pg/l. Patients who were non-suppressors before treatment and showed a clinical remission (improvement of at least 70% from baseline on the Hamilton Rating Scale) (Hamilton 1960) after 8 weeks of treatment were selected for this study (n = 40). Patients with somatic disorders, alcohol or drug addiction were not included. The treatment given was amitriptyline (755225 mg/day; n = 15) or chlorimipramine (loo-250 mg/day; n = 11) and electroconvulsive therapy (n = 14). After eight weeks of treatment, the DST was repeated during clinical remission before patients were discharged. They were then followed up for 12 months in our out-patients clinic with lower maintenance doses of tricyclic antidepressants (50-100 mg amitriptyline or chlorimipramine). Some bipolar (n = 13) and unipolar (n = 14) patients received lithium carbonate in addition to the antidepressive treatment. The lithium doses ranged from 600 to 900 mg with plasma levels between 0.5 and 0.9 mEq/l. A semi-structured clinical interview was used blind to the DST results to ascertain possible depressive or manic relapses, together with the life events interview of Paykel (1983), covering the 12-month follow-up period. Affective relapses were considered only if the patient met the criteria of major depressive disorder, according to the RDC. The results were analyzed using the Fisher exact probability test.
Of the 40 patients studied, 10 had at least one major depressive disorder (MDD) relapse, necessitating treatment changes and/or hospitalisation, and no one had a manic relapse. Table 1 shows the clinical characteristics of the two groups of patients. They were comparable for age but more females showed relapses. There was no difference in the average number of episodes of MDD prior to the current episode in the two groups (2.9 and 2.2). The proportion of unipolar patients was higher in the relapsing group (eight unipolar, two bipolar) than in the non-relapsing group (16 unipolar, 14 bipolar). Among the nine patients whose DST remained abnormal after treatment, two had relapses (22%), and of the 31 patients whose DST was normalized, eight had relapses (25.8%) (Table 2). There was thus no significant difference in the number of patients relapsing after discharge according to the DST (P = 0.29; NS). Table 3 shows that of the 21 patients reporting one or more LE (independent of the pathology and with negative impact), four had affective relapses (19%) and of the 19 patients who reported no life events, six had relapses (31.6%). This difference is not statistically significant (P = 0.30; NS). If only bereavement concerning the immediate family and close friends is considered as a life
TABLE
1
CLINICAL CHARACTERISTICS TIENTS WITH AND WITHOUT
Mean age Female; Males Bipolars Unipolars Average number before current
of M.D.D. episode
a Major depressive
disorder.
OF DEPRESSED RELAPSES Patients with relapses (n = 10)
Patients without relapses (n = 30)
46*12 8 2 2 8
52+ 12 19 11 14 16
a 2.9&2
2.252
PA-
205 TABLE
2
RELAPSE DST a
RATE DURING
DST after acute treatment
ACCORDING
Patients without relapses
Total
2 8
I 23
9 31
10
30
40
Patients with relapses
Abnormal Normal Total
12 MONTHS
TO
Discussion
a Fisher (P = 0.293; NS).
TABLE
3
DISTRIBUTION OF PATIENTS WITH LIFE EVENTS ACCORDING TO RELAPSES a. Patients without relapses (N = 30)
Total
4 6
17 13
21 19
10
30
40
Patients with relapses (N = 30)
Patients Patients
with LE without LE
Total
(LE)
a Fisher (P = 0.30; NS)
event, it can be observed that among the ten patients who relapsed, four reported this type of life events (40%), while among the 30 patients who did not relapse, bereavement was only present in four patients (13%) (Table 4). This difference is still not signficant at the 0.05 level (P = 0.07; NS). Because the type of drug treatment may play a
TABLE
role in the rate of relapses in depressed patients, we examined separately patients who were on maintenance therapy with lithium salts. Of the ten patients who had relapses, four were taking lithium (40%) and of the 30 patients who did not show any relapse, 13 were taking lithium (43.3%). Thus no significant difference could be observed between patients treated with lithium or not in term of relapses.
4
DISTRIBUTION OF BEREAVEMENT ING TO RELAPSES =
EVENTS
ACCORD-
Our results show that the DST has no value for predicting relapses during a 12-month period in a limited sample of 40 unipolar and bipolar depressed patients. Patients in clinical remission with an abnormal DST were not at greater risk of relapse than remitted patients showing a normalisation of the DST. A follow-up of patients on maintenance therapy with tricyclics or lithium for 12 months failed to show any relationship between affective relapses and the presence of life events regardless of the type of treatment or the type of event. Among all life events recorded, bereavement of close relatives and friends was more frequently observed in patients relapsing, suggesting an effect of bereavement on affective relapses, given the small size of our sample. This study shows that ten (25%) out of the 40 affectively ill patients had depressive relapses during a one-year follow-up period on maintenance therapy. Neither the DST nor the recording of life events (except bereavement) could predict the occurrence of affective relapses in this group of patients. Whether bereavement will be shown to have a prognostic value in antidepressant maintenance therapy needs further long-term prospective controlled therapeutic trials in larger samples of affectively ill patients. Acknowledgements
Patients relapses
Patients with bereavement Patients without bereavement Total
with
Patients without relapses
Total
The study was supported C.G.E.R. and the Belgian ment and Labor.
4
4
8
6
26
32
10
30
40
by the F.R.S.M., the Ministry of Employ-
References
a Fisher (P = 0.07; NS).
Carroll, B.J., Dexamethasone contemporary confusion, 13-24.
suppression test; a review of J. Clin. Psychiatry, 46 (1985)
Carroll, B.J., Feinberg, M., Greden. J., Tarika. J., Albala, A., Haskett. R.. James. N., Kronfol, Z., Lohr, N., Steiner, M., de Vigne, J.P. and Young, E., A specific laboratory test for the diagnostics of melancholia: standardisation, validation and clinical utility, Arch. Gen. Psychiatry, 38 (1981) 15-22. Coppen, A., Abou-Saleh, M., Milia, P., Metcalf, M.. Harwood, J. and Baily, J., Dexamethasone suppression test in depression and other psychiatric illness, Br. J. Psychiatry, 142 (1983) 4988504. Finlay-Jones, R. and Brown, G.W., Types of stressful life events and the onset of anxiety and depressive disorders, Psycho]. Med. (London). 11 (1981) 803-815. Greden, J.F., Albala, A.A., Haskett, R.F., James, N., Goodman, L., Steiner, M. and Caroll, J., Normalisation of dexamethasone suppression test: a probable index of recovery among endogenous depressives, Biol. Psychiatry, 15 (1980) 449-458. Hamilton. M., A rating scale for depression, J. Neurol. Neurosurg. Psychiatry, 23 (1960) 56-62. Holsboer, F., Liebl, R. and Hofschuster, E., Repeated dexamethasone suppression test during depressive illness. Normalization of test result compared with clinical improvement, J. Affect. Disord., 4 (1982) 93-101.
Lloyd, C., Life events and depressive disorder - reviewed, Arch. Gen. Psychiatry, 37 (1980) 529-535 and 541-549. Matussek, P. and Neuner, R., Loss events preceding endogenous and neurotic depression, Acta Psychiatr. Stand.. 64 (1981) 340-350. Paykel, ES.. Life events and depression, Arch. Gen. Psychiatry, 21 (1969) 7533760. Paykel. E.S., Methodological aspects of life events research, J. Psychosom. Res., 27 (1983) 341-352. Ryner. J.C., Estimation of plasma cortisol by radio competition or radio-immunoassay. Use of commercial kits, Ann. Radio]. Clin., 36 (1978) 509-514. Spitzer, R.L., Endicott, J. and Robins, E., Research diagnostic criteria: rationale and reliability, Arch. Gen. Psychiatry, 35 (1978) 7733782. Tennant, C.. Life events and psychological morbidity: the evidence from prospective studies, Psycho]. Med. (London), 13 (1983) 483-486. Targum, SD., Persistent neuroendocrine dysregulation in major depressive disorder: a marker for early relapse, Biol. Psychiatry, 19 (1984) 3055317.