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Plasma cortisol in depressive illness
I’s.schiaf. Hcs.
Vol. I,pp.162-171.
PLASMA
Pergamon
Press Ltd.
CORTISOL
Printed in tireat
Britain
1N DEPRESSIVE
ILLNESS
JAMES L. GIBBONS, M.B.,M.R.c.P., D.P.M.*and PAUL R. MCHUGH, M.D.? The Department of Psychiatry of the Institute of Psychiatry, Maudsley
Hospital,
London,
SE.5
1NTRODUCTION IN RECENT years the activity of the adrenal cortex has been intensively studied in human subjects undergoing emotional disturbance. Earlier investigations were concerned with the assessment of indirect indices such as eosinophil levels in the peripheral blood or with the measurement of urinary metabolites of adrenocortical hormones. More recent studies have been concerned with the plasma concentration of cortisol, as this appears to be a more direct index of adrenocortical activity. It has been shown in several centres that emotional turmoil or distress is accompanied by a raised plasma cortisol level. In groups of such sub,jects the mean value, assayed by the technique of NELSON and SAMUELS(~) has consistently been found to be about 18-2Opg compared with a normal mean value of 12-14pg/lOO ml. This is so when the emotional disturbance is a direct response to a distressing life situation, as in relatives accompanying casualties to hospitalc2) or in patients awaiting major surgery@), and also when it is part of a psychiatric illness such as acute schizophrenia@) or severe anxietyc4). The anxious patient in particular has been very thoroughly studied(“). Depressive illness is well suited for the study of adrenocortical activity in relation to emotional distress since it is a common illness and since most depressed patients recover or improve within a comparatively short time. Two papers from the Michael Reese hospital have dealt with plasma cortisol levels in depression (6~7). The authors found significantly higher mean values in depressed patients than in normal controls (19.5pg vs. 12.3 pg/ 100 ml). The more emotional distress the patient was undergoing, the higher was the cortisol level. Subsequent testing revealed that the levels generally fell, although a few patients who had received electroconvulsive therapy showed increasing levels after hospital admission. It was suggested that the latter patients, whose depression had been severe and prolonged, might have been suffering from adrenal exhaustion at the time of admission. None of the patients, however, was tested for longer than 2 weeks. It seemed to us that further information might be gained from repeated estimations of plasma cortisol for several weeks, until the patient had recovered or was at least ready for discharge.
*Senior Lecturer. iFormerly Clinical Assistant. Supported by a Special Fellowship of Neurological Diseases and Blindness, U.S. Public Health Service. 162
(BT-676) from the National
Institute
PLASMA
CASE
C~KTIWL
MATERIAL
IN ~PKESSIVE
AND
ILLNESS
METHODS
The investigation was conducted on seventeen patients, eleven male and six female. One patient was seen during two separate admissions (cases 6 and 18) so that there were eighteen periods of observation in all. The age range was 14-70. The patients were considered by their physicians to be suffering from moderate or severe depressive illnesses of a typical nature, and in each case it was believed that the illness was a primary affective disorder. The syptoms in every case included persistent depression of mood with at least feelings of unworthiness or self-blame and often frank delusions of guilt. Other universal features were impairment of concentration, lack of initiative, interest and energy, difficulty in sleeping and decrease in appetite. Alteration in motor activity was usual, either in the direction of retardation or agitation. While precipitating factors were evident in a minority of cases, the clinical features were those of so-called endogenous depression. No attempt was made to differentiate involutional melancholia from depression in general. Eight patients had had previous depressive illnesses. The diagnosis was later called into question in case 14, who was thought to be probably schizophrenic. One patient showed evidence of chronic, mild organic impairment (case 2) and another was considerably malnourished (case 13). Otherwise the patients were in reasonably good physical health. Case 3 was a 14-year-old cyclothymic girl who suffered from phases of retarded depression lasting about a fortnight followed by mild elation for three to four weeks. No patient was receiving antidepressive treatment when the investigation was begun, although several had taken antidepressive drugs without lasting benefit before admission. All except case 3 received small amounts of barbiturate hypnotics because of insomnia; the usual dose was 200400 mg of sodium amylobarbitone. Later treatment consisted of electroconvulsive treatment (ECT) in twelve cases and an antidepressive drug (Imipramine) in five (of whom two had ECT as well). The dosage of imipramine was 25 to 50 mg thrice daily. Three patients (3, 16 and 18) received no ‘specific’ antidepressive treatment. On two occasions a patient left hospital prematurely while still obviously depressed, despite some improvement (cases 2 and 18); the remaining sixteen were considered to be recovered or to be suffering from only mild residual symptoms at the time of discharge. Plasma cortisol was measured at weekly intervals until the patient was discharged. The first estimation was not carried out until at least a week after admission (except in cases 7 and 10 when early treatment was proposed) since the experience of admission to hospital may be an adrenocortical stimulus (8). 25 ml of venous blood were drawn between 9.0 and 9.30 a.m. on the same day of each week and collected in a heparinized bottle. The plasma was separated immediately by centrifuging and was then frozen and stored. Usually several samples from one patient were analyzed together. Cortisol was measured by the method of PETERSONet al.@), with the minor modifications introduced by HATFIELD and SHUSTER~~). Each estimation was performed on duplicate 5 ml aliquots of plasma and from the duplicate results the standard deviation, calculated by the method suggested by BRAUNSBERG and JAMES(~), was approximately lpg in the range 5-3Opg per 100 ml. After blood had been drawn one of us made an assessment of the patient’s state during a brief interview, basing his judgment on the patient’s appearance and behaviour and on his replies to questions about his mood and preoccupations. The same patient was always 163
JAMES L. GIBBONS TABLE
1.
WEEKLY
PLASMA
AND
PAUL
K. MCHUGII
CORTISOL LEVELS AND
CLINICAL RATINGS
Veeks CdSe 1
1 2 23.4 d 20.0 4 4
3 21.7 3
4 11.0 3
5 6.0 2
6 9.4 0
7 P.9 0
8
24.8 e 12.7 3 3
17.3 3
13.3 2
2
27.0 4
23.6 d 15.2 3 3
13.7 3
3
27.0 3
25.0 3
19.5 1
10.8 0
7.2 0
8.0 0
6.2 0
4
16.0 e 19.0 3 2
18.0 2
10.4 2
7.4 I
7.0 1
6.0 0
5
29.4 4
13.1 3
8.6 2
14.4 0
17.0 0
3.4 0
6
20.0 3
21.5 d 15.6 3 I
3.4 0
3.5 0
7
27.8 3
20.0 e 16.0 3 1
16.0 0
12.6 0
8
17.4 4
34.0 4
7.0 2
5.0 2
9
20.6 3
-
-
23.4 2
16.0 0
10
-
14.0 1
-
-
11
35.0 4
30.0 4
12
21.4 4
e 43.4 4
21.5 3
13
18.4 4
15.8 3
14
15
P
10
I1
-__
12
__-
_~
e 17.4 3
-
IO.0 0
___
-~
-
-e 15.2 3
10.0 1
4.0 0
-
9.0 0
9.5 0 -
e
~e 21.0 3 3
14.0 1
10.0 0
18.0 3
e 15.0 2
12.0 0
10.4 2
7.2 0
7.0 0
13.4 0
e 12.2 2
14.2 0
9.6 0
10.0 e 13.0 4 3
11.7 1
11.2 0
-
10.5 3
12.0 1
7.4 0
11.7 0
10.4 d 2
8.8 2
13.0 2
10.0
4.8 1
7.4 0
9.6 0
8.0 0
5.0 0
6.0 1
-
-
9.3 0
14.0 1
22.0 1
-
-
16.5 0
-
25.4 2
18.0 2
--35.0 d 24.3 4 4
15.2 0
6.6 0
11.0 0
-
11.5 0
--
___-
--
-
16
10.0 2
18.6 2
17
15.2 3
-
18
25.0 3
21.4 2
e 24.4 1
1
8.3 0
-12.0 2
In each row the upper figures represent plasma ratings of degree of depression from 0 to 4.
cortisol
164
in pg per 100 ml, the lower figures
are the clinical
PLASMA CORTISOL IN DEPRESSIVEILLNESS
assessed by the same observer. Depression was rated on a 5 point scale as follows: 0 - no evident depression, 1 -mild blueness, 2 - significant depression, not of itself incapacitating, 3 - depression severe enough to warrant admission to hospital, 4 - severe and deep depression. The presence or absence of moderate or marked agitation or retardation was also noted. The ratings were written down at the time of observation so that the clinical measurements were independent of the subsequent chemical findings. It must be stressed that this was an assessment of the patient’s clinical state at the time of venepuncture and not of his overall state during a particular week. Hence a rating of 0 means that the patient showed no evidence of depressed mood, but does not imply that he was necessarily free from all the symptoms that make up the clinical picture of depressive illness. RESULTS
Plasma cortisol levels and clinical ratings of depression are shown in Table 1. One week elapsed between each estimation. When no chemical data were available the omission is indicated by a dash. The week during which treatment was begun is indicated in the table by ‘e’ in the case of ECT, ‘d’ in the case of drug treatment. In case 1, for example, one estimation of plasma cortisol was made before drug treatment began, and in case 7 there were two estimations before ECT was begun. The mean of the first estimations was 20.8~g/lOO ml (SD.= 7*03), and of the last in each patient 10.8pg (S.D.= 3.74). The mean difference, lO.Opg, is highly significant: by the method of correlated means I = 6.105, p
Clinical rating 4 3 2
1 0
PLASMA CORTISOLLEVELSACCORDINGTO CLINICALRATINGS
No. of estimations
Mean and standard error 26.3 18.6 13.6 13.2 9.5
14 27 21 17 39
&2.36pg/lOO f 0.95 f 1.08 f 1.47 f 0.58
ml
All differences in mean plasma cortisol levels (except that between clinical ratings 2 and 1) are significant at the 1% level.
In order to illustrate the relationship between hormone levels and intensity of depression Table 2 shows the mean and standard deviation of all the cortisol levels for each depressive rating from 4 to 0. It will be seen that there is a definite tendency for the plasma cortisol to vary directly with the severity of the depression. When only the first estimations are considered, however, no difference in mean cortisol level is seen in the two most severely ill groups: the mean was 22.8~g/lOO ml for the eight patients with a depressive rating of 4, 21.6pg for the eight with a rating of 3, 10.2p.g for the two with a rating of 2. 165
JAMES L. GIBBONS AND PAUL R. TABLE
3.
CHANGES
MCHUGH
IN CORTISOL LEVELS AND
CLINICAL RATINGS
Clinical Unimproved 16 20
Increased
rating
Improved 8 9
Total 24 29
Cortisol
Unchanged
level
Decreased
I8
29
47
Total
54
46
too
X”
8.640
0.01
In Table 3 the relationship between change in mental state and change in hormone levels is examined. Each depressive rating except the first is compared with that of the previous week and the patient’s clinical state is classed as ‘improved’ if the rating is lower, ‘unimproved’ if it is unchanged or higher. Similarly the hormone level is compared with that of the week before and classed as showing an increase, a decrease, or no significant change. (A change of 3,rg or more was taken to be significant.) It is clear that there was no consistent relationship between the weekly changes in the two variables, but the most frequent association was between psychological improvement and a decline in plasma cortisol level. A chi-square test suggests that this association is not simply a random one. To express it in a different way, a decline in cortisol level occurred on twenty-nine of the forty-six occasions when improvement had occurred, but on only eighteen of the fifty-three occasions when there The difference between these fractions is statistically had been no clinical improvement. significant (p (0.01). Mean cortisol levels were calculated for the thirteen occasions when marked retardation was noted and for the eight when marked agitation was observed: these were 25. I and 24.3pg/lOO ml respectively. In each case the clinical rating of depression was either 4 or 3. Table 1 gives details of only one attack of depression in case 3. In fact she was tested during three depressed phases in 16 weeks and full details are set out in Table 4, where the symbol X is used to indicate the presence of mild elation or excitement.
TARLE
4.
FULL. DETAILS OF WEEKLY
~ORTISOL LEVELS AND
CLINICAI- KATINGS, Case
Week
1 27.0 3
2 25.0 3
3 19,s I
4 IO.8 0
5 7.2 X
6 8.0 X
I 6.2 X
8 19.0 3
Week
9 16.8 1
IO 6.0 0
II
12 X
I3 32.0 3
I4 21.5 2
I5 I I.3 0
I6 6.5 X
X
In each row the middle figure lower figure is the clinical rating with X indicating mild elation.
represents plasma cortisol in pg per 100 ml. The of severity of depression, on a scale from 0 to 4,
166
3
PLASMA CORTISOL IN DEPRESSIVEILLNESS
DISCUSSION
The mean values cited in Table 2 support the main finding of BOARD rt u/.(i), namely that depressed patients as a group have raised plasma cortisol levels, at least in the morning. Moreover, the levels fall to normal after adequate treatment. There is throughout a good correlation between hormone level and the intensity of the depression as judged clinically. The initial raised levels are unlikely to be due merely to admission to hospital or to the procedure of venepuncture and interview. All except two of the patients had been in hospital at least a week and all of them had had several interviews and at least one venepuncture since admission. That the decline in plasma cortisol level is at least in part the result of the improvement in mental state is suggested by the data of Table 3. It is hardly surprising that both increases and decreases in the cortisol level occurred in the presence of an unchanged mental state; no one would suggest that emotion is the sole determinant of Moreover our assessment referred only to the clinical state plasma cortisol concentration. at the time of interview, while the patient’s overall state throughout the day or previous days may have been more closely related to his hormone level. Group statistics, however, tell only part of the story, and it is instructive to look at the findings in each individual patient. Study of Table 1 shows that in thirteen instances
Case I
25 v -, E
20 ‘-
E ; y z 7 8 ; ,” a
: E w L 0” FIG. 1.
\
Y \ \
‘1 ‘o-’
A”\ \ \ \
IS-
IO-
\ \ ‘4
\
p--4 \
5-
oq_ 32,0
T
\
\
V
/
/
/
T
Weekly plasma cortisol levels and clinical ratings of depression decline in cortisol level accompanies clinical improvement.
in case 1. A fluctuating
(cases 1-13) there was a general decline in plasma cortisol, sometimes with considerable fluctuations, during the patient’s stay in hospital. Examples are displayed in Figs. 1 and 2. In case 2 the fluctuating decline was accompanied by only partial psychological improve167
JAMES L.
GIBBONS
AND
PAUL R. MCHUGH
ment; the patient was still mildly depressed when he discharged himself. In cases 8 and 12 there was an initial considerable increase, reminiscent of the increase reported by BOARD et CT/.(~)in their group of severe depressives who received ECT. These were the only two cases of our series in which this phenomenon occurred. Both were severely depressed, but the same was true of six other patients who had a rating of 4. The sharp increase followed ECT in only one patient, and in neither of them had any detectable clinical improvement occurred. No obvious explanation of this phenomenon comes to mind.
f
&TTT___ 0” O FIG. 2.
Weekly plasma cortisol levels and clinical ratings of depression in case 2. Again clinical improvement is accompanied by a gradual decline in plasma cortisol.
In five cases (14 to 18) a definite decline in hormone level did not occur, and they repay closer scrutiny. In three instances (cases 14, 15, 16: see Fig. 3) the levels were consistently rather low. Cases 15 and 16 had only mild depressive symptoms, never being given a high rating and this may account for it. Case 14, however, had symptoms of severe depression and also suffered a sharp relapse, all without any elevation of his plasma cortisol level. It was suggested (on purely clinical grounds and without knowledge of our findings) that he was probably suffering from schizophrenia with depressive features. This can hardly explain our findings, however, since BLISS et al.@) found elevated plasma cortisol levels in schizophrenic patients undergoing emotional turmoil. The same authors pointed out that not every emotional disturbance is associated with increased hormone levels, and they quote the case of one subject, judged to be experiencing extreme tension and anxiety, who had the low plasma level of 6pg/lOO ml. It would have been of interest to have measured the plasma ascorbic acid level in our patient if we had been aware at the time of the findings 168
PLASMA CORTEOL IN DEPRESSIVE ILLNESS
of GRGSZ(~~), which suggest that an adequate plasma concentration of ascorbic acid is necessary for an optimal adrenocortical response to a stressful stimulus. In two other patients (cases 17 and 18) hormone levels were consistently rather high. Case 18 was considered to be still rather depressed at the time of his discharge and from his account when he was readmitted it is probable that the severity of his depression was underestimated. In case 17 all depressive symptoms disappeared. The patient, however, had always been an anxious man and he was still anxious at the time of his discharge. It is possible that his persistent anxiety accounted for the absence of a definite decline in plasma cortisol. i nie I5
FIG. 3.
Weekly plasma cortisol levels and clinical ratings of depression in case 15. Depression was never severe and the plasma cortisol remained essentially unchanged throughout.
None of our patients showed an overall cortisol decline without noticeable improvement. The one patient who remained severely depressed for several weeks (case 11, Fig. 2) had rather variable but persistently high hormone levels during this time. It might be argued that some affective change other than depression-perhaps anxiety or anger-was primarily responsible for the raised levels in our patients. In fact, however, five of the patients with a clinical rating of 4 (cases I, 2, 5, 8, 12) were retarded depressives without any evidence of anxiety or irritability and a glance at Table 1 shows that their pretreatment levels were no lower than those of the other patients. The mean initial level in this group was 23.7r/-g/100 ml. The best evidence for a direct relationship between mood and cortisol level is afforded by our cyclothymic patient, case 3. Table 4 shows how each phase of depression was accompanied by high hormone levels, which approached the normal mean when she became well. Her phases of mild elation, in which she was definitely overactive, were accompanied by quite low levels. It may be remarked here that there are scarcely any data in the literature on plasma cortisol levels in untreated manic patients. There is a single report of high values in a patient seen by BLISS et LA.(~) and we ourselves found a normal 169
JAMES L.
GIBBONS
AND
PACJL R. MCHUGH
morning level of 12.5pg/lOO ml in a hypomanic man. Most manic patients are now very promptly treated with large doses of phenothiazine drugs, which themselves may influence adrenocortical activity. A possible persistent effect of ECT was looked for by comparing the first hormone level after the beginning of treatment with the immediately preceding one: a significant rise had occurred in four cases, a fall in six, and no change in one. This argues against any consistent effect of ECT and supports the view expressed by BOARD et a/.(‘) ECT does, of course, produce a transient immediate rise in plasma cortisol, the level returning to normal within a few hoursua). We have not found any evidence in the available literature of a direct effect of imipramine on plasma cortisol. When the five patients who received the drug are considered, it is seen that in two cases (1, 15) there was no obvious change in cortisol levels during the next two weeks. In two other cases (2, 11) there was a sharp fall in plasma cortisol, with a subsequent rise to the previous level after a further one or two weeks: the In the fifth patient (case 6) falling cortisol levels clinical ratings remained unchanged. accompanied clinical improvement. It is possible, then, that imipramine may sometimes induce a transient fall in plasma cortisol without affecting mood. lnvestigation of a much larger number of patients will be required to clarify this point. It has been demonstrated that cortisol ordinarily accounts for ninety to ninety-five per cent of the Porter-Silber chromogen measured by the technique used in this investigationcg). It is just conceivable that some other steroid, or even some other substance might be responsible for the raised levels found in the present investigation. Hence it will be desirable to demonstrate by a more specific method that a rise in true plasma cortisol occurs. Granted that this is so, it has also to be shown that the raised level is due to an increased output of hormone by the adrenal cortex. This has been shown to be the case in the anxious subject (full list of references in PERSKYet al.(“)) and preliminary studies with an isotope dilution method derived from that described by Cope and Black suggest that it is true of the depressed patient also. The limitations involved in the selection of a single point in time in the diurnal cycle of plasma cortisol levels should be borne in mind. Not all individuals have their morning peak level at the same time, and one depressed subject may have a lower 9 a.m. level than another merely because his peak level is attained an hour or two earlier than the other subject’s peak. It is also possible that the timing of the peak may alter in an individual subject. A change of this sort would not account for the initial high levels of our patients, but the later declining levels might be a manifestation of an ever earlier morning peak. This seems an unlikely explanation, and it is not supported by our preliminary results with the isotope dilution method already referred to: the increased cortisol output of the depressed patient appears not to be sustained after recovery. The timing of the morning peak and indeed the whole diurnal cycle in depression remains, however, a topic that is worth investigating carefully. It must be confessed that it is not yet certain that the depressed patient derives any benefit Lts biological importance depends in part from his raised plasma cortisol concentration. on whether it is maintained. It has been shown that the raised levels in Cushing’s syndrome persist throughout the twenty-four hours( 16) whereas in the anxious subjects studied by MASON@) morning plasma cortisol levels were high but night levels were normal. Even 170
PLASMA C~HTISOL IN DEPRESSIVE ILLNESS
more significant is the extent to which the additional hormone is free or protein-bound, since it is probable that only the free steroid is biologically active(lfi). This also is a subject worthy of further investigation. SUMMARY
Plasma cortisol was measured at weekly intervals in seventeen depressed patients during eighteen periods of stay in hospital. Elevated levels were found before treatment, and in general the more severe the depression, the higher the cortisol level. In thirteen cases the process of recovery was accompanied by a decline in cortisol levels. The five cases that failed to conform to this pattern are discussed. Details are presented of a cyclothymic patient during three successive cycles of depression and mild elation. Suggestions are made for further work to assess the degree of adrenocortical activity in depression and to determine its biological importance. Acknowledgements the research fund of Maudsley Hospital Laboratories for the
- The investigation was supported by grants from the Ford Foundation and from the Bethlem Royal and Maudsley Hospitals. We wish to thank the physicians of the who allowed us to investigate patients under their care. We are indebted to Glaxo generous gift of a quantity of pure cortisol and to Dr. R. CAWLEY for statistical advice.
REFERENCES
5. 6. 7. 8. 9. 10. 11. 12. 13.
14. 15. 16.
NELSON, D. H. and SAMUELS, L. T. A method for the determination of 17-hydroxycorticosteroids in blood: 17-hydroxycorticosterone in the peripheral circulation. J. clin. Endocrin., 12, 519, 1952. BLISS, E. L., MIGEON, C. J., BRANCH, C. H. H. and SAMUELS, L. T. Reaction of the adrenal cortex to emotional stress. Psychosom. Med., 18, 56, 1956. PRICE, D. B., THALER, M. and MASON, J. W. Preoperative emotional states and adrenal cortical activity. Arch. Neural. Psychiat., Chicago, 77, 646, 1957. PERSKY. H.. GRINKER. R. R.. HAMBURG. D. A.. SABSHIN. M. A.. KORCHIN, S. J.. BASOWITZ, H. and CHEVALIER, J. A. Adrenal cortical function in anxious human subjects. Arch. Neural. Psychiut., Chicago, 76, 549, 1956. PERSKY, H., MAROC, J., CONRAD, E. and DEN BREEIJEN, A. Blood corticotropin and adrenal weightmaintenance factor levels of anxious patients and normal subjects. Psychosom. Med., 21, 379, 1959. BOARD, F., PERSKY, H. and HAMBURG, D. A. Psychological stress and endocrine functions. Psychosom. Med., 18, 324, 1956. BOARD, F., WADESON, R. and PERSKY, H. Depressive affect and endocrine functions. Arch. Neural. Psychiat., Chicago, 78, 612, 1957. MASON, J. W. Psychological influences on the pituitary-adrenal cortical system. Recent Progr. Horr~~onc Res., 15, 345, 1959. PETERSON, R. E., KARRER, A. and GUERRA, S. L. Evaluation of Silber-Porter procedure for determination of plasma hydrocortisone. Analyt. Chem., 29, 144, 1957. HATFIELD, C. B. and SHUSTER, S. The inhibitory effect of triamcinolone on adrenal function. J. clin. Path., 12, 140, 1959. BRAUNSBERG, H. and JAMES, V. H. T. The determination of cortisol and corticosterone in blood: a review. J. c/in. Endocrin., 21, I 146, 1961. GROSZ, H. J. The relation of serum ascorbic acid level to adrenocortical secretion during experimentally induced emotional stress in human subjects. J. psychosom. Res., 5, 253, 1961. BLISS, E. L., MIGEON, C. J., NELSON, D. H., SAMUELS, L. T. and BRANCH, C. H. H. Influence of ECT and insulin coma on level of adrenocortical steroids in peripheral circulation. Arch. Neural. Psychiat. Chicago, 72, 352, 1954. COPE, C. L. and BLACK, E. The production rate of cortisol in man. Brit. med. J., 1, 1020, 1958. EKMAN, H., HAKANSSON, B., MCCARTHY, J. D., LEHMANN, J. and SJ~~GREN, B. Plasma 17hydroxycorticosteroids in Cushing’s syndome. J. clin. Endocrin., 21, 684, 1961. MILLS, I. H. The transport state of steroid hormones. Mem. Sot. Endocrin., 11, 81, 1961. 171
Vol. I,pp.162-171.
PLASMA
Pergamon
Press Ltd.
CORTISOL
Printed in tireat
Britain
1N DEPRESSIVE
ILLNESS
JAMES L. GIBBONS, M.B.,M.R.c.P., D.P.M.*and PAUL R. MCHUGH, M.D.? The Department of Psychiatry of the Institute of Psychiatry, Maudsley
Hospital,
London,
SE.5
1NTRODUCTION IN RECENT years the activity of the adrenal cortex has been intensively studied in human subjects undergoing emotional disturbance. Earlier investigations were concerned with the assessment of indirect indices such as eosinophil levels in the peripheral blood or with the measurement of urinary metabolites of adrenocortical hormones. More recent studies have been concerned with the plasma concentration of cortisol, as this appears to be a more direct index of adrenocortical activity. It has been shown in several centres that emotional turmoil or distress is accompanied by a raised plasma cortisol level. In groups of such sub,jects the mean value, assayed by the technique of NELSON and SAMUELS(~) has consistently been found to be about 18-2Opg compared with a normal mean value of 12-14pg/lOO ml. This is so when the emotional disturbance is a direct response to a distressing life situation, as in relatives accompanying casualties to hospitalc2) or in patients awaiting major surgery@), and also when it is part of a psychiatric illness such as acute schizophrenia@) or severe anxietyc4). The anxious patient in particular has been very thoroughly studied(“). Depressive illness is well suited for the study of adrenocortical activity in relation to emotional distress since it is a common illness and since most depressed patients recover or improve within a comparatively short time. Two papers from the Michael Reese hospital have dealt with plasma cortisol levels in depression (6~7). The authors found significantly higher mean values in depressed patients than in normal controls (19.5pg vs. 12.3 pg/ 100 ml). The more emotional distress the patient was undergoing, the higher was the cortisol level. Subsequent testing revealed that the levels generally fell, although a few patients who had received electroconvulsive therapy showed increasing levels after hospital admission. It was suggested that the latter patients, whose depression had been severe and prolonged, might have been suffering from adrenal exhaustion at the time of admission. None of the patients, however, was tested for longer than 2 weeks. It seemed to us that further information might be gained from repeated estimations of plasma cortisol for several weeks, until the patient had recovered or was at least ready for discharge.
*Senior Lecturer. iFormerly Clinical Assistant. Supported by a Special Fellowship of Neurological Diseases and Blindness, U.S. Public Health Service. 162
(BT-676) from the National
Institute
PLASMA
CASE
C~KTIWL
MATERIAL
IN ~PKESSIVE
AND
ILLNESS
METHODS
The investigation was conducted on seventeen patients, eleven male and six female. One patient was seen during two separate admissions (cases 6 and 18) so that there were eighteen periods of observation in all. The age range was 14-70. The patients were considered by their physicians to be suffering from moderate or severe depressive illnesses of a typical nature, and in each case it was believed that the illness was a primary affective disorder. The syptoms in every case included persistent depression of mood with at least feelings of unworthiness or self-blame and often frank delusions of guilt. Other universal features were impairment of concentration, lack of initiative, interest and energy, difficulty in sleeping and decrease in appetite. Alteration in motor activity was usual, either in the direction of retardation or agitation. While precipitating factors were evident in a minority of cases, the clinical features were those of so-called endogenous depression. No attempt was made to differentiate involutional melancholia from depression in general. Eight patients had had previous depressive illnesses. The diagnosis was later called into question in case 14, who was thought to be probably schizophrenic. One patient showed evidence of chronic, mild organic impairment (case 2) and another was considerably malnourished (case 13). Otherwise the patients were in reasonably good physical health. Case 3 was a 14-year-old cyclothymic girl who suffered from phases of retarded depression lasting about a fortnight followed by mild elation for three to four weeks. No patient was receiving antidepressive treatment when the investigation was begun, although several had taken antidepressive drugs without lasting benefit before admission. All except case 3 received small amounts of barbiturate hypnotics because of insomnia; the usual dose was 200400 mg of sodium amylobarbitone. Later treatment consisted of electroconvulsive treatment (ECT) in twelve cases and an antidepressive drug (Imipramine) in five (of whom two had ECT as well). The dosage of imipramine was 25 to 50 mg thrice daily. Three patients (3, 16 and 18) received no ‘specific’ antidepressive treatment. On two occasions a patient left hospital prematurely while still obviously depressed, despite some improvement (cases 2 and 18); the remaining sixteen were considered to be recovered or to be suffering from only mild residual symptoms at the time of discharge. Plasma cortisol was measured at weekly intervals until the patient was discharged. The first estimation was not carried out until at least a week after admission (except in cases 7 and 10 when early treatment was proposed) since the experience of admission to hospital may be an adrenocortical stimulus (8). 25 ml of venous blood were drawn between 9.0 and 9.30 a.m. on the same day of each week and collected in a heparinized bottle. The plasma was separated immediately by centrifuging and was then frozen and stored. Usually several samples from one patient were analyzed together. Cortisol was measured by the method of PETERSONet al.@), with the minor modifications introduced by HATFIELD and SHUSTER~~). Each estimation was performed on duplicate 5 ml aliquots of plasma and from the duplicate results the standard deviation, calculated by the method suggested by BRAUNSBERG and JAMES(~), was approximately lpg in the range 5-3Opg per 100 ml. After blood had been drawn one of us made an assessment of the patient’s state during a brief interview, basing his judgment on the patient’s appearance and behaviour and on his replies to questions about his mood and preoccupations. The same patient was always 163
JAMES L. GIBBONS TABLE
1.
WEEKLY
PLASMA
AND
PAUL
K. MCHUGII
CORTISOL LEVELS AND
CLINICAL RATINGS
Veeks CdSe 1
1 2 23.4 d 20.0 4 4
3 21.7 3
4 11.0 3
5 6.0 2
6 9.4 0
7 P.9 0
8
24.8 e 12.7 3 3
17.3 3
13.3 2
2
27.0 4
23.6 d 15.2 3 3
13.7 3
3
27.0 3
25.0 3
19.5 1
10.8 0
7.2 0
8.0 0
6.2 0
4
16.0 e 19.0 3 2
18.0 2
10.4 2
7.4 I
7.0 1
6.0 0
5
29.4 4
13.1 3
8.6 2
14.4 0
17.0 0
3.4 0
6
20.0 3
21.5 d 15.6 3 I
3.4 0
3.5 0
7
27.8 3
20.0 e 16.0 3 1
16.0 0
12.6 0
8
17.4 4
34.0 4
7.0 2
5.0 2
9
20.6 3
-
-
23.4 2
16.0 0
10
-
14.0 1
-
-
11
35.0 4
30.0 4
12
21.4 4
e 43.4 4
21.5 3
13
18.4 4
15.8 3
14
15
P
10
I1
-__
12
__-
_~
e 17.4 3
-
IO.0 0
___
-~
-
-e 15.2 3
10.0 1
4.0 0
-
9.0 0
9.5 0 -
e
~e 21.0 3 3
14.0 1
10.0 0
18.0 3
e 15.0 2
12.0 0
10.4 2
7.2 0
7.0 0
13.4 0
e 12.2 2
14.2 0
9.6 0
10.0 e 13.0 4 3
11.7 1
11.2 0
-
10.5 3
12.0 1
7.4 0
11.7 0
10.4 d 2
8.8 2
13.0 2
10.0
4.8 1
7.4 0
9.6 0
8.0 0
5.0 0
6.0 1
-
-
9.3 0
14.0 1
22.0 1
-
-
16.5 0
-
25.4 2
18.0 2
--35.0 d 24.3 4 4
15.2 0
6.6 0
11.0 0
-
11.5 0
--
___-
--
-
16
10.0 2
18.6 2
17
15.2 3
-
18
25.0 3
21.4 2
e 24.4 1
1
8.3 0
-12.0 2
In each row the upper figures represent plasma ratings of degree of depression from 0 to 4.
cortisol
164
in pg per 100 ml, the lower figures
are the clinical
PLASMA CORTISOL IN DEPRESSIVEILLNESS
assessed by the same observer. Depression was rated on a 5 point scale as follows: 0 - no evident depression, 1 -mild blueness, 2 - significant depression, not of itself incapacitating, 3 - depression severe enough to warrant admission to hospital, 4 - severe and deep depression. The presence or absence of moderate or marked agitation or retardation was also noted. The ratings were written down at the time of observation so that the clinical measurements were independent of the subsequent chemical findings. It must be stressed that this was an assessment of the patient’s clinical state at the time of venepuncture and not of his overall state during a particular week. Hence a rating of 0 means that the patient showed no evidence of depressed mood, but does not imply that he was necessarily free from all the symptoms that make up the clinical picture of depressive illness. RESULTS
Plasma cortisol levels and clinical ratings of depression are shown in Table 1. One week elapsed between each estimation. When no chemical data were available the omission is indicated by a dash. The week during which treatment was begun is indicated in the table by ‘e’ in the case of ECT, ‘d’ in the case of drug treatment. In case 1, for example, one estimation of plasma cortisol was made before drug treatment began, and in case 7 there were two estimations before ECT was begun. The mean of the first estimations was 20.8~g/lOO ml (SD.= 7*03), and of the last in each patient 10.8pg (S.D.= 3.74). The mean difference, lO.Opg, is highly significant: by the method of correlated means I = 6.105, p
Clinical rating 4 3 2
1 0
PLASMA CORTISOLLEVELSACCORDINGTO CLINICALRATINGS
No. of estimations
Mean and standard error 26.3 18.6 13.6 13.2 9.5
14 27 21 17 39
&2.36pg/lOO f 0.95 f 1.08 f 1.47 f 0.58
ml
All differences in mean plasma cortisol levels (except that between clinical ratings 2 and 1) are significant at the 1% level.
In order to illustrate the relationship between hormone levels and intensity of depression Table 2 shows the mean and standard deviation of all the cortisol levels for each depressive rating from 4 to 0. It will be seen that there is a definite tendency for the plasma cortisol to vary directly with the severity of the depression. When only the first estimations are considered, however, no difference in mean cortisol level is seen in the two most severely ill groups: the mean was 22.8~g/lOO ml for the eight patients with a depressive rating of 4, 21.6pg for the eight with a rating of 3, 10.2p.g for the two with a rating of 2. 165
JAMES L. GIBBONS AND PAUL R. TABLE
3.
CHANGES
MCHUGH
IN CORTISOL LEVELS AND
CLINICAL RATINGS
Clinical Unimproved 16 20
Increased
rating
Improved 8 9
Total 24 29
Cortisol
Unchanged
level
Decreased
I8
29
47
Total
54
46
too
X”
8.640
0.01
In Table 3 the relationship between change in mental state and change in hormone levels is examined. Each depressive rating except the first is compared with that of the previous week and the patient’s clinical state is classed as ‘improved’ if the rating is lower, ‘unimproved’ if it is unchanged or higher. Similarly the hormone level is compared with that of the week before and classed as showing an increase, a decrease, or no significant change. (A change of 3,rg or more was taken to be significant.) It is clear that there was no consistent relationship between the weekly changes in the two variables, but the most frequent association was between psychological improvement and a decline in plasma cortisol level. A chi-square test suggests that this association is not simply a random one. To express it in a different way, a decline in cortisol level occurred on twenty-nine of the forty-six occasions when improvement had occurred, but on only eighteen of the fifty-three occasions when there The difference between these fractions is statistically had been no clinical improvement. significant (p (0.01). Mean cortisol levels were calculated for the thirteen occasions when marked retardation was noted and for the eight when marked agitation was observed: these were 25. I and 24.3pg/lOO ml respectively. In each case the clinical rating of depression was either 4 or 3. Table 1 gives details of only one attack of depression in case 3. In fact she was tested during three depressed phases in 16 weeks and full details are set out in Table 4, where the symbol X is used to indicate the presence of mild elation or excitement.
TARLE
4.
FULL. DETAILS OF WEEKLY
~ORTISOL LEVELS AND
CLINICAI- KATINGS, Case
Week
1 27.0 3
2 25.0 3
3 19,s I
4 IO.8 0
5 7.2 X
6 8.0 X
I 6.2 X
8 19.0 3
Week
9 16.8 1
IO 6.0 0
II
12 X
I3 32.0 3
I4 21.5 2
I5 I I.3 0
I6 6.5 X
X
In each row the middle figure lower figure is the clinical rating with X indicating mild elation.
represents plasma cortisol in pg per 100 ml. The of severity of depression, on a scale from 0 to 4,
166
3
PLASMA CORTISOL IN DEPRESSIVEILLNESS
DISCUSSION
The mean values cited in Table 2 support the main finding of BOARD rt u/.(i), namely that depressed patients as a group have raised plasma cortisol levels, at least in the morning. Moreover, the levels fall to normal after adequate treatment. There is throughout a good correlation between hormone level and the intensity of the depression as judged clinically. The initial raised levels are unlikely to be due merely to admission to hospital or to the procedure of venepuncture and interview. All except two of the patients had been in hospital at least a week and all of them had had several interviews and at least one venepuncture since admission. That the decline in plasma cortisol level is at least in part the result of the improvement in mental state is suggested by the data of Table 3. It is hardly surprising that both increases and decreases in the cortisol level occurred in the presence of an unchanged mental state; no one would suggest that emotion is the sole determinant of Moreover our assessment referred only to the clinical state plasma cortisol concentration. at the time of interview, while the patient’s overall state throughout the day or previous days may have been more closely related to his hormone level. Group statistics, however, tell only part of the story, and it is instructive to look at the findings in each individual patient. Study of Table 1 shows that in thirteen instances
Case I
25 v -, E
20 ‘-
E ; y z 7 8 ; ,” a
: E w L 0” FIG. 1.
\
Y \ \
‘1 ‘o-’
A”\ \ \ \
IS-
IO-
\ \ ‘4
\
p--4 \
5-
oq_ 32,0
T
\
\
V
/
/
/
T
Weekly plasma cortisol levels and clinical ratings of depression decline in cortisol level accompanies clinical improvement.
in case 1. A fluctuating
(cases 1-13) there was a general decline in plasma cortisol, sometimes with considerable fluctuations, during the patient’s stay in hospital. Examples are displayed in Figs. 1 and 2. In case 2 the fluctuating decline was accompanied by only partial psychological improve167
JAMES L.
GIBBONS
AND
PAUL R. MCHUGH
ment; the patient was still mildly depressed when he discharged himself. In cases 8 and 12 there was an initial considerable increase, reminiscent of the increase reported by BOARD et CT/.(~)in their group of severe depressives who received ECT. These were the only two cases of our series in which this phenomenon occurred. Both were severely depressed, but the same was true of six other patients who had a rating of 4. The sharp increase followed ECT in only one patient, and in neither of them had any detectable clinical improvement occurred. No obvious explanation of this phenomenon comes to mind.
f
&TTT___ 0” O FIG. 2.
Weekly plasma cortisol levels and clinical ratings of depression in case 2. Again clinical improvement is accompanied by a gradual decline in plasma cortisol.
In five cases (14 to 18) a definite decline in hormone level did not occur, and they repay closer scrutiny. In three instances (cases 14, 15, 16: see Fig. 3) the levels were consistently rather low. Cases 15 and 16 had only mild depressive symptoms, never being given a high rating and this may account for it. Case 14, however, had symptoms of severe depression and also suffered a sharp relapse, all without any elevation of his plasma cortisol level. It was suggested (on purely clinical grounds and without knowledge of our findings) that he was probably suffering from schizophrenia with depressive features. This can hardly explain our findings, however, since BLISS et al.@) found elevated plasma cortisol levels in schizophrenic patients undergoing emotional turmoil. The same authors pointed out that not every emotional disturbance is associated with increased hormone levels, and they quote the case of one subject, judged to be experiencing extreme tension and anxiety, who had the low plasma level of 6pg/lOO ml. It would have been of interest to have measured the plasma ascorbic acid level in our patient if we had been aware at the time of the findings 168
PLASMA CORTEOL IN DEPRESSIVE ILLNESS
of GRGSZ(~~), which suggest that an adequate plasma concentration of ascorbic acid is necessary for an optimal adrenocortical response to a stressful stimulus. In two other patients (cases 17 and 18) hormone levels were consistently rather high. Case 18 was considered to be still rather depressed at the time of his discharge and from his account when he was readmitted it is probable that the severity of his depression was underestimated. In case 17 all depressive symptoms disappeared. The patient, however, had always been an anxious man and he was still anxious at the time of his discharge. It is possible that his persistent anxiety accounted for the absence of a definite decline in plasma cortisol. i nie I5
FIG. 3.
Weekly plasma cortisol levels and clinical ratings of depression in case 15. Depression was never severe and the plasma cortisol remained essentially unchanged throughout.
None of our patients showed an overall cortisol decline without noticeable improvement. The one patient who remained severely depressed for several weeks (case 11, Fig. 2) had rather variable but persistently high hormone levels during this time. It might be argued that some affective change other than depression-perhaps anxiety or anger-was primarily responsible for the raised levels in our patients. In fact, however, five of the patients with a clinical rating of 4 (cases I, 2, 5, 8, 12) were retarded depressives without any evidence of anxiety or irritability and a glance at Table 1 shows that their pretreatment levels were no lower than those of the other patients. The mean initial level in this group was 23.7r/-g/100 ml. The best evidence for a direct relationship between mood and cortisol level is afforded by our cyclothymic patient, case 3. Table 4 shows how each phase of depression was accompanied by high hormone levels, which approached the normal mean when she became well. Her phases of mild elation, in which she was definitely overactive, were accompanied by quite low levels. It may be remarked here that there are scarcely any data in the literature on plasma cortisol levels in untreated manic patients. There is a single report of high values in a patient seen by BLISS et LA.(~) and we ourselves found a normal 169
JAMES L.
GIBBONS
AND
PACJL R. MCHUGH
morning level of 12.5pg/lOO ml in a hypomanic man. Most manic patients are now very promptly treated with large doses of phenothiazine drugs, which themselves may influence adrenocortical activity. A possible persistent effect of ECT was looked for by comparing the first hormone level after the beginning of treatment with the immediately preceding one: a significant rise had occurred in four cases, a fall in six, and no change in one. This argues against any consistent effect of ECT and supports the view expressed by BOARD et a/.(‘) ECT does, of course, produce a transient immediate rise in plasma cortisol, the level returning to normal within a few hoursua). We have not found any evidence in the available literature of a direct effect of imipramine on plasma cortisol. When the five patients who received the drug are considered, it is seen that in two cases (1, 15) there was no obvious change in cortisol levels during the next two weeks. In two other cases (2, 11) there was a sharp fall in plasma cortisol, with a subsequent rise to the previous level after a further one or two weeks: the In the fifth patient (case 6) falling cortisol levels clinical ratings remained unchanged. accompanied clinical improvement. It is possible, then, that imipramine may sometimes induce a transient fall in plasma cortisol without affecting mood. lnvestigation of a much larger number of patients will be required to clarify this point. It has been demonstrated that cortisol ordinarily accounts for ninety to ninety-five per cent of the Porter-Silber chromogen measured by the technique used in this investigationcg). It is just conceivable that some other steroid, or even some other substance might be responsible for the raised levels found in the present investigation. Hence it will be desirable to demonstrate by a more specific method that a rise in true plasma cortisol occurs. Granted that this is so, it has also to be shown that the raised level is due to an increased output of hormone by the adrenal cortex. This has been shown to be the case in the anxious subject (full list of references in PERSKYet al.(“)) and preliminary studies with an isotope dilution method derived from that described by Cope and Black suggest that it is true of the depressed patient also. The limitations involved in the selection of a single point in time in the diurnal cycle of plasma cortisol levels should be borne in mind. Not all individuals have their morning peak level at the same time, and one depressed subject may have a lower 9 a.m. level than another merely because his peak level is attained an hour or two earlier than the other subject’s peak. It is also possible that the timing of the peak may alter in an individual subject. A change of this sort would not account for the initial high levels of our patients, but the later declining levels might be a manifestation of an ever earlier morning peak. This seems an unlikely explanation, and it is not supported by our preliminary results with the isotope dilution method already referred to: the increased cortisol output of the depressed patient appears not to be sustained after recovery. The timing of the morning peak and indeed the whole diurnal cycle in depression remains, however, a topic that is worth investigating carefully. It must be confessed that it is not yet certain that the depressed patient derives any benefit Lts biological importance depends in part from his raised plasma cortisol concentration. on whether it is maintained. It has been shown that the raised levels in Cushing’s syndrome persist throughout the twenty-four hours( 16) whereas in the anxious subjects studied by MASON@) morning plasma cortisol levels were high but night levels were normal. Even 170
PLASMA C~HTISOL IN DEPRESSIVE ILLNESS
more significant is the extent to which the additional hormone is free or protein-bound, since it is probable that only the free steroid is biologically active(lfi). This also is a subject worthy of further investigation. SUMMARY
Plasma cortisol was measured at weekly intervals in seventeen depressed patients during eighteen periods of stay in hospital. Elevated levels were found before treatment, and in general the more severe the depression, the higher the cortisol level. In thirteen cases the process of recovery was accompanied by a decline in cortisol levels. The five cases that failed to conform to this pattern are discussed. Details are presented of a cyclothymic patient during three successive cycles of depression and mild elation. Suggestions are made for further work to assess the degree of adrenocortical activity in depression and to determine its biological importance. Acknowledgements the research fund of Maudsley Hospital Laboratories for the
- The investigation was supported by grants from the Ford Foundation and from the Bethlem Royal and Maudsley Hospitals. We wish to thank the physicians of the who allowed us to investigate patients under their care. We are indebted to Glaxo generous gift of a quantity of pure cortisol and to Dr. R. CAWLEY for statistical advice.
REFERENCES
5. 6. 7. 8. 9. 10. 11. 12. 13.
14. 15. 16.
NELSON, D. H. and SAMUELS, L. T. A method for the determination of 17-hydroxycorticosteroids in blood: 17-hydroxycorticosterone in the peripheral circulation. J. clin. Endocrin., 12, 519, 1952. BLISS, E. L., MIGEON, C. J., BRANCH, C. H. H. and SAMUELS, L. T. Reaction of the adrenal cortex to emotional stress. Psychosom. Med., 18, 56, 1956. PRICE, D. B., THALER, M. and MASON, J. W. Preoperative emotional states and adrenal cortical activity. Arch. Neural. Psychiat., Chicago, 77, 646, 1957. PERSKY. H.. GRINKER. R. R.. HAMBURG. D. A.. SABSHIN. M. A.. KORCHIN, S. J.. BASOWITZ, H. and CHEVALIER, J. A. Adrenal cortical function in anxious human subjects. Arch. Neural. Psychiut., Chicago, 76, 549, 1956. PERSKY, H., MAROC, J., CONRAD, E. and DEN BREEIJEN, A. Blood corticotropin and adrenal weightmaintenance factor levels of anxious patients and normal subjects. Psychosom. Med., 21, 379, 1959. BOARD, F., PERSKY, H. and HAMBURG, D. A. Psychological stress and endocrine functions. Psychosom. Med., 18, 324, 1956. BOARD, F., WADESON, R. and PERSKY, H. Depressive affect and endocrine functions. Arch. Neural. Psychiat., Chicago, 78, 612, 1957. MASON, J. W. Psychological influences on the pituitary-adrenal cortical system. Recent Progr. Horr~~onc Res., 15, 345, 1959. PETERSON, R. E., KARRER, A. and GUERRA, S. L. Evaluation of Silber-Porter procedure for determination of plasma hydrocortisone. Analyt. Chem., 29, 144, 1957. HATFIELD, C. B. and SHUSTER, S. The inhibitory effect of triamcinolone on adrenal function. J. clin. Path., 12, 140, 1959. BRAUNSBERG, H. and JAMES, V. H. T. The determination of cortisol and corticosterone in blood: a review. J. c/in. Endocrin., 21, I 146, 1961. GROSZ, H. J. The relation of serum ascorbic acid level to adrenocortical secretion during experimentally induced emotional stress in human subjects. J. psychosom. Res., 5, 253, 1961. BLISS, E. L., MIGEON, C. J., NELSON, D. H., SAMUELS, L. T. and BRANCH, C. H. H. Influence of ECT and insulin coma on level of adrenocortical steroids in peripheral circulation. Arch. Neural. Psychiat. Chicago, 72, 352, 1954. COPE, C. L. and BLACK, E. The production rate of cortisol in man. Brit. med. J., 1, 1020, 1958. EKMAN, H., HAKANSSON, B., MCCARTHY, J. D., LEHMANN, J. and SJ~~GREN, B. Plasma 17hydroxycorticosteroids in Cushing’s syndome. J. clin. Endocrin., 21, 684, 1961. MILLS, I. H. The transport state of steroid hormones. Mem. Sot. Endocrin., 11, 81, 1961. 171