Limbic System-Adrenal Cortex Regulation in Depression and Schizophrenia BERNARD J. CARROLL, MB, DPM, PHD

Hypothalamo-pituitary-adrenal (HPA) activation and abnormal HPA regulatory mechanisms have been observed in depressed patients. Depressed and schizophrenic patients were studied to determine whether the HPA disturbances in depression are specific to this psychiatric illness or are mediated by nonspecific breakdown of psychological defense mechanisms. Despite the presence of severe ego defense breakdown and considerable secondary depressive symptomatology , the schizophrenic patients had normal HPA function. The depressed patients had elevated urine free cortisol excretion, high CSF cortisol levels, and did not show normal HPA suppression in response to dexamethasone. Within the depressed group significant correlations of HPA parameters were obtained with somatic features but not with ego breakdown features. After recovery depressed patients had more normal HPA function. The results indicate that HPA dysfunction can occur in association with primary depressive illness, that a psychoendocrine distinction can be made between primary depressive illness and secondary depressive symptomatology, and that psychological defense breakdown is not related to these neuroendocrine observations. Attention is drawn to the utility of urinary free cortisol measurement as a valuable index of HPA activation in psychoendocrine studies.

INTRODUCTION

termined primarily by psychological factors. Laboratory evidence of moderately inMason suggested in his review of this creased adrenal cortical activity is com- area (10) that the adrenal cortical activamonly found in patients with psychiatric tion is not related to a specific affective illnesses. Elevated values for plasma state, but reflects an undifferentiated state cortisol levels, urinary 17-hydroxy- of emotional arousal or involvement; that corticosteroid (17-OHCS) excretion, the type and effectiveness of psychological urinary free cortisol excretion, or cortisol defenses against anxiety are important varsecretion rate have been reported in anxi- iables; and that the factors operating in ety states (1,2), depression (3-7), and psychopathological states, where emoschizophrenia (8,9). Such findings have tional disorganization and behavioral usually been thought to reflect activation of breakdown occur, are essentially the same the brain-pituitary-adrenal cortex axis, de- factors as operate in normal persons under stress. Clinical studies appear to support Mason's conclusions in normal subjects •(11,12), depressed patients (13,14), and schizophrenic patients (8,15). In a recent From the Department of Psychiatry, University of study of depressed patients by Sachar and Michigan, Ann Arbor, Michigan 48104. Presented at the Annual Meeting, American his colleagues (6) changes in cortisol proPsychosomatic Society, Denver, Colorado, April 8, duction rate were reported to correlate 1973. closely with changes in rated items indiReceived for publication December 2, 1974; final cating psychological defense breakdown. revision received November 5, 1975. 106

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Copyright ° 1976 by the American Psychosomatic Society, Inc. Published by American Elsevier Publishing Company, Inc.

PSYCHOENDOCRINOLOGY OF DEPRESSION

The investigators concluded that adrenal cortical activation in depression was related "not to the depressive illness per se, but rather to more universal ego phenomena such as . . . neurotic 'signal' anxiety or psychotic 'disintegrative' anxiety." An opposite view suggested by some investigators and clinicians over the years is that depressive illness might be an exception to the general rule, that there might be a particular association between depression and pituitary-adrenal cortex activation. This suggestion originates in the unusual clinical association between mood disorders and pituitary-adrenal disturbances. Rubin and Mandell (16) foreshadowed subsequent developments clearly in their 1966 review of this area with the statement, "It may be that 'functional' depressive states are concomitants of a supra-hypophyseal brain dysfunction which is also responsible for hyperstimulation of the anterior pituitary." In other words, depression and pituitary-adrenal activation might be linked through the hypothalamus and limbic system, which regulate both mood and the release of adrenocorticotrophic hormone (ACTH). A specific link between depressive illness and hypothalamo-pituitary-adrenal (HPA) activity was soon identified by three independent groups who began to study the central mechanisms that regulate ACTH release (17-19). Each group reported that some depressed patients failed to exhibit a normal suppression of the HP A axis in response to dexamethasone. Other psychiatric patients, however, had normal HPA suppression responses, no matter how anxious, distressed, or psychotic they were (19). Furthermore, this abnormality of HPA suppression (which is similar to that found in Cushing's disease) was observed in depressed patients with an "en-

dogenous" clinical presentation, rather than in those with neurotic or reactive depressions (20); after treatment, normal HPA suppression responses to dexamethasone were then obtained in these patients (19). Despite the finding that this HPA regulatory disturbance was observed only in psychiatric patients with a primary depressive illness, some investigators held that these results could still be consistent with the traditional view that HPA activation in depression is determined by the breakdown of ego defense mechanisms. In discussing these suppression findings with reference to their own work Sachar and his colleagues (6) stated that it was "more than likely that those depressed patients who fail to show suppression of plasma cortisol in response to dexamethasone are the patients with high levels of emotional arousal.. . . " In order to resolve this issue a further study was carried out in two groups of patients with severe breakdown of ego defenses-acute schizophrenics and newly admitted depressives.

PATIENTS AND METHODS Twenty-one depressed and 10 schizophrenic patients were studied after admission, and 11 of the depressed patients were tested a second time after successful treatment with electroconvulsive therapy (ECT). Fifteen of the depressives were women and six were men; their mean age was 57.8 years (range 22-80 years). Of the schizophrenics, three were women and seven were men; their mean age was 28.5 years (range 15-70 years). The diagnoses of primary depressive illness and schizophrenia were made independently by two psychiatrists following essentially the criteria of Feighner, Robins, Guze, Woodruff, Winokur, and Munoz (21). All the subjects were inpatients admitted to the Royal Melbourne Hospital or the Parkville Psychiatric Unit. Clinical ratings and endocrine testing were carried out one week after hospitalization, during which time the only drugs allowed were chloral hydrate or nitrazepam for sleep.

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BERNARD J.CARROLL These drugs were not given on the night of dexamethasone administration. The severity of depression was estimated by the author with the Hamilton Rating Scale for Depression (22) using the original 17 items. All the patients were rated in this way, the information being obtained from a detailed clinical interview, supplemented by nurses' observations and the histories given by close relatives. This scale is not a diagnostic instrument but is designed to quantify the severity of depressive symptoms (22,23). The Hamilton scores thus indicate the severity of illness in the patients with a primary depressive diagnosis and reflect the extent of secondary depressive symptoms in the schizophrenic patients. To estimate the degree of breakdown of ego defense mechanisms the criteria and scoring guide designed by Sachar (6) were employed. The Sachar Scale contains 42 items and is an elaboration of the Hamilton Scale. Included in the Sachar Scale are eight items that reflect the breakdown of psychological defenses. These items are affective sadness and arousal; psychic anxiety; somatic anxiety; ideas of reference; feelings of bodily disintegration; feelings of depersonalization and unreality; feelings of loss of control; fluid delusions. These'eight items were grouped as a "core" score (6) to indicate ego defense breakdown. In completing the Sachar Scale ratings the same procedure for information gathering was followed as for the Hamilton Scale. The "core" items in particular were rated with close reference to the criteria of Sachar; they are defined in more detail elsewhere (6,24).

puncture was performed for cortisol measurement in cerebrospinal fluid at 1100 hr in those patients who consented (14 depressed, 5 schizophrenic). In the 11 depressed patients studied after treatment at least 1 week from the last ECT was allowed before the dexamethasone test and clinical ratings were repeated.

LABORATORY METHODS

Cortisol was measured in plasma, urine, and cerebrospinal fluid (CSF) by competitive protein binding (CPB) techniques. For plasma the method of Murphy (26) with a micro-scale system was employed. For urine Murphy's method (27) was modified slightly by the use of corticosterone tracer instead of hydrocoru'sone, by the use of florisil rather than Fuller's earth as the adsorbent, and by the use of multiple rather than single aliquots of the dichloromethane extracts. These modifications improved the performance of the assay and have also been adopted by other workers (28,29). Cortisol in CSF was measured by Murphy's, ultra-micro method (26) with the same modifications as for urine. In every assay two doses of sample extract, each in duplicate, were carried through the procedure to yield a quadruplicate estimate for every sample; the mean of all four values was recorded. For statistical computations of correlation coefficients (Pearson product moment) and Student's t values the urinary free cortisol, CSF cortisol, and day 2 plasma cortisol results were log-transformed, since these variables are known to be distributed in a log-normal manner (30,31). Accordingly, this proceENDOCRINE PROTOCOL dure yields a standard deviation range rather than a Hypothalamo-pituitary-adrenal (HPA) function simple standard deviation for each of the variables was determined in all patients with the collection of mentioned (32,33). Student's t values are two-tailed base-line data for 24 hr, followed by a dexamethasone unless specified as one-tailed. suppression test. On day 1 urine was collected for free cortisol measurement for 24 hr from midnight to midnight. An oral dose of 2 mg dexamethasone was RESULTS given at the end of this first 24-hr period and urine collection was then continued for another 24 hr (day The depressed patients were severely ill 2). Blood was taken for plasma cortisol measurement at 0830 hr on days 1 and 2 in all patients. In addition, as judged by their mean Hamilton score of blood for plasma cortisol was taken at 1630 hr on days 30.4. The schizophrenic patients also dis1 and 2 from 14 of the 21 depressed patients and from played considerable secondary depres5 of the 10 schizophrenic patients. With this singlesion, with a mean Hamilton score of 25.4. dose midnight dexamethasone test normal subjects show suppression of plasma cortisol levels to values This difference was significant (p < 0.05). of about 4 ng'100 ml for the following 24 hr (25). Both groups also showed a high level of Three days after the dexamethasone test a lumbar ego defense breakdown by Sachar's 108

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criteria. The mean "core" score in the depressed patients was 22.7; in the schizophrenic group it was slightly but not significantly higher at 27.9. The two groups therefore showed comparably severe breakdown of ego defense mechanisms (Table 1). On day 1 of the dexamethasone test both groups had similar plasma cortisol levels at 0830 and 1630 hr (Table 1). There was, however, a substantial difference between the two groups when their day 1 urine free cortisol (UFC) excretions were compared (Table 1 and Fig. 1). The mean UFC of the. schizophrenics was close to the normal mean of 40 fig 124 hr reported by Murphy (27). The mean for the depressives was 104 fig /24 hr (SD range 52-206) and in 12 of the 21 individuals the value exceeded

the upper normal limit of 120 fig. All of the values from the schizophrenics fell below this level (Fisher exact p < 0.002J. On day 2, after the midnight dose of dexamethasone, further differences between the two groups were found (Table 1). At 0830 hr 5 of the 21 depressives had a plasma cortisol level greater than 7 jug /100 ml while all the schizophrenics suppressed below this level. At 1630 hr 7 of the 14 depressives tested had a plasma cortisol level greater than 7 fig /100 ml while all of 5 schizophrenics remained suppressed at this time. These differences became more apparent when the day 2 UFC results were compared (Table 1 and Fig. 2). The 10 schizophrenic patients showed marked suppression of their UFC excretions (mean 9.7 fig 124 hr). The depressed pa-

TABLE 1. Comparison of Depressed and Schizophrenic Patients (Means ± SD: SD Ranges Where Appropriate) Depressed

Hamilton score "Core" score

Schizophrenic

30.4 (5.4)

25.4 (6.0)

22.7 (8.8)

27.9(7.8)

17.8(7.5) 11.6(4.6)

14.6(5.8)

t

df

P

2.3 1.6

29 29

0.05

1.2

NS NS

3.2

29 17 29

0.01

1.84

29

0.05

2.6

17

0.01

4.0

29

0.001

3.8

17

0.005

NS

Day 1 Plasma cortisol a 0830 hr 1630 hr UFC

104.0 (52-206)

10.7(6.8) 39.0 (14-107)

0.32

Day 2 Plasma cortisol *

5.1

3.1

(2.5-10.4)

(1.6-6.0)

0830 hr 1630 hr

6.0

1.8 (0.9-3.7)

UFCb

(2.4-15.0) 49.0 (15-158)

(4.5-21)

CSF cortisol d

11.4 (6.7-19.6)

a

fig/100

9.7 3.9 (2.2-6.7)

ml.

b

Urine free cortisol-jug/24 hr. c One-tailed. rf ng/ml.

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BERNARD J.CARROLL

URINE

FREE

DAY

URINE FREE COKTISOL

CQRTISOL

1

DAY 2 24 hr 200 100

••*

SO .! 20

•*

•

10

:

Fig. 1. Individual values of urine free cortisol excretion of 21 depressed and 10 schizophrenic patients on base-line day 1 before dexamethasone. Note logarithmic scale. Upper limit of normal range is 120 jig /24 hr.

COBIIiOL

IN

CERCBI

Fig. 3. Individual values of cortisol concentration in cerebrospinal fluid of 14 depressed and 5 schizophrenic patients. Note logarithmic scale. 110

Fig. 2. Individual values of urine free cortisol excretion of 21 depressed and 10 schizophrenic patients on day 2 after dexamethasone. Note logarithmic scale.

tients did not show such complete suppression; their mean UFC excretion was 49 /xg/24 hr, and the individual results ranged up to levels that would be considered elevated even on base-line day 1. This difference is highly significant (p < 0.001). Nine of the 10 schizophrenics had UFC excretions less than 20 jtxg /24 hr on day 2, while only 3 of the 21 depressed patients suppressed their UFC excretion below that level (Fisher exactp < 0.0001). In the cerebrospinal fluid the five schizophrenic patients tested had a mean cortisol level of 3.9 ng /ml, which is close to the normal mean value of 4.0 ng /ml originally reported by Murphy, Cosgrove, Mcllquham, and Pattee (34). The 14 depressed patients had higher CSF cortisol levels, with a mean value of 11.4 ng/ml (Table 1 and Fig. 3). This difference between the depressed and schizophrenic pa-

Psychosomatic Medicine Vol. 38, No. 2 (March-April 1976)

PSYCHOENDOCRINOLOGY OF DEPRESSION TABLE 2. Endocrine-Clinical Correlations (Product-Moment) Depressives (21)

Schizophrenics (10)

1 UFC-"Core items 1 UFC-Hamilton score 1 UFC-Hamilton somatic 1 UFC-Sachar somatic

+0.06 + 0.23 +0.38 + 0.43

-0.20 -0.03 -0.61 ' -0.26

Day 2 UFC-"Core" items Day 2 UFC-Hamilton score Day 2 UFC-Hamilton somatic Day 2 UFC-Sachar somatic

+0.30 +0.26 +0.45 +0.36

-0.46 -0.23 -0.53 -0.44

Comparison Day Day Day Day

3

p < 0.05.

tients is also highly significant (p < 0.005). ENDOCRINE-CLINICAL CORRELATIONS

these two conditions. Age alone is known to have no effect on UFC excretion in adults (35) or on overnight dexamethasone suppression (36), and within the group of depressed patients there was no indication of an age effect on UFC excretion either before or after dexamethasone (Table 3).

In each patient group product-moment correlations were calculated between the UFC results and the rated clinical features. The "core" score was obtained by sumCHANGES FOLLOWING ECT ming the ego defense breakdown items described above. A Hamilton somatic score Eleven of the depressed patients were was obtained by summing the scores of the tested and rated again following successitems weight loss, gut symptoms, middle ful treatment with ECT. At least 1 week insomnia, and delayed insomnia. The after the last treatment, and when the pasame items were summed from the Sachar tients were ready for discharge from hospiScale to yield a Sachar somatic score. The tal, the same procedure excepting the Hamilton somatic and Sachar somatic lumbar puncture was carried out as in the scores correlated +0.84 in the overall initial testing. group of 31 patients. At this time the mean Hamilton score of Among the depressed patients all the these 11 patients had fallen from 31.4 to rated scores correlated positively with the 10.0 and their mean "core" score from 23.3 UFC results. Only the correlations with the to 11.1 (with Sachar's rating convention somatic scores, however, reached statistical significance (Table 2). In particular, the "core" score did not correlate strongly TABLE 3. Age and Urinary Free Cortisol Excretion in Depressed Patients (Means; pig/24 hr) with the UFC results. By contrast, all the UFC-Day 2 UFC-Day 1 N Age rated items among the schizophrenic patients showed negative correlations with 1 29 52 40 53 92 7 40-50 the UFC results. 28 4 109 51-60 The depressed patients were much 98 139 3 61-70 older than the schizophrenics, as would be 52 112 6 71-80 expected from the usual age-incidences of Psychosomatic Medicine Vol. 38, No. 2 (March-April 1976)

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BERNARD J.CARROLL TABLE 4. Comparison of 11 Depressed Patients before and after Treatment (Means ± SD; SD Ranges Where Appropriate) Recovered

Paired t

P

31.4(5.8) 23.3 (9.0)

10.0(5.1) 11.1 (2.2)

8.48 4.15

0.001 0.001

16.3 (8.0) 12.2(5.0) 134 (91-197)

18.0(5.1) 8.5 (4.5) 79 (54-115)

-0.78 3.68 3.29

NS 0.005 0.01

4.7 (2.2-9.9) 6.5 (2.4-17.4) 60 (23-154)

2.0 (0.7-5.8) 2.0 (0.8-5.0) 13 (3.5-48)

2.28

0.05

3.25

0.01

3.26

0.01

Depressed Hamilton score "Core" score Day 1 Plasma cortisola 0830 hr 1630 hr

UFO Day 2 Plasma cortisola 0830 hr 1630 hr UFO

'Vg/100 ml. *" Urine free cortisol, /ag/24 hr

the minimum possible "core" score is 8). These ratings confirm the clinical judgment that the patients had recovered. The endocrine test results in these patients are given in Table 4. Significant decrements were seen in the plasma cortisol levels at 1630 hr on day 1 and at both 0830 and 1630 hr on day 2. The mean UFC excretion on day 1 fell from 134 to 79 /xg /24 hr (p < 0.01) and on day 2 this measure fell from 60 |U,g /24 hr to the normal level of 13 ^g/24 hr (p < 0.01). There were no correlations of significance between change in the endocrine measures and change in the rated scores on the Sachar and Hamilton scales. In particular, the change in "core" score correlated poorly with change in day 2 UFC excretion (Spearman rankr = 0.009). DISCUSSION The validity of the endocrine measures selected for this study requires some dis112

cussion before the results that were obtained are considered. The plasma and CSF cortisol assays can be dealt with briefly. For plasma a standard CPB method was employed; it detects not only cortisol but also corticosterone and cortisone (26), whereas the earlier colorimetric procedures for 17-hydroxycorticosteroids (17-OHCS) (37) measure only cortisol and cortisone (38). Fluorometric methods in common use [e.g. (39)] measure cortisol and corticosterone (38). The advantage of the CPB method for "plasma cortisol" determination is that it is less subject to interfering substances and gives values that are closest to true cortisol levels as determined by more tedious but specific techniques (40). Similarly, the CSF cortisol levels determined by CPB techniques (26) are closer to true values (41,42) than those obtained by fluorometry (43), which is the only practical alternative. The measurement of urinary free cortisol (UFC) as an indicator of adrenocorti-

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cal function has been recommended for many years by clinical endocrinologists (44) but it has not been generally applied in psychoendocrine studies. Instead, the urinary measures most commonly employed by psychiatrists have been 17-hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS), which have limitations, especially in the diagnosis of doubtful cases of hypercortisolism (44,45). For a number of years there has been good evidence that within and somewhat above the range of normal activity (i.e., in the "psychoendocrine" range) 17-OHCS and 17-KGS measurements bear only an approximate relationship to the cortisol secretion rate (35,44,46,47). Urinary 17-OHCS excretion in particular is influenced by multiple determinants (48) and correlates poorly with plasma 17-OHCS levels in normal subjects (49). Circulating plasma cortisol is largely bound to plasma proteins, especially corticosteroid-binding globulin (CBG) (50), or transcortin (51). Less than 10% of the total plasma cortisol is normally unbound, and this fraction is thought to mediate the tissue effects of cortisol (52,53). The excretion of free cortisol in urine is related directly to this plasma unbound cortisol level (54). The UFC provides an integrated measure of plasma free cortisol levels over time (54,55). At low or normal levels of cortisol secretion the UFC indicates changes in cortisol production rate within individual subjects. In normal subjects, for example, the UFC excretion in 2-hourly urine samples clearly reflects the changes in secretion rate of cortisol that occur over the circadian cycle (56). At high levels of cortisol secretion the plasma CBG binding capacity is saturated and free cortisol levels rise more rapidly than below the CBG saturation point. This critical point occurs at a total plasma cortisol

concentration of between 15 and 20 fi.% /100 ml (54), and thus with increasing rates of cortisol secretion the UFC increases exponentially, whereas urinary 17-OHCS and 17-KGS increase in a linear manner (44,51,57). In states of adrenal hyperactivity, then, the UFC reflects the effective ("free") level of circulating plasma cortisol (46,54,58-60). Because of this fact the UFC excretion has become well established as a laboratory measure for the diagnosis of Cushing's disease (27,29,44,45,55-57,61-64). For the same reasons, the UFC is a very sensitive indicator of suppression of high levels of adrenocortical activity by synthetic steroids (29,44-^6). In addition, the UFC excretion is not raised in obesity, whereas the other urinary measures and also the cortisol secretion rate are often grossly elevated in this condition (27,29,46,56,61-63). Similarly in hyperthyroid states, where increased cortisol secretion rates and 17-OHCS excretions are found, the UFC is normal, reflecting the essentially euadrenal status of such patients, who do not have raised plasma free cortisol levels despite the rapid turnover rate of cortisol (46). Since patients with severe depression are known to have elevated cortisol secretion rates, sometimes into the range seen in Cushing's disease (5-7,65), the UFC measurement is considered more appropriate and sensitive for the present study than measurements of urinary 17-OHCS or 17-KGS. In most psychoendocrine studies of the HPA axis urinary 17-OHCS or 17-KGS measures have been used to infer differences between subject groups or changes within individual subjects. The 17-KGS excretion accounts for 80% or more of the total cortisol metabolites, while the 17-OHCS measure accounts at best for only about 50% of total cortisol metabolites

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(66). Even the 17-KGS measure, however, correlates poorly with the cortiscl secretion rate (CSR) when the CSR is within or slightly above the normal range (47). Urinary 17-OHCS or 17-KGS measures do provide an approximate indication of alterations in CSR. More confidence can be placed in these measures when differences within subjects, rather than between subjects, are observed. For single 24-hr urine 17-OHCS measurements in normal subjects 34% of the variance was shown to be due to day-to-day differences within subjects and 63% due to differences between subjects; it has been suggested that an acceptably reliable estimate of an individual's true mean 17-OHCS excretion can only be obtained by urine collection for 5 consecutive days (67). It is likely that similar sources of variance between and within subjects apply to the UFC measure also. The UFC excretion, like the 17-OHCS and 17-KGS measures, also provides an approximate indication of CSR differences within the normal or near-normal range. The available data on the correlation between UFC and CSR (at CSR values less than 30 mg /day) indicate that within this rangeUFC-CSRcorrelations (35,44,57)are at least as good as 17-KGS-CSR correlations (44,47). It was mentioned earlier that circadian changes in HPA activity are reflected clearly in UFC excretion over the 24-hr period (in normal subjects) (56). The same finding was reported by another group (68) who showed that circadian changes in UFC excretion parallel closely the circadian pattern of 17-OHCS excretion in normal subjects. These results again suggest that UFC excretion can adequately reflect CSR changes within the normal range of HPA activity. The UFC measure merits further comparative studies as a psychoendocrine index within 114

the normal range of adrenocortical activity. As discussed earlier, UFC excretion is a very good measure for the detection of major stimulation of the HPA axis, such as occurs in Cushing's disease and severe depression. For the laboratory determination of UFC excretion several procedures of varying specificity and practicality are available. The most specific techniques call for chromatographic separation of cortisol (44,61,64). CPB methods are much more practical for most purposes (27,29). The values obtained by CPB methods are higher than those given by the more specific methods but their clinical performance is fully comparable. Some investigators include additional preparative steps to remove interfering substances from the sample extracts before quantitation by CPB methods; this becomes important especially when resolution of very low UFC values is being attempted (28,57). When radioimmunoassay rather than CPB quantitation is employed sample purification can be especially important, depending on the specificity of the antibody being used (69). The least specific method available is a fluorometric procedure (70), which gives values five times higher than the CPB methods, but which also has a very good performance, with a sensitivity from a clinical point of view equal to the CPB radioassay (45). Because of the serious lack of specificity of the fluorometric method, however, a CPB technique is preferable. In this study the depressed patients differed markedly from the schizophrenic patients on the endocrine measures. With respect to the clinical ratings, however, the two groups showed comparable degrees of ego defense breakdown and the schizophrenic patients also displayed considerable secondary depressive symptomatol-

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PSYCHOENDOCRINOLOGY OF DEPRESSION

ogy. These results, therefore, do not support Sachar's suggestion that breakdown of ego defenses is the determinant of the HP A abnormality (6). If this were the case the schizophrenic patients also would have been expected to manifest HPA disturbances, whereas their endocrine values were in fact quite normal. Furthermore, within the group of depressed patients the endocrine measures that were most abnormal (UFC on days 1 and 2) correlated best with the rated somatic features than with the items that indicate ego disintegration (Table 2). This finding also contradicts Sachar's (6) proposal that "those depressed patients who fail to show suppression. . . in response to dexamethasone are the patients with high levels of emotional arousal. . . . " The correlation with somatic features does support the previously published conclusion that failure of HPA suppression is related to the severity of somatic depressive symptoms (71). In addition the negative correlations seen in the schizophrenic patients between somatic symptoms and the UFC results (Table 2) indicate that abnormal HPA suppression is not related to these somatic symptoms per se but rather to somatic symptoms in the context of a primary depressive illness. In the 1970 report from Sachar's group (6) change in cortisol production rate in depressed patients following treatment was found to correlate with change in rated items reflecting ego defense breakdown. In the present study there was no such correlation observed between the changes of the clinical and endocrine variables. The present results would indicate that HPA activation and failure of HPA suppression are related to the depressive illness as such rather than to the ego phenomena of psychological defense breakdown.

Two case vignettes illustrating this divergence of the results from the customary view are presented to emphasize this point. Case 1 involves a schizophrenic patient with massive ego defense breakdown and normal endocrine values. This patient is a 26-year-old woman who had suffered three previous episodes of schizophrenic decompensation. Two months before admission she stopped taking her medication (trifluoperazine) and experienced a recurrence of symptoms over a 10-day period before hospitalization. At the time of rating considerable affective arousal and frequent weeping were evident; she had marked psychic anxiety, being constantly apprehensive and easily startled. Multiple somatic anxiety symptoms were present also; her attitude and conversation were paranoid in quality with clear ideas of reference that were beginning to organize into a delusional system. She had other fluid delusions, still partly questioned, of being pregnant and formal thought disorder was present as well. She expressed feelings of falling apart bodily and had episodes of severe depersonalization with panic attacks. In addition to these schizophrenic and anxiety symptoms there were many secondary depressive features. As noted above she displayed sadness of affect and weeping; she described a profound loss of interests and satisfaction, extreme fatigue, and loss of appetite; she had noticeable agitation at times and pervasive motor retardation. Despite these severe features of ego defense breakdown and secondary depression her morning plasma cortisol levels were 16.9 and 5.0 /i.g/100 ml and her urinary free cortisol excretions were 38.8 and 2.0 fx% /24 hr on days 1 and 2, respectively. Her "core" score on the Sachar scale was 34. Case 2 is a patient with severe endogen-

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ous depression, minimal ego defense breakdown, and abnormal endocrine values. This 80-year-old woman had suffered one previous episode of severe depression and had been ill for 3 months before this admission. She presented as a classic retarded depressive with extreme apathy, social withdrawal, and psychomotor retardation, quite unresponsive to environmental change. She had severe middle and late insomnia, loss of appetite, and fatigue. At the same time she displayed minimal affective arousal or sadness and was unable to weep. She had low somatic and psychic anxiety, no paranoid trends, no depersonalization, no ideas of bodily disintegration, no anxiety about loss of control, and no delusions of any kind. Her morning plasma cortisol levels were 29.4 and 15.6 (U.g/100 ml and her urinary free cortisol excretions were 130.0 and 117.2 jLtg/24 hr on days 1 and 2, respectively. These values indicate marked impairment of suppression by dexamethasone on day 2. This patient's "core" score on the Sachar scale was 12. The significance of the impaired responses to dexamethasone in the depressed patients has been discussed in previous reports (19,72). The dexamethasone suppression test is used routinely in the evaluation of patients with Cushing's syndrome (25,73-75). The site of action of the drug is the central nervous system, i.e., the median eminence of the hypothalamus and the limbic areas involved in the regulation of corticotrophin releasing factor (CRF) and ACTH release (76). The failure of dexamethasone to cause normal suppression may indicate that the extrahypothalamic limbic regulatory areas (such as amygdala, hippocampus, septal region) are causing an overriding "drive" on hypothalamic CRF release in the depressed patients. This possibility is 116

strengthened by the facts that closely related limbic circuits are involved in the control of affect (77-79) and that the neuroendocrine abnormality reverted toward normal after the depressed patients had recovered. These findings give support to the idea put forward in 1966 by Rubin and Mandell (16) that depression may be related to a supra-hypophyseal brain dysfunction that also causes hyperstimulation of the anterior pituitary. The results obtained in the schizophrenic patients indicate further that the limbic system dysfunction is linked with the process of a primary depressive illness rather than with depressive symptoms as such. A number of authors have drawn attention to the presence of depressive symptomatology in patients with a primary diagnosis of schizophrenia (8,80-82). While some emphasize the appearance of depressive features during recovery from the acute psychotic phase, others have identified these symptoms throughout the course of the schizophrenic illness; during recovery they are recognized more easily (83). The mean Hamilton score of the schizophrenic group in this study would, in depressives, indicate severe illness, possibly requiring ECT. The differential endocrine results of this study thus provide a psychoendocrine distinction between primary depressive behavior and secondary depressive symptomatology, and complement the same distinction that can be made on clinical grounds (80) and in terms of response to treatment (81). Several conclusions may be drawn from this study. There is a hypothalamic-limbic system dysfunction to be observed in some patients with primary depressive illness. This dysfunction is similar to but less severe than that which occurs in diencephalic Cushing's disease. With the exception of anorexia nervosa (84) it is rarely

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seen in other psychiatric illnesses. It is re- depressive illnesses may not be simply a lated to somatic and "endogenous" fea- stress response, as such responses are usutures of the depressive illness rather than ally envisioned, and as described during to nonspecific features of ego defense the course of neurotic depressive reactions breakdown. It is not observed in patients (87), but rather another reflection of apwith secondary depressive symptomatol- parent limbic system dysfunction, along ogy, but only in subjects with a primary with disturbances in mood, affect, appedepressive illness. tite, sleep, aggressive and sexual drives, Recently venous catheter studies with and autonomic nervous system activity" frequent blood sampling have been carried (65). This suggestion of a limbic system out by Sachar and associates (65) to dysfunction in depression is similar to a document in greater detail the HPA dis- possibility advanced for the finding of imturbances in depression. Abnormal diur- paired suppression by dexamethasone, nal patterns of cortisol release were i.e., that "the steroid-sensitive neurones identified, characterized by frequent pulse are subjected to an abnormal drive from release episodes for cortisol and increased other limbic areas" (88). daily cortisol production. This disturThus, very similar conclusions about bance was especially marked during the the nature of the HPA dysfunction in denight hours when inhibition of cortisol pression have been reached by Sachar and secretion normally occurs (85). Similarly by this investigator. The resemblance bewe now find that nonsuppressed plasma tween the neuroendocrine abnormalities cortisol levels are found most frequently seen in severe depression and those seen late on day 2, particularly in the late even- in diencephalic Cushing's disease (89,90) ing (86), whereas normal subjects and is compelling and lends support to the other psychiatric in-patients remain sup- early intuition of Rubin and Mandell (16). pressed for a full 24 hr (25). In addition, The two immediate areas suggested by high night time plasma cortisol levels be- these neuroendocrine findings for future fore dexamethasone is given are strongly research are, firstly, a systematic study of predictive of impaired suppression during psychiatric patients to determine the day 2 (86). Thus, both the HPA dysfunc- speci/icity of the HPA dysfunction and, tion described by Sachar et al. (65) and secondly, a neuropharmacologic study to that described in this report may be seen as determine the mechanism of the observed indicating the same basic neuroendocrine disturbances at a neurotransmitter level. defect in depressed patients, namely, a As has been pointed out previously failure of the normal circadian inhibitory (65,91,92), such a pharmacologic apmechanism of ACTH-cortisol release. proach could in principle generate clinical A further point of consensus can be evidence relevant to the biogenic amine noted also since Sachar et al. have now theories of depression. identified severely depressed patients without marked psychotic disorganization who show severe HPA abnormality by catheter studies (65). As a result Sachar has now reconsidered his previous conceptual scheme (6) and has proposed that "the hypersecretion of cortisol in certain

SUMMARY Twenty-one depressed and 10 schizophrenic patients were studied to examine the relationship between limbic system-

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pituitary-adrenal cortical activation and integrity of psychological defense mechanisms. The schizophrenic patients had normal endocrine function despite the presence of severe ego defense breakdown and secondary depressive symptoms. The depressed group had elevated urine free cortisol excretion, high cortisol concentrations in cerebrospinal fluid, and incomplete suppression of limbic systempituitary-adrenal activity by dexamethasone. It was concluded that psychological defense breakdown does not correlate with these neuroendocrine abnormalities, in view of the normal results seen in the schizophrenic group. Within the depressed group somatic rather than psychological features correlated with the endocrine findings. Following treatment the depressed patients showed more normal neuroendocrine function.

The results provide a psychoendocrine distinction between primary depressive illness and secondary depressive behavior and suggest that the primary mood disorder in some patients is associated with limbic system-pituitary-adrenal disturbances resembling those found in diencephalic Cushing's disease. Brian M. Davies, Professor and Chairman of Psychiatry, University of Melbourne, AustraJia, encouraged and supported this study of patients under his care. Dr. Edward Sachar aJso encouraged this study and kindly provided copies of his rating scale with instructions for its use. Dr. Graham Burrows assisted in the evaluation of some patients at the Parkville Psychiatric Unit. This work was supported by the NationaJ Health and Medical Research Council of Australia.

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