Relationship of cortisol hypersecretion to brain CT scan alterations in depressed patients

191

Psychiatr_~ Research, 8, 191-197 (1983) Elsevier Biomedical Press

Relationship Alterations

of Cortisol Hypersecretion in Depressed Patients

Charles H. Kellner, David R. Rubinow,

to Brain CT Scan

Philip W. Gold, and Robert M. Post

Received October 26, 1982; revised version received January 3. 1983; accepted January 18. 1983.

Abstract. Preliminary data showing a correlation between urinary free cortisol levels and ventricular-brain ratio in 10 affectively ill patients are presented. The literature on hypercortisolism and computed tomography (CT scan) abnormalities is reviewed. The authors suggest that the increased cortisol production in some psychiatric patients might be capable of altering the gross structure of the brain and that such alterations might be reversible. Key Words. Ventricular-brain ratio, computed tomography free cortisol, affective disorder.

(CT scan), urinary

Hypersecretion of cortisol secondary to activation of the hypothalamic-pituitaryadrenal (HPA) axis in depressed patients is one of the best documented findings in biological psychiatry (Carroll, 1982; Rubinow et al., 1983). Another active area of recent investigation and great interest, computed tomography (CT scan) of psychiatric patients, has revealed that a substantial percentage of schizophrenic patients have abnormally large cerebral ventricles (Johnstone et al,, 1976; Weinberger et al., 1979). More recently, this finding has also been reported in some affectively ill patients (Jacoby and Levy, 1980; Pearlson and Veroff, 1981). Ventricular enlargement and cerebral atrophy have been previously documented in patients with disparate causes of hypercortisolism such as Cushing’s Syndrome and therapeutic steroid or adrenocorticotropic hormone (ACTH) administration (Momose et al., 1971; Heinz et al., 1977; Bentson et al., 1978; Lagenstein et al., 1979; Okuno et al., 1980). To explore the possible link between hypercortisolism and ventricular enlargement in depression, we report here a study which correlates the ventricular-brain ratio (VBR) and mean 24-hour urinary free cortisol (MUFC) excretion in patients with primary affective disorder. Methods Our patient sample consisted of 10 manic-depressive patients admitted to a clinical research unit at the National Institute of Mental Health. All patients met Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for either major depressive disorder or bipolar (I or II) illness. They ranged in age from 27 to 69 years (mean 43.5, SD 14.5). Except for their psychiatric illness they

Charles H. Kellner, M.D., David R. Rubinow, M.D., Philip W. Gold, M.D., and Robert M. Post, M.D. (Acting Chief). are in the Biological Psychiatry Branch, Bldg. 10, Room 3S239, National Institute of Mental Health, 9000 Rockville Pike, Bethesda, MD 20205, USA. (Reprint requests to Dr. C.H. Kellner.) 01651781/83/0000-0000/$3.00

0 Elsevier Science Publishers

192

were in good health. None of the patients had any known serious neurologic, metabolic or collagen-vascular disease, or a history of alcoholism. All patients received a baseline CT brain scan without intravenous contrast material during a period of medication-free evaluation. The scans consisted of 12 cuts at different brain levels, angled 15’ from the orbito-meatal line. They were performed on an EM1 scanner, model 1005 or 1010. VBR was measured by polar planimetry using the method described by Weinberger et al. (1982). Briefly, this consists of selecting the CT slice showing the greatest area of the lateral ventricles, measuring the area of the ventricles and the area within the inner table of the skull on that slice, and computing a ratio of the two areas. In addition to measurement of VBR. cerebral atrophy was rated on a O-3 scale (0 q normal, I = mild atrophy, 2 q moderate atrophy, and 3 q severe atrophy) as previously described by Rieder et al. (1979). Scans were read by two investigators who were unaware of the patients’ laboratory data. The MU FC data were obtained by averaging the values of at least three complete 24-hour urine collections. Urinary free cortisol was measured by radioimmunoassay with antibody from Hazelton Laboratories. Samples were analyzed in duplicate with intra- and interassay coefficients of variation of 6.7% and 12.3%. respectively. MUFC was chosen because it has been described as the best urinary measure of the effective level of plasma cortisol over time and is thus a useful index of the hypothalamic-pituitary-adrenal (HPA) axis activity and hypersecretion (Carroll et al.. 1976). With one exception, urine collections and CT scans were performed with patients in the same clinical state, which ranged from mild to severe depression. Mean depression ratings on the Bunney-Hamburg scale (1963) for the 3 days of urine collection ranged from 5.8 to 10.3, with a group mean of 8.05 f 1.30 (mean * SD). One patient was euthymic at the time of CT scan but moderately depressed at the time of urine collections. Results The VBR was correlated with the degree of 24-hour excretion of urinary free cortisol (r = 0.80, p < 0.01)(Fig. 1). VBR was not correlated with age in this subgroup (r = 0.06, NS). In fact, the largest VBR (10.9) was found in a 27-year-old patient. The mean VBR in this 10 patient sample (5.48 f SD 2.74) is very similar to the mean VBR we have found in another sample of affective patients (5.93 f SD 2.17, n = 12) and age-matched medical controls (5.46 k SD 2.84, n 12) studied on a GE model 8800 scanner (Kellner et al., unpublished data). Only one or two of the patients in this study with the largest VBRs would be considered to have ventricular enlargement on a clinical reading of their CT scans. Using the criterion suggested by Weinberger et al. (1982) that a VBR of greater than 10 is suggestive of a central nervous system (CNS) abnormality, only one of our patients would be abnormal. The mean 24-hour urinary free cortisol values in this sample (96.2 f SD 47.7 yg/24 hours) and those observed in our larger population of depressed patients (69.1 + SD 3 I .8, n = 54) are both significantly elevated compared to normal volunteers (55.5 * 22.8, n = 42) (Rubinow et al., 1983). The three patients with the largest VBRs were all cortisol hypersecretors. Two other hypersecretors had small ventricles. We also examined the sulcal atropy scores in relation to MUFC. The correlation was in the same direction (Y = 0.45) but was not significant. Neither MUFC nor VBR was correlated with depression ratings. q

Discussion Our findings suggest that in affectively ill patients degree of cortisol hypersecretion. These findings

ventricular size may be related do not appear to be an artifact

to the of age

193 Fig. 1. Relationship

of MUFC to VBR in affectively ill patients

r -.80 PC.01 N=lO

lo0

I 2.0

I I I 6.0 8.0 4.0 Ventricular-Braw Ratio

I 10.0

or history of alcohol use. Moreover, several different patient groups have previously been reported to show ventricular enlargement or “apparent” cortical atrophy on CT scans (or pneumoencephalograms) in conjunction with hypercortisolism (Table 1). These include patients receiving exogenous steroids or ACTH and patients with Cushing’s syndrome. It should be noted that while there is some overlap in MUFC values between depressed patients and patients with Cushing’s syndrome, the latter group often have values greatly exceeding 200 pg/24 hours (Burke and Beardwell, 1973). Patients with anorexia nervosa also show similar CT scan abnormalities (Heinz et al., 1977) and often display HPA axis dysfunction (Gerner and Gwirtsman, 198 I), but the possible link between these two findings has not yet been examined. Of great interest is the finding that such structural changes evident on the CT scan are reversible in some cases when the metabolic abnormality is corrected or drug treatment discontinued (Heinz et al., 1977; Bentson et al., 1978; Lagenstein et al., 1979; Okuno et al., 1980). The time course of the reversal of apparent atrophy may be as little as weeks or months. An additional group of patients, abstinent chronic alcoholics, has been shown by Carlen et al. (1978) to exhibit reversible cerebral atrophy. Thus, what has previously been assumed to be a fixed, irreversible structural lesion in neuropsychiatric patients may, in fact, be a state-dependent condition. It is not inconceivable that some depressed patients who episodically secrete abnormally large amounts of steroid hormone may have concomitant episodic ventricular enlargement. It would be instructive to follow individual patients with serial CT scans in different clinical states.

1. Pneumoencephalogram

31

a

Petit mal epilepsy treated with ACTH and dexamethasone

syndrome1

15

Lennox syndrome and infantile spasms treated with ACTH

Cushing’s

15

Autoimmune diseases treated with highdose steroids

findings.

1

Gushing’s

syndrome

n

Patient group

+ +

+ +

+

+

+

+

+

Sulcal atrophy

CT findings

Not reported

+

+ (12 out of 15 patients showed resolution of changes at > 1 month after ACTH therapy

+ j Reported for 2 cases only)

+

Reversibility

et al. (1978)

Momose

i

et al. (1979) et al. (1971

Lagenstein

Okuno et al. (1980)

Bentson

Heinz et al. (1977)

Authors

associated with excess steroid or ACTH

Increased ventricular size

Table 1. Evidence for CT scan abnormalities

195 However, ethical concerns about excessive radiation exposure may preclude obtaining this information in a systematic way. The CT scan studies showing abnormally large ventricles in schizophrenic patients do not address the issue of hypercortisolemia as a possible explanation for this finding. An early report of elevated urinary 17-hydroxycorticosteroids in a group of firstepisode schizophrenic patients (Sachar et al., 1963) as well as a recent report of a 30% incidence of dexamethasone nonsuppression in a group of chronic schizophrenic patients (Dewan et al., 1982), suggests the importance of this possibility. The assumption of Weinberger et al. (1982) that ventricular enlargement predates the onset of psychosis (and their inference that it is a relatively stable “trait” marker) in schizophrenics may need to be reevaluated in light of evidence that atrophy or ventricular enlargement as seen on CT scan may occur acutely and may be reversible. The functional significance of increased ventricular size has been studied in schizophrenic patients. Both Johnstone et al. (1976) and Golden et al. (1980) found that cognitive impairment was correlated with cerebral ventricular size. Recent work by Rubinow et al. (in press) has demonstrated that MUFC in patients with depression correlates with the number of errors on the Halstead categories test, a measure of cognitive abstracting ability. Thus, one might raise the question whether large ventricles, high cortisol, or some other factor is responsible for the observed cognitive impairment in these patient groups. Again, more complete characterization of larger numbers of patients will be needed to shed light on this issue. The preliminary data that we present must be interpreted cautiously. The inherent problems of VBR measurements have been extensively discussed in the literature (Jernigan et al., 1982; Weinberger et al., 1982). In our study the temporal relationship of CT scan to the urine collections is not optimally controlled. Ideally, the urine collections should be done within a few days of the CT scan and both procedures repeated during different clinical states to see whether the CT abnormalities are variable and related to the degree of hypercortisolism. It is tempting to speculate that hypercortisolism directly causes the ventricular enlargement seen in these patients. Such a hypothesis is supported by the reports of exogenous steroid or ACTH administration causing ventricular enlargement in other patient groups (Table 1). The mechanism by which steroids may cause this structural change is debated in the literature and remains largely speculative (Momose et al., 1971; Bentson et al., 1978). An alternative but less likely explanation for the relationship of hypercortisolism to ventricular enlargement is that increased steroid production in our depressed patients is the result, not the cause, of the brain alteration revealed on CT scan or its associated biochemical underpinnings. In conclusion, our preliminary data and the evidence cited from the literature suggest that increased endogenous cortisol production or exogenous administration of ACTH or corticosteroids can alter cerebral ventricular size and, in some cases, the degree of apparent cortical atrophy. Furthermore, some of the CT scan changes observed in psychiatric patient populations may represent state-related alterations and be potentially reversible. The authors thank Ronald 0. Rieder, M.D., Daniel Weinberger, M.D., Wade Berrettini, M.D., and Lee S. Mann, M.A., for their help in collecting the VBR data presented in this article.

Acknowledgment.

196

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