Relationships between brain ct scan findings and cortisol in psychotic and nonpsychotic depressed patients

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Relationships Between Brain CT Scan Findings and Cortisol in Psychotic and ~onpsy~hotic Depressed Patients Anthony J. Rothschild,

Francine Benes, Nancy Hebben,

Bryan Woods, Monica Luciana, Erin Bakanas, Jacqueline A. Samson, and Alan F. Schatzberg

In this report, data are presented on pre- und postdexamethasone cortisol levels, neuropsychological testing, and computed tomography (CT) scan findings in 30 depressed patients (1.5 psychotic and 15 nonpsychotic). Particularly significant jndings were observed when data from the ~in~polar subgroup (n = 22) were analyzed separately. ~~ipoiar psychotic depressed patients had sig?li~~a~tl~ larger ( p < 0.05) anterior pole and cella media ventricle-to-brain ratios (VBRs) and significantly greater ( p < 0.05) left and right inferior parietal brain “atrophy” than nonpsychotic depressed patients. Higher rates of Dexamethasone Suppression Test (DST) nonsuppression were observed in ps~~chotic depressed patients and in patients with larger cella VBRs. Inferior purietal brain i~troph~~ atzd large VBRs were also associated with greater cognitive imp~~~rment on p.~~~hometric testing. Implications qf these endings are discussed.

Introduction Hypothalamic-pituitary-adrenal (HPA) dysfunction with hypersecretion of cortisol in unipolar depressed patients has been well documented (Carroll et al. I98 1; APA Task Force on Laboratory Tests in Psychiatry 1987). Patients with delusional depression have been reported to demonstrate among the highest rates of dexamethasone nonsuppression, and our group and others have reported that patients with psychotic major depression have markedly elevated postdexamethasone cortisol levels (Mendlewicz et al. 1982; Rothschild et al 1982; Rudorfer et al. 1982; Evans et al. 1983; Rhimer et al. 1984). We have hypothesized that the development of delusions in depressed patients is secondary to the effects of hypercortisolemia on dopaminergic systems (Schatzberg et al. 19X5), as glucocorticoids increase dopamine (DA) levels in human plasma (Rothschild et al. 1984) and in rat brains (Rothschild et al. 1985).

From the Affective Disease Program. McLean Hospital. (A.J.R., M L., E.8 . J.A.S.. A.F.S.); the Depanmcnt of Ne~r&,~~. McLean Hospital (N.H.. B.W.): the Ralph Lowell Laboratwies, McLean Hospital (F.B.); the Depanment of Psychiatry. Haward Medal School (A.J.R.. F.B.. N.H.. J.A.S.. A.F.S.): and the Depanment of Neurology, Harvard Medical School tB.W.), Boston, MA. Supported in par? by NIMH Grant MH-38671, a grantfrom the Poitras Charitable Foundation, and by a grant tl,,m the Ruth Rothstein Greif Fund. Addrers reprint requests to Dr. Anthony J. Rothschild, McLean Hospital, I Ii, Mill Strert. Belmont. MA ()2I’7~ Received July 26. 1988; revi& December 24. 1988.

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Recently, others have reported that affectively ill patients have abno~aliy large ventricles on computed tomography (CT) scans (Jacoby and Levy 1980; Pearlson and Veroff 1981). Targum and colleagues (1983) studied 38 melancholic depressed hospitalized patients (unipolars and bipolars) and found that the mean ventricle brain ration (VBR) of the psychotically depressed patients was greater (although not significantly) than the nonpsychotic depressed patients or the neurological controls. Moreover, 5 of the 20 psychotically depressed patients (25%) had VBRs greater than 2 standard deviations from the mean of the 26 neurological controls, in contrast to none of the 18 nonpsychotic depressed patients. Relationships between psychosis and enlarged ventricles in depressed patients have been subsequently reported by two other groups (Luchins and Meltzer 1983; Schlegel and Kretzschmar 1987). Ventricular enlargement and cerebral atrophy have also been documented in patients with disparate causes of hyperco~isolism, such as Cushing’s disease and exogenous steroid or adrenocorticotrophic hormone (ACTH) administration (Momose et al. 197 1; Heinz et al. 1977; Bentson et al. 1978; Lagenstein et al. 1979; Okuno et al. 1980). Kellner and colleagues (1983) reported a significant, positive correlation between 24-hr excretion of urinary free cortisol and VBR in 10 affectively ill patients. Given the high cortisol levels and enlarged VBRs found in psychotically depressed patients, we compared cortisol, CT scan data. and neuropsychological testing in psychotic and nonpsychotic depressed patients.

Methods In this study, 30 depressed patients (1.5 psychotic and 15 nonpsy~hotic), ranging in age from 19 to 65 years (mean 38.1 _t 14.4), were studied. Five of the patients were over the age of 55. The patients all had a CT scan and a Dexamethasone Suppression Test (DST). In 17 patients, neuropsychological testing data were gathered as part of their diagnostic evaluation. All had been medication-free for at least 2 weeks prior to the DST. None had a history of eiectroconvulsive therapy or substance abuse for at least 6 months prior to evaluation, and none had a medical, neurologic~, or endocrine disorder. The patients were diagnosed according to DSM-III (American Psychiatric Association 1980) criteria by at least two experienced clinicians who were blind to the cortisol, CT, and neuropsychological data. For the patients to be included, the two raters had to be in agreement about the Axis I diagnoses. Patients met DSM-III criteria for the following disorders: major depression (n = 22), bipolar disorder, depressed (n = 5), bipolar disorder, mixed (n = l), or schizoaffective disorder, depressed (n = 2). Mean Hamilton Depression Rating Scale (HAM-D) (Hamilton 1960) scores were 25.1 tr 7.9 for the total sample and 26.2 + 7.7 for the unipolar group. Blood was drawn for cortisol measurement at 4:00 PM before and after a I-mg oral dose of dexamethasone given at 11:OO PM. Plasma cortisols were determined by radioimmun~ssay (RIA) methods described previously by our group (Schatzberg et af. 1983: Rosenbaum et al. 1984). Nonsuppression was defined as a 4:00 PM postdexamethasone cortisol level 2 5 pg/dl (Carroll et al. 198 1). There was no significant difference between the age of DST suppressors and DST nonsuppressors. CT scans were performed both with and without contrast on a Toshiba TCT 20A scanner. Scans were performed within 1 month of the DST while the patients were symptomatic. VBR was determined at both the level of the anterior poles and the cella media by a method similar to that of Weinberger and colleagues (1982). The anterior

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to the region of the ventricular system that lies in a rostra1 location where the foramen of Munro establishes communication between the third and lateral ventricles, The cella media is the portion of the lateral ventricles where the left and right sides are in close opposition. Measurement consisted of calculating the area of the ventricle and the inner table of the skull, and the VBR was then computed as the ratio of the two areas. Measurements were performed on a Bioquant Image Analysis System (R & M Biometrics, Nashville, TN), a computer-assisted system that permits measurement of anatomical structures by tracing them on a Houston Hipao digitalizing board interfaced with a Wyse 286 personal computer. The software takes the digitalized information and computes the area. Cortical “atrophy” was determined by two of the investigators (F.B. and E.B.), who were blind to the diagnosis and cortisol measurements, by the method described by Benes and colleagues (1983). This consisted of rating several cortical regions on the following scale: 0-sulci not visualized; 1-sulci visualized but narrow; 2-sulci visualized and prominent, but cortical tissue appears normal; 3-sulci moderately enlarged, and cerebral tissue somewhat mottled; &sulci very enlarged, and cortical tissue grossly mottled. The left and right brain areas studied were: prefrontal (Brodman areas 9 and lo), inferior parietal (Brodman areas 39 and 40), superior temporal (Brodman area 22), tertiary visual (Brodman area 19), primary and secondary motor areas (Brodman areas 4 and 6), and primary and secondary somatosensory (Brodman areas 3,1,2,5,7). Neuropsychological testing was performed by an experienced neuropsychologist (N.H.) who was blind to the patient’s final diagnosis and laboratory data. The testing consisted of a standard clinical battery, including the Wechsler Adult Intelligence Scale (WARS), expanded Wechsler Memory Scale, Finger Tapping, and the McLean Neuropsychological Screening Exam, which includes tests of language function, praxis, visuospatial and constructional functioning, motor functions, and frontal and parietal functioning. Data were analyzed using SPSS programs for Analysis of Variance (ANOVA). Anterior pole and cella media VBRs and cortisol values were all log-corrected before the ANOVAs were performed because the values were not normally distributed. Data were also analyzed using Fisher exact tests, Pearson product-moment, and Spearman rank-order correlations.

pole refers

Result

S

In the overall group, there was a trend toward higher VBRs in psychotically depressed patients when compared to nonpsychotic depressed patients (Table 1). Psychotically depressed patients also exhibited more atrophy in the right inferior parietal brain area than did their nonpsychotic counterparts (Table 1). However, when the data were analyzed separately for the 22 unipolar major depressed patients, greater differences between psychotic and nonpsychotic patients were found. Unipolar major psychotically depressed patients had significantly larger anterior pole and cella media VBRs and more left and right inferior parietal brain atrophy when compared with their unipolar major nonpsychotic depressed counterparts (Table 2). Specifically, for inferior parietal atrophy, the scores for both left and right in the unipolar psychotic group were: 0 (1 patient); 1 (5 patients); and 2 (4 patients), as compared with the nonpsychotic group, which had 0 (6 patients), 1 (5 patients), and 2 (1 patient). Thus, only 1 of 10 unipolar psychotic depressed patients had the lowest atrophy score (0), in contrast to 6 of 12 nonpsychotic unipolar depressed patients (two-tail Fisher exact, p = 0.072). Differences between the psychotic and nonpsychotic groups were not due to age,

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1989;26:565-57.5

Table 1. CT Scan Measurements

in Depressed

Patients Psychotic

Nonpsychotic (n = 15)

VBR: Anterior pole VBR: Cella media Inferior parietal (left) Inferior parietal (right)

(n = 15)

ANOVA

Mean

SD

Mean

SD

F

0.015 0.061 0.600

0.008 0.026 0.633

0.021 0.079

I .ooo

0.010 0.022 0.756

3.325 3.102 2.471

co. c-0. NS

0.533

0.640

1.133

0.640

6.593

c-o.05

P

I I

gender, height, weight, length of current episode, length of total illness, history of substance abuse, or Ham-D score. No significant differences were found between psychotic and nonpsychotic depressed patients in the prefrontal, superior temporal, tertiary visual, primary and secondary motor, and primary and secondary somatosensory areas. Unipolar psychotically depressed patients were more likely than unipolar nonpsychotic depressed patients to have cella VBRs above 0.061 (Fisher exact, p = 0.030) (Figure 1 and Table 3). Using ANOVA, unipolar psychotically depressed patients had significantly higher postdexamethasone cortisol levels (F = 4.23, p < 0.05) than did unipolar nonpsychotic depressed patients. There was also a trend for unipolar psychotically depressed patients to have higher predexamethasone cortisol levels than did unipolar nonpsychotic depressed patients (F = 3.23, p = 0.088). Dexamethasone nonsuppressors were also more likely regardless of diagnosis to have larger cella media VBRs than suppressors (Fisher exact, p = 0.067) (Table 4). ANOVA performed on the neuropsychological testing data revealed that unipolar psychotically depressed patients did significantly worse for both left (F = 7.383, p = 0.022) and right (F = 8.58, p = 0.017) hands on the “m’s and n’s” subtest, a measure of frontal lobe function, than did their nonpsychotic counterparts. They also had significantly lower scores (F = 5.77, p = 0.037) than nonpsychotic patients on the drawing quality test, a measure of frontal and temporal lobe function. Pearson correlations performed on the data indicated an association between enlarged ventricles on CT and global cognitive impairment (Table 5). Specifically, patients with larger cella media VBRs did significantly worse (p < 0.01) on the animal naming test (test of posterior cortical region). Patients with larger anterior pole VBRs did significantly worse on visually reproduced

Table 2. CT Scan Measurements

in Unipolar Depressed

Nonpsychotic (n = 12) Mean

Patients Psychotic (n = IO)

ANOVA

SD

Mean

SD 0.009 0.016

VBR: Anterior pole VBR: Cella media Inferior parietal (left)

0.016 0.060 0.58

0.008 0.028 0.67

0.024 0.085 1.30

Inferior parietal (right)

0.58

0.67

1.30

F

P

0.67

4.666 4.982 6.214

<0.05 10.05 <0.05

0.67

6.214

<0.05

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0.110

569

-0

0.100 0.090

0

0.080

t

8 @Q-J

0.070 0.060 0.050

0

0.040 0.030 0

0.020 0

0.010 0.000

CELLA

ANTERIOR

POLE

Figure 1. Ventricle to brain ratios (VBRs) at level of cella or anterior pole in unipolar depressed patients (N = 22); a

= psychotic

(N = 10) and 0

= non-psychotic

(N = 12).

immediate memory (nondominant hemisphere test, p < O.Ol), immediate recall of word pairs (temporal/frontal regions, p < 0.05), immediate drawing quality (frontal/temporal regions, p < O.Ol), delayed drawing quality (frontal/temporal regions, p < 0.05), animal naming (posterior cortex, p < O.Ol), block design (frontal-pa~etal, p < 0.0.5), and digit span (global measure, p < 0.05). Patients with inferior parietal brain atrophy exhibited significantly poorer scores (p < 0.05) on immediate and delayed drawing quality recall (frontal-temporal), Finger Tapping (frontal-motor areas), m’s and n’s test (frontal), digit span (global measure), and digit symbol (global measure) (Table 5). A comparison between DST suppressors and nonsuppressors revealed that DST nonsuppressors had a poorer performance on the word pairs recaI1 (fronta~/temporal, p < 0.05) and memory passages recall (temporal, p < 0.01). The effect of age on the correlations between the CT scan and the neuropsychological

Table 3. Psychotic/Nonpsychotic

IJnipolar Depression VBR < 0.061

Nonpsychotic Psychotic

5 0

and Cella VBR VBR 3 0.061

Fisher exact

7 IO

0.030

570

A.J. Rothschild

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Table 4. DST Results and Cella VBR in Unipolar Depressed Patients

VBR 3 0.061

VBR < 0.061 Suppressor

4

5

Nonsuppressor

I

12

Fisher exact 0.067

testing data was analyzed by looking at the effect of age on each individual CT and neuropsychological measure. Although there was some correlation between age and these measures, when the effect of age was partialled out, the direction of the findings did not change. When the data were analyzed partialling out the effect of severity (as measured by total HAM-D scores), the findings also did not change. Studies on larger samples, however, will be required to ferret out the specific effects of cortisol status, age, psychosis, and severity on DST and neuropsychological findings.

Discussion The results of this study indicate that when compared to their nonpsychotic counterparts, unipolar psychotically depressed patients have significantly larger cella and anterior pole VBRs, greater inferior parietal brain “atrophy,” and higher pre- (trend) and postdexamethasone cortisol levels. Furthermore, larger VBRs and greater inferior parietal brain atrophy correlated with poor performance on psychometric testing. The changes in the

Table 5. Neuropsychological Test Results with VBR” and Inferior Parietal Abnormality Unipolar Psychotic and Nonpsychotic Depressed Patients: Correlation Matrix

VBR Test Visual Reproduction immediate Word Pairs immediate recall Drawing Quality immediate Drawing Quality delayed Animal Naming MS & Ns test, right hand Finger Tapping, right hand Digit Span Digit Symbol Block Design

in

Inferior parietal areas*

”

Cella media

Anterior pole

Right

Left

12

-0.42

- 0.66’

NS

- 0.45

12

NS

- 0.55‘

-0.46

12

0.41

- 0.65“

0.48

0.55’

12

0.43

0.50

0.52’

NS

9 II

- 0.77” NS

-0.75d NS

NS 0.64d

NS NS

12

NS

NS

12 12 12

NS NS NS

-0.63* NS -0.56

NS - 0.53’ -0.61d - 0.62d

NS

- 0.50’ -0.52’ -0.58’ -0.48

“VBRs log-corrected prior to analysis. ‘Spearman rank-order correlations used for inferior parietal areas; all others are Pearson product-moment correlations, ‘p < 0. IO.

“p i 0.05. ‘I, < 0.01.

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CT scans, ~though signi~cant, were subtle, as all but two had been read as clinically normal by the radiologist. The observation that unipolar patients who were nonsuppressors to dexamethasone were more likely to have larger cella media VBRs than suppressors is in contrast to previous studies (Targum et al. 1983; Schlegel and Kretzschmar 1987); however, these earlier studies included both unipolar and bipolar patients. A higher frequency of nonsuppression to dexamethasone in unipolar psychotically depressed patients than in nonpsychotic depressed patients was observed, confiding previous studies by our group and others (Mendlewicz et al. 1982; Rudorfer et al. 1982; Evans et al. 1983; Schatzberg et al. 1983; Rhimer et al. 1984). However, as has been the case in previous studies on biological markers in affective disorders, different findings were obtained when the unipolar depressed group was separated out from the bipolar and schizoaffective depressed groups (Schild~aut et al. 1978; Beckmann and Goodwin 1980; Rothschild et al. 1982). In the present study, more robust findings were observed when the unipolar group was separated out. Our observation that psychotically depressed patients have larger VBRs than nonpsychotic depressed patients is consistent with previous reports (Luchins and Meltzer 1983; Targum et al. 1983; Schlegel and Kretzschmar 1987). Enlarged ventricles have been reported in patients with schizophrenia (Weinberger et al. 1982), but the signi~cancc of this finding to the etiology of this illness is unclear. However, several studies have found that patients with increased cerebral ventricular size (Johnstone et al. 1976; Golden et al. 1980) or sulcal prominence (Rieder et al. 1979) on CT scans had greater cognitive impairment. Of particular relevance to this study are the observations that (1) in patients with Gushing’s disease or those who have received exogenous steroids, ventricles appear enlarged and sulci atrophied (Momose et al. 1971; Heinz et al. 1977; Bentson et al. 1978; Lagenstein et al. 1979; Okuno et al. 1980); (2) in depressed patients, urinary free cortisol levels and VBRs are strongly correlated (Kellner et al. 1983); and (3) elevated cortisol levels and the administration of glucocorticoids have also been associated with cognitive disturbances. In depressed patients, Rubinow and colleagues (1984) reported that urinary free cortisol (UFC) correlated significantly with cognitive dysfunction and that all hypersecretors were cognitively impaired as determined by the number of errors on the Halstead Categories Test, a measure of cognitive abstracting ability. Reus and colleagues (19X4), studying a group of 50 psychiatric inpatients, reported that nonsuppressors on the DST had significantly larger VBRs than either psychiatric inpatients who suppressed cortisol to dexamethasone or a control population, with age accounted for as a covariate. VBR showed a significant negative correlation with orientation, short-term memos, and response on a similarities subtest (Reus et al. 1984). Wolkowitz and colleagues (1988) have shown that in normal controls, acute doses of dexamethasone or chronic treatment with prednisone resulted in a significant increase in intrusion errors and incorrect identification of distracters on psychometric testing. The poorer performance on cognitive testing was reversible after the steroid was discontinued. These studies also suggest possible associations between an inability to completely integrate cues from the environment, cortisol hypersecretion, and enlarged ventricles and may help explain the cognitive disturbances frequently seen in psychotically depressed patients. indeed, findings in this present study suggest that the marked hypercortisolemia in psychotically depressed patients may be responsible for both the cognitive disturbance and CT scan findings. The question as to whether the changes we observed on CT scan are reversible or not is presently unanswered. In patients with Cushing’s disease or in those treated with exogenous steroids, the CT scan abnormalities have, in many cases, been reversible upon

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correction of the metabolic abnormality (Heinz et al. 1977; Bentson et al. 1978; Lagenstein et al. 1979; Okuno et al. 1980). In addition, chronic alcoholics have been shown to exhibit reversal of apparent cerebral atrophy when abstinent (Carlen et al. 1978). Further studies of this question are needed, and investigations are currently underway to study this group of patients, as well as a larger sample with serial CT scans and neuropsychological testing in different clinical states. The mechanism by which steroids may cause structural changes in the brain is not known, but several hypotheses have been proposed. One possible explanation is that steroid-induced protein catabolism may be responsible (Momose et al. 1971), based on the observed atrophic changes in skin, muscle, blood vessels, and bone of patients with Cushing’s disease. Another possibility is loss of brain volume secondary to loss of water (Bentson et al. 1978), perhaps by reduction of vascular permeability (Maxwell et al. 1971). Dexamethasone, for example, has been shown to promote water and sodium diuresis, with measureable decreases of each in the brains of experimental animals (Yamaguchi et al. 1975). Conversely, the rapid withdrawal of steroids may produce a synwhich is probably due to the resultant drome of “benign intracranial hypertension,” cerebral edema (Neville and Wilson, 1970). However, studies to date have looked only at the short-term effects of steroids. Studies are still needed to investigate possible longterm effects of steroids on cerebral dehydration, protein loss, and other changes, as this would shed more light on any deleterious effects of the hypercortisolism seen in psychiatric patients. The size of the lateral ventricles as measured by CT scan in the normal population increases with age (Barron et al. 1976). Thus, the brains of the young psychotically depressed patients seen in this study resemble the brains of older normals. Similarly, in rats, prolonged stress or exposure to corticosterone accelerates cell loss in the hippocampus, analogous to the changes seen in aged rats (Sapolsky 1988). Further studies are needed in the psychotically depressed patients to ascertain whether or not the changes seen on CT scan are similar to the changes seen during the normal aging process and whether or not the changes are reversible. Conversely, investigation of these psychiatric disease states may lead to a better understanding of normal aging. As corticosteroids may increase dopamine (DA) and homovanillic acid (HVA) levels in humans or laboratory animals (Rothschild et al. 1984, 1985; Wolkowitz et al. 1985, 1987), and psychotically depressed patients have higher DA levels than nonpsychotic depressed patients (Rothschild et al. 1987), further research is needed to determine whether or not those psychotically depressed patients with elevated DA levels are the same’patients that exhibit cortical atrophy. Studies are currently in progress that are simultaneously measuring cortisol, catecholamines, and CT scan measurements in a group of psychotic and nonpsychotic depressed patients to help answer those intriguing questions.

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