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Clinical Studies |
School of Nursing, University of Pittsburgh (L.D.D.), Pittsburgh, Pennsylvania 15261; Developmental Endocrinology Branch, National Institute of Child Health and Human Development (L.D.D., G.P.C.), and the Departments of Behavioral Pediatrics (B.D.) and Clinical Neuroendocrinology (P.W.G.), National Institute of Mental Health, Bethesda, Maryland 20892; Butler Hospital, Brown University (E.S.B.), Providence, Rhode Island 02912; and Cedar-Sinai Medical Center (T.C.F.), Los Angeles, California 90048
Address all correspondence and requests for reprints to: Dr. L. D. Dorn, University of Pittsburgh, School of Nursing, Pittsburgh, Pennsylvania 15261.
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Abstract |
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Introduction |
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In an earlier report we showed that over 50% of patients with active CS present with symptoms of atypical depression (6), a phenomenon compatible with the fact that patients with active CS exhibit glucocorticoid-induced suppression of their CRH neurons (9, 10, 17). Thus, the possibility exists in these patients that atypical depression is a result of high concentrations of cortisol, low concentrations of CRH, or both. In the majority of patients with CS, the function of the CRH neuron gradually returns to normal within 12 months after curative surgery, while the patients are receiving daily glucocorticoid replacement (17). The time course of alleviation of the symptoms of atypical depression as well as other less frequent psychopathology symptoms after the correction of chronic hypercortisolism remains unknown or, at best, unclear.
The purpose of this investigation was 3-fold: first, to determine the longitudinal psychological course of patients with CS 3, 6, and 12 months after correction of hypercortisolism; second, to determine whether the recovery of the hypothalamic-pituitary-adrenal (HPA) axis, as indicated by morning cortisol levels and/or cortisol response in an ACTH stimulation test, was related to psychological recovery; and third, to define whether psychopathology before or during CS or the duration of CS was related to the occurrence or intensity of psychopathology after cure.
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Subjects and Methods |
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The patient group (n = 33) included 28 women and 5 men consecutively admitted to the NIH Clinical Center for the evaluation and treatment of CS. The sample has been described previously (6). In brief, subjects ranged in age from 19–50 yr (mean, 36.4; SD, 9.1). Thirty-one patients were Caucasian, and 2 were African-American. Twenty-nine of the patients had Cushing’s disease (pituitary adenoma), 3 had the ectopic ACTH syndrome, and 1 had an adrenal adenoma. On the average, patients had symptoms of CS for 5.63 yr (SD = 4.7), as determined from the medical history. One third (n = 11) of the patients had had at least 1 previous surgery for an unsuccessful pituitary adenoma resection, and 1 of the 11 also had irradiation to the pituitary. After admission to this institution, 22 patients had pituitary adenoma resection, 4 had bilateral adrenalectomy, 2 had pituitary irradiation, and 2 had thoracotomy for resection of an ectopic ACTH-secreting tumor. After remission of hypercortisolism at 3, 6, and 12 month follow-up, as many as 6 patients routinely saw a therapist, 7 reported taking antidepressants or antianxiolytics, and 2 reported psychiatric hospitalizations.
Protocol
The study was approved by the institutional review board. Written informed consent was obtained from each subject. Eligibility criteria included fluency in English; age between 18–50 yr; documented CS by elevated morning and evening serum cortisol levels, elevated 24-h 17-hydroxycorticosteroids per g creatinine excretion, and elevated 24-h urinary free cortisol (UFC) excretion per m2 body surface area (micrograms per m2); findings from bilateral inferior petrosal sinus sampling; computed tomography and magnetic resonance imaging scans as appropriate; and surgical and pathological findings.
Design
A prospective longitudinal study was conducted. Patients participated in the psychological testing during the 2-week diagnostic phase of their hospital admission (time 1). All patients had documented CS and were hypercortisolemic at the time of the first interview. Follow-up psychological testing was completed during repeat hospital admissions 3, 6, and 12 months after treatment. Twenty-eight patients were surgically cured by our previously established criteria, with a morning plasma cortisol level less than 3 µg/dL and a UFC less than 20 µg/day on day 4 or 5 postoperatively. These patients were placed on glucocorticoid replacement (12–15 mg hydrocortisone/m2 body surface area·day) until their 60-min cortisol response to ACTH-(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) became 18 µg/dL or more, or indefinitely in the patients treated with bilateral adrenalectomy. The level of 18 µg/dL represents 2 SD below the mean cortisol response in healthy subjects (18). Five patients treated with pituitary irradiation and/or medically with an adrenolytic agent or a steroidogenesis enzyme inhibitor were considered cured if their UFC was within the normal range (20–90 µg/day or <70 µg/m2 body surface area·day).
Psychological and endocrine evaluation
All measures employed have been used extensively in psychiatric research and in clinical settings and have good reliability and validity. The interviews described in the following paragraphs were conducted by the first author, who was trained in the administration of the instruments.
Interviews
Schedule of Affective Disorders and Schizophrenia–Lifetime
Version (SADS-LA). The SADS-LA (19) is an interview focusing on
psychiatric diagnoses that are based on both the Diagnostic and
Statistical Manual IIIR (20) as well as research diagnostic criteria
(21). In determining psychiatric diagnoses, the criterion of organic
factors as a cause of psychopathology was eliminated. That is, patients
could still receive a diagnosis of depression even though there was a
presumed endocrine cause. Thus, we could examine the full range of
psychopathology exhibited, regardless of its presumed endocrine cause.
Interrater agreement on the presence or absence of a psychiatric
diagnosis was made on approximately 32% of the posttreatment
interviews throughout the course of the study. The average 
coefficient (22) was 0.87.
Atypical Depression Diagnostic Scale (ADDS). The ADDS (23) is an interview designed to ascertain symptoms of depression that reflect reverse vegetative features such as hyperphagia and hypersomnia rather than the hypophagia and hyposomnia often expressed in major depressive disorder of the melancholic type. Mood reactivity is one of the key features assessed by the interview along with rejection sensitivity. The ADDS categorizes subjects as follows: 4 = definite atypical depression; mood reactivity was 50% or more, and two or more symptoms were positive (e.g. hyperphagia, hypersomnia, severe fatigue, leaden paralysis, etc.); 3 = probable atypical depression; mood reactivity was 50% or more, and one symptom was positive; 2 = simple mood reactive depression; mood reactivity was 50% or more, but no symptom was positive; 1 = no atypical depression; mood reactivity was less than 50%. If a subject was not depressed, a score of 0 was assigned. In this report, a diagnosis of atypical depression was given if the patient scored 3 or 4 on the interview.
The Hamilton Rating Scale for Depression. The Hamilton Rating Scale for Depression (24) consists of 21 items and yields scores of depression severity from 0–65. Scores greater than 20 generally coincide with major depression, whereas those between 12–20 may indicate depressed mood or subsyndromal depression.
Self-report instruments
Symptom Checklist 90-revised (SCL-90R) (25) requests that subjects rate the amount of discomfort experienced over the last week that resulted from the stated 90 items (e.g. headaches, crying easily, feeling annoyed or irritated). The scale yields 9 primary symptom dimensions as well as 3 global indexes of distress. Scoring of the instrument was based on nonpsychiatric patient norms. t scores are reported. Thus, the mean is indicated by a score of 50, and the SD is 10. The psychotic subscale does not indicate a diagnosis of psychosis, but, rather, refers to symptoms of withdrawal and social isolation. Higher scores indicate higher distress or disturbance on the dimension described.
Profile of Mood States (POMS). POMS (26) requests that subjects rate how they have been feeling over the past week on 65 adjectives (e.g. grouchy, anxious, guilty). Six independent factors can be scored from the instrument as well as a total mood disturbance score. Higher scores indicate higher distress or disturbance on the dimension described.
State Trait Anxiety Inventory. The State Trait Anxiety Inventory (27) uses a 4-point Likert scale for 20 items measuring state anxiety and 20 items measuring trait anxiety. Computed scores were based on norms of nonpatient adults. A higher score indicates higher anxiety.
Endocrine assessment and medical information
Recovery of the HPA axis was determined from the baseline morning serum cortisol level and the cortisol response to an ACTH stimulation test. All patients were changed from their usual replacement dose of hydrocortisone (12–15 mg hydrocortisone/m2 body surface area·day) to an equivalent dose of dexamethasone approximately 1 day before the ACTH test. An iv catheter was inserted between 0700–0800 h, 1 h before the administration of 250 µg cosyntropin (Cortrosyn, Organon, West Orange, NJ). Serum was drawn at baseline (0 min) and 30 and 60 min post-ACTH administration. Serum cortisol (28) was measured by RIA as previously described. The detection limit of the assay ranged from 5–28 nmol/L. Intra- and interassay coefficients of variation were 5% and 11%, respectively. Recovery of the HPA axis was defined as reaching a cortisol concentration of 18 µg/dL or more 30 min or 60 min after ACTH administration (16).
The duration of CS was determined from the medical history of the patient.
Statistical analysis
SPSS-X (29) was used in all statistical analyses. Measures of
central tendency and frequency distributions were used to describe the
sample. Spearman’s 
or Pearson’s correlation coefficients were
used to examine relations among the response of the HPA axis, previous
psychiatric diagnoses, and current psychopathology. Repeated measures
ANOVA or covariance was used to examine trends across time (linear,
quadratic, and cubic) for the continuous measures of psychopathology.
Cohran’s Q was the nonparametric test to determine repeated
measures of the presence or absence of a psychiatric diagnosis.
McNemar’s tests were used for pairwise comparisons to determine where
the differences were found across time. The level of significance was
set at P 
0.05.
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Results |
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Longitudinal psychological course of patients with CS
Psychiatric diagnoses. Table 1
shows the
medical diagnosis, psychiatric diagnoses, and response to the ACTH
stimulation test for each patient across the study period.
[Cross-sectional data from time 1 (active CS) were reported in detail
previously (6) and are summarized here.] At the initial hospital
admission at this institution, 18 of 33 (54.6%) patients met criteria
for a psychiatric illness using Diagnostic and Statistical Manual IIIR
or research diagnostic criteria. Of these 18 patients, 17 were
categorized as having atypical depression; 3 of them also met criteria
for major depression, and 5 of them met criteria for other psychiatric
disorders (e.g. hypomania, panic, and drug and alcohol
abuse). Comorbidity was evident; thus, reported diagnoses do not
represent individual patients.
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At the 6 month posttreatment visit, 9 (36%) met criteria for a psychiatric illness. Diagnoses in the 25 returning patients included 8 (32%) with atypical depression, 3 (12%) with MDD, 2 (8%) with drug or alcohol abuse, and 1 (4%) with suicidality.
At the 12 month posttreatment visit, 7 subjects (24.1%) met diagnostic criteria for a psychiatric illness. Diagnoses in the 29 returning patients included 5 (17.2%) with atypical depression, 2 (6.9%) with MDD, 1 (3.5%) with drug abuse, and 1 (3.5%) who reported suicidality.
In the longitudinal sample, Cochran’s Q was used to determine whether there was an increase or decrease across time for the presence of a psychiatric diagnosis. For atypical depression, there was a significant decrease across time in the number of individuals reporting this disorder [Q = 10.8; df(3, 22); P = 0.013]. Pairwise comparisons using McNemar’s test shows that the presence of atypical depression was significantly higher at time 1 (active CS) vs. 3 months posttreatment (P = 0.039) and higher at time 1 vs. 12 months posttreatment (P = 0.013). There also was a trend, although not significant, for a decrease across time in the presence of any diagnosis using the SADS-LA [Q = 7.2; df(3, 24); P = 0.066]. Pairwise comparisons using McNemar’s test showed that the presence of a psychiatric diagnosis was significantly different when comparing 3 months posttreatment vs. 12 months posttreatment (P = 0.039).
Across the study, 4 patients had no history of a psychiatric disorder before or during CS, yet did exhibit a disorder following correction of hypercortisolism. Four patients never had a psychiatric diagnosis, and 11 patients had a diagnosis throughout the course of their illness and also after correction of hypercortisolism.
For the Hamilton ratings, there were no significant differences in depression severity across time (F = 1.2; P = 0.36) using a repeated measures ANOVA.
Self-report instruments. Repeated measures ANOVA with polynomial trends was computed on the longitudinal sample to determine changes in self-reported psychological functioning from time 1 with active CS and 3, 6, and 12 months posttreatment. For the self-report instruments, the Bonferonni correction was employed because of multiple analyses. Thus, for these analyses, the accepted P value was set at 0.003 or (0.05/21).
Symptom Checklist 90R: In general, for these subscales,
symptoms fell from pretreatment to 3 months postoperatively and then
further declined at 6 months, as noted by the linear and quadratic
trends (see Table 2 and Fig. 1). There
were significant changes across time in the following subscales of the
SCL-90R: obsessive-compulsive, depression, anxiety, paranoia,
psychotic, general severity, and positive symptom distress. Changes in
symptoms of the following subscales were not significant after the
Bonferonni correction was employed: somatization, interpersonal
sensitivity, hostility, phobia, and positive symptom total.
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). No significant trends across
time were noted after Bonferonni correction for depression-dejection,
anger-hostility, vigor, fatigue, or total mood score.
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ACTH stimulation tests were performed in those patients with pituitary adenoma resection or an ectopic source. The frequencies of a normal cortisol response (NRM) of 18 µg/dL or more and an abnormal cortisol response (ABN) of less than 18 µg/dL to the ACTH stimulation test were as follows: 3 months: NRM, 3 (13.6%); ABN, 19 (86.4%); 6 months: NRM, 5 (21.7%); ABN, 18 (78.3); and 12 months: NRM, 12 (50%); ABN, 12 (50%). Thus, the number of patients with HPA axis recovery increased across time.
Spearman’s correlations were computed to determine the concurrent
relations between recovery of the HPA axis (NRM/ABN response) and 1)
the presence or absence of a psychiatric diagnosis, and 2) the level of
psychological functioning from self-report questionnaires 3, 6, and 12
months after correction of hypercortisolism. There were no significant
(P > 0.05) correlations after the Bonferonni
correction of the HPA axis response with the diagnosis of atypical
depression or any diagnosis from the SADS-LA or for the self-report
measures.
Fisher’s exact tests were computed to determine whether having a psychiatric diagnosis after correction of hypercortisolism was independent from recovery of the HPA axis. All tests were nonsignificant (P > 0.05), showing independence between psychiatric diagnoses after correction of hypercortisolism and HPA axis recovery. To further examine whether psychological functioning was related to HPA axis recovery, we used the latter as a covariate in the above repeated measures ANOVA for the self-report measures. The covariate was not significant for any of these analyses, indicating that the change in measures of psychopathology was independent of the HPA axis response.
Next, we examined the relationship between self-report measures of
psychopathology and concentrations of cortisol at 0 (baseline), 30, and
60 min after the morning ACTH stimulation test. No significant
relations were noted 3 months after correction of hypercortisolism. Six
and 12 months after correction of hypercortisolism, lower morning
baseline concentrations of cortisol were related to higher numbers of
symptoms on many of the subscales of the SCL-90R (see Table 5). Few correlations were evident with self-report
measures and the cortisol concentration measured at 30 or 60 min. Six
months after correction of hypercortisolism for the POMS, patients
reporting more vigor had higher concentrations of cortisol at baseline
(r = 0.66; P = 0.001), 30 min (r = 0.58;
P = 0.005), and 60 min (r = 0.66;
P = 0.001). Similarly, 12 months after correction of
hypercortisolism, the correlations were r = 0.57
(P = 0.008) at baseline and r = 0.47
(P = 0.045) at 30 min. No significant correlations were
noted with the Hamilton score 3, 6, or 12 months after correction of
hypercortisolism.
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Spearman’s correlations were computed to determine the
relationship between having a diagnosis of atypical depression or any
other psychiatric diagnosis after correction of hypercortisolism with
having either 1) a psychiatric diagnosis before the reporting of any
symptoms of CS or 2) symptoms during CS. No significant correlations
were noted. The duration of CS was positively related to numerous
subscales on the SCL-90R, the POMS, and the Hamilton scale.
Significance ranged from P = 0.042 to 0.004. However,
to remain significant after the Bonferonni correction, a significance
level of P = 0.003 would have had to be reached.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Along with atypical depression in our sample, there was a decrease in the majority of symptoms of distress reported by patients in the self-report checklists, but not representing psychiatric diagnostic criteria. Such findings indicate that symptoms at levels below those of diagnostic criteria may be changing as well in the period after correction of hypercortisolism. We were conservative in our interpretation of these group differences by using the Bonferonni correction in our statistical analyses. Thus, additional group differences are plausible.
Comorbidity was evident in many of the patients during active CS as well as after remission of hypercortisolism. Comorbid conditions included panic and suicidal ideation, even at their follow-up visits, and thus obviously should not be ignored. Although only two patients met diagnostic criteria for panic disorder after treatment, several others reported panic attacks or symptoms of panic that did not reach the diagnostic threshold, yet were alarming to the patients. The emergence of panic anxiety in patients cured of the disorder may result from the relative glucocorticoid deficiency of these patients, which probably allows unrestrained increases in catecholamines (31). The nonhuman primate literature shows that plasma concentrations of norepinephrine are augmented by glucocorticoid deficiency during stress, indicating that the sympathetic system is not properly restrained by glucocorticoids in these animals (32).
Panic, suicidal ideation, and depression should provide a warning to those caring for patients with CS. Patients and family members should be given information that psychopathology may persist into the postoperative period or new psychopathology may emerge. Patients are often informed that they are cured after the surgery has been completed; yet they should be informed that "cure" from a quality of life or psychological perspective may take additional months. This is evidenced by the reporting of as many as 6 patients who saw a therapist on a routine basis and by the fact that psychological intervention was recommended to as many as 12 patients after remission of hypercortisolism, including 2 who required psychiatric hospitalization.
The pattern is puzzling regarding the presence or absence of a
psychiatric diagnosis across the longitudinal study. Our findings
reveal that a psychiatric diagnosis that was premorbid or concurrent
with CS did not influence the incidence of psychopathology after
correction of hypercortisolism. Importantly, of the 29 patients with
follow-up data, 4 (
14%) only had psychiatric diagnoses after
treatment, which may indicate that the return of the HPA axis to normal
may itself be unveiling or triggering psychopathological manifestations
not precipitated previously by hypercortisolism and vice
versa. Others reported that postoperative depression was a
predictor of both nonremission and relapse after pituitary surgery of
Cushing’s disease (33). This makes sense and is compatible with our
data, but is of limited value.
Our findings also revealed that having a psychiatric diagnosis after cure of CS was not strictly related to recovery of the HPA axis. As anticipated, recovery of the HPA axis did increase from 13.6% of the patients at 3 months posttreatment to 54.6% at 12 months posttreatment, numbers comparable to our earlier findings (17, 34). During this time there was a parallel decrease in the presence of psychiatric diagnoses. Although HPA axis recovery from an endocrine perspective is considered at a cortisol response of 18 µg/dL anytime during the rapid ACTH stimulation test, psychological recovery may not fit that same criterion. Importantly, when we examined the relationship of the concentration of cortisol rather than an all or none response, we did find a relationship. Lower morning baseline concentrations of cortisol were related to more psychopathology, as reported by the patients on the SCL-90R and POMS, particularly 6 and 12 months after correction of hypercortisolism. This relationship was not apparent 3 months after correction of hypercortisolism, presumably when concentrations of cortisol were generally too low to allow a proper correlation. This suggests that the spontaneous secretory activity of the CRH neuron may be a more important psychological determinant.
Certainly, the psychological recovery of cured patients with CS is multifactorial from both a neuroendocrine and a psychosocial perspective. Sonino and colleagues (35) recently reported that more stressful life events may play a causal role in the expression of depression in pituitary-dependent Cushing’s disease. This is compatible with our idea that hypercortisolism or hypocortisolism, and hence altered secretion of hypothalamic CRH, increase the vulnerabilities of an individual to stressors and, in turn, the expression of depression in response to such stressors.
Received August 8, 1996.
Revised November 26, 1996.
Accepted December 4, 1996.
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