Prednisone Effects on
and Behavior
Preliminary Findings
Owen M. Wolkowitz, MD; David Rubinow, MD; Allen R. Doran, MD; Alan Breier, MD; Wade H. Berrettini, MD,
Mitchel A. Kling, MD; David Pickar, MD
\s=b\ To evaluate the neurochemical, neuroendocrine, and behav-
ioral effects of exogenous corticosteroids in humans, we admin-
istered prednisone (80 mg/d orally for 5 days) in a double-blind
manner to 12 medically healthy volunteers. Behavioral measures
were assessed before, during, and after prednisone administra-
tion in all 12 subjects, and cerebrospinal fluid biochemistry was
assessed before and during prednisone administration in 9 of the
subjects. Prednisone administration was associated with de-
creases in cerebrospinal fluid levels of corticotropin, norepi-
nephrine, \g=b\-endorphin,\g=b\-lipotropin,and somatostatinlike immu-
noreactivity. No significant changes were noted in cerebrospinal
fluid levels of \g=a\-melanocyte-stimulatinghormone, corticotropin-
releasing hormone, 3-methoxy-4-hydroxyphenylglycol, homo-
vanillic acid, or 5-hydroxyindoleacetic acid. No consistent or
significant group mean changes were observed in structured
behavioral ratings, although 9 (75%) of the volunteers studied
reported mild behavioral changes while receiving prednisone.
Correlations between the neurochemical and behavioral
changes are discussed.
{Arch Gen Psychiatry. 1990;47:963-968)
administration of corticosteroids is fre¬
Pharmacol
For
quently ogie
associated with behavioral alterations in humans.
example, medically
in ill patients treated systemically
with exogenous corticosteroids, a fluctuating array of symp¬
toms may develop, such as mood lability, depression, irritabil¬
ity, insomnia, poor concentration, and even psychosis.1'10 The
reported incidence of such side effects varies from study to
study, ranging from 1.8% to 57%z'""7; the individual risk factors
for experiencing them are unclear. Clinical investigations of
these effects have been hampered by méthodologie difficul¬
ties, including the study of patients with acute medical illness¬
es, the lack of prospective study designs, and the lack of
baseline (presteroid) assessments. The majority of prior stud¬
ies, therefore, have been unable to separate behavioral re¬
sponses directly attributable to corticosteroids from those
attributable to the underlying concurrent medical illnesses.
The biologic mechanisms by which corticosteroids may af¬
fect behavior are also not fully understood. A large body of
evidence now suggests that corticosteroids have direct and
indirect effects on the central nervous system in animals and in
humans,11"1' and corticosteroid receptors are densely located
Accepted for publication October 18,1989.
From the Department of Psychiatry, University of California, San Francisco
(Dr Wolkowitz); the National Institute of Mental Health, Bethesda, Md (Drs
Rubinow, Berrettini, Kling, and Pickar); the Department of Psychiatry, Uni-
versity of California, Davis, Sacramento (Dr Doran); and Maryland Psychiatric
Research Center, University of Maryland School of Medicine, Baltimore (Dr
Breier).
Read before the 26th Annual Meeting of the American College of Neuropsy-
chopharmacology, San Juan, Puerto Rico, December 9,1987.
Reprint requests to Department of Psychiatry, University of California, San
Francisco, 401 Parnassus Ave, San Francisco, CA 94143 (Dr Wolkowitz).
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Neurochemistry
PhD;
not only in the hypothalamus and pituitary gland, but also in
the hippocampus, septum, and amygdala,1118 areas ofthe brain
believed to be intimately involved in behavior, mood, and
memory. Many central nervous system effects of corticoste¬
roids are mediated via genomically related events (ie, tran¬
scription). Other effects may be related to more rapid changes
in brain excitability and synaptic transmission that are pro¬
duced by altering cyclic nucleotide metabolism,19 by interact¬
ing directly with neuronal membranes,20 by altering specific
ionic conductances,19 and by altering central carbohydrate,
protein, and lipid metabolism.19 Prior studies have also sug¬
gested that corticosteroids alter the activities of monoamine
neurotransmitters1112,16 and of proopiomelanocortin and other
neuropeptides.21"23 Few studies, however, have prospectively
assessed corticosteroid effects on human neurochemistry and
neuroendocrinology, and few studies have concurrently as¬
sessed the behavioral and neurochemical effects of corticoste¬
roids to examine which of these reflections of central nervous
system activity are altered in concert.
In this study, we employed a prospective, double-blind
method and assessed behavioral and concomitant biochemical
effects in an attempt to delineate the biologic correlates of
specific corticosteroid-induced behavioral changes. Because
important differences are likely to exist between the central
nervous system effects of endogenous and exogenous cortico¬
steroids,11 our study was designed to investigate possible
mechanisms for exogenous corticosteroid-induced central ner¬
vous system changes.
SUBJECTS AND METHODS
Subjects
Twelvemedically healthy volunteers (4 women, 8 men; aged 21 to
41 years) participated in this institutional review board-approved
study after granting written informed consent. All volunteers were
screened for absence of medical illness, including endocrinopathies,
by thorough history, physical examination, and laboratory examina¬
tion. Psychiatric history was elicited by structured interview (Sched¬
ule for Affective Disorders and Schizophrenia).24 The Schedule for
Affective Disorders and Schizophrenia interview sheets were re¬
viewed by two research psychiatrists, blind to study outcome, and
consensus diagnoses were arrived at according to DSM-IH-Rr and
Research Diagnostic Criteria.26 All volunteers were psychiatrically
healthy when studied and for at least 2 years before the beginning of
the study. However, 6 of the subjects had a personal or family
psychiatric history; personal histories were of generally minor sever¬
ity (eg, adjustment disorder; Table 1). The remaining 6 subjects were
free of such personal or family histories. In particular, all volunteers
met Research Diagnostic Criteria for "currently not mentally ill, " and
7 met Research Diagnostic Criteria for "never mentally ill." Volun¬
teers were free of all medications, including birth control pills and
steroid-containing dermatologie preparations, for at least 1 year, and
were free of significant alcohol or other drug use for at least 21k years
before beginning this study. Volunteers were maintained on a caf-
 Biochemical Measures
Table 1 .—Subject Demographics and Behavioral
Responses to Prednisone Lumbar punctures were performed on all volunteers during the
initial placebo period. Repeated lumbar punctures were performed on
Psychiatric History nine of the volunteers on the morning following the last dose of
DSM IHR prednisone; the three remaining volunteers (all from the subgroup of
Patient Behavioral volunteers with personal or family psychiatric histories) refused re¬
No./Sex/ Personal Responses to peated lumbar punctures. In women, repeated lumbar punctures
Age, y (Age)* Family Prednisonet were always performed in the same menstrual phase. Lumbar punc¬
1/F/22 Adjustment Depressed, tearful, tures were performed at 9 AM with the volunteers in the lateral
disorder (20) light-headed, hot decubitus position and at bed rest following an overnight fast (to
flashes; guarded minimize artifactual contaminants such as motor activity or recently
(WD) ingested food). The 7th through 16th milliliters of cerebrospinal fluid
2/F/24 Irritable, decreased (CSF) were collected as a pool, preserved with 20 µL of 100% glacial
sleep, increased acetic acid, placed on ice at the bedside, and then frozen at 80°C until
appetite; mild assayed for ß-endorphin (BE; CSF buffered), norepinephrine (NE),
-

depression (WD) 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid

3/F/22 Alcohol Warm, sweaty (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). The 17th through
dependence 26th milliliters of CSF were collected as a pool without preservative,
4/F/23 Adjustment More talkative placed on ice at the bedside, and then frozen at -80°C until assayed
disorder (20) for corticotropin, corticotropin-releasing hormone (CRH), and a-me-
5/M/22 Adjustment Major Giddy, more active, lanocyte-stimulating hormone ( -MSH). The 27th and 28th milliliters
disorder (19); depression polydipsia of CSF were collected on dry ice, preserved with 100 µ , of IN acetic
hallucinogen acid, and frozen at 80°C until assayed for somatostatinlike immuno-
hallucinosis (19) reactivity (SLI). The 29th and 30th milliliters were collected on dry ice
-

6/M/28 Adjustment Slight elevation of without preservative and frozen at 80°C until assayed for ß-lipotro-
disorder (26) mood, restless pin (BLPH) and cortisol. -

sleep All CSF samples were assayed in duplicate in the same assay batch,
7/M/21 Irritable (WD), and paired samples (ie, baseline and prednisone) were from the same
trouble sequential aliquots. Cerebrospinal fluid corticotropin was assayed in
concentrating extracted CSF by radioimmunoassay (RIA).27 The intra-assay coeffi¬
(WD) cient of variation (CV) equals 4.4%, and the sensitivity was 3 to 5
8/M/21 Irritable, angry, pg/mL. The CSF CRH was assayed in extracted CSF by RIA.28 The
increased energy, intra-assay CV was equal to 6.0%, and the sensitivity was 1.5 to 2.0 pg
anxiety, per tube. The CSF SLI was assayed by RIA29 employing tyrosine-io-
confusion, dine 125-somatostatin synthetic cyclic somatostatin standards, rabbit
depersonalization, antisomatostatin antiserum, and charcoal separation. The intra-assay
racing thoughts, CV was equal to 5.1%, and the sensitivity was less than 1.0 pg per
mildly elated tube. The CSF BE was assayed by RIA.30 The intra-assay CV was less
9/M/41 Irritable, polyuria, than 1.5%, and the sensitivity was 15 pg/mL. The antibody cross-
difficulty reacted with BLPH at the 10% level. The CSF BLPH was assayed by
concentrating RIA.30 The intra-assay CV was less than 1.5%, and the sensitivity was
10/M/34 Polyuria 20 pg/mL. The CSF -MSH was assayed by RIA.30 The intra-assay
11/M/23 Mildly "high," CV was less than 1.5%, and the sensitivity was 5 pg/mL. The CSF for
labile mood, HVA, NE, MHPG, and 5-HIAA was assayed using high-pressure
depersonalization liquid chromatography with electrochemical detection.3,32 Intra-as¬
12/M/32 Alcohol "Buzzed," say CV was equal to 5%, 7%, 4.5%, and 2.0%, respectively. Sensitiv¬
intoxication (28) decreased sleep ities were 200 nmol/mL, 0.17 pmol/mL, 80 nmol/mL, and 100
*Age (years) at which diagnosis was applicable. All subjects were free of nmol/mL, respectively. The CSF for cortisol was assayed by RIA33;
psychiatric illness for at least 2 years before beginning the study. intra-assay CV was equal to 6%, and sensitivity was 0.2 µg/dL.
fSymptoms reported in unstructured subjective logs or nurses' observations Blood was collected via standard forearm venipuncture at 8 AM for
during prednisone treatment, except those followed by WD reported during assay of prednisolone, the active metabolite of prednisone, on the final
postprednisone placebo (withdrawal) period. day of the initial placebo period and on the last 2 days of prednisone
administration. Blood was collected on ice in an edetic acid-containing
tube and centrifuged at 3000 rpm for 10 minutes. Plasma was stored at
20°C until assayed for prednisolone by RIA following extraction and
feine-restricted, low-monoamine diet beginning 3 days before the chromatography.34 The intra-assay CV was equal to 9.4%, and the
-

study. sensitivity was 14 to 30 pg per tube. The antibody cross-reacts with

prednisone (30%) and cortisol (9.2%). Blood for cortisol was collected
Procedure daily in serum separator tubes and allowed to clot at room tempera¬
ture. Resultant serum was assayed by RIA33 (intra-assay CV 6%, =

Volunteers were hospitalized as inpatients on a National Institutes of interassay C V 6.6%).

=

Health (Bethesda, Md) Clinical Center research ward for 20 days. For
the first 3 days no studies were performed to allow volunteers to
acclimate to their surroundings and to begin the low-monoamine diet.
Following that, placebo capsules were administered for 5 days, followed
by prednisone (80 mg/d orally at 10 AM) for 5 days, followed by placebo
again for 7 days. All medications were administered in a double-blind
manner (ie, subjects, nurses, and raters were unaware of medication
status or of study design). The dose of prednisone and the length of
administration were chosen to match those at which some medically ill
patients being treated with corticosteroids begin to experience behav¬
ioral reactions.2 Previous experience in healthy volunteers with this dose
and regimen in the National Institute of Allergy and Infectious Diseases,
Bethesda, Md, has established that no medical complications were likely
if subjects were screened to exclude those with diabetes mellitus, gastric
ulcer, tuberculosis, or other occult infections (H. Clifford Lane, MD, oral
communication, December 11,1984).
Behavioral Measures
Behavioral measures were obtained daily at the same time of day
throughout the study. Self-ratings, completed between 10 AM and
noon, consisted of the Symptom Checklist 90 (SCL-90),35 which as¬
sesses a variety of behavioral symptoms, and a group of 10 specially
designed visual analogue scales (VAS) rating sadness, anxiety, rest¬
lessness, energy, general well-being, confusion, sensory sharpness,
happiness, irritability, and sexual arousal. Each VAS consisted of a
100-mm horizontal line with polar adjectives as anchor points on either
end (eg, "most sad ever" and "least sad ever"). Volunteers were
instructed to place a perpendicular line through the scale line to
indicate how they were feeling along that dimension then. The score
was determined by measuring the distance in millimeters from the left
end of the scale line to the volunteer's mark. For purposes of analysis,

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Prednisone-associated changes (mean ± SE) in cerebrospinal fluid
levels of proopiomelanocortin-related peptides at baseline (open
bars) and following 5 days of prednisone administration (shaded
bars). BLPH indicates ß-lipotropin; BE, ß-endorphin; -MSH,
-melanocyte-stimulating hormone; and asterisk, P<.03 (paired f
test [corticotropin and BLPH], Wilcoxon Signed-Rank Test [BE]).
the four VAS items energy, happiness, irritability, and sexual arousal
were averaged into one "hypomania" scale. In addition to the self-
ratings, psychiatrists blind to medication status and study design
rated the volunteers' behavior daily (between noon and 1 pm) with the
modified 24-item Brief Psychiatric Rating Scale.36 Finally, subjects
were asked to keep unstructured logs (diaries) of their experiences
throughout the study, and on completion of the experimental protocol
volunteers were specifically asked if they could discern any distinct
behavioral changes during the protocol. Their responses, as well as
unstructured behavioral reports from blinded nursing staff (gleaned
from nursing daily progress notes), were tabulated for descriptive
purposes.
Statistics
Changes in CSF biochemistry values were analyzed by matched
pair t tests unless otherwise specified. Behavioral rating data were a
priori divided into five periods for purposes of analysis: baseline, early
steroid (days 1 to 3), late steroid (days 4 to 5), early withdrawal (days 1
to 3), and late withdrawal (days 4 to 7). Analysis of these data was by
analysis of variance (ANOVA) with repeated measures, with post hoc
t tests to determine significant differences between specific periods.
For correlational analyses of behavioral changes with biologic
changes, we a priori defined a behavioral ratings change as the
difference between the mean rating in the baseline period and the
mean rating in the late steroid period. Correlative analyses between
changes in CSF biochemistry values and changes in behavioral ratings
were performed with the Pearson Product-Moment Correlation and
the Spearman Rank-Order Correlation coefficients as indicated in the
text. Because of our interest in steroidal associations with affective
states, we were most interested in biologic associations with changes
in VAS-rated sadness and hypomania and total SCL-90 ratings. How¬
ever, we also present the full matrix of correlations between CSF
neurochemical changes and changes in the remainder of the behavior¬
al measures to generate hypotheses for testing in more focused follow-
up studies.
Because of the large number of variables tested in this study,
significance levels were adjusted with the multistage Bonferroni
correction.37 We thought that in this exploratory study it was appro¬
priate to select a relatively large familywise (ie, for the entire study,
not individual comparisons) value, .20, to minimize the likelihood of
a type II error,38 recognizing that the likelihood of a type I error is
thereby increased. In all, we tested 10 CSF biochemical variables, 9
behavioral variables, and 90 biochemical-behavioral correlations. In¬
dividual test values were thus determined to be .022 for the behav¬
ioral tests,. 002 for the biochemical-behavioral correlations,. 02 for the
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Table 2— Effects of Prednisone on Cerebrospinal
Fluid Biochemistry*
Placebo Prednisone
(Mean ± SD) (Mean ± SD)
CRH, pg/mL 35.1 ±11.4 31.7±11.4
SLI, pg/mL 37.9±11.1 32.3±13.2f
NE, pmol/mL 0.66 + 0.15 0.52±0.15t
MHPG, pmol/mL 38.0 ±10.8 37.6 ±8.4
HVA, pmol/mL 203.0±83.4 198.2±83.7
5-HIAA, pmol/mt 93.8 ±43.2 94.3 ±41.4
Cortisol, µg/dL 0.67±0.22 0.20±0.0
*CRH indicates corticotropin releasing hormone; SLI, somatostatinlike ¡m-
munoreactivity; NE, norepinephrine; MHPG, 3-methoxy-4-hydroxyphenylgly-
col; HVA, homovanillic acid; and 5-HIAA, 5-hydroxyindoleacetic acid.
fP<.01, paired (test.
<.001, paired?test.
first stage of the CSF biochemical tests, .025 for the second stage, and
.029 for the third stage.
Two additional aspects of our data analysis were addressed. Be¬
cause half of the subjects studied had personal or family history of
psychiatric illness, we separately analyzed the data of the six subjects
without such histories to ascertain whether any of our major findings
were altered in this fully normal subgroup. Second, we anticipated
that examination of group mean changes in specific behavioral vari¬
ables might fail to detect the fluctuating and multidirectional behav¬
ioral changes that we hypothesized would occur, based on previous
studies.1,3 We therefore also descriptively present behavioral data
from the unstructured reports of the blinded subjects and ward
nurses.
RESULTS
Biochemical Measures
Prednisone administration was associated with significant de¬
creases in CSF levels of SLI (i[8] 3.40, P<.01),21 NE ( [8] 4.33,
= =
P<.01), corticotropin (i[8] 2.75, P .025), BLPH (i[8] 2.69,
= = =
=.028), and BE (Wilcoxon Signed-Rank Test: T+=6, =.027;
Figure and Table 2). The BE decrease was unaltered when BE levels
were corrected for BLPH cross-reactivity. The CSF levels of MHPG,
HVA, 5-HIAA, -MSH, and CRH were not significantly altered
(Figure and Table 2). Changes in CSF levels of CRH were, however,
directly correlated with changes in CSF levels of corticotropin
(r=.69, P<.05). These CSF biochemical alterations remained un¬
changed when the subgroup of six subjects without personal or family
psychiatric history was examined separately, with the exception of
the decrease in CSF BE levels (P<.20); also, a decrease in CSF CRH
levels was apparent in this subgroup (t 2.68, P<.05).
=
-
Behavioral Measures
No significant main effects were observed on any of the subjective
VAS scales with the exception of "sensory sharpness," which tended
to show an increase during the prednisone administration period
compared with both placebo periods (ANOVA, F[2,22] 4.15, P<.03
=
[near significant by Bonferroni criteria]; post hoc t tests comparing
baseline with steroid, P<.05; comparing steroid with withdrawal,
P<.05). There were similarly no significant drug effects on group
SCL-90 or Brief Psychiatric Rating Scale ratings.
In contrast to the lack of effect on group mean behavioral measures,
9 of the 12 individual volunteers experienced prednisone-associated
behavioral changes (recorded by unstructured report of the subjects
or of the blinded nursing staff) with discrete onset during the predni¬
sone administration period (Table 1). In contrast, only 1 subject
experienced a behavioral change during the baseline period (mild
euphoria) and 3 subjects experienced behavioral changes during the
withdrawal period. The reported behavioral changes during the ste¬
roid period included mild hypomania (eg, irritability, feeling high or
speeded or more talkative; 8 subjects), decreased sleep (3 subjects),
loss of concentration (2 subjects), mild depression (1 subject), and
depersonalization (2 subjects). The unstructured reports of symptoms
were substantiated by increases (3=10 mm) in individual subject VAS
ratings: 7 reported more happiness, energy, irritability, or restless-
 Table 3.—Correlation Matrix of Changes in CSF Biochemistry and Changes in Behavioral Ratings*
AVAS

Sensory
ASCL-90 Sad Anxious Restless Well-being Confused Sharpness Hypomanic ABPRS
ASLI -60t .68+ .47 -.07 .50 -.25 .14 .68+ .54
75§ .03 .10 .18 .00 -.21 .18 60f .45

ACorticotropin .43 .07 .24 .01 -.15 .45 .40 -85II

ABE .911 .48 .05 .03 .20 .08 .43 .28 .56
ABLPH .32 .22 .52 .901 .42 .901 .37 .22 .15
Aa-MSH .42 .08 .34 .21 .35 .60t .06 .32 .30
ACRH .14 .01 .30 62t .17 .43 .53 -.03 .44
AMHPG .45 .21 .04 .25 .20 -.27 .04 .07
AHVA .17 .02 .28 ,63t .27 711 .17 .18 .30
A5-HIAA .49 .43 60t ,64t .56 .59t .09 .38 .41
Values correlation coefficients. values
are areuncorrected; the critical value for statistical significance using the Bonferroni procedure, as described in the
"Subjects and Methods" section, is .875 (P<.002). CSF indicates cerebrospinal fluid; SCL-90, Symptom Checklist 9035; VAS, visual analogue scale; BPRS, Brief
Psychiatric Rating Scale36; SLI, somatostatinlike immunoreactivity; NE, norepinephrine; BE, ß-endorphin; BLPH, ß-lipotropin; -MSH, -melanocyte-stimulating
hormone; CRH, corticotropin releasing hormone; MHPG, 3-methoxy-4-hydroxyphenylglycol; HVA, homovanillic acid; and 5-HIAA, 5-hydroxyindoleacetic acid.
fP<.1.
<.05.
§P<.02.
||P<.01.
1P<.002.

ness, 5 more sadness, 4 more tiredness, 3 more anxiety, and 2 more
confusion during the steroid period compared with the baseline peri¬
od. There was no difference in the incidence or type of behavioral
reactions between the groups with and without psychiatric histories.
Biochemical-Behavioral Correlations
A correlation matrix of the prednisone-associated changes in CSF
biochemistry and changes in behavioral ratings is given in Table 3.
Relatively high correlation coefficients (rs=.60) were observed be¬
tween changes in CSF levels of SLI, NE, and BE and changes in SCL-
90 ratings and/or VAS sadness and hypomania ratings. The BE-
behavioral correlations were unchanged when BE levels were
corrected for BLPH cross-reactivity. Additionally, changes in CSF
levels of BLPH, -MSH, CRH, HVA, and 5-HIAA were correlated
with changes in VAS-rated restlessness and confusion, and changes in
CSF levels of corticotropin were correlated with changes in Brief
Psychiatric Rating Scale ratings. The relationships between these
biochemical and behavioral changes were also reflected in the sub¬
group of subjects without psychiatric histories. When the more strin¬
gent Bonferroni approach is used to consider the large number of
variables tested, only the correlations of changes in CSF levels of BE
and BLPH with changes in SCL-90 ratings and VAS-rated restless¬
ness and confusion, respectively, remain significant. Specifically,
lesser suppression of CSF BE levels was associated with increased
SCL-90 ratings, and greater suppression of CSF BLPH levels was
associated with increased ratings of restlessness and confusion.
Prednisolone and Cortisol Levels
All volunteers showed an increase in plasma prednisolone levels
during prednisone administration (mean ± SD baseline level, 1.7 ± 0.9
ng/mL, steroid level, 23.9±15.4 ng/mL; <[11]=4.95, P<.001). This
increase was unaltered when prednisolone levels were corrected for
cortisol cross-reactivity. The volunteers also showed significant pred¬
nisone-associated decreases in CSF cortisol levels (¿[8] 6.27, =
P<.001) and in plasma cortisol levels (F[2,22] 24.92, P<.0001) with
=
return of plasma cortisol to baseline levels following prednisone with¬
drawal. Changes in plasma prednisolone levels and in CSF and plasma
cortisol levels were not significantly correlated with changes in behav¬
ioral ratings or with changes in CSF neurochemistry.
COMMENT
We studied the biologic and behavioral effects of predni¬
sone administration in a heterogeneous group of volunteers
not currently suffering from psychiatric or medical illness.
We observed that prednisone administration was associated
with decreases in CSF levels of several biologically and behav-
iorally active neuropeptides or transmitters. There was, how¬
ever, a clear absence of significant prednisone effects on group
mean behavioral measures, although a high percentage of our
volunteers (75%) described or exhibited subtle, diverse be¬
havioral alterations during prednisone administration. Fur¬
thermore, certain behavioral alterations were correlated with
specific prednisone-associated neurochemical alterations.
These preliminary data, derived from the only prospective,
double-blind study of corticosteroid effects in humans to date,
represent a first step toward a better understanding of the
effects of exogenous corticosteroids on human biologic and
behavioral function.
There are a number of important considerations in our
study, however, that limit the inferences that may be drawn
from it: (1) Although all of our volunteers were free of psychi¬
atric illness for at least 2 years, the presence of personal or
family psychiatric histories in half of our volunteers may limit
the generalizability of our findings to individuals without such
histories. The significance of this in the present study is
mitigated somewhat by our use of each subject as his or her
own control and by our demonstration that the major findings
were unaltered in the subgroup of subjects without personal
or family psychiatric histories. Indeed, heterogeneous sam¬
ples, such as we employed, may more closely approximate the
psychiatrically unselected population that is clinically pre¬
scribed synthetic corticosteroids for medical illnesses. (2) Our
use of the small sample size increases the risk of a type II
error; nonetheless, we were able to demonstrate several sig¬
nificant findings. (3) Our analysis of multiple comparisons
poses a further limitation. In exploratory studies such as this,
it is frequently desirable to assess a variety of dependent
measures.38 However, definitive conclusions based on our
study must be tempered because the experiment (familywise)
error rate based on the Bonferroni correction is 0.20. Our data
must, therefore, be considered preliminary and as hypothesis-
generating for future larger-scale and more focused studies.
(4) Since all of our subjects received lumbar punctures in the
same sequence (baseline followed by steroid), it is impossible
to discount the possibility that the observed decreases in
neuropeptide and transmitter levels were secondary to the

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 subjects' adaptation to the lumbar puncture procedure. This
explanation is unlikely, however, in light of our previous
report that CSF levels of lipotropin, corticotropin, iV-terminal
fragment of proopiomelanocortin, BE, -MSH, CRH, and
SLI are reliably reproducible across two lumbar punctures,
spaced at least 3 weeks apart, in normal volunteers.39 (5)
Finally, it is important to emphasize that we examined the
effects of subchronic administration of the synthetic cortico-
steroid prednisone. The relevance of our findings for under¬
standing the behavioral or biochemical disturbances associat¬
ed with endogenous hypercortisolemia4"2 is unclear since
endogenous and exogenous corticosteroids may have different
central nervous system effects," and since, in the case of
hypercortisolemic major depression (for example), the hyper-
cortisolemia is more chronic and insidious, is of a lower magni¬
tude (compared with levels achieved during pharmacologie
administration), and is likely secondary to central alter¬
ations.53
Our preliminary data suggest that CSF corticotropin,
BLPH, BE, SLI, and NE are suppressed by exogenous corti¬
costeroids in humans. This contrasts with studies of the ef¬
fects of exogenous corticosteroids on hypothalamic or whole-
brain peptide levels in animals,** although there may be
interspecies differences, and differences may exist between
corticosteroid effects on brain vs CSF peptide levels. Prior
studies have noted decreased levels of some of these sub¬
stances in the CSF of patients with Cushing's syndrome and in
the CSF of hypercortisolemic or dexamethasone-resistant
patients with a variety of psychiatric illnesses.22,5M8 If endoge¬
nous hyperactivity of cortisol systems in humans has similar
effects to those observed herein with prednisone, it is possible
that these neurochemical changes are at least partially sec¬
ondary to hypercortisolemia. Our finding that CSF levels of a-
MSH were unaffected by prednisone is consistent with the
notion that CSF -MSH may be regulated independently from
other proopiomelanocortin-related peptides.30 Our failure to
find a significant effect of prednisone on levels of CSF CRH in
the total sample is inconclusive since changes in levels of CSF
CRH were directly correlated with changes in levels of CSF
corticotropin and since the subgroup of psychiatrically normal
volunteers did show a decrease in levels of CRH.
In contrast to these biochemical findings, no significant
prednisone-associated changes were noted in group mean
behavioral ratings (with the exception of a near-significant
increase in self-rated sensory sharpness). More prolonged
prednisone administration obviously might have led to a dif¬
ferent pattern or severity of reactions. Analysis of individual
volunteers' VAS ratings and of their (and nurses') unstruc¬
tured reports revealed that 75% of them experienced mild
behavioral alterations during the prednisone administration
period. These alterations were varied but were predominant¬
ly affective, especially hypomanic, in nature. These prelimi¬
nary data are consistent with the data of Hall et al,3 who found
that affective symptoms and "sensory flooding" were the most
commonly reported behavioral symptoms in medically ill pa¬
tients receiving corticosteroids but that the "typical" behav¬
ioral presentation was of a fluctuating transient constellation
of diverse symptoms. This variability and transiency of symp¬
tom development in our sample may have been evidenced by
the absence of significant group mean changes on most of the
specific individual rating scales. No significant correlation
was observed between plasma prednisolone levels and behav¬
ioral responses, further highlighting the variability of re¬
sponse. Our data do not rule out the possibility, however, of
plasma level-response correlations within individual volun¬
teers. The incidence of individuals experiencing behavioral
changes in our study was higher than that generally reported
in medically ill patients being treated with corticosteroids,17
presumably because we included even mild, subjectively ex¬
perienced symptoms, whereas prior studies generally have
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included only severe observer-rated behavioral changes such
as those that would require psychiatric consultation. In a
recent open-label study in which subtle behavioral changes in
prednisone- or corticotropin-treated medically ill patients
were specifically assessed, a high incidence (100%) of symp¬
toms was also noted.8
We observed that prednisone-associated changes in CSF
levels of BE were directly correlated with changes in total
SCL-90 ratings and that changes in CSF levels of BLPH were
inversely correlated with changes in ratings of restlessness
and confusion. A number of studies support a role of central
opioids in mood regulation,5960 although the nature of this
regulation is controversial. Some61 but not all60 investigators
report that CSF opioid levels are increased in patients with
depression and are directly correlated with anxiety and de¬
pression ratings in patients with depression60 and chronic
pain,62 respectively. Furthermore, intrathecal admimstration
of BE in a patient with metastatic cancer produced marked
behavioral changes, including confusion, hypomanic-manic
behavior, and psychosis.63 Prednisone-associated decreases in
CSF levels of SLI and NE were correlated with increases in
SCL-90 or self-rated sadness ratings and with decreases in
self-rated hypomania ratings. While nonsignificant by Bonfer-
roni criteria, these latter correlations do suggest possibilities
to be explored in future studies. The correlation of sadness
ratings with SLI levels is especially intriguing since investiga¬
tors have previously reported decreased CSF SLI levels in
patients with depression64,66 and inverse correlations of sad¬
ness ratings with CSF SLI levels in patients with senile
dementia.66 The decreases in CSF SLI levels we observed
following subchronic prednisone administration, however,
were of considerably lower magnitude than those observed in
patient groups compared with normal subjects.58,64,66
The subchronic administration of a synthetic corticosteroid
such as prednisone may provide a useful model of the behav¬
ioral and biologic changes seen following pharmacologie ad¬
ministration of corticosteroids to medically ill patients. We
and others have previously used such strategies to investigate
the acute effects of dexamethasone on plasma HVA and
MHPG,6'68 on plasma DA and NE,69 and on attention and
memory52 in depressed and normal humans. Future more
focused studies examining larger samples of volunteers will be
needed more fully to characterize the biologic and behavioral
profile of action of corticosteroids in humans.
Somatostatin antiserum was kindly supplied by Seymour Reichlin, MD.
We gratefully acknowledge the nursing support of the 4E Clinical Center
nursing staff; the assay support and manuscript review of Philip W. Gold, MD;
the statistical and manuscript review by John Bartko, PhD; the clinical advice
of H. Clifford Lane, MD; the technical assistance of Chris Hoban, Candy Davis,
Stacy Bellar, Mary Sutton, Luisa Manfredi, and Cathy Argabright; and the
secretarial and editorial assistance of Natasha Page Carroll and Andrea Hobbs.
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