319
Journal of Ajfect~oe Disorders, 5 (1983) 319-332
Elsevier
Steroid-induced
A Report
Psychiatric
of 14 Cases and a Review of the Literature
David A. Lewis and Robert
Department
of Psychiatry,
Syndromes
E. Smith
University of Iowa Hospitals and Clinics, Iowa City, IA 52242 (U.S.A.)
(Received 8 February,
(Accepted 10 March,
1983)
1983)
Summary
Although it is well-established
that psychiatric symptoms can develop in association with the administration
of corticosteroids,
the nature of this relationship
is
poorly understood.
We reviewed 14 previously unreported
cases of steroid-induced
psychiatric
syndromes,
79 cases from the literature and 29 studies of the clinical
efficacy of steroids in various medical illnesses. Our findings indicate that severe
psychiatric reactions occur in approximately
5% of steroid-treated
patients, and that
a large proportion
of these patients have affective and/or
psychotic symptoms.
Psychiatric disturbances
usually occur early in the course of steroid therapy. Female
sex, systemic lupus erythematosus
and high doses of prednisone may be risk factors
for the development
of a steroid-induced
psychiatric
syndrome.
Treatment
with
steroid-taper,
neuroleptics
or electroconvulsive
therapy is generally effective, although tricyclic antidepressants
do not appear to be useful therapeutic agents. Most
patients recover within several weeks of the onset of symptoms.
Introduction
The occurrence of psychiatric
symptoms in association
with the clinical use of
corticosteroids
and adrenocorticotropic
hormone
(ACTH) has been documented
since the introduction
of steroids as therapeutic agents over 30 years ago. However,
the nature of this relationship
has been difficult to evaluate. There are some studies
in the literature which address limited aspects of this problem, but there are no
adequately
controlled
comprehensive
studies of the psychiatric
effects of steroid
therapy. Consequently,
we reviewed case records at the University of Iowa Hospitals,
previous case reports and other sources of information
in the literature in order to
improve our understanding
of these disorders.
0165-0327/83/$03.00
0 1983 Elsevier Science Publishers
B.V.
320
Methods
Review of the University of Iowa Hospital records from July 1976 through June
1981 revealed 14 cases of significant psychiatric syndromes occurring in association
with the administration
of steroid therapy. From a review of the case notes and the
consulting psychiatrist’s evaluation we were able to obtain the following information
about each patient:
age; sex; history of previous psychiatric
illness; premorbid
adjustment
and personality characteristics;
medical indication for steroid treatment;
type, dose and duration
of steroid treatment;
history of other courses of steroid
therapy; type and duration of psychiatric
symptoms;
response to treatment;
outcome.
Review of the literature (Borman and Schmallenberg
195 1; Galdston et al. 195 1;
Brody 1952; Clark et al. 1952; 1953; Cleghorn 1952; Lidz et al. 1952; Ritchie 1952:
Rome and Braceland 1952; Glaser 1953; Toone and Irby 1955; Stern and Robbins.
1960; Train and Winkler 1962; Garner and Falk 1967; Baloch 1974; Villareal et al.
1974; Gilles and Shellshear 1975; Sergent et al. 1975; Blazer et al. 1976; Hall et al.
1979; Pies 1981; Kaufmann
et al. 1982). revealed a total of 102 case reports of
psychiatric symptoms occurring in association with the use of steroids. Twenty-three
cases were excluded from further analysis. In two cases the development
of psychiatric symptoms was more clearly associated with the withdrawal,
than with the
administration,
of steroids (Clark et al. 1952; Ritchie 1952). One case was excluded
because steroids were administered
in an attempt to treat a psychotic disturbance
(Rome and Braceland 1952). Sixteen cases were excluded because the case records
revealed only mild isolated psychiatric symptoms without evidence of a recognizable
psychiatric
syndrome, or because the amount of data recorded was inadequate
to
make further analysis possible (Brody 1952; Lidz et al. 1952; Ritchie 1952; Stern
and Robbins 1960; Blazer et al. 1976). The remaining 79 case reports were reviewed
for the same information
noted above. A complete set of such data was not available
in every case.
In an attempt to find additional
information
about the incidence
and other
aspects of steroid-induced
psychiatric syndromes, we also reviewed 29 studies of the
clinical efficacy of corticosteroids
and ACTH in various medical illnesses. In these
studies, the authors commented,
in varying amounts of detail, on the occurrence of
psychiatric side effects.
Parametric data were analyzed with the Student t-test, using Cochran’s method
for unequal variances when necessary. Categorical
data were analyzed with the
chi-square
test, Fisher’s exact test or McNemar’s exact test, as indicated (Rosner
1982).
Results
Incidence
In 11 uncontrolled
studies (Margolis and Caplan 195 1; Ward et al. 195 1; Goolker
and Schein 1953; Taran et al. 1953; Engleman et al. 1954; De la Riva 1958; Kirsner
321
et al. 1959; Nielsen et al. 1963; Treadwell et al. 1964; Cass et al. 1966; Rosenberg et
al. 1976) involving 935 patients, the incidence of psychiatric symptoms was found to
vary from 13% to 62% with a weighted average of 27.6%. Although the types of
psychiatric
symptoms were not specified in some studies, most of these symptoms
appear to have been mild to moderate changes in mood without the development
of
a full affective syndrome. Other uncontrolled
studies (Margolis and Caplan 1951;
Bunim et al. 1955; Toone and Irby 1955; Kirsner et al. 1959; Cass et al. 1966; Hall
et al. 1967; Marx and Barker 1967; Michael et al. 1967; Smyllie and Connolly 1968;
Hayreh and Watson 1970; Cade et al. 1973; Sergent et al. 1975; Rosenberg et al.
1976) involving 2 555 patients, report the frequency of occurrence of severe psychiatric syndromes,
or constellations
of significant
psychiatric
symptoms.
In these
studies the incidence of psychiatric
syndromes
ranged from 1.6% to 50% with a
weighted average of 5.7%, There was no difference (x2 = 0.167, df= 1, P > 0.50) in
average incidence when the studies reported before 1960 (5.4%) were compared with
later studies (5.8%).
Further information
regarding the incidence of psychiatric syndromes, as well as
the causal nature of steroids in producing
these reactions,
can be found in 4
controlled
studies in the literature. Kirsner et al. (1959) reported on 240 patients
with ulcerative colitis who were treated with several different steroid preparations.
Using the patients as their own controls, these investigators
found that whereas 4.2%
of the patients had experienced
a psychotic disturbance
at some time in their life
prior to the initiation of steroid therapy, 6.3% suffered a psychotic disturbance
while
receiving steroids. Marks and Barker (1967) also studied patients with ulcerative
colitis. Of 50 such patients who were treated with steroids, 12% experienced
a
psychotic disturbance,
whereas only 2.6% of 80 control patients had similar reactions.
Smyllie and Connolly (1968) reviewed the case records of 550 patients who had
been treated with steroids for various respiratory
diseases. They compared
these
patients with 499 patients who had not received steroids over the preceding year.
The 2 groups were approximately
matched for age, sex, type of illness, and year of
entry to hospital. Mental disturbance,
defined as “serious enough to require psychiatric advice and treatment”,
was found in 1.8% of the steroid-treated
group and in
3.2% of the control group. This difference was not statistically significant (x2 = 2.09,
df= 1, P > 0.10).
The clearest evidence that steroids produce psychiatric disturbances
was reported
in a study of patients
with lupus nephritis
who were randomly
assigned to 4
treatment
groups, 2 of which involved the use of prednisone
(Cade et al. 1973).
“Overt psychoses” developed in 32% of the prednisone
treated patients and in only
3.8% of the patients
who did not receive prednisone.
This finding was highly
statistically
significant (Fisher’s exact test, P = 0.012).
Types of psychiatric syndromes
As previously mentioned,
changes in mood or affect, such as mild euphoria or
depression,
are the psychiatric
symptoms most frequently seen in association
with
steroid use. There are no clearly satisfactory methods of categorizing the psychiatric
322
syndromes seen in association with steroids, in large part because the presence and
severity of individual
symptoms can fluctuate dramatically
during the course of the
illness (Hall et al. 1979). One approach to classifying these disorders is to define
them on the basis of the predominant
psychiatric syndrome seen during the course
of the illness. Table 1 lists the frequency of different types of predominant
psychiatric syndromes seen in the 79 case reports in the literature. Depression is the most
common psychiatric disturbance,
accounting for over 40% of the cases, and over 75%
of the patients suffered from an affective syndrome. Ten percent of the patients had
a delirium characterized
by a clouding of consciousness,
disorientation,
changes in
psychomotor
activity, and rapid fluctuations
in symptoms. Fourteen percent of the
cases suffered from a psychotic disorder without evidence of a significant
mood
change or features of a delirium. Disturbance
in reality testing was present in 7 1% of
the patients, whereas 29% had no evidence of psychotic features.
This high incidence of affective syndromes and of psychotic features is confirmed
by our findings that among 14 cases, 8 suffered from an affective syndrome and 9
had psychotic features (Table 2). However, our series differs from the previous case
reports in that a manic syndrome (50%) was much more commonly
seen in our
patients
than was a depressive syndrome
(7%). This difference was statistically
significant (Fisher’s exact test, P = 0.021).
Duration of steroid treatment
In our series, the
psychiatric symptoms
of treatment
was 11
during the first week
weeks of the initiation
obtained from the 70
TABLE
duration
of treatment
with steroids betore the onset of
ranged from 1 day to 54 days (Table 2). The median duration
days. Forty-three
percent of the cases developed symptoms
of treatment, 57% within the first 2 weeks, and 93% within 6
of steroid therapy. These figures are very comparable to those
case reports in the literature which documented
the necessary
1
DISTRIBUTION
OF TYPES OF STEROID-INDUCED
PSYCHIATRIC
CASES PREVIOUSLY
REPORTED
IN THE LITERATURE
SYNDROMES
AMONG
79
(Borman and Schmallenberg
1951; Brody 1952; Clark et al. 1952, 1953; Cleghorn 1952; Lidz et al. 1952;
Ritchie 1952; Rome and Braceland 1952; Glaser 1953; Toone and Irby 1955; Stern and Robbins 1960;
Train and Winkler 1962; Garner and Falk 1967; Baloch 1974; Gilles and Shellshear 1975; Sergent et al.
1975; Blazer et al. 1976; Falk et al. 1979; Hall et al. 1979; Pies 1981).
Psvchiatric
svndrome
Psychotic
Total (‘%)
features
Present
Absent
Depression
Mania
Depression/mania
Psychosis
Delirium
18
16
6
11
5
14
6
0
0
3
32
22
6
11
8
Total
56
23
79 (100)
(40.5)
(27.8)
(7.6)
(13.9)
(10.1)
323
information.
Although
the range of duration
of treatment
before the onset of
symptoms was greater in the cases in the literature (1 day-2 10 days), the median was
very similar (11.5 days). In addition, symptoms developed in 39% of the cases within
the first week of treatment, in 62% of the cases within the first 2 weeks of treatment,
and in 89% of the cases within the first 6 weeks of steroid treatment.
Steroid dose
Evidence regarding the relationship
of the dose of a specific steroid, prednisone,
to the development
of a psychiatric
syndrome
is summarized
in Table 3. The
dose-response
effect of prednisone
on the induction
of psychiatric symptoms was
most clearly demonstrated
in the Boston Collaborative
Drug Surveillance
Project
(1972) in which 676 patients who received prednisone therapy were evaluated for the
development
of acute psychiatric syndromes. These investigators
found a statistically
significant
increased incidence of psychiatric disturbances
with increasing average
daily doses of prednisone (Table 3). Subsequent studies by Sergent et al. (1975) and
Rosenberg et al. (1976), as well as a collection of 22 case reports in the literature
(Train and Winkler 1962; Gilles and Shellshear 1975; Sergent et al. 1975; Blazer et
al. 1976; Garner and Falk 1967; Hall et al. 1979; Pies 1981; Kaufmann
et al. 1982)
appear to substantiate
these findings (Table 3). The evidence from our series also
supports this dose-response
effect; only 23% of the patients had been receiving less
than 40 mg/day of prednisone before the onset of symptoms, whereas 77% had been
receiving greater than 40 mg/day.
Combining
our case reports with those in the
literature, we were unable to find any significant
correlation
between the average
daily dose of prednisone
and the duration of treatment before the onset of symptoms, the duration of symptoms or the type of psychiatric syndrome.
Other courses oj steroid therapy
Although our sample size was too small to investigate this issue, the combination
of our case reports with those previously reported in the literature (Clark et al. 1952;
Clark et al. 1953; Glaser 1953; Train and Winkler 1962; Baloch 1974; Sergent et al.
1975) produced a total of 17 patients with a steroid-induced
psychiatric syndrome
who had received other courses of steroid therapy. Six of these patients
had
experienced
severe psychiatric
symptoms during other courses of steroid therapy,
whereas 11 patients had not. Statistical analysis, comparing the response to the first
course of steroid treatment
with the response to the second course, provided no
evidence that the presence or absence of a psychiatric disturbance
during the initial
course of steroid treatment
predicted
the response
to a subsequent
course of
treatment (McNemar’s exact test, P = 0.79).
49
The patients in our series tended to be slightly older (mean age 50 years) than
those patients which had previously been reported in the literature (mean age 38
years). When all cases were considered together the age ranged from 8 years to 71
years with a mean of 39.6 years. This age distribution
is very similar to the range
(4-84 years) and mean (42.7 years) age found in over 1400 patients treated with
F
F
58
47
53
M
62
8
F
48
F
M
F
61
48
M
62
7
(YO
N
Y
N
N
N
N
N
N
_
ABNL
NL
NL
ABNL
ABNL
NL
ABNL
NL
Case Age Sex Past psy- Premorbid
personality
chiatric
history
IOWA RECORDS
CLINI~AL~HARA~TERISTICSOF
TABLE 2
Asthma
Lung cancer
Crohn’s
disease
COPD
Asthma
Asthma
Kidney
transplant
Idiopathic
thrombotic
ourwra
. .
Medical
illness
8
100
asone
Prednisone
60
60
60
60
40
29
N
N
4
4
21
Y
Y
?
8
7
Mania
N
5
Mania
Mania
Delirium
Mania
Mania
Depression
N
2
Mania
N
Other h Psychiatric
., steroid
Type
therapy
54
(days)
Mean dose Duration
(m&day)
Dexameth-
Prednisone
Prednisone
Prednisone
Prednisone
Prednisone
Prednisone
Type
Steroid treatment
N
Y
N
Y
Y
N
Y
Y
Psychotic
features
syndromes
30
21
I
27
23
14
60
7
Duration
(days)
Steroid taper
Steroid taper
Haloperidol
Lithium
carbonate
Steroid taper
Haloperidol
Steroid taper
Steroid taper
Haloperidol
Antidepressants
ECT
Steroid taper
Haloperidol
Steroid taper
Haloperidol
Treatment
I~~A~E~~FSTER~ID-INDU~EDP~Y~HIATR~~SYNDR~MESOBTAINEDFR~MTHEUN~VERSIT~OF
._ _
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
No effect
Recovery
Outcome
F
M
M
M
18
53
62
71
36
10
11
12
13
14
N
N
Y
N
N
N
NL
NL
ABNL
NL
ABNL
NL
Systemic
IllpUS
erythematosus
idiopathic
thrombotic
purpura
COPD
Systemic
1UpUS
erythematosus
Systemic
lupus
erythematosus
Idiopathic
thrombotic
purpura
Prednisone
Prednisone
Prednisone
Prednisone
Prednisone
Prednisone
48
60
20
97
60
70
Y
N
21
32
Y
N
N
Y
1
34
14
21
ABNL = abnormal; COPD = chronic obstructive pulmonary disease; NL = normal
a Duration of treatment before the onset of psychiatric symptoms.
b Cases 7 and 12 developed a psychiatric syndrome during other courses of steroid therapy;
M
F
22
9
N
N
?
7
2
33
Y
Y
7
?
Y
Y
cases X,9, and 14 did not.
Delirium
Delirium
Delirium
Mania
Psychosis
Psychosis
Steroid taper
Lithium
carbonate
Steroid taper
Haloperidol
Steroid taper
Steroid taper
Haloperidol
None
Steroid taper
Recovery
Persistent
memory
impairment
Recovery
Recovery
Recovery
Recovery
326
TABLE
3
DOSE-RESPONSE
DROMES
EFFECT
OF PREDNISONE
Reference
n
The Boston Collaborative Drug
Surveillance Program
1972
Sergent et al. 1975
676
ON THE INDUCTION
Mean dose (mg/day)
(E with psychiatric
Rosenberg et al.
1916
Case reports
UI cases
(1.3)
syndrome)
(4.6)
h
> 80
(18.4)
28
< 40
41-80
> 80
107
(33)
c 100
(50)
101-180
(58)
> 180
22
(0)
< 20
(16)
21-40
(55)
b 40
13
(0)
< 20
(23)
21-40
(15.3)
(77)
b 40
(7.7)
SYN-
a
41-80
< 40
OF PSYCHIATRIC
(77)
a In the Rosenberg
et al. (1976) study the dose of prednisone
represents the maximum daily dose of
prednisone;
the mean daily dose was not reported.
b In the case reports sections, the figures in parentheses
represent the percent of cases receiving that
average daily dose of prednisone.
steroids in various clinical trials (Margolis and Caplan 195 1; Goolker and Schein
1953; Levin et al. 1953; Bunim et al. 1955; Kirsner et al. 1959; Treadwell et al. 1964;
Michael et al. 1967; Hayreh and Watson 1970; The Boston Collaborative
Drug
Surveillance
Program
1972; Cade et al. 1973; Chan et al. 1981). The striking
similarity in age distribution
between these two groups suggests that age is not a risk
factor for the development
of a steroid-induced
psychiatric syndrome.
Sex
There were an equal number of males and females among our 14 cases. However,
of the 79 cases reported in the literature, 68% were females and only 32% were males.
When cases with systemic lupus erythematosus
(SLE) or rheumatoid arthritis (which
have 9 : 1 and 3 : 1 female-to-male
ratios, respectively) were excluded, there was still
a female predominance
(58% vs. 42%) although it was less marked.
More convincing
evidence that the incidence of steroid-induced
psychiatric syndromes is higher in females can be found in a review of clinical trials in which the
incidence of psychiatric syndromes was reported by sex (Boland 195 1; Taran et al.
1953; Bunim et al. 1955; Toone and Irby 1955; Nielsen et al. 1963; Cade et al.
1973). In these studies, 19.7% of steroid-treated
females developed a psychiatric
disturbance,
whereas only 3.3% of the males did. This difference
was highly
statistically
significant (x2 = 16.9, df = 1, P < 0.001). This finding remained highly
significant, (17.3% versus 2.6%) even when patients with SLE were excluded.
Coexistent medical illness
The incidence of psychiatric
syndromes
in patients
who receive steroid
therapy
32-l
for SLE (Drinkard
et al. 1970; Cade et al. 1973; Sergent et al. 1975) or pemphigus
(Rosenberg et al. 1976) is 32.9% and 20.6%, respectively. Both these incidence rates
are significantly
higher (P < 0.001) than the 5.7% incidence seen when all diseases
are considered together. The incidence of steroid-induced
psychiatric syndromes in
patients with lymphoma
(Hall et al. 1967) multiple sclerosis (Cass et al. 1966)
ulcerative
colitis (Kirsner
et al. 1959; Marx and Barker 1967) or rheumatoid
arthritis (Boland et al. 195 1; Margolis and Caplan 195 1; Levin et al. 1953; Bunim et
al. 1955; Toone and Irby 1955) does not significantly
differ from the expected
incidence.
Past psychiatric history and premorbid personality
None of our 14 cases had a past history of psychiatric illness unrelated to steroid
therapy. Six (43%) were thought to have evidence of a premorbid
personality
disorder. Among 41 cases in the literature,
17% had a prior history of psychiatric
illness unrelated to steroids. Fifty-two percent of 29 cases were reported to have had
an abnormal
premorbid
personality.
No comparable
control data were available
which could be used to determine
whether past psychiatric
illness or premorbid
personality
disturbances
were risk factors for the development
of a steroid-induced
psychiatric syndrome.
Duration of psychiatric syndromes
Among our cases the duration of symptoms ranged from 2 days to 60 days, with a
mean of 21.0 days, irrespective of treatment.
In 56 cases from the literature, the
duration of symptoms ranged from 1 day to 150 days, with a mean of 22.0 days.
Among these 56 cases, 38% had symptoms lasting less than one week, 55% less than
2 weeks, and 93% less than 6 weeks.
When all 68 cases were considered together, patients who developed a delirium
had a significantly
shorter duration of symptoms (mean + SD 5.4 & 3.7 days) than
did patients with either a depressive (26.7 k 36 days) or manic (23.8 + 18 days)
reaction (P < 0.05). There were no statistically significant differences in the duration
of symptoms among the depressive, manic or psychotic (19.3 f 18.8 days) groups.
Outcome
Ninety-three
percent of our cases had a complete recovery from their steroid-induced psychiatric
syndrome;
1 patient (case 13) continued
to have some mild
impairment
in cognitive function during the time of follow-up. Among the cases in
the literature for which outcome was specified, 93% had a complete recovery, 4% had
continued or recurrent psychiatric symptoms, and 3% committed suicide.
Treatment response
Table 2 lists the response to various forms of treatment among our cases. When
our cases were combined with those in the literature, we found that clinical recovery
occurred in 92% of 36 patients treated with steroid taper only, 84% of 25 patients
who received neuroleptics
only, 100% of 8 patients treated with neuroleptics
and
steroid taper or lithium, and 100% of 11 patients who received electroconvulsive
328
therapy. However, none of the 6 patients
improved with that therapy.
who received
tricyclic
antidepressants
Discussion
Our review of 29 studies of the clinical efficacy of corticosteroids
in medical
illness revealed the average incidence of steroid-induced
psychiatric syndromes to be
5.7%, with a maximum incidence of 50%. These findings are quite similar to those
reported in a review of the literature over 20 years ago (5% and 58%, respectively)
(Smyth et al. 1960). These similarities
suggest that the overall incidence of these
disorders has not changed despite differences in the types of steroids used, or other
changes in prescribing
practices. The variation in incidence among the studies is
probably
due to a number of factors including
steroid dose. sex distribution
of
patients, underlying
medical illness and definition of severe psychiatric disturbance.
The causal nature of corticosteroids
in producing
psychiatric
syndromes
is
apparent
from the controlled
studies in the literature, 3 of which demonstrated
a
higher incidence of psychiatric syndromes in steroid-treated
patients than in controls
(Kirsner et al. 1959; Marx and Barker 1967; Cade et al. 1973). Smyllie and Connolly
(1968) did not find a higher incidence of mental disturbance
in their steroid-treated
patients; however, over 94% of their patients were receiving less than 20 mg/day of
prednisone.
Because there is a dose-response
effect of prednisone
on the induction
of psychiatric
symptoms,
this finding suggests that their steroid-treated
patients
would not be expected to have a significantly
higher risk of developing a psychiatric
disturbance
than their controls.
The distribution
of types of psychiatric syndromes found in our review of 79 cases
in the literature is very similar to that reported by Ling et al. (1981). These authors
found that among 55 anecdotal cases (of which 46 were included in our 79 cases),
40% had a depressive syndrome, 31% had a manic syndrome,
11% had both manic
and depressive
symptoms
and 16% experienced
acute psychotic reactions.
Our
findings also confirm the high incidence of psychotic features (58%) found by these
authors.
In our 14 cases, a manic syndrome
was more commonly
seen than was a
depressive
syndrome.
This difference
might possibly be related to the higher
frequency
of prednisone
use in these 14 cases (93%) than in the cases from the
literature (24%). However, among the 22 cases in the literature in which prednisone
was used, the incidence of a depressive syndrome was 45.5% and the incidence of a
manic syndrome was 36.4%. This finding demonstrates
that prednisone
administration is not associated
with a greater frequency
of manic reactions
than is the
administration
of other types of steroids. Since most of our cases were identified
because they had been referred for psychiatric
consultation,
a more plausible
explanation
of our findings
may be that nonpsychiatric
physicians
feel more
comfortable
managing a depressive syndrome than a manic one.
Our 14 cases and those in the literature suggest that adverse psychiatric reactions
to steroid therapy usually occur early in the course of treatment. This pattern is also
329
confirmed by the report of Smyllie and Connolly (1968) who observed that during a
3-year follow-up of patients receiving steroids, most of the psychiatric
reactions
occurred within the first month of treatment.
This time clustering of psychiatric
symptoms may be due to the dose-response
effect of steroids and consequently
it
may reflect the prescribing
pattern for steroids; that is, steroids are frequently
administered
with an initial large dose and subsequent
tapering of the daily dose.
Although
early investigators
were unable to find any consistent
relationship
between the dose of steroids and the onset of psychiatric disorders (Goolker and
Schein 1953) it is clear from the evidence summarized
in Table 3 that increasing
doses of at least one steroid, prednisone,
are associated with an increased risk of a
psychiatric
reaction. Our failure to find any significant
correlation
between the
average daily dose of prednisone
and the duration of treatment before the onset of
symptoms,
the duration
of symptoms
or the type of psychiatric
syndrome
is
consistent with the findings of other investigators
(Clark et al. 1953; Glaser 1953).
The lack of association between the psychiatric responses to the first and second
courses of steroid treatment
demonstrated
in this study confirms the opinions of
other investigators
(Clark et al. 1953; Guze 1967; Hall et al. 1979). This finding
implies that the presence or absence of a psychiatric reaction to a previous course of
steroids is not helpful diagnostically
in assessing patients who develop psychiatric
symptoms while receiving steroids. In addition, this evidence suggests that it is not
reasonable
to withhold further steroid therapy solely on the basis of a history of a
steroid-induced
psychiatric disturbance,
Age does not appear to be a risk factor for the development
of steroid-induced
psychiatric syndromes. However, females do appear to be at higher risk than males.
This difference
cannot be explained
by the higher incidence
of a predisposing
medical illness (SLE) in females. It was not possible though, to control for a possible
influence
of steroid dose on the higher incidence
of steroid-induced
psychiatric
syndromes seen in females.
Patients with SLE clearly have a higher incidence of psychiatric disturbances
in
association with steroid administration
than do patients with other medical illnesses.
Although psychiatric
symptoms can be a manifestation
of SLE alone, Cade et al.
(1973) clearly demonstrated
a significantly
higher incidence of psychiatric reactions
in patients with SLE who received steroid therapy than in controls. Thus, although
steroid treatment is not a necessary nor a sufficient cause for the development
of
psychiatric
symptoms
in patients
with SLE, these two factors are additive in
producing
a higher incidence of psychiatric
symptoms than would be seen in the
presence of either factor alone. It should be noted though, that the possible influence
of sex or steroid dose could not be controlled for in this analysis.
It is not possible to determine from our data whether past psychiatric illness or
premorbid
personality
disturbances
are risk factors for the development
of a
steroid-induced
psychiatric syndrome. Although some early investigators
felt that a
history of psychosis was a contraindication
to steroid therapy (Copeman et al. 1954),
other investigators
found no evidence that prior psychiatric
illness predisposed
patients to the development
of a mental disturbance
during steroid therapy (Clark et
al. 1952, 1953; Lewis and Fleminger
1954; Hall et al. 1979). The only controlled
330
data on this topic were reported by Goolker et al. (1953) who found no differences
among 3 categories of premorbid personality adjustment
in the incidence of mental
disturbances
during steroid therapy.
Although
some patients have a protracted
course, over 50% of cases recover
within 2 weeks and over 90% are well within 6 weeks of the onset of symptoms.
Patients with a delirium have a significantly
shorter duration of symptoms than do
patients who develop an affective syndrome.
Our data, as well as that previously reported in the literature, indicate that most
patients with a steroid induced psychiatric
syndrome
experience a complete recovery, although a small percentage
of patients have persistent
symptoms.
The
outcome data also indicate that suicide potential must be carefully assessed in these
patients.
Treatment
with steroid-taper,
neuroleptics
or electroconvulsive
therapy,
depending
on the clinical picture, is generally effective in these patients. However,
tricyclic antidepressants
do not appear to be useful therapeutic
agents, and may
actually exacerbate
the symptoms
induced by steroids (Hall et al. 1978). Prophylactic treatment with lithium carbonate has been reported in a single study to be
useful in decreasing the incidence of steroid-induced
psychiatric syndromes (Falk et
al. 1979).
References
Baloch, N.. ‘Steroid Psychosis’ - A case report, Brit. J. Psychiat., 124 (1974) 545-546.
Blazer, D.G., Petrie, W.M. and Wilson, W.P., Affective psychosis following renal transplant.
Dis. New.
Syst., 37 (1976) 663-667.
Boland, E.W., Prolonged uninterrupted
cortisone therapy in rheumatoid
arthritis, Br. Med. J.. II (1951)
191-199.
Bolton, W.K., Atuk, N.O., Sturgill, B.C. and Westervelt,
F.B., Therapy of the idiopathic
nephrotic
syndrome with alternate day steroids, Am. J. Med., 62 (1977) 60-70.
Borman, M.C. and Schmallenberg,
H.C., Suicide following cortisone treatment, J. Amer. Med. Ass.. 146
(195 1) 337-338.
The Boston Collaborative
Drug Surveillance Program, Acute adverse reactions to prednisone in relation
to dosage, Clin. Pharmacol. Ther., 13 (1972) 694-698.
Brody, S., Psychiatric observations
in patients treated with cortisone and ACTH, Psychosom. Med., 14
(1952) 94-103.
Bunim, J.J., Ziff, M. and McEwen, C., Evaluation of prolonged cortisone therapy in rheumatoid arthritis.
Amer. J. Med., 18 (1955) 27-40.
Cade, R., Spooner, G., Schlein, E., Pickering, M., De Quesada. A., Holcomb. A.. Juncos, L., Richard, G.,
Shires, D., Levin, D., Hackett, R.. Free, J., Hunt, R. and Fregly, M., Comparison
of azathioprine.
prednisone,
and heparin alone or combined in treating lupus nephritis, Nephron, 10 (1973) 37-56.
Cass, L.J., Alexander, L. and Enders, M., Complications
of corticotropin
therapy in multiple sclerosis, J.
Amer. Med. Ass., 197 (1966) 105-l 10.
Chan, L., French, M.E., Oliver, D.O. and Morris, P.J., High- and low-dose prednisolone,
Transplant.
Proc., 13 (1981) 336-338.
Clark, L.D., Bauer. W. and Cobb, S., Preliminary
observations
on mental disturbances
occurring
in
patients under therapy with cortisone and ACTH, N. Engl. J. Med.. 246 (1952) 205-216.
Clark, L.D., Quarton,
G.C., Cobb, S. and Bauer, W., Further observations
on mental disturbances
associated with cortisone and ACTH therapy, N. Engl. J. Med., 249 (1953) 178-183.
Cleghorn, R.A., Drugs that produce deviations in mood, including anxiety, presumably without impairing
capacities for orientation
or at least secondarily to changes in mood, Amer. J. Psychiat., 108 (1952)
568-571.
331
Copeman,
W.S.C.. Savage, O., Dodds, C., Glyn, J.H. and Fearnley, M.E., Management
of rheumatoid
arthritis with prolonged cortisone administration,
Br. Med. J., I (1954) 1109-l 113.
De la Riva. G.E., Psychic and somatic changes observed in allergic children after prolonged
steroid
therapy, South. Med. J., 51 (1958) 865-868.
Drinkard.
J.P., Stanley, T.M., Dornfeld, L., Austin, R.C., Barnett. E.V.. Pearson, CM., Vernier. R.L..
Adams, D.A., Latta, H. and Gonick, H.C., Azathioprine
and prednisone
in the treatment of adults
with lupus nephritis, Medicine (Baltimore). 49 (1970) 41 I-432.
Engleman, E.P., Krupp, M.A., Saunders, W.W., Wilson, L.E. and Fredell. E.W., Rheumatoid
arthritis ~
An evaluation of long-term treatment with cortisone, California Med., 80 (1954) 3699374.
Falk,. W.E., Mahnke. M.W. and Poskanzer, D.C., Lithium prophylaxis
of corticotropin-induced
psychosis, J. Amer. Med. Ass., 241 (1979) 1011~1012.
Galdston,
M., Weisenfield.
S., Benjamin, B. and Rosenbluth,
M.B.. Effect of ACTH in chronic lung
disease, Amer. J. Med., 10 (1951) 166-175.
Garner, H.H. and Falk, M.A.. Toxic psychosis ~ Pemphigus and psychiatric disease. Psychosomatics.
8
(1967) 133-137.
Gilles, A.H.B. and Shellshear, I.D., Unwanted corticosteroid
effects in childhood bone marrow failure.
renal failure and brain damage - Case report, N.Z. Med. J., 81 (1975) 4244427.
Glaser, G.H., Psychotic reactions induced by corticotropin
(ACTH) and cortisone. Psychosom. Med. 15
(1953) 280-291.
Goolker, P. and Schein, J., Psychic effects of ACTH and cortisone. Psychosom. Med., 15 (1953) 5899613.
Guze, S.B., The occurrence of psychiatric illness in systemic lupus erythematosus,
Amer. J. Psychiat.. 123
(1967) 1562-1570.
Hall. R.C.W.. Popkin. M.K. and Kirkpatrick.
B., Tricyclic exacerbation
of steroid psychosis, J. Nerv.
Ment. Dis., 166 (1978) 738-742.
Hall, R.C.W., Popkin, M.K.. Stickney, S.K. and Gardner. E.R.. Presentation
of the steroid psychoses. J.
Nerv. Ment. Dis., 167 (1979) 229-236.
Hall, T.C., Choi, OS., Abadi, A. and Krant, M.J., High-dose corticoid therapy in Hodgkin’s disease and
other lymphomas,
Ann. Intern. Med., 66 (1967) 1144-I 153.
Hayreh, S.S. and Watson, P.G., Prednisolone-21-stearoylglycolate
in scleritis, Brit. J. Ophthal.. 54 (1970)
394-398.
Kaufmann,
M., Kahaner, K., Peselow, ED. and Gershon. S., Steroid psychoses ~ Case report and brief
overview, J. Clin. Psychiat., 43 (1982) 75-76.
Kirsner. J.B., Palmer, W.L., Spencer. J.A.. Bicks, R.O. and Johnson, C.F., Corticotropin
(ACTH) and the
adrenal steroids in the management
of ulcerative colitis - Observations
in 240 patients, Ann. Intern.
Med., 50 (1959) 891-927.
Levin. M.H., Rive. J.B., Scott, W., Figueroa, W.G., Fred, L. and Barrett, T.F.. The prolonged treatment
of rheumatoid
arthritis with cortisone and corticotropin,
Amer. J. Med., 14 (1953) 2655274.
Lewis, A. and Fleminger, J.J.. The psychiatric
risk from corticotrophin
and cortisone, Lancet, i (1954)
383-386.
Lidz, T., Carter, J.D., Lewis, B.I. and Surratt, C., Effects of ACTH and cortisone on mood and mentation,
Psychosom. Med., 14 (1952) 3633377.
Ling, M.H.M., Perry, P.J. and Tsuang, M.T., Side effects of corticosteroid
therapy - Psychiatric aspects,
Arch. Gen. Psychiat., 38 (1981) 471-477.
McGehee, E.H. and MacLean,
K., Experiences with A.C.T.H. and cortisone - A note on long-term
therapy, Brit. Med. J., I (1954) 1171-1175.
Margolis, H.M. and Caplan. P.S., Effects of pituitary adrenocorticotropic
hormone (ACTH) in rheumatoid
arthritis. J. Amer. Med. Ass., 145 (1951) 382-388.
Marx, F.W. and Barker, W.F.. Surgical results in patients with ulcerative colitus treated with and without
corticosteroids,
Am. J. Surg., 113 (1967) 1577 163.
Medical
Research
Council
Panel on the Dermatological
Applications
of A.C.T.H.
and Cortisone,
Treatment of skin disorders with A.C.T.H. and cortisone, Brit. Med. J., II (1954) 1307- 13 13.
Michael, A.F., Vernier. R.L., Drummond.
K.N., Levitt, J.I., Herdman. R.C.. Fish, A.J. and Good, R.A.,
Immunosuppressive
therapy of chronic renal disease, N. Engl. J. Med., 276 (1967) 817-828.
332
Nielsen, J.B., Drivsholm,
A., Fischer, F. and Brochner-Mortensen,
K., Long-term
treatment
with
corticosteroids
in rheumatoid
arthritis (over a period of 9 to 12 years), Acta Med. Stand., 173 (1963)
177-183.
Pies, R., Persistent bipolar illness after steroid administration,
Arch. Intern. Med., 141 (1981) 1087.
Rees, L., Psychological
concomitants
of cortisone and ACTH therapy, J. Ment. Sci., 99 (1953) 497-504.
Ritchie, E.A., Toxic psychosis under cortisone and corticotrophin.
J. Ment. Sci., 102 (1952) 830-837.
Rome, H.P. and Braceland, F.J., Psychological
response to corticotropin,
cortisone, and related steroid
substances. J. Amer. Med. Ass., 148 (1952) 27-30.
Rosenberg,
F.R., Sanders, S. and Nelson, C.T., Pemphigus - A 20-year review of 107 patients treated
with corticosteroids,
Arch. Dermatol.,
112 (1976) 962-970.
Rosner, B., Fundamentals
of Biostatistics, Duxbury Press, Boston, MA, 1982.
Sergent, J.S., Lockshin, M.D.. Klempner,
M.S. and Lipsky, B.A.. Central nervous system disease in
systemic lupus erythematosus
- Therapy and prognosis, Amer. J. Med., 58 (1975) 644-654.
Smyllie, H.C. and Connolly,
C.K., Incidence
of serious complications
of corticosteroid
therapy in
respiratory
disease, Thorax, 23 (1968) 571~581.
Smyth, C.J., Black, R.L., Demartini, F.E., Duff, I.F., Engleman, E.P., Graham, D.C., Montgomery,
M.M.,
Polley, H.F., Rosenberg, E.F., Sacasa, C.F., Steinbrocker,
O., Waine, M. and Wilson, G.M., Rheumatism and arthritis - Review of american and english literature of recent years, Ann. Intern. Med., 53
(1960) l-365.
Stern, M. and Robbins, ES., Psychoses in systemic lupus erythematosus,
Arch. Gen. Psychiat., 3 (1960)
205-2 12.
Taran, L.M., Gulotta, G.A., Szilagyi, N., Jablon, J.M. and Lane, W.K.. Effect of cortisone and ACTH on
the protracted
phase of rheumatic carditis in children, Amer. J. Med.. 14 (1953) 275-283.
Toone, E.C. and Irby, R., Effect of cortisone in the long-term treatment of rheumatoid
arthritis, Amer. J.
Med., 18 (1955) 41-50.
Train, G.J. and Winkler, E.G., Homicidal psychosis while under ACTH - Cortico-steroid
therapy for
pemphigus vulgaris during involution, Psychosomatics,
3 (1962) 3 17-322.
Treadwell, B.L.J., Sever, E.D., Savage, 0. and Copeman, W.S.C., Side-effects of long-term treatment with
corticosteroids
and corticotrophin.
Lancet 1 (1964) 112 I- 1123.
Villareal, S.V., Escande, M. and Levet, C., A propos des psychoses cortisoniques,
Ann. Med. Psychol.. 132
(1974) 523-530.
Ward, L.E., Slocumb, C.H., Polley, H.F., Lowman, E.W. and Hench, P.S., Clinical effects of cortisone
administered
orally to patients with rheumatoid
arthritis, Proc. Mayo Clin.. 26 (1951) 361-370.