Original Research Reports

Corticosteroid-Induced Psychotic and Mood Disorders

Diagnosis Defined by DSM-IV and Clinical Pictures

KEN WADA, M.D., NORIHITO YAMADA, M.D.

TOSHIKI SATO, M.D., HIROSHI SUZUKI, M.D.
MASAHITO MIKI, M.D., YOMEI LEE, M.D.
KAZUFUMI AKIYAMA, M.D., SHIGETOSHI KURODA, M.D.

The authors investigated long-term outcome and treatment strategy of corticosteroid-induced psy-
chotic and mood disorders as defined by DSM-IV. Review of medical records of 2,069 referral
patients revealed 18 applicable patients. Their clinical characteristics, longitudinal courses, and
treatments were studied. The authors identified 15 patients with mood disorder and 3 patients
with psychotic disorder. Increasing doses or resumption of corticosteroids had the strongest influ-
ence on the psychiatric course. These two corticosteroid-induced psychiatric disorders may have
different pathophysiological substrates closely related to patient vulnerability. Effective psycho-
pharmacological treatment options were indicated with consideration being given to the underly-
ing diseases. (Psychosomatics 2001; 42:461–466)

C orticosteroids often induce psychiatric syndromes, in-

cluding depression, mania, psychosis, and delir-
1–8
ium. The syndromes are conventionally known as “ste-
roid psychosis,” which is regarded to be a representative
exogenous psychiatric disorder. However, steroid psycho-
sis is not a specific clinical entity but consists of hetero-
geneous syndromes with obviously different pathophysio-
logical mechanisms. Established diagnostic criteria such as
those in DSM-IV have scarcely been used in previous stud-
ies to evaluate the psychiatric symptoms. Both the symp-
toms and the diagnosis of steroid psychosis are ambiguous.
Corticosteroids can provoke both mania and depression
that clinically appear opposite to each other. Conversely, it
is suggested that abnormality of the hypothalamo-pituitary-
adrenal axis is associated with pathophysiology in mood
disorders.9 Thus, clinical studies of psychiatric syndromes
induced by corticosteroid treatment are challenging and
can shed some light on the pathomechanisms of endoge-
nous psychiatric disorders. There is an urgent need for
clinical research focused on the longitudinal course and
therapeutic response of these cases.
Patients treated with corticosteroids should receive in-
tensive or long-term maintenance treatment because of ex-
acerbations of their underlying diseases. Recurrent psychi-
atric syndromes induced by corticosteroids can therefore
be observed in clinical practice. When corticosteroid-
induced psychiatric syndromes emerge, physicians have
difficulty in treating the underlying medical diseases. Al-
though convincing data on recurrence and prophylaxis are
needed for psychiatric intervention, previous studies of
“steroid psychosis” have directed little attention to long-
term outcome and treatment strategy.10–16
This study of patients with corticosteroid-induced psy-
chotic and mood disorder, as defined by DSM-IV, ad-
Received November 15, 2000; revised March 23, 2001; accepted March
12, 2001. From the Department of Neuropsychiatry, Okayama Univer-
sity Medical School 2-5-1, Shikata-cho, Okayama 700-8558, Japan, De-
partment of Psychiatry, Hiroshima City Hospital, 7-33, Moto-machi,
Naka-ku, Hiroshima 730-8518, Japan. Address correspondence and re-
print requests to Dr. Wada Department of Psychiatry, Hiroshima City
Hospital, 7-33, Moto-machi, Naka-ku, Hiroshima 730-8518, Japan.
E-mail: kenwada@do3.enjoy.ne.jp
Copyright 䉷 2001 The Academy of Psychosomatic Medicine.

Psychosomatics 42:6, November-December 2001 461

Steroid Psychosis
dressed the following questions. 1) Which is the more fre-
quent manifestation, psychosis or mood disorder? 2) Are
there any symptomatological characteristics in each pa-
tient group? 3) What influences the longitudinal course?
4) What is the appropriate therapeutic intervention?
METHODS
From 1990 to 1999, 2,069 patients were referred from other
departments to the Department of Neuropsychiatry, Oka-
yama University Medical School. Review of the records
from our department revealed that 18 patients fulfilled the
following criteria: 1) no previous psychiatric history and
first referral to our department during the examination pe-
riod; 2) DSM-IV criteria for corticosteroid-induced psy-
chotic or mood disorder; and 3) psychiatric symptoms con-
tinuing for at least 1 week. Although DSM-IV criteria do
not specify the duration of symptoms for substance-
induced psychotic or mood disorder, the third criterion was
employed to exclude transient mood change. By reviewing
notes and evaluations of these cases by consultant psychi-
atrists, we aimed to elucidate the clinical characteristics
including the frequency of recurrence, psychiatric symp-
tomatology, response to treatment, and outcome.
The nonparametric Mann-Whitney U test was used for
statistical analyses, with a significance level of P⬍0.05.
RESULTS
We identified 15 patients with mood disorder and 3 patients
with psychotic disorder. The prevalence rate of these dis-
orders among the referred cases was 0.87%. The sample
consisted of 4 men and 14 women whose age at onset
ranged from 18 to 68. Their first psychiatric episode oc-
curred 1 to 20 weeks after commencement of corticosteroid
treatment. Oral prednisolone was most frequently admin-
istered. Intravenous methylprednisolone was given to pa-
tients for corticosteroid pulse therapy at a dose of 500 mg
or 1 g/day for 3 consecutive days.
Eight of the mood disorder patients had a single epi-
sode and seven had recurrent episodes (Table 1). It is in-
teresting that the first mood episode was manic or hypo-
manic in five patients each in both the single-episode and
recurrent subgroups. All except two patients had their first
mood episode after the first corticosteroid treatment. The
average age of the recurrent subgroup was lower than that
of the single-episode subgroup. Maximum prescribed
doses of corticosteroid and latency to the onset were not
different between the two patient subgroups. According to
462
underlying diseases and disease severity, doses equivalent
to prednisone 30–60 mg/day were initially prescribed.
Recurrent patients showed several interesting clinical
features (Table 1).17 All seven patients presented bipolar
disorder and none had recurrent depressive disorder. These
patients presented 19 mood disorder episodes, 11 manic
and 8 depressive. Five of the seven recurrent patients had
manic episodes accompanied by psychotic features such as
auditory hallucinations and persecutory delusions. During
the follow-up period, five patients showed mood episodes
(four depressive and one manic) that were not related to
either alterations in dose or resumption of corticosteroids.
Various psychosocial stressors, such as occupational diffi-
culties and marital problems, preceded their mood epi-
sodes. Four of the five patients who received high doses of
intravenous methylprednisolone rapidly became manic or
hypomanic. Depressive stupor was observed in two pa-
tients and two other patients attempted suicide by self-mu-
tilation. Six patients showed depressive episodes, four of
whom were diagnosed as severe. No patient developed a
depressive episode that coincided with psychotic features.
Among the single-episode patients (n⳱8), one
showed manic episode with psychotic features and two be-
came rapidly depressive after steroid pulse therapy. Each
of three depressive episodes was relatively mild, and no
patient developed either depressive stupor or suicidality.
Because underlying medical diseases of the eight patients
were brought under control, corticosteroids were with-
drawn or titrated to a low maintenance level. Neither in-
creasing doses nor resumption of corticosteroids was in-
dicated as the triggering factor in these patients except one
patient who showed manic episodes after the second course
of treatment.
The mood disorder patients were treated with mood
stabilizers, antipsychotics, and antidepressants (Table 2).
Corticosteroids were simultaneously tapered as quickly as
possible. Manic episodes were treated with antipsychotics
alone or in combination with mood stabilizers. Carbamaz-
epine and valproate were the preferred mood stabilizers.
Antipsychotics were effective at relatively low doses. De-
pressive episodes were effectively treated with antidepres-
sants (including tricyclics), except for one patient who ex-
hibited drowsiness as an adverse effect. Intravenous
clomipramine was very effective in two patients with de-
pressive stupor. No patient became more depressed after
receiving antidepressants for depressive symptoms. One
patient with four previous mood episodes experienced no
recurrence under maintenance treatment with carbamaze-
pine (600 mg/day) despite receiving three additional
Psychosomatics 42:6, November-December 2001
 Wada et al.

TABLE 1. Clinical characteristics of mood disorder patients

Subgroup Gender Age at Onset (years) Underlying Disease Polarity Psychotic Features Pulse Therapy
Recurrent
Case 1 F 18 Nephrotic syndrome M-D*-D-M Ⳮ Rapidly induced mania
2 F 21 Polymyositis D-M-D* - Rapidly induced mania
3 F 23 Ulcerative colitis M-D* Ⳮ Not done
4 F 31 SLE D-M Ⳮ Induced depression
5 M 47 SLE M-M Ⳮ Not done
6 M 42 Kidney transplant M-M-D-M* Ⳮ Rapidly induced mania
7 M 68 Nephrotic syndrome M-D* - Rapidly induced mania

Single Episode
Case 1 F 43 Nephrotic syndrome D - Done without exacerbation
2 F 46 Polymyositis D - Rapidly induced depression
3 F 47 SLE D - Rapidly induced depression
4 F 50 Pemphigus vulgaris M - Not done
5 F 54 Polyarteritis nodosa M Ⳮ Not done
6 F 58 Dermatomyositis M - Not done
7 F 63 Bullous pemphigoid M - Not done
8 M 65 Nephrotic syndrome M - Not done

Note: M ⳱ manic and hypomanic episode; D ⳱ depressive episode; * ⳱ mood episode unrelated to steroid therapy; SLE ⳱ systemic lupus
erythematosus.

courses of corticosteroid pulse therapy. No severe adverse were Systemic lupus erythematosus (SLE) (two patients)
effects were observed except for rashes induced by car- and bullous pemphigoid. All three patients initially showed
bamazepine. Each episode of these 15 patients had a rela- typical schizophrenic symptoms such as persecutory de-
tively good outcome with full remission after 1–3 months. lusions, auditory hallucinations and disorganized behav-
Two of the three psychotic disorder patients were re- iors. However, the two recurrent patients had atypical
current. Underlying medical diseases of these three patients symptoms, including depressed mood, agitation, and pro-
gressive reduction in contact and reactivity, in the follow-
ing episodes. Latency of onset ranged from 2 to 4 weeks.
Maximum oral dosage of corticosteroid did not differ from
TABLE 2. Effective treatments for mood disorder patients
that of mood disorder patients. Only one patient received
Subgroup Mania Depression Prophylaxis
corticosteroid pulse therapy without showing any exacer-
Recurrent
bation of psychotic symptoms. Every patient was effec-
Case 1 CBZ nTCAⳭCZP CBZ
2 AP TCA Li tively treated with a relatively low dose of haloperidol (ⱕ3
3 AP TCA Not done mg/day).
4 AP TCA AP
5 AP No episodes Not done
6 VPA nTCA VPA DISCUSSION
7 CBZ nTCA None

Single Episode 1) Which is the more frequent manifestation, psychosis or

Case 1 No episodes TCA Not done mood disorder?
2 No episodes Steroid tapering only Not done
It is widely accepted that affective symptoms are the
3 No episodes nTCA Not done
4 AP No episodes Not done most prominent clinical features in “steroid psychosis.”2–8
5 VPA No episodes Not done Lewis and Smith4 reported that there were seven mania,
6 AP No episodes Not done one depression and two psychoses in their original series.
7 AP No episodes Not done
8 VPA No episodes Not done They also cited 60 mood disorders and 11 psychoses from
their review of the literature. Ling et al.5 found 45 patients
Note: AP ⳱ antipsychotic; CBZ carbamazepine; CZP clonazepam; with mood disorder and 9 with acute psychosis. In keeping
Li lithium carbonate; nTCA non-tricyclic antidepressant; TCA with these studies, we identified more mood disorders than
tricyclic antidepressant; VPA valproate.
psychotic disorders [15:3], as defined by DSM-IV. Of the

Psychosomatics 42:6, November-December 2001 463

Steroid Psychosis
15 mood disorder patients, 6 (40%) had manic episodes
with psychotic features, indicating a higher incidence of
psychotic features in corticosteroid-induced mania than in
primary mania. Goodwin and Jamison18 estimated that
among patients with primary mania, 18% had auditory hal-
lucinations and 28% had persecutory delusions. This re-
search shows that corticosteroids tend to induce mood dis-
order, which is frequently accompanied by psychotic
features and, at a lower incidence, psychotic disorder.
Corticosteroids can affect various psychiatric functions,
including mood, cognition, and thought, and can induce
different psychiatric syndromes based on the patient’s
vulnerability. Furthermore, we did not observe any recur-
rent patients who emerged into other types of disorder
during the examination period. These two corticosteroid-
induced psychiatric syndromes may have distinct patho-
physiological substrates.
2) Are there any “symptomatological characteristics”
in each patient group?
Among 15 mood disorder patients, 10 were manic or
hypomanic at onset and 12 presented with bipolar disorder.
Although there is a possibility that not every patient with
mild affective symptoms was referred to a psychiatrist, we
identified no patient with recurrent monopolar depressive
episodes. Therefore, it is quite plausible that corticosteroid-
induced mood disorder and primary bipolar disorder have
common biological substrates. In primary bipolar disor-
ders, both manic and depressive episodes are considered to
occur with equal frequency, and the latter are predominant
in female patients in the longitudinal course.18 Although
some previous reports of “steroid psychosis”4,5 demon-
strated a higher incidence of depression than mania, recur-
rent cases were rarely included in these studies. Taken to-
gether, our findings from a predominantly female sample
confirm a higher incidence of mania in corticosteroid-in-
duced mood disorder.17
A number of previous studies reported that steroid
psychosis often involves variable and atypical clinical fea-
tures. This characteristic could have resulted from the het-
erogeneity of the study subjects who were not diagnosed
according to established criteria. However, our findings
suggest that it partially accounts for manic episodes, which
are frequently accompanied by psychotic features. Our two
psychotic disorder patients recurred with atypical symp-
toms, which is consistent with previous findings.2,4,5
It is of clinical interest that 16 of the 18 patients
showed subacute onset ranging from 2 to 12 weeks in their
first psychiatric episode. This may indicate that psychiatric
episodes develop after a certain secondary intracerebral
464
change, such as gene expression and receptor sensitivity
following corticosteroid treatment. Recurrent episodes did
not occur sooner after corticosteroid resumption or esca-
lation than did earlier episodes. Although rather acute onset
has been reported previously,2,4,5 this is probably because
acute heterogeneous syndromes such as delirium and tran-
sient mood change were included.
3) What influences the longitudinal course?
Increased doses or resumption of corticosteroids,
whether the underlying medical disease continues to be
stable or not, had the strongest influence on the psychiatric
course. In all nine patients with single episodes, cortico-
steroids were withdrawn or titrated to low maintenance
doses during the examination period. However, five of the
seven recurrent mood disorder patients became manic or
depressive without altering the dosage of corticosteroids.
This finding suggests that some patients could acquire sus-
ceptibility to mood disorders once corticosteroids are
given. These patients would probably show recurrent
course due equally to subsequent treatment and psycho-
social stressors. In other words, this intrinsic susceptibility
would not be specific to subsequent corticosteroid chal-
lenge. Despite our small number of subjects, we could not
observe recurrences unrelated to corticosteroid treatment
in psychotic disorder patients. It may be speculative that
some differences exist in the tendency to acquire suscep-
tibility after initial corticosteroid treatment between these
two corticosteroid-induced psychiatric syndromes.
A significant age difference was observed between
two mood disorder patient subgroups. Our data could not
fully explain why age at onset is lower in recurrent patients.
There is a possibility that repeated corticosteroid treatment
might be required for younger patients with onset of un-
derlying medical diseases. Alternatively, younger patients
may acquire the susceptibility mentioned above more eas-
ily than older patients. However, single-episode mood dis-
order patients might have had recurrences, with subsequent
corticosteroid treatment or dose increases.
4) What is the appropriate therapeutic intervention?
A few reports11,12,19 have suggested that lithium car-
bonate is effective for both mania and depression induced
by corticosteroids. However, in clinical practice, diseases
treated with corticosteroids, such as nephrotic syndromes
or SLE, are often accompanied by renal dysfunction. Lith-
ium carbonate is contraindicated and should be avoided in
such patients. In our series, carbamazepine was effective
in two patients and valproate was effective in three other
patients. Carbamazepine also appeared to have prophylac-
tic effect in one patient. The most beneficial mood stabi-
Psychosomatics 42:6, November-December 2001

lizer must be chosen, taking into consideration the under-
lying somatic dysfunction.14,15,20 Carbamazepine and
valproate should be evaluated as alternative treatments and
for prophylaxis.
To treat manic episodes as quickly as possible, anti-
psychotics were used singly or in combination with mood
stabilizers. Although some previous reports2,13,19 indicated
the effectiveness of phenothiazines, in our series butyro-
phenones4 and zotepine, a thiepin derivative widely used
as an antimanic agent in Japan, were very effective. Recent
treatment guidelines for mania in primary bipolar disor-
ders21 recommend adjuvant use of high-potency antipsy-
chotics. If they are indicated, antipsychotics should be
given for corticosteroid-induced mania.
Some previous reports2,10 demonstrated that antide-
pressants were contraindicated for steroid psychosis. How-
ever, we experienced no exacerbated cases among the eight
patients who received antidepressants. Even intravenous
clomipramine was apparently effective in two patients who
had deteriorated into depressive stupor. The four exacer-
bated cases reported by Hall et al.2 manifested some hy-
pomanic or mixed symptoms for which antidepressants are
not primarily recommended. Severe depressive episodes
with suicidality often occur in corticosteroid-induced mood
disorder.22 The indication for antidepressants, including
newer agents such as selective serotonin reuptake inhibi-
tors,16 must be re-examined in these patients.
Good therapeutic response to low doses of haloperidol
is a characteristic of corticosteroid-induced psychotic dis-
order.4,10 It may have pathophysiological substrates in
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