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Corticosteroid Induced Psychotic and Mood Disorders

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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 psychotic 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 influence on the psychiatric course. These two corticosteroid-induced psychiatric disorders may have
different pathophysiological substrates closely related to patient vulnerability. Effective psychopharmacological treatment options were indicated with consideration being given to the underlying diseases.
(Psychosomatics 2001; 42:461–466)
C
orticosteroids often induce psychiatric syndromes, including depression, mania, psychosis, and delir1–8
ium. The syndromes are conventionally known as “steroid psychosis,” which is regarded to be a representative
exogenous psychiatric disorder. However, steroid psychosis is not a specific clinical entity but consists of heterogeneous syndromes with obviously different pathophysiological mechanisms. Established diagnostic criteria such as
those in DSM-IV have scarcely been used in previous studies to evaluate the psychiatric symptoms. Both the symptoms 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-pituitaryadrenal 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 endogenous psychiatric disorders. There is an urgent need for
clinical research focused on the longitudinal course and
therapeutic response of these cases.
Psychosomatics 42:6, November-December 2001
Patients treated with corticosteroids should receive intensive or long-term maintenance treatment because of exacerbations of their underlying diseases. Recurrent psychiatric syndromes induced by corticosteroids can therefore
be observed in clinical practice. When corticosteroidinduced psychiatric syndromes emerge, physicians have
difficulty in treating the underlying medical diseases. Although convincing data on recurrence and prophylaxis are
needed for psychiatric intervention, previous studies of
“steroid psychosis” have directed little attention to longterm outcome and treatment strategy.10–16
This study of patients with corticosteroid-induced psychotic and mood disorder, as defined by DSM-IV, adReceived November 15, 2000; revised March 23, 2001; accepted March
12, 2001. From the Department of Neuropsychiatry, Okayama University Medical School 2-5-1, Shikata-cho, Okayama 700-8558, Japan, Department of Psychiatry, Hiroshima City Hospital, 7-33, Moto-machi,
Naka-ku, Hiroshima 730-8518, Japan. Address correspondence and reprint 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.
461
Steroid Psychosis
dressed the following questions. 1) Which is the more frequent manifestation, psychosis or mood disorder? 2) Are
there any symptomatological characteristics in each patient 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, Okayama 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 period; 2) DSM-IV criteria for corticosteroid-induced psychotic or mood disorder; and 3) psychiatric symptoms continuing for at least 1 week. Although DSM-IV criteria do
not specify the duration of symptoms for substanceinduced psychotic or mood disorder, the third criterion was
employed to exclude transient mood change. By reviewing
notes and evaluations of these cases by consultant psychiatrists, we aimed to elucidate the clinical characteristics
including the frequency of recurrence, psychiatric symptomatology, 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 disorders 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 occurred 1 to 20 weeks after commencement of corticosteroid
treatment. Oral prednisolone was most frequently administered. Intravenous methylprednisolone was given to patients 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 episode and seven had recurrent episodes (Table 1). It is interesting that the first mood episode was manic or hypomanic 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 difficulties and marital problems, preceded their mood episodes. Four of the five patients who received high doses of
intravenous methylprednisolone rapidly became manic or
hypomanic. Depressive stupor was observed in two patients and two other patients attempted suicide by self-mutilation. 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 became 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 withdrawn or titrated to a low maintenance level. Neither increasing doses nor resumption of corticosteroids was indicated 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. Carbamazepine and valproate were the preferred mood stabilizers.
Antipsychotics were effective at relatively low doses. Depressive episodes were effectively treated with antidepressants (including tricyclics), except for one patient who exhibited drowsiness as an adverse effect. Intravenous
clomipramine was very effective in two patients with depressive 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 carbamazepine (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
2
3
4
5
6
7
F
F
F
F
M
M
M
18
21
23
31
47
42
68
Nephrotic syndrome
Polymyositis
Ulcerative colitis
SLE
SLE
Kidney transplant
Nephrotic syndrome
M-D*-D-M
D-M-D*
M-D*
D-M
M-M
M-M-D-M*
M-D*
Ⳮ
Ⳮ
Ⳮ
Ⳮ
Ⳮ
-
Rapidly induced mania
Rapidly induced mania
Not done
Induced depression
Not done
Rapidly induced mania
Rapidly induced mania
Single Episode
Case 1
2
3
4
5
6
7
8
F
F
F
F
F
F
F
M
43
46
47
50
54
58
63
65
Nephrotic syndrome
Polymyositis
SLE
Pemphigus vulgaris
Polyarteritis nodosa
Dermatomyositis
Bullous pemphigoid
Nephrotic syndrome
D
D
D
M
M
M
M
M
Ⳮ
-
Done without exacerbation
Rapidly induced depression
Rapidly induced depression
Not done
Not done
Not done
Not done
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
effects were observed except for rashes induced by carbamazepine. Each episode of these 15 patients had a relatively good outcome with full remission after 1–3 months.
Two of the three psychotic disorder patients were recurrent. Underlying medical diseases of these three patients
TABLE 2.
Effective treatments for mood disorder patients
Subgroup
Mania
Depression
Prophylaxis
Recurrent
Case 1
2
3
4
5
6
7
CBZ
AP
AP
AP
AP
VPA
CBZ
nTCAⳭCZP
TCA
TCA
TCA
No episodes
nTCA
nTCA
CBZ
Li
Not done
AP
Not done
VPA
None
No episodes
No episodes
No episodes
AP
VPA
AP
AP
VPA
TCA
Steroid tapering only
nTCA
No episodes
No episodes
No episodes
No episodes
No episodes
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Single Episode
Case 1
2
3
4
5
6
7
8
Note: AP ⳱ antipsychotic; CBZ carbamazepine; CZP clonazepam;
Li lithium carbonate; nTCA non-tricyclic antidepressant; TCA
tricyclic antidepressant; VPA valproate.
Psychosomatics 42:6, November-December 2001
were Systemic lupus erythematosus (SLE) (two patients)
and bullous pemphigoid. All three patients initially showed
typical schizophrenic symptoms such as persecutory delusions, auditory hallucinations and disorganized behaviors. However, the two recurrent patients had atypical
symptoms, including depressed mood, agitation, and progressive reduction in contact and reactivity, in the following episodes. Latency of onset ranged from 2 to 4 weeks.
Maximum oral dosage of corticosteroid did not differ from
that of mood disorder patients. Only one patient received
corticosteroid pulse therapy without showing any exacerbation of psychotic symptoms. Every patient was effectively treated with a relatively low dose of haloperidol (ⱕ3
mg/day).
DISCUSSION
1) Which is the more frequent manifestation, psychosis or
mood disorder?
It is widely accepted that affective symptoms are the
most prominent clinical features in “steroid psychosis.”2–8
Lewis and Smith4 reported that there were seven mania,
one depression and two psychoses in their original series.
They also cited 60 mood disorders and 11 psychoses from
their review of the literature. Ling et al.5 found 45 patients
with mood disorder and 9 with acute psychosis. In keeping
with these studies, we identified more mood disorders than
psychotic disorders [15:3], as defined by DSM-IV. Of the
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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 hallucinations and 28% had persecutory delusions. This research shows that corticosteroids tend to induce mood disorder, 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 recurrent patients who emerged into other types of disorder
during the examination period. These two corticosteroidinduced psychiatric syndromes may have distinct pathophysiological 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 corticosteroidinduced mood disorder and primary bipolar disorder have
common biological substrates. In primary bipolar disorders, 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 demonstrated a higher incidence of depression than mania, recurrent cases were rarely included in these studies. Taken together, our findings from a predominantly female sample
confirm a higher incidence of mania in corticosteroid-induced mood disorder.17
A number of previous studies reported that steroid
psychosis often involves variable and atypical clinical features. This characteristic could have resulted from the heterogeneity 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 symptoms, 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 escalation 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 transient 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, corticosteroids 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 susceptibility to mood disorders once corticosteroids are
given. These patients would probably show recurrent
course due equally to subsequent treatment and psychosocial stressors. In other words, this intrinsic susceptibility
would not be specific to subsequent corticosteroid challenge. 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 susceptibility 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 underlying medical diseases. Alternatively, younger patients
may acquire the susceptibility mentioned above more easily than older patients. However, single-episode mood disorder 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 carbonate 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. Lithium 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 prophylactic effect in one patient. The most beneficial mood stabiPsychosomatics 42:6, November-December 2001
Wada et al.
lizer must be chosen, taking into consideration the underlying 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, antipsychotics were used singly or in combination with mood
stabilizers. Although some previous reports2,13,19 indicated
the effectiveness of phenothiazines, in our series butyrophenones4 and zotepine, a thiepin derivative widely used
as an antimanic agent in Japan, were very effective. Recent
treatment guidelines for mania in primary bipolar disorders21 recommend adjuvant use of high-potency antipsychotics. If they are indicated, antipsychotics should be
given for corticosteroid-induced mania.
Some previous reports2,10 demonstrated that antidepressants were contraindicated for steroid psychosis. However, 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 exacerbated cases reported by Hall et al.2 manifested some hypomanic 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 inhibitors,16 must be re-examined in these patients.
Good therapeutic response to low doses of haloperidol
is a characteristic of corticosteroid-induced psychotic disorder.4,10 It may have pathophysiological substrates in
common with some schizophrenia patients who show remarkable response to low doses of antidopaminergic
agents. Further longitudinal investigations of corticosteroid-induced psychotic disorder patients seem warranted to
clarify this hypothesis.
Steroid pulse therapy, represented by high-dose methylprednisolone, is commonly used for more rapid effectiveness and less toxicity. To date, no study has shown that
psychiatric complications occur more frequently with pulse
therapy than with oral administration.23–25 In our series,
four patients became rapidly manic or hypomanic and two
became rapidly depressive after pulse therapy. These rapid
exacerbations may indicate that extremely high doses of
corticosteroids induce significant psychological and behavioral changes in susceptible subjects. We suggest that
pulse therapy must be carefully prescribed for patients
with corticosteroid-induced mood disorders.
Continuous support by psychiatrists and their close cooperation with other physicians will contribute to the quality of life of patients undergoing long-term corticosteroid
treatment. These patients often suffer from recurrence of
underlying diseases and inevitably experience various psychosocial difficulties. Preventive strategies for psychiatric
relapses from psychosocial stressors are strongly needed,
since these episodes are not rare. Particular attention should
be paid to younger patients with onset of corticosteroidinduced mood disorders, since they are more likely to have
recurrences and psychotic features. Psychiatrists should advise other physicians on corticosteroid treatment plans, especially the indications of steroid pulse therapy.
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