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Psychiatric Adverse Drug Reactions:
Richard C.W. Hall, M.D.
Medical Director, Psychiatric Programs
Clinical Professor of Psychiatry
University of Florida, Gainesville
Director of Research Monarch Health Corporation
Each year there are 1 1/2 million hospitalizations caused by adverse
drug reaction in the United States. As many as 5% of all hospital
admissions are directly or indirectly caused by these problems which
are responsible for almost 15% of all hospital days. Thirty percent
of patients admitted for an adverse drug reaction experience a second
such reaction while hospitalized. Adverse drug reactions are often
misdiagnosed early in their course. It is estimated that three billion
dollars a year are spent treating adverse drug reactions and that
between 18 and 30% of patients who are hospitalized for other reasons
will experience a significant adverse drug reaction during their
hospital stay. If a patient does experience an adverse drug reaction,
it is likely that his hospital days will be doubled. Adverse drug
reactions have been implicated in up to 5% of hospital deaths.
The purpose of this paper is to review the adverse psychiatric
effects produced by corticosteroids; to define their incidence and
symptom presentation and to make recommendations for their management.
The early literature concerning the mental changes produced by corticosteroids
was confused and at times quite contradictory. Much of this was
no doubt related to the fact that the early preparations were not
well standardized, that these medications were often initially prescribed
for the most severely ill patients and that they were generally
prescribed concurrently with several other medications. All these
factors, we have subsequently learned, greatly effect both the incidence
and presentation of steroid induced mental changes, the specific
nature of which remained uncertain for many years. Various authors
reported euphoria and depression to be the major presentations of
steroid psychosis while others reported mania, paranoid reactions,
schizophrenia and various toxic syndromes.
A study undertaken by my colleagues and I reported in 1979 defined
the symptoms of steroid psychosis in 14 patients who had no central
nervous system lesions. This study suggested that patients receiving
daily doses of greater than 40mg of Prednisone or its equivalent
were at greatest risk for developing a steroid psychosis. These
reactions were twice as likely to occur during the first five days
of treatment as subsequently. Premorbid personality, a history of
previous psychiatric disorder or a history of a previous steroid
psychosis did not clearly increase the patient's risk of developing
a psychotic reaction during any given course of subsequent therapy.
The steroid psychoses we saw presented as a spectrum psychosis with
symptoms ranging from affective through schizophreniform to those
of organic brain syndrome. No characteristic stable presentation
was observed in these 14 patients, but the most prominent symptom
constellation to appear during the course of the illness consisted
of emotional lability, anxiety, distractibility, pressured speech,
sensory flooding, insomnia, depression, perplexity, agitation, auditory
and visual hallucinations, intermittent memory impairment, mutism,
disturbances of body image, delusions, apathy and hypomania. We
found that phenothiazines administered in low to moderate doses,
(50-200mg CPZ or equivalent daily) produced an excellent response
in all the patients studied. We cautioned against the use of tricyclic
antidepressants while patients remained on steroids as in all situations
where this regimen was tried, the patient's clinical condition worsened.
Since our study, several other critical reviews of the literature
and new studies have become available. This newer literature provides
longitudinal insight into the nature of steroid induced mental change.
The incidence of steroid psychosis varies widely in the literature
ranging from 13 to 62%, with a weighted average of 27.6% for some
steroid induced mental change, the vast majority of which are mild
to moderate and do not herald the development of a full-blown psychosis
or affective syndrome. The incidence of a severe psychiatric syndrome
in the more than 2,500 patients reported in the literature ranges
from 1.6 to 50% with a weighted average of 5.7%. The incidence of
steroid psychoses in patients with lymphoma, multiple sclerosis,
severe intractable asthma, ulcerative colitis, regional enteritis,
idiopathic thrombocytopenic purpura, rheumatoid arthritis, and severe
poison ivy or oak is estimated at between 3 and 6%. The patients
most at risk for developing steroid psychosis are those with systemic
lupus erythematosus (39%) and pemphigus (21%).
Steroid psychoses are twice as likely to occur in females as in
males, but if one corrects for the higher incidence in females of
the disorders for which steroids are typically used, particularly
systemic lupus erythematosus with a nine to one female incidence
and rheumatoid arthritis with a three to one female incidence, then
the total incidence of steroid induced psychosis in men and women
is roughly equal with a slight female predominance.
The type of psychiatric disturbance seen is in fact, difficult
to classify as patient's symptoms tend to change radically during
the course of the illness. Overall, approximately 40% of patients
present predominantly with a depressive disorder, 25% with mania,
5% with a bipolar disorder-cyclical form; 15% with an agitated schizophreniform
or paranoid psychosis and 10% as an acute progressive delirium.
Three-quarters of all patients with steroid psychosis evidence affective
symptoms some time during the course of their illness. A frank psychotic
state without mood disturbance occurs in 10 to 15% of patients while
some psychotic features, (i.e., a marked impairment of reality testing)
associated with affective symptoms occurs in 70% of patients.
The dose of the steroid administered has a clear relationship to
the likelihood of the patient developing a subsequent steroid psychosis.
There is a statistically significant increase in the incidence of
psychiatric disturbances with increasing daily doses of steroid.
Patients treated with a mean daily dose of Prednisone below 40mg/day
in The Boston Collaborative Drug Surveillance Study, had an incidence
of psychotic symptoms of 1.3% while patients treated with doses
between 41 and 80mg/day had an incidence of 4.6%. Patients receiving
more than 80mg/day of Prednisone or its equivalent had an incidence
of steroid psychosis of 18.4%. The average daily dose of steroids
for patients who developed psychosis was 59.5mg/day of Prednisone
or equivalent as compared with 31.1mg/day for patients who did not
develop adverse psychiatric effects.
Several studies have shown that no relationship exists between
the response to the first course of steroid treatment and response
to a second course of drug, that is, the presence or absence of
a psychiatric disturbance during the initial course of steroid treatment,
does not predict response to a subsequent course of treatment.
A previous history of psychological difficulties does not predict
the development of steroid psychosis. Litz, in his study at Johns
Hopkins, noted that even the most "highly unstable and poorly integrated"
patients did not experience any untoward emotional reactions after
ACTH or cortisone therapy when compared to their more emotionally
stable counterparts. Thus, a patient's past psychiatric history
is not a reliable predictor of developing a future steroid psychosis.
In a review of the steroid literature approximately 20% of the patients
reported to have developed a steroid psychosis had a history of
previous psychiatric disorders, 80% did not.
Steroid psychoses tend to be acute in their onset and although
mental changes can occur at any time during the course of therapy,
most occurred within the first six to 10 hours following the administration
of ACTH, or within the first four to six days following the oral
administration of corticosteroids. The most frequent initial presentation
of an impending steroid psychosis was a state of cerebral hyperexcitability,
clearly perceived and reported by the patient. Patients characterize
these states as being marked by increased irritability, lability
of mood, a profound dysphoria, hyperacusis, and pressured or driven
thought processes. These changes often antecede other more serious
disturbances of cognition by 72 to 96 hours. Once a steroid psychosis
is fully defined it is likely to present as a spectrum psychosis,
with the most prominent symptoms consisting of profound distractibility,
pressured speech, anxiety, emotional lability, severe insomnia,
sensory flooding, depression, perplexity, auditory and visual hallucinations,
agitation, intermittent memory impairment, mutism, delusions, disturbances
of body image, apathy and hypomania. Prior to the advent of treatment
with phenothiazines, it was noted that these conditions spontaneously
remitted in from two weeks to seven months after the discontinuation
of steroids, with 80% of the cases reported in the literature having
remitted untreated by the sixth week. Administration of phenothiazines
dramatically reduces this period. The current duration of psychiatric
symptoms in patients who develop a steroid psychosis treated with
phenothiazines ranges in the literature from one to 150 days with
a mean duration until total recovery of 22 days. However, it should
be noted that 40% of patients begun on timely treatment with a low
to moderate dose of phenothiazines, respond within one week and
that 55% of all such patients are fully recovered within two weeks.
More than 90% of all patients with steroid psychosis treated with
phenothiazines in whom steroids are discontinued will recover within
six weeks. Delirium is the presentation with the shortest duration
of symptoms. Such cases clear quite rapidly following institution
of appropriate treatment and cassation of steroid therapy, usually
within six days. Patients who develop a full blown affective syndrome
have the longest treated course with an average duration of symptoms
of 25 days.
Once a diagnosis is made and treatment instituted, the literature
suggests that a complete recovery is likely to occur in 90% of patients.
Three percent of patients with steroid psychosis commit suicide.
The remaining 5-7% will have an ongoing psychotic or depressive
disorder or develop recurrent psychiatric symptoms. Ninety two percent
of patients who have steroids tapered fully recover, while 84% of
patients who are maintained on steroids but treated with antipsychotic
medicines show full recovery of symptoms. ECT, in the 11 cases reported
in the literature has been universally effective in reversing the
course of steroid psychosis.
Several studies have shown that patients, even those with affective
disorder produced by steroids, tend to do poorly when treated concurrently
with tricyclic antidepressants and steroids. These patients may
also show an exacerbation of symptoms even after the tapering of
steroids, when tricyclics are used. For this reason it is recommended
that tricyclic and other antidepressant medications be withheld
until after the patient's steroid psychosis has been appropriately
treated with neuroleptics.
Various treatment approaches are available for steroid psychosis.
The most widely used and effective treatment strategy is to discontinue
steroids where possible, and to treat the patient with phenothiazines
or other antipsychotic medications. The most frequently used drug
regimens include Mellaril 50 to 200mg q.d.; Thorazine 50 to 200mg
p.o., q.d. or Haloperidol 2 to 10mg p.o., q.d. Our study suggested
that Mellaril is probably the agent of choice as it was highly efficacious
and was considerably less likely than Haloperidol to produce a dystonia
or dyskinesia which would require further drug treatment. Additional,
Falk and colleagues have shown that prophylactic treatment with
lithium carbonate may be useful to prevent the development of corticotropin
induced psychosis. In their study, 27 patients treated with lithium
carbonate, whose blood level was maintained at between 0.8 to 1.2
mEq/l for a 31-day course of ACTH treatment for multiple sclerosis
or retrobulbar neuritis, failed to develop any significant mental
effects, while an untreated control group of 44 patients had a 14%
incidence of steroid induced psychoses. Further studies confirming
this finding are needed.
Steroids alter the central nervous system through a variety of
mechanisms. It is because of their wide ranging metabolic effects
that the presentations and course of the steroid psychoses may change
so dramatically. Recent research has shown that corticosteroids
alter the sodium potassium pump and ion flux across membranes effecting
ATP and norepinephrine metabolism particularly in the reticular
activating system. Steroids have a direct effect on major target
cells in the hippocampus as well as on limbic neurons, increasing
norepinephrine uptake in cells of both the limbic system and cerebral
cortex. Glucocorticoids have been shown to potentiate ischemic injury
to neurons, an important effect in patients with vasculitis such
as those with systemic lupus erythematosus. These findings may explain
the high incidence of steroid psychosis in patients with lupus and
pemphigus. Corticosteroids also effect carrier proteins, displacing
drugs and other toxic substances and decrease central nervous system
serotonin levels by shunning tryptophane metabolism from the tryptophan-serotonin
pathway to the tryptophane-kynurenine pathway and by altering cyclical
AMP, cyclical GAMP, actycholine, dopamine and endorphines in the
central nervous system.
In conclusion, steroid induced mental changes are common. The overall
incidence of steroid psychosis when steroids are used to control
systemic medical disorders varies between 3 and 6%. The clinician
usually has a window of from 24 to 96 hours to initiate treatment
and abort the full-blown picture of steroid psychosis. Early treatment
with psychotropic medications and discontinuation of steroids where
possible, produces rapid clearing and control of the steroid psychoses.
1. Hall RCW, Popkin M, Stickney S, et al: Presentation of "steroid
psychosis". J Nerv Ment Dis 167:229-236, 1979
2. Hall RCW, Popkin M, Kirkpatrick B: Tricyclic exacerbation of
steroid psychosis. J Nerv Ment Dis 166(10)738-742, 1978
3. Hall RCW(ed): Psychiatric Presentations of Medical Illness: Somatopsychic
Disorders. New York, Spectrum Publications, 1980
4. Lewis DA, Smith RE: Steroid-induced psychiatric syndromes: A
report of 14 cases and a review of the literature. J Affect Dis
5. Hall RCW, Beresford TP: Psychiatric manifestations of physical
illness, in Michels R, Cavenar JO, Brodie HKH et al(eds): Psychiatry,
Vol 2, 1989, Philadelphia, J.B. Lippencott Co, chapter 88, p 9
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