1. No category

Concurrent Treatment of Steroid-Related Mood and Psychotic Symptoms With
Risperidone
Sirirat Ularntinon, Dan Tzuang, Gary Dahl and Richard J. Shaw
Pediatrics 2010;125;e1241; originally published online April 12, 2010;
DOI: 10.1542/peds.2009-1815
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/125/5/e1241.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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CASE REPORTS
Concurrent Treatment of Steroid-Related Mood and
Psychotic Symptoms With Risperidone
AUTHORS: Sirirat Ularntinon, MD,a Dan Tzuang, MD,a
Gary Dahl, MD,b and Richard J. Shaw, MB, BSa
a
Departments of Psychiatry and Behavioral Sciences and
bPediatrics, Stanford University School of Medicine and Lucile
Packard Children’s Hospital, Palo Alto, California
KEY WORDS
corticosteroid, pediatrics, risperidone, psychosis
ABBREVIATIONS
ALL—acute lymphoblastic leukemia
HPA— hypothalamic-pituitary-adrenal
www.pediatrics.org/cgi/doi/10.1542/peds.2009-1815
doi:10.1542/peds.2009-1815
Accepted for publication Jan 6, 2010
Address correspondence to Richard J. Shaw, MB, BS,
Department of Psychiatry and Behavioral Sciences, Stanford
University School of Medicine, 401 Quarry Rd, Palo Alto, CA
94305-5719. E-mail: [email protected]
abstract
Corticosteroid treatment is an important therapeutic modality for
many pediatric medical conditions including acute lymphoblastic leukemia. However, steroid-induced behavioral and mood abnormalities
are common and potentially disabling adverse effects that have been
widely reported in the pediatric literature. From this case series, we
report the efficacy of risperidone in 3 children with acute lymphoblastic leukemia who developed steroid-related mood and psychotic symptoms during treatment with prednisone and dexamethasone. Risperidone is an effective short-term pharmacologic agent for controlling
steroid-related psychiatric adverse effects when cessation or dose
reduction of steroid therapy is not an option. Pediatrics 2010;125:
e1241–e1245
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2010 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
PEDIATRICS Volume 125, Number 5, May 2010
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e1241
Steroid-induced psychiatric disturbances, including mood disturbances
and psychotic symptoms, have been
widely reported in pediatric patients
with both neoplastic and nonneoplastic conditions. Study results have suggested an incidence that ranges from
5% to 75%.1–7 In recent literature reviews for the period 1979 –2008 there
were 17 pediatric case reports of
steroid-induced psychosis and 1 case
series.8–10 It has been postulated that
patients with acute lymphoblastic leukemia (ALL) seem to be at elevated risk
as a result of the need for higher steroid doses.1,2,7
Although psychotic symptoms generally resolve after discontinuation or reduction of the steroid dose,8 steroids
play a crucial role in the treatment of
hematologic malignancy, and cessation is usually not an option. In
these situations, pharmacotherapy for
steroid-related psychosis is indicated.
In adult populations, both mood stabilizers and antipsychotic medications
have been studied.11–17 However, a review of treatment of steroid-related
psychosis in the pediatric oncology literature identified only 2 case reports,
both for patients with ALL, including a
14-year-old girl who was treated with
risperidone18 and a 2-year-old boy who
was treated with promethazine.19 To
further contribute to this limited literature base, we describe here a case
series of 3 patients in whom risperidone was used to treat steroid-related
psychiatric symptoms (see Table 1).
CASE REPORTS
rent steroid-induced mood symptoms
that responded well to the administration of risperidone.
Case A
Case-patient A is an 8-year-old boy with
a history of T-cell ALL. He started a chemotherapy induction regimen that included prednisone (2 mg/kg per day)
and intrathecal methotrexate. On day
12 of treatment, he was noted to have
mood changes ⬃30 minutes after his
evening dose of prednisone. He later
reported psychotic symptoms that included stating that there was “an electric chair in the room in which he
wanted to kill himself” and that he
wanted to “suffocate himself with a
skunk.” His parents reported no previous history of psychiatric symptoms
and no family history of psychotic or
mood disorders.
Case-patient A was admitted overnight
and received 0.25 mg of risperidone
orally with his evening dose of prednisone. The dose was increased 1 day
later to 0.25 mg twice per day, by which
time his parents reported a significant
decrease in the frequency and intensity of his anger and irritability and no
recurrence of his psychotic symptoms.
Risperidone was continued for 1 week
at a total daily dose of 0.5 mg concurrent with his prednisone treatment.
His subsequent treatment plan included the routine administration of
risperidone given concurrently with
every cycle of prednisone during
his chemotherapy regimen. During a
6-month follow-up period, case-patient
A had intermittent episodes of recur-
Case B
Case-patient B is a 16-year-old boy
with no previous psychiatric history
who was diagnosed with Philadelphia
chromosome–positive ALL and enrolled onto a high-risk ALL-treatment
protocol that included 12 mg of
dexamethasone daily during days 1
through 5 and 29 through 33 of each
cycle. Seven months after initiating
therapy, he developed personality and
mood changes after concluding a
5-day pulse of dexamethasone. He expressed delusional beliefs about receiving messages through the lyrics of
his favorite music that were sent to
him by God. For example, he stated that
“I am the Messiah, and my mission is to
convince every person in the world to
activate the same thing inside of them
so that they can be more than just their
potential ” and that “everyone should
kill themselves to prove that God is
real.” His other significant manic
symptoms included flight of ideas, tangential thinking, and bizarre behaviors
such as dressing in a pin-striped suit.
He reported 3 days of insomnia and
extreme irritability. There was no family history of psychotic or mood disorder. Case-patient B was assessed as
having steroid-induced mood and personality changes and commenced
treatment with 0.5 mg of risperidone
orally twice per day, increased to 1.5
TABLE 1 Case Series of Treatment for Steroid-Related Mood and Psychotic Symptoms in Children
Case
Patient
Age, y
Gender
Diagnosis
Steroid Dose
A
8
Male
T-cell ALL
Prednisone 2 mg/kg per d
B
16
Male
Pre–B-cell ALL
Dexamethasone 12 mg/d
pulse therapy
C
10
Male
Pre–B-cell ALL
Dexamethasone 0.25 mg/kg
per d pulse therapy
Clinical Presentation
Treatment
Irritability, mood lability, and suicidal
ideations
Manic symptoms manifested through
decreased sleep, religious
grandiosity, and psychosis
Agitation, irritability, and thoughts of
harming others
Risperidone 0.25 mg PO BID during
prednisone administration
Risperidone 0.5 mg PO QAM and 1 mg PO QHS
during dexamethasone administration
Risperidone 0.5 mg PO as needed for
agitation
PO indicates orally; BID, twice per day; QAM, every morning; QHS, every night at bedtime.
e1242
ULARNTINON et al
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CASE REPORTS
mg daily, which was effective in reducing his mood swings and irritability
and reestablishing his sleep routine.
Case-patient B continued to have a predictable cycle of behavior after starting dexamethasone pulses, including
initial mood lability, sleep disturbance,
and irritability followed by the onset of
manic symptoms 7 to 10 days later.
These symptoms included having “too
many ideas at once,” having irrational
plans to convert his home into a homeless shelter, and getting into random
arguments with grocery-store employees related to having to pay for a soda.
Recommendations were made for routine treatment with 0.5 mg of risperidone orally every morning and 1 mg at
bedtime to be initiated concurrently at
the start of all dexamethasone pulses
and continuing 1 week after the conclusion of his steroid treatment. There
was no recurrence of psychotic behavior after this intervention was
implemented.
Case C
Case-patient C is a 10-year-old boy who
was diagnosed with pre–B-cell ALL. He
received induction chemotherapy and
subsequent maintenance chemotherapy, which included 5-day pulses of
dexamethasone at doses of 0.25 mg/kg
per day. Fifteen months after starting
treatment, he developed symptoms
of acute agitation and irritability. His
parents stated that he was “wired”
and losing control and made several
attempts to harm his younger sister.
Case-patient C had a history of autism
and major depressive disorder, which
had been effectively treated with fluoxetine 20 mg/day. He had no symptoms
of depression in the 2 months leading
up to his diagnosis of ALL. Psychiatric
consultation suggested that the recent
onset of symptoms was attributable to
steroid-induced changes in his mood
and personality. Recommendations
were made for treatment with risperiPEDIATRICS Volume 125, Number 5, May 2010
done at a dose of 0.25 mg every night at
bedtime and increased over 2 days to
0.25 mg twice per day. The effect of the
risperidone was noted within 1 hour of
its administration. Follow-up treatment included the use of risperidone
0.5 mg/day given concurrently on days
2 through 5 of his steroid pulses to
manage symptoms of irritability, aggression, and insomnia. He tolerated
this medication well with excellent
therapeutic benefits.
DISCUSSION
Although there are limited data
regarding the prevalence of steroidinduced psychotic symptoms in pediatric patients, they can be an oftenunpredictable yet disabling adverse
effect of prednisone treatment in the
pediatric oncology setting. Families
and patients rate psychiatric symptoms to be the most deleterious to
quality of life.20 The mechanism
by which steroid-induced psychiatric symptoms, particularly psychotic
symptoms, develop is unknown but is
the subject of considerable speculation. They are likely mediated through
several complex and diverse pathways
that involve monoamine (serotonin,
dopamine, catecholamines) and neuropeptide neurotransmitters. There is
evidence to suggest that increased dopaminergic activity and decreased
central and peripheral serotoninergic
secretion occurs as a result of enhancement in corticosteroid activity.19,21 Symptoms seem to be dose
dependent. Several neuroendocrine
studies have identified the hippocampus as the most important target site
of glucocorticoid activity in the brain,
and there is interest in hippocampal
damage caused by exogenous glucocorticoids.10,22–23 Altered negative
feedback control of the hypothalamicpituitary-adrenal (HPA) axis has also
been proposed, because high-dose
glucocorticoid therapy usually leads to
a suppression of the HPA axis. How-
ever, studies on HPA-axis suppression
and correlation with psychopathology
in patients who receive glucocorticoids have not been conducted.7
One possible additional factor is the increased susceptibility of patients with
cancer to steroid-induced adverse effects. For example, there is evidence of
increased permeability of the bloodbrain barrier, which has been suggested as a risk factor for steroidinduced psychiatric disorders in
patients with systemic lupus erythematosus.24 Although there are no data to
suggest damage to the blood-brain
barrier in ALL, some studies have reported increased permeability as a result of chemotherapy agents, including
intrathecal methotrexate, and cranial
irradiation.25,26 In addition, chemotherapy agents may have a direct synergistic effect with steroids through the
mechanism of neuronal cell damage,
particularly in the hippocampal area.27
There is also evidence that patients
with steroid-induced psychosis have
increased corticosteroid receptor
messenger RNA, and there may be a
genetic susceptibility to this problem
associated with genetic mutations.28
Although most reports have suggested
the use of mood stabilizers such as
lithium and carbamazepine14,15 to treat
steroid-related mood disorders and
psychoses, there are many practical
limitations. Lithium is associated with
hematologic adverse effects including leukocytosis and thrombocytosis,
whereas agranulocytosis has been reported in patients who have received
carbamazepine.29 Moreover, the complex pharmacokinetic interactions of
these agents may complicate the use
of other medications used for ALL. This
case series illustrates the efficacy of
risperidone for the treatment and prevention of steroid-related mood and
psychotic symptoms in the pediatric
oncology setting. Although the onset of
mood-stabilizing and antipsychotic ef-
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e1243
fects of risperidone may take up to 2
weeks, compelling advantages include
the more rapidly noted effect on symptoms of agitation, the ability to target
effects with small as-needed dosing,
and the absence of a significant discontinuation syndrome.30,31 Theoretical
support for the use of antipsychotic
medications has been found in the results of studies that have suggested a
role of disturbance in dopamine and
5HT2 activity, because the mechanisms
of action of risperidone have been attributed to 5HT2 antagonism and the blockade of the dopamine D2 receptor.32,33
It is noteworthy that in all 3 patients,
low doses of risperidone (0.5–1.5
mg/day) were effective and well tolerated without any adverse shortterm adverse effects. In addition, reports of hematologic adverse effects
with risperidone have been absent.34
Although the risk of risperidonerelated cardiac toxicity, specifically
prolongation of the QTc segment and
torsades de point,35,36 may be of concern for patients who are receiving
cardiotoxic chemotherapy agents,
these issues were not noted in our
series. Nonetheless, careful monitoring, including a routine electrocardiography before treatment is required.
Other aspects of risperidone-related
adverse events that require careful
monitoring include weight gain, hy-
perglycemia, and symptomatic prolactinemia. Full disclosure of potential
adverse effects and appropriate consent procedures should be provided along with access to psychiatric
consultation.
dren and adolescents. Arch Dis Child. 2005;
90(5):500 –506
French J, Khan A, White H. Steroid induced
psychosis in an asthmatic child: case report & 10 year literature review. Can Child
Adolesc Psychiatr Rev. 2003;12(4):117–118
Hochhauser CJ, Lewis M, Kamen BA, Cole PD.
Steroid-induced alterations of mood and
behavior in children during treatment for
acute lymphoblastic leukemia. Support
Care Cancer. 2005;13(12):967–974
Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin
Proc. 2006;81(10):1361–1367
Sirois F. Steroid psychosis: a review. Gen
Hosp Psychiatry. 2003;25(1):27–33
Wada K, Yamada N, Sato T, et al. Corticosteroidinduced psychotic and mood disorders: diagnosis defined by DSM-IV and clinical pictures. Psychosomatics. 2001;42(6):461– 466
Stiefel FC, Breitbart WS, Holland JC. Corticosteroids in cancer: neuropsychiatric
complications. Cancer Invest. 1989;7(5):
479 – 491
Brown ES, Chandler PA. Mood and cognitive
changes during systemic corticosteroid
therapy. Prim Care Companion J Clin Psychiatry. 2001;3(1):17–21
Brown ES, Chamberlain W, Dhanani N,
Paranjpe P, Carmody TJ, Sargeant M.
An open-label trial of olanzapine for
corticosteroid-induced mood symptoms. J
Affect Disord. 2004;83(2–3):277–281
Falk WE, Mahnke MW, Poskanzer DC. Lithium
prophylaxis of corticotropin-induced psychosis. JAMA. 1979;241(10):1011–1012
18. Kramer TM, Cottingham EM. Risperidone in
the treatment of steroid-induced psychosis.
J Child Adolesc Psychopharmacol. 1999;
9(4):315–316
Currently, there is no pediatric evidence base to guide the clinician
about prophylaxis versus treatment
of steroid-related adverse effects or
comparative efficacy between different antipsychotic agents. Similarly,
the adult literature does provide
support for the use of both olanzapine and risperidone.16,37 Future studies will be needed to clarify these
issues.
REFERENCES
1. Drigan R, Spirito A, Gelber RD. Behavioral
effects of corticosteroids in children with
acute lymphoblastic leukemia. Med Pediatr
Oncol. 1992;20(1):13–21
2. Harris JC, Carel CA, Rosenberg LA, Joshi P,
Leventhal BG. Intermittent high dose corticosteroid treatment in childhood cancer:
behavioral and emotional consequences.
J Am Acad Child Psychiatry. 1986;25(1):
120 –124
3. Hall AS, Thorley G, Houtman PN. The effects
of corticosteroids on behavior in children
with nephrotic syndrome. Pediatr Nephrol.
2003;18(12):1220 –1223
4. Klein-Gitelman MS, Pachman LM. Intravenous corticosteroids: adverse reactions
are more variable than expected in children. J Rheumatol. 1998;25(10):1995–2002
5. Kayani S, Shannon DC. Adverse behavioral
effects of treatment for acute exacerbation
of asthma in children: a comparison of two
doses of oral steroids. Chest. 2002;122(2):
624 – 628
6. Bender BG, Lerner JA, Kollasch E. Mood and
memory changes in asthmatic children receiving corticosteroids. J Am Acad Child
Adolesc Psychiatry. 1988;27(6):720 –772
7. Felder-Puig R, Scherzer C, Baumgartner M,
et al. Glucocorticoids in the treatment of
children with acute lymphoblastic leukemia
and Hodgkin’s disease: a pilot study on the
adverse psychological reactions and possible associations with neurobiological, endocrine, and genetic markers. Clin Cancer
Res. 2007;13(23):7093–7100
8. Stuart FA, Segal TY, Keady S. Adverse psychological effects of corticosteroids in chil-
e1244
ULARNTINON et al
9.
10.
11.
12.
13.
14.
15.
16.
17.
19. Ingram DG, Hagemann TM. Promethazine
treatment of steroid-induced psychosis in a
child. Ann Pharmacother. 2003;37(7– 8):
1036 –1039
20. McGrath P, Pitcher L. “Enough is enough”:
qualitative findings on the impact of
dexamethasone during reinduction/
consolidation for pediatric acute lymphoblastic leukemia. Supportive Care Cancer.
2002;10(2):146 –155
21. Schatzberg AF, Rothschild AJ, Langlais PJ,
Bird ED, Cole JO. A corticosteroid/dopamine
hypothesis for psychotic depression and related states. J Psychiatr Res. 1985;19(1):
57– 64
22. Brown ES, Woolston DJ, Frol A, et al. Hippocampal volume, spectroscopy, cognition,
and mood in patients receiving corticosteroid therapy. Biol Psychiatry. 2004;55(5):
538 –545
23. Brown ES, Vera E, Frol AB, Woolston DJ,
Johnson B. Effects of chronic prednisone
therapy on mood and memory. J Affect Disord. 2007;99(1–3):279 –283
24. Wolkowitz OM, Reus VI, Canick J, Levin B, Lupien S. Glucocorticoid medication, memory
and steroid psychosis in medical illness.
Ann N Y Acad Sci. 1997;823:81–96
25. Nishimura K, Harigai M, Omori M, Sato E,
Hara M. Blood-brain barrier damage as a
risk factor for corticosteroid-induced psychiatric disorders in systemic lupus ery-
Downloaded from pediatrics.aappublications.org by guest on August 22, 2014
CASE REPORTS
thematosus. Psychoneuroendocrinology.
2008;33(3):395– 403
26. Balis FM, Poplack DG. Central nervous system pharmacology of antileukemic drugs.
Am J Pediatr Hematol Oncol. 1989;11(1):
74 – 86
27. Riccardi R, Riccardi A, Lasorella A, Servidei
T, Mastrangelo S. Cranial irradiation and
permeability of blood-brain barrier to cytosine arabinoside in children with acute leukemia. Clin Cancer Res. 1998;4(1):69 –73
28. Dietrich J, Monje M, Wefel J, Meyers C. Clinical patterns and biological correlates of
cognitive dysfunction associated with cancer therapy. Oncologist. 2008;13(12):
1285–1295
29. Oyesanmi O, Kunkel EJ, Monti DA, Field HL.
PEDIATRICS Volume 125, Number 5, May 2010
30.
31.
32.
33.
Hematologic side effects of psychotropics.
Psychosomatics. 1999;40(5):414 – 421
Walker E, Mittal V, Tessner K. Stress and the
hypothalamic pituitary adrenal axis in the
developmental course of schizophrenia.
Annu Rev Clin Psychol. 2008;4:189 –216
Goff DC. Risperidone. In: Schatzberg AF,
Nemeroff CB, eds. Textbook of Psychopharmacology. Arlington, VA: American Psychiatric Publishing, Inc; 2004:495– 450
Gardner DM, Baldessarini RJ, Waraich P.
Modern antipsychotic drugs: a critical overview. CMAJ. 2005;172(13):1703–1711
Kapur S, Seeman P. Does fast dissociation
from the dopamine D2 receptor explain the
action of atypical antipsychotics? A new hypothesis. Am J Psychiatry. 2001;158(3):
360 –369
34. Ichikawa J, Ishii H, Bonaccorso S, Fowler
WL, O’Laughlin IA, Meltzer HY. 5-HT(2A) and
D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor
activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem. 2001;76(5):
1521–1531
35. Casey DE. Side effect profiles of new antipsychotic agents. J Clin Psychiatry. 1996;
57(suppl 11):40 – 45
36. Collaborative Working Group on Clinical
Trial Evaluations. Adverse effects of the
atypical antipsychotics. J Clin Psychiatry.
1998;59(suppl 12):17–22
37. Dasilva CC, Murse MC, Vokey K. Steroid induced psychosis treated with risperidone.
Can J Psychiatry. 2002;47(4):388 –389
Downloaded from pediatrics.aappublications.org by guest on August 22, 2014
e1245
Concurrent Treatment of Steroid-Related Mood and Psychotic Symptoms With
Risperidone
Sirirat Ularntinon, Dan Tzuang, Gary Dahl and Richard J. Shaw
Pediatrics 2010;125;e1241; originally published online April 12, 2010;
DOI: 10.1542/peds.2009-1815
Updated Information &
Services
including high resolution figures, can be found at:
http://pediatrics.aappublications.org/content/125/5/e1241.full.
html
References
This article cites 36 articles, 6 of which can be accessed free
at:
http://pediatrics.aappublications.org/content/125/5/e1241.full.
html#ref-list-1
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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