Risperidone in the Treatment of Autism
Grace E. Jackson, MD
August 2, 2005
Introduction
Recently, a series of clinical investigations have explored the
efficacy of risperidone (Risperdal) as a treatment for aggression in
children diagnosed with autism or developmental delays. These
studies have prompted opinion leaders in the field of psychiatry to
recommend the use of antipsychotic medication - specifically,
risperidone - as a first-line therapy for children. A
critical inspection of the relevant data recommends a more cautious
view.
Endocrine Effects: Dysregulation of Prolactin, Glucose, and Fats
(Lipids)
Among the so-called "atypical" or second generation antipsychotics,
risperidone is the one drug which has been consistently associated with
sustained, abnormal elevations in prolactin
(hyperprolactinemia).1-3 While most patients are believed
to experience this effect as a result of dopamine blockade outside the
brain, it is notable that the drug's manufacturer only recently (June
2005) acknowledged a possible link between risperidone and benign
tumors of the pituitary gland.4 This link would certainly explain
the induction of hyperprolactinemia in some (but certainly not most)
consumers of risperidone.
Although the medical literature has not revealed a connection between
hyperprolactinemia and a reduction in the growth rates of prepubertal
patients, the long term consequences of hyperprolactinemia in children
remain unknown. Of particular concern to many
endocrinologists is the negative effect of hyperprolactinemia upon peak
bone mass. This physical attribute refers to the bone mineral
accretion which occurs during adolescence, and which many professionals
regard as a critical protection against osteoporosis and bone fragility
in adulthood and old age.5-7
Aside from its effects upon bone metabolism, however,
hyperprolactinemia remains a risk factor for additional health
problems,8 including infertility (suppression of libido, ovulation,
sperm production, and sexual functioning); breast cancer,
ischemic heart disease (possibly via estrogen effects), and prostatic
hypertrophy. While many of these changes may seem irrelevant with
respect to young children, it is notable that hyperprolactinemia has
been shown by researchers to exert variable effects upon the timing and
quality of puberty in human and non-human species (i.e., associated
with both precocious puberty and pubertal delay). 9-10 Moreover,
animal studies have demonstrated an association between
hyperprolactinemia in childhood, and the eventual development of
inflammatory changes within the prostate of adults.11
Like other serotonin-dopamine antagonists, risperidone has been
associated with hyperglycemia, insulin resistance, and weight
gain.12 As of February 2002, the FDA's MedWatch Drug Surveillance
System (a database of spontaneously reported adverse events) included
12 reports of risperidone-associated diabetes in children.
In a Letter to the Editor which appeared in a 2004 issue of the journal
Pediatrics, several FDA employees recommended vigilant monitoring of
young patients for this problem, albeit a presumably rare occurrence.13
One metabolic effect of risperidone which has not occurred
infrequently, though, is the induction of weight gain. In a study
of 33 children and adolescents exposed to risperidone for a period of
six months, researchers at Yale University14 found a steady progression
of weight gain on the order of 1.2 kg per month. By the end of
their study, the investigators concluded that risperidone was
associated with clinically significant weight gain in 78% of their
patients - an effect that was not correlated to drug dose, pubertal
status, baseline weight, or gender. Unfortunately, the
psychological and social consequences of medication-induced weight gain
(i.e., effects upon self-esteem, peer support, and quality of life)
remain problems which few research teams have addressed
adequately. Furthermore, many risperidone patients have developed
abnormalities in the metabolism of fats, leading to abnormally high
levels of triglycerides and cholesterol. These changes are
believed to contribute to the development of the "metabolic syndrome"
(high blood pressure, insulin resistance, hyperlipidemia, and obesity)
which many physicians associate with vascular, renal, and retinal
disease.15
Neurological Effects: Movement disorders, Sleep Disturbance, and
Strokes
Although the serotonin-dopamine antagonists (second generation
antipsychotics) were originally hailed as drug therapies devoid of the
extrapyramidal side effects which plagued their progenitors, an
increasing body of research and clinical evidence has ultimately
contradicted this expectation. Risperidone, particularly in
higher doses (> 6-8 mg per day), has been associated with
parkinsonism, tardive dyskinesia, and neuroleptic malignant
syndrome.16-20 Each of these problems has appeared in children,
as well as adults, and even among patients exposed to low doses of
medication, over short durations of time. In studies of sleep
architecture, risperidone has been shown to decrease the quantity of
REM sleep.21 Such an effect may impair the processes of learning
and memory, and may worsen symptoms of irritability and
psychosis.22 A potentially lethal neurological effect of
risperidone is the induction of strokes and transient ischemic attacks
(mini-strokes). Although this finding has been limited to elderly
patients who received the drug for psychotic symptoms associated with
dementia, this vascular reaction was serious enough to convince the FDA
and the drug manufacturer of the need for a bold print warning on the
product label in April of 2003.23
Effectiveness
In 2002, members of the Pediatric Psychopharmacology Autism Network
published the results of a multi-site, double-blind trial involving 101
children with autism.24 The patients were randomly assigned to
receive risperidone (n = 49) or placebo (n = 52) for a period of eight
weeks. Subjects were evaluated in this study for improvement in
disruptive behaviors (using the Clinical Global Impression scale, or
CGI) and irritability (using a subscale of the Aberrant Behavior
Checklist). At the end of two months, 30% of the children had
failed to respond to treatment. When patients in the risperidone
group were subsequently continued on medication in a six-month
extension phase of the trial, a full 33% failed to maintain their
response to drug therapy. Thus, by the time that the study
results were published, 53% of the original risperidone recipients had
failed to demonstrate either an acute or sustained response to
treatment. These results were consistent with the findings
of other investigators. For example, in 2004, researchers in
Italy25 published the results of their trial in which 20 autistic
children (aged 3 to 10) were exposed to risperidone for twelve weeks of
treatment. By the end of the Italian study, only eight of
the twenty children (40%) met criteria for "response" to drug
therapy. Most subjects demonstrated only minimal improvements.
Conclusion
· Opinion leaders in the field of psychiatry
have recently endorsed the use of risperidone as a first-line therapy
for the treatment of autism and/or developmental delay(s).
· The effectiveness of risperidone in these
populations appears to be limited, with fewer than 50% of the exposed
subjects demonstrating a sustained positive response, and with most
changes of minimal or equivocal significance.
· The safety risks of risperidone are
substantial. Short-term effects include significant (and
potentially lethal) endocrine and neurological disturbances.
Long-term effects have not been characterized.
· Given the poor utility of risperidone
(limited efficacy, substantial hazards), its emerging status as a
privileged therapy in the treatment of autism and/or other behavioral
disorders of childhood remains contestable.
· The demonstrated utility of less toxic,
non-pharmacological interventions deserves review. Future
research efforts might focus upon the comparative effectiveness and
safety of nutritional approaches (e.g., gluten free diet, omega-3
supplementation, antioxidants), psychotherapy (e.g., Pre-Therapy,
expressive therapies), and other psycho-neuro-somatic modalities of
care (e.g., physical therapy, massage, exercise, etc.).
References
1 E. Saito, C.U. Correll, K. Gallelli, M. McMeniman, U.H. Parikh, A.K.
Malhotra, and V. Kafantaris, "A prospective study of hyperprolactinemia
in children and adolescents treated with atypical antipsychotic
agents," Journal of Child and Adolescent Psychopharmacology 14 (2004):
350-358.
2 G. Masi, A. Cosenza, and M. Mucci, "Prolactin levels in young
children with pervasive developmental disorders during risperidone
treatment," Journal of Child and Adolescent Psychopharmacology 11
(2001): 389-394.
3 S. Gupta, B. Frank, and S. Madhusoodanan, "Risperidone-associated
galactorrhea in a male teenager," Journal of the American Academy of
Child and Adolescent Psychiatry 40 (2001): 504-505.
4 No author, "J&J drug explored for tumor link," June 17, 2005
accessed on 29 June 2005 at:
http://money.cnn.com/2005/06/17/news/fortune500/jnj.reut/?cnn=yes
5 L.K. Bachrach, "Bone mineralization in childhood and adolescence,"
Current Opinion in Pediatrics 5 (1993): 467-473.
6 E. Seeman, C. Tsalamandris, and C. Formica, "Peak bone mass, a
growing problem?"
International Journal of Fertility and Menopausal Studies 38 suppl 2
(1993): 77-82.
7 J. Bonjour, "Delayed puberty and peak bone mass," European Journal of
Endocrinology 139 (1998): 257-259.
8 Grace E. Jackson, Rethinking Psychiatric Drugs: A Guide for Informed
Consent
(Bloomington, IN: AuthorHouse, 2005), pp. 91-93, 138-139.
9 R. Kauli, A. Schoenfeld, Y. Ovadia, S. Math, S. Assa, and Z. Laron,
"Delayed puberty and hypoplastic uterus associated with
hyperprolactinemia: successful treatment with bromocriptene," Hormone
Research 22 (1985): 68-73.
10 J.P. Advis, W.W. Andrews, and S.R. Ojeda, "Studies on the central
effects of prolactin in inducing precocious puberty in the female rat,"
Brain Research Bulletin
8 (1982): 449-458.
11 T.E. Stoker, C.L. Robinette, B.H. Britt, S.C. Laws, and R.L. Cooper,
"Prepubertal exposure to compounds that increase prolactin secretion in
male rat: effects on the adult prostate," Biology of Reproduction 61
(1999): 1636-1643.
12 B.J. McConville and M.T. Sorter, "Treatment challenges and safety
considerations for antipsychotic use in children and adolescents with
psychoses," Journal of Clinical Psychiatry 65 Suppl 6 (2004): 20-29.
13 E. A. Koller, J.T. Cross, and B. Schneider, "Risperidone-Associated
Diabetes Mellitus in Children," Pediatrics 113 (2004): 421-422.
14 A. Martin, J. Landau, P. Leebens, K. Ulizio, D. Cicchetti, L.
Scahill, and J.F. Leckman, "Risperidone-associated weight gain in
children and adolescents: a retrospective chart review," Journal of
Child and Adolescent Psycopharmacology
10 (2000): 259-268.
15 D.I. Shaw, W.L. Hall, C.M. Williams, "Metabolic Syndrome: what is it
and what are the implications?" Proceedings of the Nutrition Society 64
(2005): 349-357.
16 J.D. Sherr and G. Thaker, "Progression of abnormal involuntary
movements during risperidone treatment," Journal of Clinical Psychiatry
59 (1998): 478-479.
17 M. Spivak and M. Smart, "Tardive dyskinesia from low-dose
risperidone," Canadian Journal of Psychiatry 45 (2000): 202.
18 S. Kumar and D.M. Malone, "Risperidone implicated in the onset of
tardive dyskinesia in a young woman," Postgraduate Medicine Journal 76
(2000): 316-317.
19 K.S. Hong, S.S. Cheong, J. Woo, and E. Kim, "Risperidone-Induced
Tardive Dyskinesia," American Journal of Psychiatry 156 (1999): 1290.
20 A.S. Robb, W. Chang, H.K. Lee, and M.S. Cook, "Case study.
Risperidone-induced neuroleptic malignant syndrome in an adolescent,"
Journal of Child and Adolescent Psychopharmacology 10 (2000): 327-330.
21 A.L. Sharpley, Z. Bhagwagar, S. Hafizi, W.R. Whale, H.J. Gijsman,
P.J. Cowen, "Risperidone augmentation decreases rapid eye movement
sleep and decreases wake in treatment-resistant depressed patients,"
Journal of Clinical Psychiatry 64 (2003):
192-196.
22 G.E. Jackson, Rethinking Psychiatric Drugs: A Guide for Informed
Consent,
pp. 134-138.
23 C. Cote, "Dear Healthcare Provider," MedWatch Safety Alert on
Risperdal,
April 16, 2003 accessed on 01 AUG 2005 at:
http://www.fda.gov/medwatch/SAFETY/2003/risperdal.htm
24 J.T. McCracken, J. McGough, B. Shah, P. Cronin, D. Hong, et. al.,
"Risperidone in children with autism and serious behavioral problems,"
NEJM 347 (2002): 314-321.
25 A. Gagliano, E. Germano, G. Pustorino, C. Impallomeni, C. D'Arrigo,
F. Calamoneri, and E. Spina, "Risperidone treatment of children with
autistic disorder: effectiveness, tolerability, and pharmacokinetic
implications," Journal of Child and Adolescent Psychopharmacology 14
(2004): 39-47.