Rabbit Syndrome Secondary to Risperidone
Jenifer S. Hoy, Bruce Alexander, Pharm.D.
http://www.medscape.com/viewarticle/432398
Pharmacotherapy 22(4):513-515, 2002. © 2002 Pharmacotherapy
Publications
Abstract and Introduction
Abstract
After taking risperidone for 4 months, a 38-year-old man with a majordepressive
disorder experienced rabbit syndrome. This uncommon extrapyramidal side effect
is characterized by rhythmic movements of the mouth and may be caused by typical
antipsychotics and risperidone secondary to blockade of dopamine D2 receptors.
The syndrome, whose exact mechanism is unknown, responded to anticholinergic
treatment in this patient. A literature review indicated that most recent cases
have occurred as reactions to the atypical antipsychotic risperidone. Changing
treatment to an atypical antipsychotic other than risperidone, such as
olanzapine 10 mg/day, may lead to suppression or elimination of the syndrome.
Introduction
Rabbit syndrome, first reported in 1972, [1] is described as involuntary
perioral movements that mimic the chewing motions of a rabbit. In a search of
the English-language medical literature, we found 22 cases of rabbit syndrome
secondary to antipsychotics.[1-10] The disorder has been associated with
exposure to typical antipsychotic drugs -- haloperidol, thioridazine, and
zuclopenthixol (not available in the United States) alone or in
combination.[3-5] Of the 22 reported cases, 12 were associated with haloperidol.
Eight were due to various combinations of typical antipsychotic drugs, and the
remaining two were due to risperidone, an atypical antipsychotic. [2, 10]
Case Report
A 38-year-old man with a diagnosis of major depressive disorder with psychotic
features was treated with paroxetine 40 mg and risperidone 4 mg/day. He had no
other major medical conditions. In addition, he was taking simvastatin 10
mg/day, thiamine 100 mg/day, and folic acid 1 mg/day. After 4 months he came to
a regularly scheduled outpatient appointment with worsening symptoms of
depression, mild agitation, and rocking; lip smacking was also noted, although
he said he was unaware of the behavior. He was then admitted to an inpatient
psychiatric unit. After admission, his daily doses of paroxetine and risperidone
were increased to 60 mg and 6 mg, respectively. Three days later, because his
longitudinal diagnosis was thought to be bipolar affective disorder, divalproex
sodium was started, and paroxetine was tapered and discontinued. Due to
continued mouth movements, which were diagnosed as rabbit syndrome, benztropine
1 mg twice/day was started. The syndrome continued, and 2 days later his
benztropine dosage was increased to 1 mg 3 times/day. The next day his mouth
movements decreased significantly. Because of dry mouth and blurred vision,
however, benztropine was decreased back to 1 mg twice/day. At discharge, the
patient continued taking benztropine 1 mg twice/day, divalproex 750 mg/day, and
risperidone 6 mg/day, with no detectable mouth movements.
The patient's antipsychotic drug was not changed because he was doing well with
risperidone, and the physician did not want to risk a relapse of symptoms. In
addition, the inpatient team decided that after 4 more months, his risperidone
and benztropine should be discontinued for a period to determine whether the
patient needed to continue taking them. If psychotic symptoms and rabbit
syndrome returned, then the patient was to be considered for a trial period with
olanzapine.
Discussion
Rabbit syndrome, an antipsychotic-induced extrapyramidal side effect, is
characterized by rhythmic movements of the mouth, often accompanied by lip
sounds.[5] Only about 50 cases have been reported in the English and non-English
literature.[4] Its estimated prevalence is 1.5-4% in patients taking typical
antipsychotics alone.[4,9] Most case reports involve middle-aged and elderly
patients; 66% are women.[8] Only one patient, a 36-year-old Japanese woman with
no significant medical or psychiatric history, had non-drug-induced (idiopathic)
rabbit syndrome.[11] The exact mechanism of rabbit syndrome is unknown. It may
be due to basal ganglia dysfunction or hypersensitive dopamine D2
receptors.[5,9] Therefore, the syndrome has been linked with other typical
antipsychotic-induced extrapyramidal side effects, such as tardive dyskinesia
and drug-induced parkinsonism, which are the result of D2 receptor blockade.[6]
However, physiologic and clinical differences exist. Mouth movements of rabbit
syndrome are rapid and rhythmic, in contrast to movements of tardive dyskinesia,
which are usually irregular and slow. [7]
Tardive dyskinesia typically occurs after years of taking an antipsychotic,
whereas rabbit syndrome occurs within 1 year after antipsychotic treatment is
begun.[2,9] In rabbit syndrome, but not in tardive dyskinesia, movements
continue during stage 1 of non-rapid eye movement sleep.[8] In addition, tardive
dyskinesia may involve abnormal movements of the tongue, trunk, and extremities,
which are not affected in rabbit syndrome.[6,7] Because intravenous haloperidol
temporarily suppresses the perioral movements, which also occurs with tardive
dyskinesia, rabbit syndrome may be a transitional form of tardive dyskinesia.[8]
Adding anticholinergic agents, which significantly reduce or eliminate rabbit
syndrome, either is ineffective or may aggravate or unmask the dyskinetic
movements of tardive dyskinesia.[9] Finally, physostigmine, a cholinergic
agonist that worsens rabbit syndrome, may improve tardive dyskinesia
temporarily.[7,12]
Rabbit syndrome is similar to drug-induced parkinsonism in that movements occur
during stage 1 of non-rapid eye movement sleep. In addition, drug-induced
parkinsonism, like rabbit syndrome, can be treated successfully with
anticholinergic agents. [2, 3] However, these disorders do not share common
signs and symptoms. Typical antipsychotics often produce parkinsonian syndrome
within 3 months of the start of treatment. [13] Risperidone, like other atypical
antipsychotics, is a selective antagonist of serotonergic (5-HT2) and
dopaminergic (D2) receptors. It causes extrapyramidal side effects, both early
onset (e.g., akathisia, parkinsonism) and long term (e.g., tardive dyskinesia).
[13] At dosages greater than 6 mg/day, risperidone's dopaminergic effect may
predominate, leading to an increased rate of early-onset extrapyramidal side
effects. [13]
This finding has led some researchers to classify risperidone not as an atypical
antipsychotic but as a novel agent. Rabbit syndrome has not been reported with
administration of other atypical antipsychotics available in the United States,
such as olanzapine, clozapine, ziprasidone, or quetiapine, but the latter two
have been on the market for less time than risperidone. Rabbit syndrome may be
less likely to occur with these other antipsychotic agents because they have a
more favorable 5-HT2:D2 ratio than risperidone. [13]
In one patient, rabbit syndrome improved within 2-3 weeks after zuclopenthixol
therapy was replaced with olanzapine 10 mg/day. [5] We found no reports of
clozapine, quetiapine, or ziprasidone being used to treat rabbit syndrome. In
one patient, idiopathic rabbit syndrome was treated unsuccessfully with the
atypical antipsychotic tiapride (not available in the United States). [11]
Diazepam, trihexyphenidyl, levodopa, and a b-blocker also had no effect. The
effectiveness of dopamine agonists in treating rabbit syndrome is unclear as
they have not been studied extensively.
Time of onset of risperidone-induced rabbit syndrome is consistent with cases
caused by typical antipsychotics.[9] Our patient had been taking risperidone 4
mg/day for 4 months when rabbit syndrome became evident. In another patient,
onset occurred after 4 months of therapy with risperidone 4 mg/day and mianserin
(not available in the United States) 30 mg/day.[2] In a third patient, the
syndrome appeared after 7 months of treatment with risperidone 6 mg/day for 4
months, then 4 mg/day for 3 months.[10] Rabbit syndrome secondary to typical
antipsychotics has been treated successfully with anticholinergic agents, such
as trihexyphenidyl, benztropine, and biperiden.[2,4,7,9,12] In the three
patients discussed above, all signs of risperidone-induced rabbit syndrome were
eliminated with benztropine 2 mg/day, benzhexol 10 mg/day,[2] and biperiden 2 mg
twice/day,[10] respectively. In patients with rabbit syndrome induced by
risperidone or typical antipsychotics, signs often improved within 4-5 days and
were eliminated completely after 2-3 weeks of anticholinergic
therapy.[2,4,7,9,10,12] When anticholinergic drugs were discontinued, rabbit
syndrome returned and then subsided again when the drugs were restarted.[12]
Dose-ranging studies to determine the minimum effective dosage of
anticholinergic agents have not been conducted. The time course of rabbit
syndrome after discontinuation of the offending antipsychotic also is unknown.
Anticholinergic agents may have a preventive effect. In a study of 266
inpatients, rabbit syndrome was diagnosed in only 6 (4.4%) of the 137 receiving
antipsychotics alone and in 0 of the 129 receiving an anticholinergic agent
combined with an antipsychotic agent.[9] However, because rabbit syndrome occurs
infrequently, prophy-lactic treatment with anticholinergic agents is not
recommended.
Our patient also was receiving a selective serotonin reuptake inhibitor (paroxetine),
but we found no published reports of rabbit syndrome associated with these
agents. Paroxetine may have increased risperidone levels through cytochrome P450
2D6 enzyme inhibition, which may have contributed to the development of rabbit
syndrome in our patient. [14] Serum levels of paroxetine and risperidone were
not available, thus this possible interaction could not be investigated.
Conclusion
Rabbit syndrome, an infrequently reported adverse effect of typical
antipsychotics, most recently has been reported with the atypical antipsychotic
risperidone. Changing treatment to an atypical antipsychotic other than
risperidone, such as olanzapine 10 mg/day, may lead to suppression or
elimination of the syndrome. Although experience is limited, this should be a
first-line management consideration to avoid adding a second drug to treat a
drug-induced side effect. However, if changing to another antipsychotic agent is
not possible (e.g., the patient is receiving a long-acting injectable typical
antipsychotic because of noncompliance), then an anticholinergic agent would be
an effective suppressive treatment. Rabbit syndrome responds completely within 3
weeks of starting therapy with benztropine 2 mg/day, trihexyphenidyl 10 mg/day,
or biperiden 2 mg/day. If the syndrome is treated with an anticholinergic agent,
it is advisable to discontinue the drug periodically (e.g., every 3 months) to
determine whether treatment needs to be continued. Exact etiology, time course,
and long-term outcome of rabbit syndrome are unknown.
References
Villeneuve A. The rabbit syndrome: a peculiar extrapyramidal reaction. Can
Psychiatry Assoc J 1972;17(suppl 2):69-72.
Schwartz M, Beny A, Sharf B. Risperidone-induced rabbit syndrome [letter]. Br J
Psychiatry 1998;173:267-8.
Schwartz M, Weller B, Erdreich M, Sharf B. Rabbit syndrome and tardive
dyskinesia: two complications of chronic neuroleptic treatment [letter]. J Clin
Psychiatry 1995;56:212.
Chiu HF, Lam LC, Chung DW, Wing YK, Shum PP. Prevalence of the rabbit syndrome
in Hong Kong. J Nerv Ment Disord 1993;181:264-5.
Durst R, Katz G, Zislin J, Raskin S, Kalman I. Rabbit syndrome treated with
olanzapine [letter]. Br J Psychiatry 2000;176:193.
Todd R, Lippmann S, Manshadi M, Chang A. Recognition and treatment of rabbit
syndrome: an uncommon complication of neuroleptic therapies. Am J Psychiatry
1983;140:1519-20.
Deshmukh DK, Joshi VS, Agarwal MR. Rabbit syndrome: a rare complication of
long-term neuroleptic medication [letter]. Br J Psychiatry 1990;157:293.
Wada Y, Yamaguchi N. The rabbit syndrome and antiparkinsonian medication in
schizophrenic patients. Neuropsychobiology 1992;25:149-52.
Yassa R, Lal S. Prevalence of the rabbit syndrome. Am J Psychiatry
1986;143:656-7.
Levin T, Heresco-Levy U. Risperidone-induced rabbit syndrome: an unusual
movement disorder caused by an atypical antipsychotic. Eur Neuropsychopharm
1999;9:137-9.
Miwa H, Sasaki Y, Hatori K, Tanka S, Mizuno Y. Idiopathic rabbit syndrome: a
case report. No To Shinkei 1999;51:907-9.
Weiss KJ, Ciraulo DA, Shader RI. Physostigmine test in the rabbit syndrome and
tardive dyskinesia. Am J Psychiatry 1980;137:627-8.
Worrel JA, Marken PA, Beckman SE, Ruetcher VL. Atypical antipsychotics: a
critical review. Am J Health-Syst Pharm 2000;57:238-58.
Hamilton S, Malone K. Serotonin syndrome during treatment with paroxetine and
risperidone. J Clin Psychopharmacol 2000;20:103-5.
Reprint Address
Address reprint requests to Bruce Alexander, Pharm.D., BCPP, Pharmacy Service
(119), Iowa City DVAMC, 601 Highway 6 West, Iowa City, IA 52246.
From the Departments of Pharmacy and Psychiatry, Iowa City Department of
Veterans Affairs Medical Center (Dr. Alexander), and the Colleges of Pharmacy
and Medicine (Dr. Alexander), University of Iowa, Iowa City, Iowa.
