BRIEF REPORT

Rabbit Syndrome, Antidepressant Use, and

Cerebral Perfusion SPECT Scan Findings
L. Fornazzaril, M. Ichise2, G. Remington', I. Smith'
'Neuropsychopharmacology Research Unit, Clarke Institute of Psychiatry, Toronto, Ontario
2Department of Nuclear Medicine, Mount Sinai Hospital, Toronto, Ontario
Accepted October 7, 1991

The rabbit syndrome is an extrapyramidal side effect associated with chronic neuroleptic therapy.
Its occurrence in a patient being treated with imipramine is described, representing the first reported
case of this syndrome in conjunction with antidepressants. Repeated cerebral perfusion SPECT scans
revealed decreased basal ganglia perfusion while the movement disorder was present, and a return
to normal perfusion when the rabbit syndrome resolved.

Keywords: rabbit sydrome, antidepressants, imipramine, SPECT

The 'rabbit syndrome' is a late onset extrapyramidal side CASE REPORT

effect occurring in approximately 2-5% of patients chronic-
ally treated with neuroleptics (Villeneuve 1972; Yassa and
Lal 1986). It is characterized by rapid, regular movements
(4-6 Hz) of the oral and masticatory musculature which
mimic the movements of a rabbit's mouth (Todd et al 1983;
Decina et al 1990). Its onset is more common in middle-
aged or elderly individuals, and the risk may increase in
patients with a history of brain injury (Sovner and Dimascio
1977). It is important that it be distinguished from tardive
dyskinesia, as the rabbit syndrome improves rather than
worsens with the addition of antiparkinsonian medication
(Sovner and Dimascio 1977; Weiss et al 1980; Todd et
al 1983; Yassa and Lal 1986; Deshmukh et al 1990).
To date the rabbit syndrome has been associated with
neuroleptic therapy in all but one case, where it was observed
in a 76-year-old female who had not been exposed to
neuroleptics, but who had undergone brain surgery for a
meningioma 16 years earlier (Truong et al 1990). We report
here a case of rabbit syndrome associated with antidepres-
sant medication, specifically imipramine, and the docu-
mented cerebral perfusion changes with single photon em-
ission computed tomography (SPECT) before and after
resolution of the movements.
Address reprint requests to: Dr. L. Fornazzari, Neuropsychophar-
macology Research Unit, Clarke Institute of Psychiatry, 250 College
Street, Toronto, Ontario, Canada, M5T I R8.
J Psychiatr Neurosci, Vol. 16, No. 4, 1991
D.A. is a 45-year-old, right-handed female meeting DSM-
Ill-R criteria for recurrent major depression, and being
treated over the last 4 years with imipramine 125-150 mg
daily. There was no history of head trauma or other medical
illness. Her mood was euthymic but in the month prior to
assessment in our Movement Disorders Clinic she noted
the onset of abnormal perioral movements, described sub-
jectively as "trembling movements" of the upper and lower
lips which increased with stress or tension. On examination
a rapid rhythmic tremor of the lips was recorded and a
diagnosis of rabbit syndrome was made. Frequency of tremor
was approximately 6 Hz and amplitude increased with
distraction.
Symptoms resolved within 2 days following discontinua-
tion of the antidepressant. She was switched to phenelzine
without incident, and at 6 month follow-up her mood
remained euthymic and no abnomal movements were noted.
A SPECT scan (Nagel et al 1991), utilizing a cerebral
perfusion radiopharmaceutical, technetium-99m hexa-
methylpropyleneamine oxime or HMPAO (Neirinckx et al
1987), was carried out under conditions of ambient light,
sound, and stimulation upon initial assessment and at the
6 month follow-up (Fig. 1). Findings were reported as
decreased perfusion in the basal ganglia while the rabbit
syndrome was present, with restoration of normal perfusion
following resolution of the movements.
228 Journal of Psychiatry & Neuroscience
R '9'_>R L L utilizing [1231]N-isopropyl iodoamphetamine reported de-
BEFORE A FTER
Fig. 1: Transaxial SPECT brain perfusion images at 4 cm
above the cantho-meatal line reveal reduced sub-
cortical grey matter perfusion, particularly in the
basal ganglia (arrows), before, ie., rabbit syndrome
present, and after its resolution. Cerebral cortical
perfusion was normal in both SPECT scans.
DISCUSSION
This is the first reported case of rabbit syndrome as-
sociated with antidepressant use, in this instance following
administration of imipramine. It is noteworthy that the
patient had been treated with imipramine for approximately
4 years before onset of the symptoms, as it has also been
described as a late onset side effect of neuroleptics (Yassa
and Lal 1986). This would suggest that the biochemical
mechanisms underlying the rabbit syndrome occur in the
context of chronic drug therapy. However, unlike tardive
movement disorders this particular side effect responds well
to antiparkinsonian therapy. In this case it was not necessary
to initiate such treatment as the the symptoms resolved upon
discontinuation of the imipramine.
The occurrence of neuroleptic-like side effects with
antidepressants is not new. Imipramine itself has been
associated with tremor, akathisia, and galactorrhea (Klein
et al 1964; Kronfol et al 1983; Zubenko et al 1987), while
dyskinesias have been reported with other antidepressants
(Fann et al 1976). More recently it has been suggested that
the newer group of selective serotonin uptake inhibitor
antidepressants, eg. fluoxetine, are capable of causing neuro-
leptic-like side effects such as akathisia through a serotonin-
mediated inhibition of dopaminergic neurotransmission
(Lipinski et al 1989; Kim and Dysken 1991). Imipramine
is not included in this new group of antidepressants, although
it is a potent inhibitor of serotonin reuptake (Buchsbaum
et al 1986; Leonard 1988). It may well be, then, that
imipramine is capable of inducing neuroleptic-like side
effects through similar neurotransmitter changes. The op-
portunity to investigate this patient using SPECT while the
rabbit syndrome was present and after it resolved proved
particularly interesting, with results indicating decreased
VoL 16, No. 4, 1991
perfusion in the region of the basal ganglia initially and
a return to normal perfusion when the movement disorder
resolved. It is important to keep in mind, however, that
altered basal gangia perfusion has been reported in a variety
of conditions. More specifically, decreased perfusion has
been reported in different extrapyramidal movement dis-
orders, including Huntington's chorea and Parkinson's dis-
ease (Podreka et al 1987; Nagel et al 1991). To date, cerebral
perfusion SPECT data in mood disorders are somewhat
limited and inconclusive, O'Connell and coworkers (1989),
creased cerebral cortical and basal ganglia perfusion in
patients with major depressive disorder, while measures of
regional cerebral blood flow with HMPAO have shown a
relative increase in perfusion following electroconvusive
therapy (Bajc et al 1989). Increased basal ganglia perfusion
has been reported in patients with schizophrenia, particularly
those with auditory hallucinations (Alavi and Hirsch 1991).
In this case, the chronology of events would suggest that
the documented SPECT changes were related to the rabbit
syndrome. The patient had been euthymic for a considerable
time before the first SPECT study, and remained so through
the second SPECT investigation. In contrast, the rabbit
syndrome was present when the first SPECT study revealed
decreased basal ganglia perfusion, and had resolved at the
time of the second SPECT scanning when a return to normal
perfusion was reported. Cerebral cortical perfusion was
normal in both SPECT scans.
In summary, the rabbit syndrome is an extrapyramidal
side effect which has been reported in patients chronically
treated with neuroleptics. This is the first report of its
occurrence with antidepressant therapy, in this case imipra-
mine. SPECT findings associated with the presence of the
rabbit syndrome in this individual, specifically decreased
perfusion in the basal ganglia, need to be confirmed with
additional patients where the syndrome is identified.
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