DE, Higa J, Haier R (1986) Effects of amoxapine and imipramine on cerebral glucose metabolism assessed by positron emission tomography. JCP Monograph ...
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 effect occurring in approximately 2-5% of patients chronically 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 middleaged 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 antidepressant medication, specifically imipramine, and the documented cerebral perfusion changes with single photon emission computed tomography (SPECT) before and after resolution of the movements. Address reprint requests to: Dr. L. Fornazzari, Neuropsychopharmacology Research Unit, Clarke Institute of Psychiatry, 250 College Street, Toronto, Ontario, Canada, M5T I R8.
J Psychiatr Neurosci, Vol. 16, No. 4, 1991
CASE REPORT
D.A. is a 45-year-old, right-handed female meeting DSMIll-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 subjectively 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 discontinuation 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 hexamethylpropyleneamine 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.
Journal of Psychiatry & Neuroscience
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L A FTER
Fig. 1: Transaxial SPECT brain perfusion images at 4 cm above the cantho-meatal line reveal reduced subcortical 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 associated 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 neuroleptic-like side effects such as akathisia through a serotoninmediated 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 opportunity 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 disorders, including Huntington's chorea and Parkinson's disease (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), utilizing [1231]N-isopropyl iodoamphetamine reported decreased 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 imipramine. 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.
REFERENCES Alavi A, Hirsch LJ (1991 ) Studies of central nervous system disorders with single photon computed tomography and positron emission tomography: Evolution over the past 2 decades. Semin Nucl Med XXI 1:(1)58-81. Bajc M, Medved V, Basic M, Topuzovic N, Babic D, Ivancevic D (1989) Acute effect of electroconvusive therapy on brain perfusion assessed by Tc99m-hexamethylpropyleneamineoxim and single photon emission computed tomography. Acta Psychiatr Scand 80:421-426. Buchsbaum MS, Tand SW, Wu JC, Hazlett E, Donoghue DE, Higa J, Haier R (1986) Effects of amoxapine and imipramine on cerebral glucose metabolism assessed by positron emission tomography. JCP Monograph 4:(2)1417. Decina P, Caracci G, Scapicchio PL (1990) The rabbit syndrome. Mov Disord 5:(3)263.
November 1991
Spect Scan Findings in Rabbit Syndrome
Deshmukh DK, Joshi VS, Agarwal MR (1990) Rabbit syndrome - A rare complication of long-term neuroleptic medication. Br J Psychiatry 157:293 . Fann WE, Sullivan JL, Richman BW (1976) Dyskinesias associated with tricyclic antidepressants. Br J Psychiatry 128:490-493. Kim SW, Dysken MW (1991 ) Potential antidopaminergic effects of serotonin reuptake inhibitors. J Clin Psychiatry 52:(1)42. Klein JJ, Segal RL, Warner RRP (1964) Galactorrhea due to imipramine. New Engl J Med 271:(10)510-512. Kronfol Z, Greden JF, Zis AP (1983) Imipramine-induced tremor: Effects of a beta-adrenergic blocking agent. J Clin Psychiatry 44:(6)225-226. Leonard BE (1988) Pharmacological effects of serotonin reuptake inhibitors. J Clin Psychiatry 49:(8,Suppl) 12-17. Lipinski JF Jr, Mallya G, Zimmerman P, Pope HG Jr (1989) Fluoxetine-induced akathisia: Clinical and theoretical implications. J Clin Psychiatry 50:(9)339-342. Nagel JS, Ichise M, Holman BL (1991) The scintigraphic evaluation of Huntington's disease and other movement disorders using single photon emission computed tomography perfusion brain scans. Semin Nucl Med XXIl: 1123. Neirinckx RD, Canning LR, Piper IM, Nowotnik DP, Pickett RD, Holmes RA, Volkert WA, Forster AM, Weisner PS, Marriott JA, Chaplin SB (1987) Technetium-99m, d,lHM-PAO: A new radiopharmaceutical for SPECT imaging of regional cerebral blood perfusion. J Nucl Med (2)19:1-202.
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O'Connell RA, Van Heertum RL, Billick SB, Holt AR, Gonzalez A, Notardonato H, Luck D, King LN (1989) Single photon emission computed tomography (SPECT) with [1 2311IMP in the differential diagnosis of psychiatric disorders. J Neuropsychiatry 1:145-153. Podreka 1, Suess E, Goldenberg G, Steiner M, Brucke T, Muller C, Lang W, Neirinckx RD, Deecke L (1987) Initial experience with technetium-99m HM-PAO brain SPECT. J Nucl Med 28:(1 1)1657-1666. Sovner R, Dimascio A (1977) The effect of benztropine mesylate in the rabbit syndrome and tardive dyskinesia. Am J Psychiatry 134:(11)1301-1302. Todd R, Lippmann S, Manshadi M, Chang A (1983) Recognition and treatment of rabbit syndrome, an uncommon complication of neuroleptic therapies. Am J Psychiatry 140:(11)1519-1520. Truong DD, Hermanowicz N, Mistura K (1990) Rabbit syndrome treated with botulin. South Med J 83:(7)854855. Villeneuve A (1972) The rabbit syndrome: A peculiar extrapyramidal reaction. Can Psychiatr Assoc J 17:6972. Weiss KJ, Ciraulo DA, Shader Rl (1980) Physostigmine test in the rabbit syndrome and tardive dyskinesia. Am J Psychiatry 1 37:(5)627-628. Yassa R, Lal S (1986) Prevalence of the rabbit syndrome. Am J Psychiatry 43:(5)656-657. Zubenko GS, Cohen Bm, Lipinski JR Jr (1987) Antidepressant-related akathisia. J Clin Psychopharmacol 7:(4)254-257.
