HUMAN PSYCHOPHARMACOMGY , VOL. 9,303-305 (1994)

CASE REPORT

Neuroleptic Malignant Syndrome Associated with the Use of Risperidone, an Atypical Antipsychotic Agent HEIDI LEE*, JAMES RYAN, GEORGE MULLETT and BRIAN A. LAWLOR Department of Psychiatry, St. James’s Hospital, Dublin 8, Ireland

Neuroleptic malignant syndrome (NMS) is a rare and sometimes fatal adverse reaction to neuroleptic drugs. Atypical antipsychotic agents, such as risperidone, are thought to be less likely to cause N M S because of their phamacologiical profile. This is a case report of NMS associated with risperidone treatment.

KEY woms-Risperidone, neuroleptic malignant syndrome, NMS, atypical neuroleptic.

INTRODUCTION

Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic and sometimes fatal reaction to neur- oleptic drugs characterized by muscular rigidity, fever, autonomic dysfunction and altered con- sciousness. =Cases of NMS have been reported associated with all typical neuroleptics (Addonizio et al., 1987). The contention that a drug’s potential to produce NMS may be related to its anti-dopami- nergic activity (Caroff, 1980; Kellam, 1987) is further supported by the occurrence of cases in non-psychiatric patients treated with metoclopra- mide (Lazarus et al., 1989) and in Parkinson’s dis- ease patients on withdrawal of their dopaminergic agonists (Henderson and Wooten, 1981).

Risperidone is a benzisoxazol-derivative with potent serotonin 5-HT2 and dopamine D2 antago- nist activity. It is defined as an atypical neuroleptic because it has been shown to produce fever extra- pyramidal side-effects (EPSE) for a given antipsy- chotic effect (Mesotten et al., 1989). There is a suggestion that the atypical neuroleptic agents which have increased serotonin antagonist activity may protect against N M S (Caroff et a)., 1991). However, cases of NMS have been reported with the prototype atypical agent clozapine (Muller et al., 1988; Das Gupta and Young, 1991). To date, to our knowledge, there have been no published reports of NMS associated with risperidone.

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* Author to whom correspondence should be addressed.

CASE REPORT Mr A. was a 24-year-old single, white man who had a five-year history of paranoid schizophrenia. During the course of his illness he had developed EPSE on various neuroleptics (chlorpromazine (on 500 mg/day)-akathisia; thioridazine (440 mgl d a y h r a l dyskinesia; perphenazine (1 6 mg/day)- cogwheel rigidity and tremor; fluphenazine deca- noate (25 mg/3 weeks)-cogwheel rigidity). Treated with sulpiride (400 mglday) he initially did reason- ably well and had taken up an unskilled job. How- ever, he later relapsed with emergence of prominent positive and negative symptoms and required increased doses of sulpiride (1 200 mglday). This, in turn, caused troublesome EPSE (tremor and cog- wheel rigidity) which were poorly controlled with anticholinergic medication. He was admitted in July 1993 for management of worsening psychosis.

At this time his behaviour was unpredictable with aggressive outbursts, paranoid delusions and prominent thought disorder. He had passivity phe- nomena believing that others had access to his thoughts and although he denied auditory halluci- nations behaved as if responding to such abnormal experiences. Following admission he was treated initially with chlorpromazine (up to 1000 mglday) and later remoxipride (up to 1350 mglday), but these failed to contain his psychosis and he conti- nued to have troublesome EPSE. After a 3-day neuroleptic-free period, he was started on risperi- done. Over the next 4 weeks his dose was gradually increased to 14 rnglday. Throughout this period

CCC 0885-622U94/040303-03 0 1994 by John Wiley & Sons, Ltd.

304 H. LEE ET AL.

he received, in addition, benztropine 2 mglday and chlordiazepoxide 10 mg four times a day. He had no intramuscular medication, nor was there a his- tory of falls. During this time, his psychosis, pre- dominantly the negative symptoms improved: Positive and Negative Syndrome Scale for schi- zophrenia (PANSS, Kay et al., 1987) positive symp- toms subscale score had fallen from 27 to 23; negative symptom subscale score from 23 to 13; general psychopathology subscale score from 62 to 43. Also, he had fewer EPSE: the parkinsonism subscale score of the Extrapyramidal Symptom Rating scale (ESRS, Chouinard et al., 1980) had fallen from 34 to 2 1.

After 33 days of treatment (9 days after the increase to 14 mg/day from 12 mg/day), he deve- loped a fever (38.5"C, rising to a maximum of 39.2"C), tachycardia (130/min), unstable blood pressure (ranging from 150/70 to 120/60 during the next 2 days; baseline blood pressure prior to start- ing risperidone was 120/70). He was sweating and markedly tremulous. He had increased tone and cogwheel rigidity in his upper limbs, but this was no worse than prior to starting the risperidone (ESRS parkinsonism subscale score was 21). Althoilgh his behaviour was often described as bizarre, nursing reports on the day prior to and the day of developing the pyrexia described him as being confused also. Physical examination revealed mild upper respiratory tract symptoms only and full septic screen including chest x-ray, urinalysis and blood cultures were normal. Full blood count was normal (white cell count 5-8 X lo9&). Risperidone was discontinued on the night he developed fever, and his temperature returned to normal within 3 days. Creatine kinase (CK) level sent on the morning after developing fever was 530 lU/L (normal range 29-195 lU/L). The CK increased to a maximum of 2129 IU/L 2 days later and then gradually decreased to normal, 174 lUL, 13 days later. A course of augmentin, started while awaiting the results of the septic screen, was com- pleted. The meteorological temperature on the day he first developed pyrexia ranged from a minimum of 5°C to a maximum of 12.3OC.

Subsequently, he was treated with chlordiaz- epoxide alone and his psychotic symptoms became progressively more severe and difficult to manage. Fourteen days after the initial pyrexia he was started on perphenazine 4 mg/day. His CK rose sharply over the next 8 days to 3293 lU/L. Although he did not develop any other symptoms suggestive of NMS, the perphenazine was discontinued and the plan now is to treat him with clozapine.

DISCUSSION This patient meets Levenson's criteria for NMS (1985), with two clearcut major manifestations: fever and elevated CK, (and an equivocal manifes- tation of rigidity as he did have EPSE prior to start- ing risperidone) and four minor manifestations: tachycardia, abnormal blood pressure, diaphoresis and altered consciousness. Additionally, he would satisfy the criteria suggested by Adityanjee et al. (1988) having confusion, pyrexia (39-2°C on second day) and autonomic dysfunction (tachycardia, dia- phoresis and fluctuating blood pressure) with the elevated CK supporting the diagnosis. Despite full medical examination and septic screen there was no other cause found for the pyrexia or other chemical manifestations. The risperidone was dis- continued within 12 h of the development of fever which may account for his rapid and uneventful recovery.

A major theory of causation of NMS, that it is caused by dopamine depletion or blockade, is supported by the fact that all implicated drugs, including non-psychiatric drugs such as metoclo- pramide, share this feature (Caroff, 1980; Kellam, 1987). Animal studies and work with pro-seroto- nergic drugs have suggested that serotonin may be involved in the pathogenesis of heat production and have an inhibitory effect on dopamine path- ways (Lazarus et al., 1989; Baldessarini and Marsh, 1990). Thus, it has been proposed that the atypical neuroleptics which have serotonin 5HT2 antagonist activity in addition to dopamine antagonist activity may protect against NMS (Caroff et al., 1991). This case report has important implications for clini- cians because it suggests that this serious and potentially fatal condition must be considered as a differential diagnosis in any patient on risperi- done who develops an unexplained fever.

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