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Olanzapine Usage Associated With Neuroleptic Malignant Syndrome

Received June 12, 2001; revised July 29, 2001; accepted August 7, 2001. From the Department of Psychiatry, University of Iowa, Iowa City, IA 52246. Address correspondence and reprint requests to Dr. Philibert, Department of Psychiatry, Room 2-126 MEB, University of Iowa, Iowa City, IA 53346. E-mail: robert-philibert{at}uiowa.edu

Key Words: Olanzapine • Neuroleptic Malignant Syndrome

Suspicion of neuroleptic malignant syndrome (NMS) is a frequent cause of emergent psychiatric consultation. This uncommon syndrome, characterized by muscular rigidity, autonomic instability, hyperthermia, and mental status changes, has been associated with conventional dopamine D₂ receptor antagonist treatments such as haloperidol or fluphenazine. Patients presenting with symptoms characteristic of NMS frequently are initially hospitalized in medical intensive care units or general medicine wards. Psychiatric consultants may be called on to assist in establishing the diagnosis of NMS, to make recommendations for management of psychiatric symptoms in NMS patients, and to reestablish neuroleptic therapy.

Despite early recognition, NMS has remained a syndrome that causes high rates of morbidity and mortality. The development of alternative antipsychotic agents that do not have NMS as a possible side effect has been a high priority for the pharmaceutical industry. The last decade has seen considerable progress in the development of these alternative medications. The introduction of the first atypical antipsychotic, clozapine, in 1990 was accompanied by hopes that this drug might cause a lower incidence of NMS. Although a reduction in NMS may have occurred, the frequency of agranulocytosis secondary to clozapine usage¹ has reduced the utility of this medication in the general psychiatric population. In an attempt to retain the unique therapeutic profile of clozapine while eliminating the risk of agranulocytosis, researchers developed a close chemical analog of clozapine, named olanzapine.² In premarketing studies of more than 2,500 patients treated with olanzapine before its introduction in 1996, no cases of NMS were reported. These results raised hopes that the new generation of antipsychotics may not cause this potentially deadly syndrome.

Unfortunately, since the introduction of this medication to the market, six cases of NMS associated with olanzapine treatment have been reported in the literature.³ We now report a seventh case of NMS in a patient treated with olanzapine.

Case Report

Mr. G. is a 52-year-old white man with 30-year history of bipolar affective disorder (BPAD) and a 10-year history of Parkinson disease who was recently admitted to a medical psychiatry unit (MPU) after leaping off a ledge. Before he was admitted to the hospital, his prescribed medication regimen for the past several years had consisted of paroxetine (20 mg), divalproex (750 mg qd), risperidone (2 mg qd), lorazepam (1 mg tid), carbidopa/levodopa (25/100 mg qid) His past treatments for BPAD included lithium, carbamazepine, divalproex, thiothixene, thioridazine, haloperidol, and clozapine. Since 1990, Mr. G. had been treated for his Parkinson disease with carbidopa/levodopa and selegiline. Otherwise, his medical and psychiatric histories were unremarkable.

After Mr. G.'s admission to the hospital, BPAD and depression were diagnosed; his paroxetine was increased to 40 mg qd and his other medications were continued. Because he had severely bruised his buttocks in his suicide attempt, Mr. G. underwent evaluation to rule out a fracture. These radiologic studies were unremarkable, and Mr. G. was treated with intravenous fluids for a transient rhabdomyolysis that resolved completely. After neurologic consultation, his risperidone, which aggravated his Parkinson disease rigidity, and selegiline, which was deemed ineffective, were discontinued. On the evening of hospital Day 3, olanzapine was added to treat continuing referential ideation and auditory hallucinations.

On hospital Day 11, Mr. G. had an unusual spell characterized by bilateral tremors and decreased responsiveness, which was initially thought to be a seizure. An electroencephalogram taken immediately after the spell was unremarkable. Mr. G. was transferred to the intensive care unit, where he was given phenytoin. On Day 12, he was transferred back to the MPU in good condition. On hospital Day 13, Mr. G. appeared slightly dazed. Over the next 24 hours, he became hyperthermic (41.5°C), hypertensive (blood pressure>186/58 mmHg), tachycardic (heart rate> 127 beats/min), tachypneic (respiratory rate> 60 breaths/min) hypoxic, incontinent, and unresponsive, necessitating transfer back to the intensive care unit. Olanzapine was discontinued, and Mr. G. was intubated and treated with intravenous fluids, dantrolene, and bromocriptine. He was also treated with levofloxacin and piperacillin for presumed pneumonia. On hospital Day 18, he was transferred back to the MPU. While in the MPU, he continued to have the intermittent spells that were observed on Day 11. Thorough examination of Mr. G., further review of his medical history, and electroencephalographic monitoring during one of these attacks led to the conclusion that these spells, which had apparently occurred for many years, were nonictal.

Mr. G. subsequently did well, and on hospital Day 26, he was transferred to an inpatient psychiatric unit for further optimization of the treatment of his Parkinson disease and his BPAD depression. His transfer medications consisted of carbamazepine (200 mg bid), paroxetine (20 mg qd), and carbidopa/levodopa (25/100 mg qid).

Discussion

Although both phenytoin and olanzapine were started within 10 days of the onset of the syndrome, the most likely cause of Mr. G.'s illness was treatment with olanzapine. The symptoms in this case fully meet the criteria for NMS set by Caroff and Mann.⁴ Furthermore, Mr. G. had comorbid diagnoses of BPAD⁵ and Parkinson disease,⁶ as well as recent trauma, which have been reported to be risk factors for NMS. Mr. G. had also been treated with risperidone until 10 days before the clear onset of the syndrome. Because he had been taking this medication for several years, however, it is unlikely that this agent induced the current presentation.

Alternatively, because Mr. G. had recently been treated with selegiline, a monoamine oxidase inhibitor, and was currently taking paroxetine, it is possible that his symptoms could have resulted from serotonin syndrome.⁷ However, his lack of myoclonus and gastrointestinal dysfunction, which are typical symptoms of serotonin syndrome, suggests that this was not the case.

Our patient's psychotic symptoms did not recur after the resolution of this episode, so repeat challenge with neuroleptic medication was not an immediate issue. Other patients have successfully resumed antipsychotic treatment after waiting for a suitable period after the resolution of the acute NMS episode.⁸ Rates of recurrence of NMS may be as high as 64% when neuroleptics are resumed within 5 days or less after symptom resolution.⁹ It is recommended that antipsychotics not be reinstituted until at least 2 weeks after the patient's symptoms are completely resolved and the patient is no longer receiving treatment for NMS.¹⁰ In the meantime, the expertise of the consultant psychiatrist may be needed to manage the patient's agitation and to determine the appropriate neuroleptic class (atypical vs. low potency) and dose to use upon reinitiation of therapy.

In summary, we report a seventh case of olanzapine-associated NMS. In the context of the previous studies, our results suggest that olanzapine-induced NMS may not be rare and that further studies are needed to assess the incidence of NMS with this atypical antipsychotic.

REFERENCES

1. Miller DD: Review and management of clozapine side effects. J Clin Psychiatry 2000; 61(Suppl 8):14-17; discussion 18-19
2. Bhana N, Foster RH, Olney R, et al: Olanzapine: an updated review of its use in the management of schizophrenia. Drugs 2001; 61:111-161[CrossRef][Medline]
3. Stanfield SC, Privette T: Neuroleptic malignant syndrome associated with olanzapine therapy: a case report. J Emerg Med 2000; 19(4):355-357
4. Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 1993; 77:185-202[Medline]
5. Hermesh H, Aizenberg D, Weizman A, et al: Risk for definite neuroleptic malignant syndrome. A prospective study in 223 consecutive in-patients. Br J Psychiatry 1992; 161:254-257[Abstract/Free Full Text]
6. Kuno S, Mizuta E, Yamasaki S: Neuroleptic malignant syndrome in parkinsonian patients: risk factors. Eur Neurol 1997; 38(Suppl 2):56-59
7. Carbone JR: The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am 2000; 18:317-325[CrossRef][Medline]
8. Slack T, Stoudemire A: Reinstitution of neuroleptic treatment with molindone in a patient with a history of neuroleptic malignant syndrome. Gen Hosp Psychiatry 1989; 11:365-367[Medline]
9. Susman VL, Addonizio G: Recurrence of neuroleptic malignant syndrome. J Nerv Ment Dis 1988; 176:234-240[Medline]
10. Rosenberg MR, Green M: Neuroleptic malignant syndrome. Arch Intern Med 1989; 149:1927-1931[Abstract/Free Full Text]

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