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Neuroleptic Malignant Syndrome Associated With Olanzapine Therapy

Received April 9, 1998; revised September 9, 1998; accepted October 7, 1998. From Consultation-Liaison Psychiatry Service, Methodist Hospital, HealthSystem Minnesota. Address reprint requests to Dr. Apple, Consultation-Liaison Psychiatry Service, Methodist Hospital, Room 653, 6500 Excelsior Boulevard, St. Louis Park, MN 55426.

Key Words: Neuroleptic Malignant Syndrome • Olanzapine

TO THE EDITOR: Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially fatal complication of antipsychotic treatment. Cardinal features include rigidity, hyperthermia, mental status changes, and autonomic instability. It has been associated with all typical antipsychotics.¹ In 1986, NMS was also linked to clozapine therapy;² in 1994, to risperidone therapy.³ Since those initial reports, many additional case reports have appeared documenting the association of NMS with these atypical antipsychotics. We believe this is the first published case of NMS associated with olanzapine therapy.

Case Report

Mr. D. is a 33-year-old Caucasian male with a history of severe mental retardation (IQ estimate: 33). He was initially admitted to a general medical hospital for weight loss of 45 pounds over the previous 18 months.

At baseline, Mr. D. was able to feed and clothe himself with assistance. He resided in a group home for developmentally disabled adults. Behavioral outbursts occurred intermittently. At these times, he would bite himself and assault staff members. His outpatient psychiatrist attempted to control these outbursts with various medication trials, including chlorpromazine, lithium, clonazepam, propranolol, risperidone, bupropion, and buspirone. Eighteen months prior to admission, he received chlorpromazine (100 mg qd), trihexyphenidyl hydrochloride (Artane; 2 mg tid), and bupropion (75 mg tid). On this regimen, Mr. D. developed ataxia. Hoping to decrease the ataxia, his outpatient psychiatrist began to taper chlorpromazine and added olanzapine (5 mg qd). One month later, olanzapine was increased to 10 mg qd. He remained on combined chlorpromazine, olanzapine, bupropion, and trihexyphenidyl therapy for 1 year. Six months prior to admission, chlorpromazine was stopped. Six days prior to admission, his outpatient psychiatrist also stopped trihexyphenidyl hydrochloride.

Mr. D.'s medical history was significant for hypothyroidism. On admission, medications included levothyroxine sodium (0.175 mg qd), olanzapine (10 mg qd), bupropion (75 mg tid), and docusate sodium (100 mg bid).

On examination, Mr. D.'s weight was 131 pounds and his height was 6 feet 2 inches. Vital signs included a blood pressure of 122/84, pulse 84, and temperature 36.8°C. He was described as "weak and thin with a ketotic breath odor." Neurologic examination was described as "non-focal, moving all extremities." The patient's muscular tone and mental status were not recorded. Laboratory examinations, including electrolytes, BUN, creatinine, CBC, TSH, and liver function tests, were all within normal limits. Urinalysis (UA) was negative and chest X-ray (CXR) was normal. HIV test and blood cultures were also negative.

Brain MRI showed a 3.2x3.5x3-cm arachnoid cyst within the cisterna magna that was unchanged from a previous MRI in 1991. The gastroenterology service was consulted and attempted to obtain an upper GI study. The patient was described as "unable or unwilling to swallow barium;" therefore, the study was not completed. The gastroenterology service thought the patient's weight loss might be secondary to depression or anorexia caused by bupropion. The psychiatry consultation-liaison service recommended holding both olanzapine and bupropion. A feeding tube was placed with the goal of improving Mr. D.'s nutritional status and weakness. Mr. D. was discharged 9 days after admission. Olanzapine was restarted by his primary care physician for unclear reasons. However, group home staff felt Mr. D. was still too weak to be cared for in their facility, and he was readmitted to the hospital the same day.

Mr. D. was reexamined by his primary care physician the next day, who found him unresponsive, with little motor activity, and unable to follow simple commands. Blood pressure fluctuated from 110/80 to 140/90, pulse was 100–120, temperature 38.2°C. He was diaphoretic and incontinent of urine and stool. Eye movements were conjugate, and pupils equal and reactive to light. He could not swallow water or saliva. Muscle tone was increased with rigidity, cogwheeling, and tremor in both upper extremities; rigidity was also present in the lower extremities. Deep tendon reflexes were brisk and symmetric with upper extremity clonus. Toes were upgoing bilaterally. The remainder of his physical examination was unremarkable. Laboratory examination showed normal electrolytes, CBC, UA, and CXR. Creatinine phosphokinase (CPK) was markedly elevated at 1,006 U/L (reference range: 60–225 U/L).

Both the psychiatry and neurology services consulted on the patient and diagnosed NMS. Mr. D. was transferred to the intensive care unit. Olanzapine was discontinued and he was started on bromocriptine (5 mg tid). On Hospital Day 3, he became more alert with decreased tone in all extremities. His CPK dropped to 704 U/L. Vital signs normalized. He was transferred to the medical floor on Hospital Day 4. On Hospital Day 22, Mr. D. received a trial of chlorpromazine (50 mg qam and 100 mg qhs) to control self-injurious behavior and aggression. Two days later, his muscle tone increased, he became somnolent, and his temperature rose to 37.7°C. Chlorpromazine was discontinued, and he received lorazepam as needed. He was transferred to a different hospital that specializes in the treatment of patients with traumatic brain injuries and behavioral difficulties on Hospital Day 31.

DISCUSSION

Risk factors for the development of NMS have been studied extensively. There are no definitive risk factors, but there is mounting evidence that psychomotor agitation, dehydration, previous episodes of NMS, rapidly increasing dosages, or parenteral medications increase risk of NMS.¹ None of these factors apply to Mr. D. However, there is evidence that suggests other factors, such as organic brain damage, antecedent withdrawal of anticholinergic medication, and intercurrent medical illness could also be risk factors for NMS.⁴ All three of these factors apply to Mr. D., who was severely retarded, recently withdrawn from trihexyphenidyl, and malnourished.

We believe this is the first published case of NMS associated with olanzapine therapy. This case illustrates two important points.

First, in large clinical trials involving 2,500 patients, no cases of NMS with olanzapine therapy were detected.⁵ Rare, idiosyncratic side effects may only be detected when new medications go into widespread use. Despite their markedly lower incidence of extrapyramidal symptoms and possibly NMS, clinicians still need to be aware that such adverse side effects can and will occur with the atypical antipsychotics.

Second, markedly impaired patients such as chronically psychotic, demented, or severely retarded persons may be unable to directly communicate discomfort or side effects. Clinicians need to determine their patients' baseline functional status and astutely observe these patients for changes. This would allow for early intervention and treatment, which is crucial to reduce or prevent the morbidity and mortality associated with NMS.⁶ Further research is needed to better understand the incidence and presentation of NMS in patients on atypical antipsychotics.

REFERENCES

1. Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 1993; 77:185–202[Medline]
2. Tsai G, Cristomo G, Rosenblat MS: Neuroloeptic malignant syndrome associated with clozapine. Ann Clin Psychiatry 1995; 7:91–95[Medline]
3. Meterissian GB: Risperidone-induced neuroleptic malignant syndrome: a case report and review. Can J Psychiatry 1996; 41:52–54[Medline]
4. Keck PE, McElroy SL, Pope HG: Epidemiology of neuroleptic malignant syndrome. Psychiatric Annals 1991; 21:148–151
5. Beasley CM, Tollefson GP, Tran PV: Safety of olanzapine. J Clin Psychiatry 1997; 58 (suppl 10):13–17
6. Velamoor VR, Swamy GN, Parmar RS, et al: Management of suspected neuroleptic malignant syndrome. Can J Psychiatry 1995; 40:545–550[Medline]

This article has been cited by other articles:

				H. SUH, B. BRONSON, and R. MARTIN Neuroleptic Malignant Syndrome and Low-Dose Olanzapine Am J Psychiatry, April 1, 2003; 160(4): 796 - 796. [Full Text] [PDF]

				I. Tofler Olanzapine and Neuroleptic Malignant Syndrome Psychosomatics, December 1, 2002; 43(6): 505 - 506. [Full Text] [PDF]

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