Letters to the Editor
Atypical Neuroleptic Malignant Syndrome Caused by Clozapine and Venlafaxine: Early Brief Treatment With Dantrolene
Dear Editor:
Clozapine can cause neuroleptic malignant syndrome (NMS) with a presentation that may be atypical in that it may occur without rigidity, fever, or changes in creatine kinase (CK) (1).
We report a case of possible atypical NMS arising from overdosage of clozapine and venlafaxine that was successfully treated with lorazepam and dantrolene.
Case Report
Mr A, aged 19 years, was diagnosed with shizoaffective disorder. Treatment for 2 years with clozapine 300 mg daily and venlafaxine 150 mg daily helped his condition. After he discontinued his medication for 2 weeks and then took 1000 mg clozapine and 900 mg venlafaxine, he presented to the emergency room, where he went into a coma and was admitted to the intensive care unit. His urine was positive for cannabinoids and clozapine but negative for alcohol, opiates, amphetamines, cocaine, and benzodiazepines. His temperature was 37.2°C.
The following day he emerged from a coma and developed delirium, agitation, fluctuating blood pressure, a temperature of 38°C, and leukocytosis. He was without extrapyramidal signs (EPS) and had normal CK. Intravenous lorazepam 12 mg daily was added to his treatment. At day 3, his CK rose to 6700 U/L, and his myoglobin rose to 597 ng/L.
Suspecting NMS, we added dantrolene 1 mg/kg 4 times daily. Twelve hours later, the patient’s CK decreased to 3600 U/L. Glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) rose to 147 U/L and 91 U/L, respectively. After 3 more days, the patient’s CK level was 1750 U/L, his temperature and myoglobin became normal, EPS were absent, consciousness was total, and paranoid delusion and depression emerged. Dantrolene was discontinued, and the patient was transferred to the psychiatric unit.
Ten days later, all parameters were normalized, especially CK, myoglobin, white blood cell count, GOT, and GPT.
After 10 more days, risperidone 2 mg daily was added and titrated to 3 mg daily. The patient improved and was discharged; 60 days later, he was in good clinical condition.
This patient presented NMS that was atypical in that muscular rigidity was absent during the periods with fever, (common with clozapine-related NMS), high CK, altered consciousness and autonomic dysregulation.
NMS occuring after a single dose of venla- faxine has been attributed to a dopamine-inhibiting effect (2) or, alternatively, it has been explained as evidence of central serotonergic overdrive (3). NMS and serotonin syndrome (SS) are often confused, and when considering their clinical overlap, many authors place NMS and SS in the spectrum of the same disorder (4), defined by some as “neurotoxic syndrome” (5) and also including catatony (6).
Dantrolene’s specificity of action remains unknown (7); however, in the case of our patient, adding dantrolene to lorazepam was crucial, even in the absence of rigidity. Early treatment with dantrolene prevented NMS from developing fully. Otherwise, the absence of rigidity is unrelated to this treatment, a characteristic of some NMS with better prognosis.
Fever, altered consciousness, and increased CK and myoglobin indicated treatment with dantrolene.
References
1. Karangianis JL, Phillips LC, Hogan KP, LeDrew KK. Clozapine associated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother 1999;33:623–30.
2. Cassidy EM, O’Kearne V. Neuroleptic malignant syndrome after venlafaxine. Lancet 2000;355:2164–5.
3. Nimmagadda SR, Ryan DH, Atkin SL. Neuroleptic malignant syndrome after venlafaxine. Lancet 2000;354:289–90.
4. Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am 2000;18:317–25.
5. Reeves RR, Mack JE, Beddingfield JJ. Neurotoxic syndrome associated with risperidone and fluvoxamine. Ann Pharmacother 2002;36:440–3.
6. Fink M, Taylor MA. The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci 2001;251(Suppl 1):8–13.
7. Tsai G, Crisostomo G, Rosenblatt ML, Stern TA. Neuroleptic malignant syndrome associated with clozapine treatment. Ann Clin Psychiatry 1995;7:91–5.
Vittorio Ferioli, MD
Allesandra Manes, MD
Chiara Melloni, MD
Samuele Nanni, MD
Giancarlo Boncompagni, MD
Bologna, Italy
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