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Olanzapine and Neuroleptic Malignant Syndrome

TO THE EDITOR: The recent article by Robert Philibert, M.D., Ph.D., et al.¹ raised some interesting questions about the apparent initiation of neuroleptic malignant syndrome or neuroleptic-induced catatonia by the atypical neuroleptic olanzapine.^2,3 This case's very striking polypharmacy seems to have been underestimated as an equal, if not greater, contributor to this patient's signs and symptoms.

First, the presence of early symptoms, signs, and changes in laboratory values similar to those of neuroleptic malignant syndrome could actually have been markers of serotonin toxicity, the so-called serotonin syndrome. Hyperserotonergic states have significant clinical overlap with neuroleptic malignant syndrome, with both conditions having autonomic instability, neuromuscular changes, mental status changes, changes in laboratory values, and fever.⁴

In the patient in this article, paroxetine (40 mg/day) or the combination of paroxetine and selegiline could have caused a toxic serotonergic reaction. The combination has been associated with the serotonin syndrome, and the Physician's Desk Reference does clearly state that this combination is contraindicated because of the potential for the serotonin syndrome.⁵

A second factor may have been the sudden discontinuation of selegiline, as recommended by the consulting neurologist. This may have caused a perturbation in—and possibly a sudden drop or imbalance in—both the central serotonergic and dopaminergic systems. A double-monoamine perturbation could potentially have triggered extrapyramidal symptoms and neuroleptic malignant syndrome. Current psychopharmacological teaching in Parkinson's treatment suggests that selegiline, even at a low dose, should not be suddenly discontinued.

In severe Parkinson's disease, a rapid decrease in dopamine levels, due to the cessation of selegiline's prodopaminergic action, could certainly exacerbate rigidity and extrapyramidal symptoms, potentially initiating a march toward neuroleptic malignant syndrome.^6–9

A third factor may have been the addition of phenytoin, another highly protein-bound agent, to divalproex treatment. This may have contributed yet another risk factor/trigger for neuroleptic malignant syndrome by increasing the free olanzapine available for D₂ blockade. Of interest, olanzapine itself actually has the highest propensity for extrapyramidal symptoms of the newer atypical antidepressants, as compared with clozapine and quetiapine. Apparently this is due to its lower dissociation constant, making it less readily displaced at the D₂ receptor. Not only should it probably not be a first-line atypical antidepressant for psychosis associated with Parkinson's syndrome because of a higher propensity for initiation of extrapyramidal symptoms, but for the same reasons, it is likely to be the newer atypical antipsychotic most likely to be associated with neuroleptic malignant syndrome.^10,11

Finally, three general but crucial factors deserve consideration as possible, if secondary, contributors to neuroleptic malignant syndrome. These include dehydration, aspiration pneumonia, and low-grade traumatic brain injury due to a possible head trauma occurring during the suicidal patient's attempt to jump from a ledge.

It becomes clearer, then, that olanzapine in this case may have only been the "straw that broke the camel's back" in the initiation of neuroleptic malignant syndrome, a multifactorial, multineurotransmitter, multiorgan, complex process involving the entire psychosomatic substrate.

The case of Dr. Philibert et al.¹ could almost serve as a template for the complex neuropsychiatric cases that are prevalent in clinical practice. It is hoped that some of the lessons derived from this case can prove helpful in preventing, in their early stages, cases of neuroleptic malignant syndrome in which fewer medical and psychiatric heroics will be required to manage a condition that can often be aborted by astute diagnosis and early treatment. The advent of more sophisticated medications, such as the atypical neuroleptics, has encouraged high expectations for elimination of all neurological and psychiatric symptoms. In situations of concurrent chronic medical or physical illness, reaching a happy medium of "good enough" control, to invoke a Winnicottian psychotherapeutic concept, may be preferable for both neurologists and psychiatrists working closely and cooperatively with these challenging patients.

REFERENCES

1. Philibert RA, Adam LA, Frank FM, Carney-Doebbeling C: Olanzapine usage associated with neuroleptic malignant syndrome. Psychosomatics 2001; 42:528-529[Free Full Text]
2. Stanfield SC, Privette T: Neuroleptic malignant syndrome associated with olanzapine therapy: a case report. J Emerg Med 2000; 19:355-357[CrossRef][Medline]
3. Apple JE, Van Hauer G: Neuroleptic malignant syndrome associated with olanzapine therapy (letter). Psychosomatics 1999; 40:267-268[Free Full Text]
4. Carbone JR: The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am 2000; 18:317-325[CrossRef][Medline]
5. Physician's Desk Reference, 56th ed. Montvale, NJ, Medical Economics, 2002, p 3267
6. Maricle RA: Psychiatric complications of Huntington's disease, Parkinson's disease and Tourette's syndrome, in Psychiatric Care of the Medical Patient, 2nd ed. Edited by Stoudemire A, Fogel BS, Greenberg D. New York, Oxford University Press, 2000, p 708
7. Ueda M, Hamamoto M, Nagayama H, Otsubo K, Nito C, Miyazaki T, Terashi A, Katayama Y: Susceptibility to neuroleptic malignant syndrome in Parkinson's disease. Neurology 1999; 52:777-781[Abstract/Free Full Text]
8. Marsh L, Lyketsos C, Reich S: Olanzapine for the treatment of psychosis in patients with Parkinson's disease and dementia. Psychosomatics 2001; 42:477-481[Abstract/Free Full Text]
9. Olanow CW, Koller WC (American Academy of Neurology): An algorithm (decision tree) for the management of Parkinson's disease: treatment guidelines. Neurology 1998; 50(March suppl 3):S1-S57
10. Kapur S, Seeman P: Does fast dissociation from the dopamine D₂ receptor explain the action of atypical antipsychotics? a new hypothesis. Am J Psychiatry 2001; 158:360-369[Abstract/Free Full Text]
11. Kapur S, Seeman P: Reply to HY Meltzer; SS Shim: Action of atypical antipsychotics (letters). Am J Psychiatry 2002; 159:154-155[Free Full Text]

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