A rationale for NMDA receptor antagonist therapy of the neuroleptic malignant syndrome

The triad of rigidity, fever, and elevation of serum creatine phosphokinase (CPK) levels, labeled 'neuroleptic malignant syndrome' (NMS), is a dangerous complication of neuroleptic drug treatment. Amantadine was introduced for the pharmacological management of NMS because of its beneficial effects in Parkinson's disease which were attributed to direct or indirect dopaminomimetic properties of amantadine. While the dopaminomimetic effects of amantadine are weak under experimental conditions, recent studies have confirmed that amantadine is an antagonist at the N-methyl-D-aspartate (NMDA) type of glutamate receptor. Two lines of evidence suggest that amantadine or other NMDA receptor antagonists could be effective drugs for the reversal of NMS symptoms. First, glutamate antagonists restore the balance between glutamatergic and dopaminergic systems when dopaminergic transmission has been antagonized by neuroleptic drugs. Second, by virtue of their effects against rigor and spasticity, NMDA antagonists may reduce increased muscle tone and prevent rhabdomyolysis. In conclusion, NMS may be considered an iatrogenic excitatory aminoacid syndrome which is amenable to NMDA receptor antagonist therapy.