To the Editor: Drs. Qureshi and Al-Habeeb endorse my thesis that sympathoadrenal hyperactivity is responsible for the clinical manifestations of neuroleptic malignant syndrome. They even go so far as to propose a new name for this disorder, namely "sympathoadrenal hyperactivity hyperpyrexia syndrome"! Beyond their support for the article’s central thesis, however, they express the view that it should have included some discussion of the potential implications for future research and treatment. Space limitations precluded consideration of these issues in my article, but I would like to comment briefly.

The handful of studies that have been done (1–3; Kawanishi et al., 1998) have not identified any genetic defects causally related to neuroleptic malignant syndrome, but there are many other, as yet untested, candidates. Most notable among these, in my opinion, are the regulatory proteins that maintain intracellular electrochemical homeostasis through their function as calcium buffers and channels. Multiple individual point mutations affecting genetic loci for several of these proteins are known to cause malignant hyperthermia. Considering the many clinical features shared by neuroleptic malignant syndrome and malignant hyperthermia, it seems reasonable to hypothesize that similar but distinct mutations affecting this heterogenous group of proteins could be the basis for vulnerability to developing neuroleptic malignant syndrome. In this model, the role of sympathoadrenal hyperactivity would be analogous to that of volatile anesthetics in malignant hyperthermia—i.e., hyperstimulated adrenoceptors interact with a genetically defective regulatory protein to produce excessive intracellular calcium levels.

This highly speculative model hints at possible alternative treatments for neuroleptic malignant syndrome. In particular, two general categories of pharmaceutical agents seem worthy of future investigation: calcium channel blockers and adrenoceptor antagonists. However, the existence of multiple types of calcium channels, the possible involvement of proteins other than as calcium channels, and the functional opposition of α- and β-adrenoceptors under normal physiological conditions (a consequence of which is that antagonizing one adrenoceptor type while leaving the other type unopposed can precipitate a medical crisis) are just some of the challenges that future studies need to surmount.I thank Drs. Qureshi and Al-Habeeb for their interest in my article and for giving me an opportunity to elaborate further on some of the ideas contained therein.