Summary
The neuroleptic malignant syndrome (NMS) is a rare phenomenon that continues to generate controversy. By definition, for its diagnosis NMS requires exposure to drugs that alter dopaminergic function [i.e. neuroleptics (antipsychotics)]. The symptoms of NMS include hyperthermia, extrapyramidal side effects (EPS), altered mental status and autonomic dysfunction. Some investigators have viewed NMS as a variant of drug-induced hyperthermia, while others (including ourselves) have adopted the viewpoint that NMS is an extreme end of the spectrum of extrapyramidal disorders that can occur with fever.
The true incidence of NMS is difficult to determine. The lack of established criteria for its diagnosis, by necessity, causes reports of incidence to vary. Young males appear to be more predisposed to NMS, but the reason for this is uncertain. There is some evidence to suggest that patients with organic brain disease may have a higher mortality rate.
Cessation of treatment with neuroleptics should always occur in patients with severe NMS, i.e. where rigidity interferes with breathing, eating and drinking. Our treatment strategy involves treating the key elements of NMS — rigidity and elevated temperature. Initially, vigorous efforts should be made to reverse neuro-leptic-induced rigidity with anticholinergics and intercurrent medical workup. If anticholinergics are ineffective (after up to 7 days’ administration) bromocriptine is a rational substitute.
After an episode of presumptive NMS, we recommend a 2-week period free of neuroleptics, followed by the use of an atypical neuroleptic such as clozapine or risperidone. The use of low dose neuroleptic regimens, atypical neuroleptics and concomitant use of benzodiazepines may significantly reduce the occurrence of NMS and potentially avoid this condition.
Similar content being viewed by others
References
Caroff SN, Mann SC, Lazarus A, et al. Neuroleptic malignant syndrome: diagnostic issues. Psychiatr Ann 1991; 21: 130–47
Fogel BS, Goldberg RJ. Neuroleptic malignant syndrome. N Engl J Med 1988: 313; 1292–3
Levinson DF, Simpson GM. Neuroleptic-induced extrapyramidal symptoms with fever. Heterogeneity of the ‘neuroleptic malignant syndrome’. Arch Gen Psychiatry 1986; 43: 839–48
Mindham RH, Gaind R, Anstee BH, et al. Comparison of amantadine, orphenadrine, and placebo in the control of phenothiazine-induced parkinsonism. Psychol Med 1972; 2: 406–13
Kellam AMP. The (frequently) neuroleptic (potentially) malignant syndrome. Br J Psychiatry 1990; 157: 169–73
Rosenberg MR, Green M. Neuroleptic malignant syndrome. Review of response to therapy. Arch Intern Med 1989; 149: 1927–31
Addonizio G, Susman VL, Roth SD. Symptoms of neuroleptic malignant syndrome in 82 consecutive inpatients. Am J Psychiatry 1986; 143: 1587–90
Levenson JL. Neuroleptic malignant syndrome (review). Am J Psychiatry 1985; 142: 1137–45
Pope Jr HG, Keck Jr PE, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry 1986; 143: 1227–33
Gurrera RJ, Chang SS, Romero JA. A comparison of diagnostic criteria for neuroleptic malignant syndrome. J Clin Psychiatry 1992; 53: 56–62
Delay J, Deniker P. Drug induced extrapyramidal syndromes. In: Vinken PJ, Brunyn GW, editors. Handbook of clinical neurology: diseases of the basal ganglia. New York: American Elsevier, 1968: 248–66
Keck Jr PE, Sebastianelli J, Pope Jr HG, et al. Frequency and presentation of neuroleptic malignant syndrome in a state psychiatric hospital. J Clin Psychiatry 1989; 50: 352–5
Shalev A, Munitz H. The neuroleptic malignant syndrome: agent and host interaction. Acta Psychiatr Scand 1986; 73: 337–47
Deng MZ, Chen GQ, Phillips MR. Neuroleptic malignant syndrome in 12 of 9,792 Chinese inpatients exposed to neuroleptics: a prospective study. Am J Psychiatry 1990; 147: 1149–55
Gelenberg AJ, Bellinghausen B, Wojcik JD, et al. A prospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital. Am J Psychiatry 1988; 145: 517–8
Keck Jr PE, Pope Jr HG, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome: a prospective study. Am J Psychiatry 1987; 144: 1344–6
Modestin J, Toffler G, Drescher JP. Neuroleptic malignant syndrome: results of a prospective study. Psychiatry Res 1992; 44: 251–6
Hermesh H, Aizenberg D, Wezman A, et al. Risk for definite neuroleptic malignant syndrome. A prospective study in 223 consecutive in-patients. Br J Psychiatry 1992; 161: 254–7
Lazarus A, Mann SC, Caroff SN. The neuroleptic malignant syndrome and related conditions. Clinical Practice Series no. 6. Washington, DC: American Psychiatric Press, 1989
Keck Jr PE, Pope Jr HG, Cohen BM, et al. Risk factors for neuroleptic malignant syndrome. A case-control study. Arch Gen Psychiatry 1989; 46: 914–8
Kaufman CA, Wyatt RJ. Neuroleptic malignant syndrome. In: Meltzer H, editor. Psychopharmacology, the third generation of progress. New York: Raven Press; 1987: 1421–30
Caroff SN, Mann SC. Neuroleptic malignant syndrome. Psychopharmacol Bull 1988; 24: 25–9
Spring G, Frankel M. New data on lithium and haloperidol incompatibility. Am J Psychiatry 1981; 138: 818–21
Friedman E, Gershon S. Effect of lithium on brain dopamine. Nature 1973; 243: 520–1
Harsch HH. Neuroleptic malignant syndrome: physiological and laboratory findings in a series of nine case. J Clin Psychiatry 1987; 48: 328–33
Eiser AR, Neff MS, Sliftein RR. Acute myoglobinuric renal failure. A consequence of the neuroleptic malignant syndrome. Arch Intern Med 1982; 142: 601–3
Schibuk M, Schachter D. A role for catecholamines in the pathogenesis of neuroleptic malignant syndrome. Can J Psychiatry 1986; 31: 66–9
Pope HG, Cole JO, Chores PT, et al. Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nerv Ment Dis 1986; 174: 493–5
Muller T, Becker T, Fritze J. Neuroleptic malignant syndrome after clozapine plus carbamazepine [letter]. Lancet 1988; 2: 1500
Miller DD, Sharufuddin MJ, Kathol RG. A case of clozapineinduced neuroleptic malignant syndrome. J Clin Psychiatry 1991; 52: 99–101
Anderson ES, Powers PS. Neuroleptic malignant syndrome associated with clozapine use. J Clin Psychiatry 1991; 52: 102–4
DasGupta K, Young A. Clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry 1991; 52: 105–7
Fernando ML, Manchanda R, Kirk C. Neuroleptic malignant syndrome: a preventive program. J Psychiatry Neurosci 1992; 17: 31–3
Castillo E, Rubin RT, Holsboer-Trachsler E. Clinical differentiation between lethal catatonia and neuroleptic malignant syndrome 1989; 146: 324–8
Gratz SS, Levinson DF, Simpson GM. Neuroleptic malignant syndrome. In: Kane JM, Lieberman J, editors. Adverse effects of psychotropic drugs. New York: Guilford Press, 1992: 266–84
McEvoy JP. The clinical use of anticholinergic drugs as treatment for extrapyramidal side effects of neuroleptic drugs. 1983; 3: 288–302
Gratz SS, Levinson DF, Simpson GM. The treatment and management of neuroleptic malignant syndrome. Prog Neuropsychopharmacol Biol Psychiatry 1992; 16: 425–43
Black HR, Qualick H, Gareleck CB. Racial differences in serum creatine kinase levels. Am J Med 1986; 81: 479–87
Simpson GM, Amin M, Kunz E. Withdrawal effects of phenothiazines. Compr Psychiatry 1965; 6: 347–51
Schvehla TJ, Herjanic M. Neuroleptic malignant syndrome, bromocriptine, and anticholinergic drugs. J Clin Psychiatry 1988; 49: 283–4
Andrade NN. Emergency treatment of the neuroleptic malignant syndrome. Hawaii Med J 1988; 47: 181–5
Mueller PS. Diagnosing and treating neuroleptic malignant syndrome [letter]. Am J Psychiatry 1986; 143: 674
Birkhimer LJ, DeVane CL. The neuroleptic malignant syndrome: presentation and treatment. Drug Intell Clin Pharmacol 1984; 18: 462–5
Coons DJ, Hillman F, Marshall RW. Treatment of neuroleptic malignant syndrome with dantrolene sodium: a case report. Am J Psychiatry 1982; 139: 944–5
Khan A, Jaffe JH, Nelson WH, et al. Resolution of neuroleptic malignant syndrome with dantrolene sodium: case report. J Clin Psychiatry 1985; 46: 244–6
May DC, Morris SW, Stewart RM, et al. Neuroleptic malignant syndrome: response to dantrolene sodium. Ann Intern Med 1983; 98: 183–4
Legras A, Hurel D, Dabrowski G, et al. Protracted neuroleptic malignant syndrome complicating long-acting neuroleptic administration. Am J Med 1988; 85: 875–8
Rosebush PI, Stewart T, Mazurek MF. The treatment of neuroleptic malignant syndrome. Are dantrolene and bromocriptine useful adjuncts of supportive care?. Br J Psychiatry 1991; 159: 709–12
Scheftner WA, Shulman RB. Treatment choice in neuroleptic malignant syndrome. Convulsive Ther 1992; 8: 267–79
Jessee SS, Anderson FG. ECT in the neuroleptic malignant syndrome: case report. J Clin Psychiatry 1989; 44: 186–8
Lazarus A. The neuroleptic malignant syndrome: a review. Can J Psychiatry 1986; 31: 670–4
Caroff SN. The neuroleptic malignant syndrome. J Clin Psychiatry 1980; 41: 79–83
Caroff SN, Rosenberg N, Fletcher J, et al. Malignant hyperthermia susceptibility in neuroleptic malignant syndrome. Anesthesiology 1987; 67: 20–5
Simpson GM, Varga E. Clozapine — a new antipsychotic agent. Curr Ther Res 1974; 15: 631–41
Weiler M, Kornhuber J. Does clozapine cause neuroleptic malignant syndrome?. J Clin Psychiatry 1993; 54: 70–1
Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994; 151: 825–35
Rosebush PI, Stewart TD, Gelenberg AJ. Twenty neuroleptic rechallenges after neuroleptic malignant syndrome in 15 patients. J Clin Psychiatry 1989; 50: 295–8
Author information
Authors and Affiliations
Additional information
An erratum to this article is available at http://dx.doi.org/10.1007/BF03259708.
Rights and permissions
About this article
Cite this article
Gratz, S.S., Simpson, G.M. Neuroleptic Malignant Syndrome. CNS Drugs 2, 429–439 (1994). https://doi.org/10.2165/00023210-199402060-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00023210-199402060-00004