Neuroleptic Malignant Syndrome Medication
- Author: Theodore I Benzer, MD, PhD; Chief Editor: Asim Tarabar, MD more...
Specific drug therapies, such as dantrolene, amantadine, and bromocriptine, have an uncertain role in the treatment of neuroleptic malignant syndrome. Recommendations for the use of these drugs are from noncontrolled prospective and retrospective studies and case reports; no controlled studies exist. While the drugs generally are felt to be helpful, they have been found to have deleterious effects in some studies.
Skeletal Muscle Relaxants
These agents stimulate muscle relaxation by modulating skeletal muscle contractions at sites beyond the myoneural junction and by acting directly on muscle itself. Benzodiazepines are used in a small number of patients with neuroleptic malignant syndrome unresponsive to other measures. In most cases, a continuous IV infusion of diazepam or lorazepam has been utilized.
Dantrolene interferes with the release of calcium from sarcoplasmic reticulum, thus directly inhibiting muscle contraction. It also prevents or reduces the increase in myoplasmic calcium ion concentration that activates acute catabolic process associated with malignant hyperthermia. It is used to treat muscular rigidity and hyperthermia associated with neuroleptic malignant syndrome.
Dantrolene is available as a sodium salt in 25-mg, 50-mg, and 100-mg capsules and in 20-mg vial for intravenous (IV) administration. The IV form is much more expensive and should be reserved for patients unable to take oral medications.
By binding to specific receptor sites, benzodiazepines appear to potentiate the effects of gamma-aminobutyric acid (GABA) and facilitate inhibitory GABA neurotransmission and the action of other inhibitory transmitters.
Diazepam modulates postsynaptic effects of gamma amino-butyric acid A (GABA-A) transmission, resulting in an increase in presynaptic inhibition. It appears to act on part of the limbic system, as well as on the thalamus and hypothalamus, to induce a calming effect. Individualize dosage and increase cautiously to avoid adverse effects.
Lorazepam is a benzodiazepine with short onset of effects and intermediate-long half-life.
By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it might depress all levels of CNS, including the limbic and reticular formation.
A dopamine agonist must stimulate D2 receptors if it is to offer clinical benefit in neuroleptic malignant syndrome. D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system or more directly by neuroleptic agents (eg, phenothiazines).
Bromocriptine is a semisynthetic, ergot alkaloid derivative that is a strong dopamine D2-receptor agonist and a partial dopamine, D1-receptor agonist. It stimulates dopamine receptors in the corpus striatum. Bromocriptine may relieve akinesia, rigidity, and tremor associated with Parkinson disease. Initiate at low dosage. Slowly increase dosage to individualize therapy. Assess dosage titration every 2 weeks. Gradually reduce dose in 2.5-mg decrements if severe adverse reactions occur.
Amantadine has been used to treat Parkinson disease and has been tried in neuroleptic malignant syndrome because it increases synaptic dopamine activity. Its antiparkinsonian activity results from blocking reuptake of dopamine into presynaptic neurons and causing direct stimulation of postsynaptic receptors.
Rosebush PI, Mazurek MF. Serum iron and neuroleptic malignant syndrome. Lancet. 1991 Jul 20. 338(8760):149-51. [Medline].
Tse L, Barr AM, Scarapicchia V, Vila-Rodriguez F. Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective. Curr Neuropharmacol. 2015. 13 (3):395-406. [Medline].
Chiou YJ, Lee Y, Lin CC, Huang TL. A Case Report of Catatonia and Neuroleptic Malignant Syndrome With Multiple Treatment Modalities: Short Communication and Literature Review. Medicine (Baltimore). 2015 Oct. 94 (43):e1752. [Medline].
DELAY J, PICHOT P, LEMPERIERE T, ELISSALDE B, PEIGNE F. [A non-phenothiazine and non-reserpine major neuroleptic, haloperidol, in the treatment of psychoses]. Ann Med Psychol (Paris). 1960 Jan. 118(1):145-52. [Medline].
Trollor JN, Chen X, Chitty K, Sachdev PS. Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics. Br J Psychiatry. 2012 Jul. 201(1):52-6. [Medline].
Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs. 2009. 23(6):477-92. [Medline].
Gurrera RJ, Caroff SN, Cohen A, Carroll BT, DeRoos F, Francis A, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry. 2011 Sep. 72(9):1222-8. [Medline].
Jauss M, Krack P, Franz M, Klett R, Bauer R, Gallhofer B, et al. Imaging of dopamine receptors with [123I]iodobenzamide single-photon emission-computed tomography in neuroleptic malignant syndrome. Mov Disord. 1996 Nov. 11(6):726-8. [Medline].
Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry. 1999 Feb. 156(2):169-80. [Medline].
Ehara H, Maegaki Y, Takeshita K. Neuroleptic malignant syndrome and methylphenidate. Pediatr Neurol. 1998 Oct. 19(4):299-301. [Medline].
Keck PE Jr, Pope HG Jr, Cohen BM, McElroy SL, Nierenberg AA. Risk factors for neuroleptic malignant syndrome. A case-control study. Arch Gen Psychiatry. 1989 Oct. 46(10):914-8. [Medline].
Paparrigopoulos T, Tzavellas E, Ferentinos P, Mourikis I, Liappas J. Catatonia as a risk factor for the development of neuroleptic malignant syndrome: report of a case following treatment with clozapine. World J Biol Psychiatry. 2009. 10(1):70-3. [Medline].
Sachdev P, Mason C, Hadzi-Pavlovic D. Case-control study of neuroleptic malignant syndrome. Am J Psychiatry. 1997 Aug. 154(8):1156-8. [Medline].
Alexander PJ, Thomas RM, Das A. Is risk of neuroleptic malignant syndrome increased in the postpartum period?. J Clin Psychiatry. 1998 May. 59(5):254-5. [Medline].
Otani K, Horiuchi M, Kondo T, Kaneko S, Fukushima Y. Is the predisposition to neuroleptic malignant syndrome genetically transmitted?. Br J Psychiatry. 1991 Jun. 158:850-3. [Medline].
Rosebush PI, Stewart TD, Gelenberg AJ. Twenty neuroleptic rechallenges after neuroleptic malignant syndrome in 15 patients. J Clin Psychiatry. 1989 Aug. 50(8):295-8. [Medline].
Manu P, Sarpal D, Muir O, Kane JM, Correll CU. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res. 2012 Feb. 134(2-3):180-6. [Medline]. [Full Text].
Gelenberg AJ, Bellinghausen B, Wojcik JD, Falk WE, Sachs GS. A prospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital. Am J Psychiatry. 1988 Apr. 145(4):517-8. [Medline].
Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007 Jun. 164(6):870-6. [Medline].
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 Sep. 147(9):1149-55. [Medline].
Chopra MP, Prakash SS, Raguram R. The neuroleptic malignant syndrome: an Indian experience. Compr Psychiatry. 1999 Jan-Feb. 40(1):19-23. [Medline].
Lazarus A. Neuroleptic malignant syndrome. Hosp Community Psychiatry. 1989 Dec. 40(12):1229-30. [Medline].
Henderson T. Neuroleptic malignant syndrome in adolescents: four probable cases in the Western Cape. S Afr Med J. 2011 May 25. 101(6):405-7. [Medline].
Croarkin PE, Emslie GJ, Mayes TL. Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: a review of published cases. J Clin Psychiatry. 2008 Jul. 69(7):1157-65. [Medline].
Modi S, Dharaiya D, Schultz L, Varelas P. Neuroleptic Malignant Syndrome: Complications, Outcomes, and Mortality. Neurocrit Care. 2016 Feb. 24 (1):97-103. [Medline].
Rani FA, Byrne P, Cranswick N, Murray ML, Wong IC. Mortality in children and adolescents prescribed antipsychotic medication: a retrospective cohort study using the UK general practice research database. Drug Saf. 2011 Sep 1. 34(9):773-81. [Medline].
Picard LS, Lindsay S, Strawn JR, Kaneria RM, Patel NC, Keck PE Jr. Atypical neuroleptic malignant syndrome: diagnostic controversies and considerations. Pharmacotherapy. 2008 Apr. 28(4):530-5. [Medline].
Oomura M, Terai T, Sueyoshi K, Shigeno K. Reversible cardiomyopathy as the autonomic involvement of neuroleptic malignant syndrome. Intern Med. 2004 Dec. 43(12):1162-5. [Medline].
Newman EJ, Grosset DG, Kennedy PG. The parkinsonism-hyperpyrexia syndrome. Neurocrit Care. 2009. 10(1):136-40. [Medline].
Ward C. Neuroleptic malignant syndrome in a patient with Parkinson's disease: a case study. J Neurosci Nurs. 2005 Jun. 37(3):160-2. [Medline].
Osman AA, Khurasani MH. Lethal catatonia and neuroleptic malignant syndrome. A dopamine receptor shut-down hypothesis. Br J Psychiatry. 1994 Oct. 165(4):548-50. [Medline].
Martin TG. Serotonin syndrome. Ann Emerg Med. 1996 Nov. 28(5):520-6. [Medline].
Dosi R, Ambaliya A, Joshi H, Patell R. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary. BMJ Case Rep. 2014 Jun 23. 2014:[Medline].
Perry PJ, Wilborn CA. Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry. 2012 May. 24(2):155-62. [Medline].
Odagaki Y. Atypical neuroleptic malignant syndrome or serotonin toxicity associated with atypical antipsychotics?. Curr Drug Saf. 2009 Jan. 4(1):84-93. [Medline].
Heiman-Patterson TD. Neuroleptic malignant syndrome and malignant hyperthermia. Important issues for the medical consultant. Med Clin North Am. 1993 Mar. 77(2):477-92. [Medline].
Vörös V, Osváth P, Fekete S, Tényi T. [Antipsychotics and rhabdomyolysis. Differential diagnosis and clinical significance of elevated serum creatine kinase levels in psychiatric practice]. Psychiatr Hung. 2009. 24(3):175-84. [Medline].
Schneider SM. Neuroleptic malignant syndrome: controversies in treatment. Am J Emerg Med. 1991 Jul. 9(4):360-2. [Medline].
Addonizio G, Susman VL. ECT as a treatment alternative for patients with symptoms of neuroleptic malignant syndrome. J Clin Psychiatry. 1987 Mar. 48(3):102-5. [Medline].
Shoirah H, Hamoda HM. Electroconvulsive therapy in children and adolescents. Expert Rev Neurother. 2011 Jan. 11(1):127-37. [Medline].
Ozer F, Meral H, Aydin B, Hanoglu L, Aydemir T, Oral T. Electroconvulsive therapy in drug-induced psychiatric states and neuroleptic malignant syndrome. J ECT. 2005 Jun. 21(2):125-7. [Medline].
Hermesh H, Aizenberg D, Weizman A. A successful electroconvulsive treatment of neuroleptic malignant syndrome. Acta Psychiatr Scand. 1987 Mar. 75(3):237-9. [Medline].
Rosebush PI, Stewart T, Mazurek MF. The treatment of neuroleptic malignant syndrome. Are dantrolene and bromocriptine useful adjuncts to supportive care?. Br J Psychiatry. 1991 Nov. 159:709-12. [Medline].
Sakkas P, Davis JM, Janicak PG, Wang ZY. Drug treatment of the neuroleptic malignant syndrome. Psychopharmacol Bull. 1991. 27(3):381-4. [Medline].
Ghaziuddin N, Dhossche D, Marcotte K. Retrospective chart review of catatonia in child and adolescent psychiatric patients. Acta Psychiatr Scand. 2012 Jan. 125(1):33-8. [Medline].