Neuroleptic Malignant Syndrome

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Background

Neuroleptic malignant syndrome (NMS) refers to the combination of hyperthermia, rigidity, and autonomic dysregulation that can occur as a serious complication of the use of antipsychotic drugs. Delay first used the term in 1960, after observing patients treated with high-potency antipsychotics.[1]

Even the newer atypical antipsychotics, which are not classified accurately as neuroleptics, can cause NMS. The list of atypical antipsychotic drugs that may cause NMS include olanzapine,[2] risperidone, paliperidone, aripiprazole, ziprasidone, amisulpride, and quetiapine.[3] Clozapine may also be associated with the development of NMS, but it appears to be less likely to manifest with extrapyramidal features, including rigidity and tremor. In general, over the past 30 years, the syndrome has been associated with a variety of drugs that lead to decreased dopamine receptor activation.[4]

While some clear risk factors for neuroleptic malignant syndrome are present, the low incidence of this syndrome and the consequent difficulty in studying it in a controlled, prospective manner make clinical features, predisposing conditions, treatment, and prognosis difficult to define.

Following is a case vignette of a patient with neuroleptic malignant syndrome that developed several days after the start of treatment with the atypical antipsychotic olanzapine.

A 66-year-old white male was hospitalized for increasingly aggressive behavior. He had no prior psychiatric admissions. On the day of admission after he sustained a fall, a CT scan of the brain revealed a subarachnoid hemorrhage at the right superior sulcus and a possible hemorrhagic contusion at the left frontal lobe. Over the course of hospitalization, the patient had a series of CT scans showing resolution of the hemorrhage. He was started on olanzapine for intermittent agitation. Olanzapine was titrated to 7.5 mg daily.

Ten days later the patient became abruptly somnolent with body temperature reaching 39.7 º C and severe muscle rigidity in both upper and lower extremities. He had severe diaphoresis and fluctuation of blood pressure and pulse. Laboratory data revealed elevation of white blood cells to 14800 K/L, creatine phosphokinase to 2800 U/L (normal < 174 U/L), and mild elevation of serum alanine and aspartate aminotransferase. MRI of the brain, CSF studies, and chest radiograph were unremarkable. A presumptive diagnosis of neuroleptic malignant syndrome was made. Olanzapine was immediately discontinued and supportive care was initiated.

Intravenous lorazepam was given as needed every 4 hours for behavioral agitation along with a fixed 0.5 mg intravenous push twice daily. The patient received a total of 8.5 mg of lorazepam in the first 24 hours and 3 mg the next day. Fever and muscular rigidity resolved in 24 hours. All other manifestations of neuroleptic malignant syndrome resolved in 9 days.

Pathophysiology

The most widely accepted mechanism by which antipsychotics cause neuroleptic malignant syndrome is that of dopamine D2 receptor antagonism. In this widely accepted model, central D2 receptor blockade in the hypothalamus, nigrostriatal pathways, and spinal cord leads to increased muscle rigidity and tremor via extrapyramidal pathways. Hypothalamic D2 receptor blockade results in an elevated temperature set point and impairment of heat-dissipating mechanisms. Peripherally, antipsychotics lead to increased calcium release from the sarcoplasmic reticulum, resulting in increased contractility, which can contribute to hyperthermia, rigidity, and muscle cell breakdown.

Beyond these direct effects, D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system. The resulting sympathoadrenal hyperactivity and dysregulation leads to autonomic dysfunction. This model suggests that patients with baseline high levels of sympathoadrenal activity might be at increased risk. While this has not been proven in controlled studies, several such states have been proposed as risk factors for neuroleptic malignant syndrome.[5]

Direct muscle toxicity also has been proposed as a mechanism of neuroleptic malignant syndrome.

Epidemiology

Frequency

United States

Neuroleptic malignant syndrome is associated with the use of various antipsychotic medicines, most frequently neuroleptics (the older antipsychotics). Development of neuroleptic malignant syndrome appears to be independent of the conditions that these medicines treat.

The syndrome can occur after any duration of treatment, although two thirds of cases occur within the first week. The frequency has been variably reported as 0.07–2.2% of patients taking neuroleptics.[6] Data largely come from case control studies rather than prospective randomized trials.

International

The frequency of neuroleptic malignant syndrome internationally parallels the use of antipsychotics, especially neuroleptics, in a given region. No data suggest geographic or racial variation. The one large randomized trial conducted in China showed an incidence of 0.12% in patients taking neuroleptics.[7] A retrospective study conducted in India showed an incidence of 0.14%.[8]

Mortality/Morbidity

Mortality from neuroleptic malignant syndrome is very difficult to quantify due both to the case report designs of most of the literature and to the inconsistency of the diagnostic parameters used.

Race

No data suggest geographic or racial variation.

Sex

Incidence is higher in males.

Age

History

Physical

Neuroleptic malignant syndrome tends to start with muscular rigidity and progress to hyperthermia with autonomic instability and a fluctuating level of consciousness. Compared to disease in adults, neuroleptic malignant syndrome in children and adolescents tends to present with more dystonia and less tremor.

Causes

All classes of antipsychotics have been associated with neuroleptic malignant syndrome, including low-potency neuroleptics, high-potency neuroleptics, and the newer (or atypical) antipsychotics. Neuroleptic malignant syndrome has been reported most frequently in patients taking haloperidol and chlorpromazine.

Laboratory Studies

Medical Care

The most important intervention is to discontinue all antipsychotics. In most cases, symptoms will resolve in 1-2 weeks. Neuroleptic malignant syndrome precipitated by long-acting depot injections of antipsychotics can last as long as a month. During the course of neuroleptic malignant syndrome, use supportive care aggressively. The value of other interventions, such as dantrolene, amantadine, bromocriptine, and electroconvulsive therapy, is uncertain.[28]

Medication Summary

Specific drug therapies, such as dantrolene, amantadine, bromocriptine, and electroconvulsive therapy, have an uncertain role in the treatment of neuroleptic malignant syndrome. While they generally are felt to be helpful, they have been found to be deleterious in some studies.

Dantrolene (Dantrium)

Clinical Context:  Stimulates muscle relaxation by modulating skeletal muscle contractions at a site beyond myoneural junction and by acting directly on the muscle itself.

Can be administered PO/IV. IV form is much more expensive and should be reserved for patients unable to take oral medications.

Class Summary

Modulate contractions of muscle cells.

Bromocriptine (Parlodel)

Clinical Context:  Strong dopamine D2 receptor agonist and partial dopamine D1 receptor agonist. Often administered with oral dantrolene.

Amantadine (Symmetrel)

Clinical Context:  Antiviral agent effective against influenza A. Has a proposed role in altering the release and uptake of dopamine and has been used to treat Parkinson disease. Infrequently used to treat NMS.

Class Summary

In order for a dopamine agonist to offer clinical benefit, it must stimulate D2 receptors. The role of other dopamine receptor subtypes currently is unclear.

Diazepam (Valium)

Clinical Context:  Depresses all levels of CNS (eg, limbic and reticular formation) possibly by increasing activity of GABA.

Individualize dosage and increase cautiously to avoid adverse effects.

Lorazepam (Ativan)

Clinical Context:  Sedative hypnotic 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 limbic and reticular formation.

Class Summary

Used in a small number of patients unresponsive to above measures. In most cases, a continuous IV infusion of diazepam or lorazepam has been utilized.

Complications

Prognosis

Author

Joseph Tonkonogy, MD, PhD, Clinical Professor of Psychiatry, University of Massachusetts Medical School; Consulting Staff, Departments of Psychiatry, University of Massachusetts Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Darius P Sholevar, MD, Fellow, Cardiovascular Disease, Albert Einstein Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Alan D Schmetzer, MD, Professor Emeritus, Interim Chairman, Department of Psychiatry, Indiana University School of Medicine; Addiction Psychiatrist, Roudebush VA Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin

Disclosure: Novartis Honoraria Speaking and teaching; Sunovion Honoraria Speaking and teaching; Otsuke Grant/research funds reseach; Merck Honoraria Speaking and teaching

Chief Editor

Iqbal Ahmed, MBBS, FRCPsych (UK), Faculty, Department of Psychiatry, Tripler Army Medical Center; Clinical Professor of Psychiatry, Uniformed Services University of the Health Sciences; Clinical Professor of Psychiatry, Clinical Professor of Geriatric Medicine, University of Hawaii, John A Burns School of Medicine

Disclosure: Nothing to disclose.

References

  1. Delay J, Pichot P, Lemperiere T, et al. [A non-phenothiazine and non-reserpine major neuroleptic, haloperidol, in the treatment of psychoses.]. Ann Med Psychol (Paris). Jan 1960;118(1):145-52. [View Abstract]
  2. Petersen AB, Andersen SE, Christensen M, Larsen HL. Adverse effects associated with high-dose olanzapine therapy in patients admitted to inpatient psychiatric care. Clin Toxicol (Phila). Dec 9 2013;[View Abstract]
  3. Su YP, Chang CK, Hayes RD, Harrison S, Lee W, Broadbent M, et al. Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome. Acta Psychiatr Scand. Nov 15 2013;[View Abstract]
  4. Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs. 2009;23(6):477-92. [View Abstract]
  5. Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry. Feb 1999;156(2):169-80. [View Abstract]
  6. Gelenberg AJ, Bellinghausen B, Wojcik JD. A prospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital. Am J Psychiatry. Apr 1988;145(4):517-8. [View Abstract]
  7. 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. Sep 1990;147(9):1149-55. [View Abstract]
  8. Chopra MP, Prakash SS, Raguram R. The neuroleptic malignant syndrome: an Indian experience. Compr Psychiatry. Jan-Feb 1999;40(1):19-23. [View Abstract]
  9. Croarkin PE, Emslie GJ, Mayes TL. Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: a review of published cases. J Clin Psychiatry. Jul 2008;69(7):1157-65. [View Abstract]
  10. Gurrera RJ, Caroff SN, Cohen A, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry. Sep 2011;72(9):1222-8. [View Abstract]
  11. Gurrera RJ, Velamoor V, Cernovsky ZZ. A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome. J Clin Psychopharmacol. Aug 22 2013;[View Abstract]
  12. Ambulkar RP, Patil VP, Moiyadi AV. Neuroleptic malignant syndrome: A diagnostic challenge. J Anaesthesiol Clin Pharmacol. Oct 2012;28(4):517-9. [View Abstract]
  13. Newman EJ, Grosset DG, Kennedy PG. The parkinsonism-hyperpyrexia syndrome. Neurocrit Care. 2009;10(1):136-40. [View Abstract]
  14. Ward C. Neuroleptic malignant syndrome in a patient with Parkinson's disease: a case study. J Neurosci Nurs. Jun 2005;37(3):160-2. [View Abstract]
  15. Osman AA, Khurasani MH. Lethal catatonia and neuroleptic malignant syndrome. A dopamine receptor shut-down hypothesis. Br J Psychiatry. Oct 1994;165(4):548-50. [View Abstract]
  16. Martin TG. Serotonin syndrome. Ann Emerg Med. Nov 1996;28(5):520-6. [View Abstract]
  17. Odagaki Y. Atypical neuroleptic malignant syndrome or serotonin toxicity associated with atypical antipsychotics?. Curr Drug Saf. Jan 2009;4(1):84-93. [View Abstract]
  18. Oomura M, Terai T, Sueyoshi K. Reversible cardiomyopathy as the autonomic involvement of neuroleptic malignant syndrome. Intern Med. 2004;43 (12):1162-5. [View Abstract]
  19. Keck PE Jr, Pope HG Jr, Cohen BM. Risk factors for neuroleptic malignant syndrome. A case-control study. Arch Gen Psychiatry. Oct 1989;46(10):914-8. [View Abstract]
  20. Otani K, Horiuchi M, Kondo T. Is the predisposition to neuroleptic malignant syndrome genetically transmitted?. Br J Psychiatry. Jun 1991;158:850-3. [View Abstract]
  21. Ehara H, Maegaki Y, Takeshita K. Neuroleptic malignant syndrome and methylphenidate. Pediatr Neurol. Oct 1998;19(4):299-301. [View Abstract]
  22. 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. [View Abstract]
  23. Sachdev P, Mason C, Hadzi-Pavlovic D. Case-control study of neuroleptic malignant syndrome. Am J Psychiatry. Aug 1997;154(8):1156-8. [View Abstract]
  24. Alexander PJ, Thomas RM, Das A. Is risk of neuroleptic malignant syndrome increased in the postpartum period?. J Clin Psychiatry. May 1998;59(5):254-5. [View Abstract]
  25. Heiman-Patterson TD. Neuroleptic malignant syndrome and malignant hyperthermia. Important issues for the medical consultant. Med Clin North Am. Mar 1993;77(2):477-92. [View Abstract]
  26. Voros V, Osvath P, Fekete S, Tenyi 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. [View Abstract]
  27. Rosebush PI, Mazurek MF. Serum iron and neuroleptic malignant syndrome. Lancet. Jul 20 1991;338(8760):149-51. [View Abstract]
  28. Rosenberg MR, Green M. Neuroleptic malignant syndrome. Review of response to therapy. Arch Intern Med. Sep 1989;149(9):1927-31. [View Abstract]
  29. Addonizio G, Susman VL, Roth SD. Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry. Aug 1987;22(8):1004-20. [View Abstract]
  30. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000:735, 795-798.
  31. Bertorini TE. Myoglobinuria, malignant hyperthermia, neuroleptic malignant syndrome and serotonin syndrome. Neurol Clin. Aug 1997;15(3):649-71. [View Abstract]
  32. Borovicka MC, Bond LC, Gaughan KN. Ziprazidone and lithium-induced neuroleptic malignant syndrome. Ann Pharmacother. 2006;40 (1):139-142. [View Abstract]
  33. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am. Jan 1993;77(1):185-202. [View Abstract]
  34. Croarkin PE, Emslie GJ, Mayes TL. Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: a review of published cases. J Clin Psychiatry. Jul 2008;69(7):1157-65. [View Abstract]
  35. Deuschl G, Oepen G, Hermle L. Neuroleptic malignant syndrome: observations on altered consciousness. Pharmacopsychiatry. Jul 1987;20(4):168-70. [View Abstract]
  36. Dickey W. The neuroleptic malignant syndrome. Prog Neurobiol. 1991;36(5):425-36. [View Abstract]
  37. Gurrera RJ, Chang SS, Romero JA. A comparison of diagnostic criteria for neuroleptic malignant syndrome. J Clin Psychiatry. Feb 1992;53(2):56-62. [View Abstract]
  38. Hammerman S, Lam C, Caroff SN. Neuroleptic malignant syndrome and aripiprazole. Journal of the American Academy of Child and Adolescent Psychiatry. June 2006;45 (6):639-41. [View Abstract]
  39. Kaplan HI, Sadock BJ, Grebb JA. Kaplan and Sadock's Synopsis of Psychiatry. Philadelphia, Pa: Lippincott, Williams, & Wilkins; 1994:1913, 2004-2005.
  40. Kaufman KR, Levitt MJ, Schiltz JF, Sunderram J. Neuroleptic malignant syndrome and serotonin syndrome in the critical care setting: case analysis. Ann Clin Psychiatry. Jul-Sep 2006;18(3):201-4. [View Abstract]
  41. Keck PE Jr, Caroff SN, McElroy SL. Neuroleptic malignant syndrome and malignant hyperthermia: end of a controversy?. J Neuropsychiatry Clin Neurosci. Spring 1995;7(2):135-44. [View Abstract]
  42. Keck PE Jr, Pope HG Jr, McElroy SL. Declining frequency of neuroleptic malignant syndrome in a hospital population. Am J Psychiatry. Jul 1991;148(7):880-2. [View Abstract]
  43. Klein JP, Fiedler U, Appel H. Massive creatine kinase elevations with quetiapine: report of two cases. Pharmacopsychiatry. 2006;39(1):39-40. [View Abstract]
  44. Mendhekar DN, Jiloha RC. Neuroleptic malignant syndrome precipitated by haloperidol following clozapine discontinuation. Aust N Z J Psychiatry. 2005;39 (10):947-8. [View Abstract]
  45. Miyaoka H, Shishikura K, Otsubo T. Diazepam-responsive neuroleptic malignant syndrome: a diagnostic subtype?. Am J Psychiatry. Jun 1997;154(6):882. [View Abstract]
  46. Rodriguez OP, Dowell MS. A case report of neuroleptic malignant syndrome without fever in a patient given aripiprazole. Journal-Oklahoma State Medical Association. July-August 2006;99(7):435-8. [View Abstract]
  47. Rosebush P, Stewart T. A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry. Jun 1989;146(6):717-25. [View Abstract]
  48. Rosebush PI, Stewart T, Mazurek MF. The treatment of neuroleptic malignant syndrome. Are dantrolene and bromocriptine useful adjuncts to supportive care?. Br J Psychiatry. Nov 1991;159:709-12. [View Abstract]
  49. Rosebush PI, Stewart TD, Gelenberg AJ. Twenty neuroleptic rechallenges after neuroleptic malignant syndrome in 15 patients [published erratum appears in J Clin Psychiatry 1989 Dec;50(12):472]. J Clin Psychiatry. Aug 1989;50(8):295-8. [View Abstract]
  50. Seitz DP, Gill SS. Neuroleptic malignant syndrome complicating antipsychotic treatment of delirium or agitation in medical and surgical patients: case reports and a review of the literature. Psychosomatics. Jan-Feb 2009;50(1):8-15. [View Abstract]
  51. Shalev A, Hermesh H, Munitz H. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry. Jan 1989;50(1):18-25. [View Abstract]
  52. Silva RR, Munoz DM, Alpert M. Neuroleptic malignant syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry. Feb 1999;38(2):187-94. [View Abstract]
  53. Trutia A, Bledowski J, Pandurangi A, Kahn DA. Neuroleptic rechallenge with aripiprazole in a patient with previously documented neuroleptic malignant syndrome. J Psychiatr Pract. Nov 2008;14(6):398-402. [View Abstract]
  54. Vancaester E, Santens P. Catatonia and neuroleptic malignant syndrome: two sides of a coine?. Acta Neurological Belgica. June 2007;107(2):47-50. [View Abstract]
  55. Warwick TC, Moningi V, Jami P, Lucas K, Molokwu O, Moningi S. Neuroleptic malignant syndrome variant in a patient receiving donepezil and olanzapine. Nature Clinical Practice Neurology. March 2008;4(3):170-4. [View Abstract]
  56. Wells AJ, Sommi RW, Crismon ML. Neuroleptic rechallenge after neuroleptic malignant syndrome: case report and literature review. Drug Intell Clin Pharm. Jun 1988;22(6):475-80. [View Abstract]