Neuroleptic malignant syndrome
- Overview
- Theory
- Diagnosis
- Management
- Follow up
- Resources
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Look out for this icon: for treatment options that are affected, or added, as a result of your patient's comorbidities.
initial episode
withdrawal of antipsychotic medication
If NMS is suspected, get a toxicology consult or advice from the Poison Center when reviewing your patient's medication. America's Poison Centers: poison help Opens in new window Antipsychotics and dopamine antagonists must be stopped, and dopamine agonists must be restored or continued. Other drugs that may be contributory (e.g., lithium, metoclopramide) may need to be stopped.[3]Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am. 1993 Jan;77(1):185-202. http://www.ncbi.nlm.nih.gov/pubmed/8093494?tool=bestpractice.com [9]Stevens DL. Association between selective serotonin-reuptake inhibitors, second-generation antipsychotics, and neuroleptic malignant syndrome. Ann Pharmacother. 2008 Sep;42(9):1290-7. http://www.ncbi.nlm.nih.gov/pubmed/18628446?tool=bestpractice.com
If the patient’s psychiatric symptoms compel resumption of antipsychotic medication, a delay of at least 2 weeks following complete resolution of the NMS episode is advisable.[52]Velamoor VR. Neuroleptic malignant syndrome. Recognition, prevention and management. Drug Saf. 1998 Jul;19(1):73-82. https://www.doi.org/10.2165/00002018-199819010-00006 http://www.ncbi.nlm.nih.gov/pubmed/9673859?tool=bestpractice.com In practice, the class of drug that is suspected to be the cause of NMS is usually added to the patient’s medical records as an allergy.
supportive therapy
Treatment recommended for ALL patients in selected patient group
Give supplemental oxygen by nasal cannula if needed; endotracheal intubation may be required for more severe cases.
Most patients are dehydrated in the acute phase of the illness; therefore, administration of fluids and monitoring and correction of electrolyte abnormalities are essential. When rhabdomyolysis occurs, vigorous hydration with intravenous fluids is recommended to prevent acute kidney injury.
Hyperthermia can be treated with physical cooling measures; antipyretics such as acetaminophen or ibuprofen do not appear to be effective in NMS.
Patients with dysphagia might require a nasogastric tube for the administration of fluids, nutrition, and pharmacologic therapy.[3]Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am. 1993 Jan;77(1):185-202. http://www.ncbi.nlm.nih.gov/pubmed/8093494?tool=bestpractice.com
pharmacologic therapy
Treatment recommended for SOME patients in selected patient group
There is limited evidence on whether pharmacologic treatments ameliorate symptoms and improve recovery. There are no specific recommendations regarding sequence or preference of one drug over the other, except that benzodiazepines are generally preferred as first-line treatment because of their lower risk in comparison with bromocriptine and dantrolene.
Benzodiazepines: oral or intravenous lorazepam may be helpful to treat NMS-associated agitation and catatonia. It also works as a muscle relaxant. Adverse effects include respiratory depression and/or worsening delirium.[2]Buckley P, Adityanjee M, Sajatovic M. Neuroleptic malignant syndrome. In: Katirji B, Kaminski HJ, Preston DC, et al, eds. Neuromuscular disorders in clinical practice. Boston, MA: Butterworth-Heinemann; 2002:1264-75.
Muscle relaxants: dantrolene given orally or intravenously may aid resolution of NMS-associated muscular rigidity and hyperthermia.[48]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. http://www.ncbi.nlm.nih.gov/pubmed/22563571?tool=bestpractice.com However, some studies show that combination of dantrolene with other drugs for the treatment of NMS is associated with a prolongation of clinical recovery; therefore, use is somewhat controversial.[38]Reulbach U, Dütsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007;11:R4. http://ccforum.biomedcentral.com/articles/10.1186/cc5148 http://www.ncbi.nlm.nih.gov/pubmed/17222339?tool=bestpractice.com [53]Rosebush PI, Stewart T, Mazurek MF. The treatment of neuroleptic malignant syndrome. Br J Psychiatry. 1991 Nov;159:709-12. http://www.ncbi.nlm.nih.gov/pubmed/1843801?tool=bestpractice.com
Dopaminergic agents: bromocriptine and amantadine are especially useful if the NMS was caused by withdrawal of anti-Parkinson medication. They are administered orally or by a nasogastric tube in patients with dysphagia.[2]Buckley P, Adityanjee M, Sajatovic M. Neuroleptic malignant syndrome. In: Katirji B, Kaminski HJ, Preston DC, et al, eds. Neuromuscular disorders in clinical practice. Boston, MA: Butterworth-Heinemann; 2002:1264-75.[3]Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am. 1993 Jan;77(1):185-202. http://www.ncbi.nlm.nih.gov/pubmed/8093494?tool=bestpractice.com [18]Takubo H, Harada T, Hashimoto T, et al. A collaborative study on the malignant syndrome in Parkinson's disease and related disorders. Parkinsonism Relat Disord. 2003 Apr:9 Suppl 1:S31-41. http://www.ncbi.nlm.nih.gov/pubmed/12735913?tool=bestpractice.com However, like dantrolene, evidence for a beneficial effect in NMS is equivocal, and their use is also controversial.[38]Reulbach U, Dütsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007;11:R4. http://ccforum.biomedcentral.com/articles/10.1186/cc5148 http://www.ncbi.nlm.nih.gov/pubmed/17222339?tool=bestpractice.com [53]Rosebush PI, Stewart T, Mazurek MF. The treatment of neuroleptic malignant syndrome. Br J Psychiatry. 1991 Nov;159:709-12. http://www.ncbi.nlm.nih.gov/pubmed/1843801?tool=bestpractice.com
Dantrolene, bromocriptine, and amantadine are often used in the treatment of NMS despite the limited evidence of their effectiveness.[1]Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007 Jun;164(6):870-6. http://www.ncbi.nlm.nih.gov/pubmed/17541044?tool=bestpractice.com [37]Mall GD, Hake L, Benjamin AB, et al. Catatonia and mild neuroleptic malignant syndrome after initiation of long-acting injectable risperidone: case report. J Clin Psychopharmacol. 2008 Oct;28(5):572-3. http://www.ncbi.nlm.nih.gov/pubmed/18794658?tool=bestpractice.com [38]Reulbach U, Dütsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007;11:R4. http://ccforum.biomedcentral.com/articles/10.1186/cc5148 http://www.ncbi.nlm.nih.gov/pubmed/17222339?tool=bestpractice.com One systematic case series analysis suggests that dantrolene and bromocriptine may be more effective in the treatment of severe NMS than supportive care alone.[54]Kuhlwilm L, Schönfeldt-Lecuona C, Gahr M, et al. The neuroleptic malignant syndrome-a systematic case series analysis focusing on therapy regimes and outcome. Acta Psychiatr Scand. 2020 Sep;142(3):233-41. https://onlinelibrary.wiley.com/doi/10.1111/acps.13215 http://www.ncbi.nlm.nih.gov/pubmed/32659853?tool=bestpractice.com
Caution is advised when using medications in association with NMS. Based on many anecdotal reports, it is generally advised that these treatments be continued until the NMS episode is fully resolved, and possibly longer (e.g., an additional 7-10 days) because NMS can return if effective treatments are terminated prematurely.
Primary options
lorazepam: 1-4 mg orally/intravenously as a single dose
Secondary options
dantrolene: consult specialist for guidance on dose
OR
bromocriptine: 2.5 to 5 mg orally three times daily
OR
amantadine: 200-400 mg/day orally given in 2 divided doses
These drug options and doses relate to a patient with no comorbidities.
Primary options
lorazepam: 1-4 mg orally/intravenously as a single dose
Secondary options
dantrolene: consult specialist for guidance on dose
OR
bromocriptine: 2.5 to 5 mg orally three times daily
OR
amantadine: 200-400 mg/day orally given in 2 divided doses
Drug choice, dose and interactions may be affected by the patient's comorbidities. Check your local drug formulary.
Show drug information for a patient with no comorbidities
Primary options
lorazepam
Secondary options
dantrolene
OR
bromocriptine
OR
amantadine
electroconvulsive therapy
Treatment recommended for SOME patients in selected patient group
Case reports and one systematic case series analysis suggest that electroconvulsive therapy (ECT) may be effective in the treatment of NMS (particularly if severe), even after failed pharmacotherapy.[54]Kuhlwilm L, Schönfeldt-Lecuona C, Gahr M, et al. The neuroleptic malignant syndrome-a systematic case series analysis focusing on therapy regimes and outcome. Acta Psychiatr Scand. 2020 Sep;142(3):233-41. https://onlinelibrary.wiley.com/doi/10.1111/acps.13215 http://www.ncbi.nlm.nih.gov/pubmed/32659853?tool=bestpractice.com [55]Trollor JN, Sachdev PS. Electroconvulsive treatment of neuroleptic malignant syndrome: a review and report of cases. Aust N Z J Psychiatry. 1999 Oct;33(5):650-9. http://www.ncbi.nlm.nih.gov/pubmed/10544988?tool=bestpractice.com [56]Ozer F, Meral H, Aydin B, et al. Electroconvulsive therapy in drug-induced psychiatric states and neuroleptic malignant syndrome. J ECT. 2005 Jun;21(2):125-7. http://www.ncbi.nlm.nih.gov/pubmed/15905757?tool=bestpractice.com [57]Davis JM, Janicak PG, Sakkas P, et al. Electroconvulsive therapy in the treatment of the neuroleptic malignant syndrome. Convuls Ther. 1991;7(2):111-20. http://www.ncbi.nlm.nih.gov/pubmed/11941110?tool=bestpractice.com [58]Scheftner WA, Shulman RB. Treatment choice in neuroleptic malignant syndrome. Convuls Ther. 1992;8(4):267-79. http://www.ncbi.nlm.nih.gov/pubmed/11941178?tool=bestpractice.com ECT is considered potentially useful in more extreme cases of NMS, but may often be impractical.
recurrence
retreatment
Recurrence of NMS is managed in the same way as initial presentation with withdrawal of antipsychotic medication, supportive therapy, and adjunctive use of pharmacologic treatments.
Recurrence of NMS is less likely if resumption of antipsychotic medication is delayed until 2 or more weeks after resolution of NMS. In practice, this might be difficult to achieve, requiring extreme diligence and seeking additional peer consultation. Vigilance is required in all subsequent antipsychotic medication trials.
About 2 weeks after resolution of NMS, treatment with an antipsychotic (not the same one that caused NMS) should be initiated at a low dose and slowly titrated in a monitored setting to assess for signs of recurrence.[1]Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007 Jun;164(6):870-6. http://www.ncbi.nlm.nih.gov/pubmed/17541044?tool=bestpractice.com [52]Velamoor VR. Neuroleptic malignant syndrome. Recognition, prevention and management. Drug Saf. 1998 Jul;19(1):73-82. https://www.doi.org/10.2165/00002018-199819010-00006 http://www.ncbi.nlm.nih.gov/pubmed/9673859?tool=bestpractice.com Some experts recommend a second-generation agent, with lower risk of extrapyramidal adverse effects, in preference to first-generation antipsychotic medications. However, there is no consensus on this view because no antipsychotic medication has been shown to have more or less risk than another.
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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer
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