Act Quickly if You Suspect Neuroleptic Malignant Syndrome

While psychotropic drugs have many common side effects that are important to consider, more severe and potentially life-threatening drug reactions that require emergency medical treatment can also occur at therapeutic doses (1). Since psychotropic drugs, when indicated and prescribed judiciously, are beneficial for many patients, they should not be withheld because of the minimal risk of these rare reactions. Instead, the best management strategy for ensuring patient safety consists of careful monitoring, informed by familiarity with adverse signs and symptoms to allow prompt recognition and rapid drug discontinuation, along with supportive or specific treatment.

Neuroleptic malignant syndrome (NMS)—a severe neurological disorder that presents in approximately 1 in 5,000 patients treated with antipsychotics—is one such condition of which you should be aware when prescribing psychotropic medications (2, 3). Risk factors for NMS may include dehydration, exhaustion, agitation, catatonia, previous episodes, and large doses of high-potency drugs given parenterally at a rapid rate of titration.

Increased awareness and the development of new antipsychotics with reduced neurologic liabilities have diminished the risk and morbidity of NMS; however, despite advances in recognition and treatment, clinical vigilance remains important as NMS is still potentially fatal in approximately 5 to 10 percent of cases.

NMS is an idiosyncratic drug reaction that occurs at therapeutic doses and may develop within hours but usually evolves over days. About two-thirds of cases occur during the first one to two weeks after drug initiation. Classic signs of NMS include elevated temperatures, muscle rigidity with tremors, altered consciousness or catatonia, and autonomic instability (4).

Laboratory findings are not pathognomonic but often reveal muscle enzyme elevations, myoglobinuria, leukocytosis, metabolic acidosis, hypoxia, elevated serum catecholamines, and low serum iron levels. A recent case report using single-photon emission computerized tomography found that patients with NMS may experience nearly complete loss of striatal dopamine transporter binding (5). Several lines of evidence strongly implicate drug-induced dopamine blockade as the primary triggering mechanism in the pathogenesis of NMS (6).

Although no single laboratory test is diagnostic for NMS, a thorough laboratory assessment and neuroimaging studies are essential for excluding other serious medical conditions. The differential diagnosis of NMS is complex, including central nervous system infections and autoimmune disorders; benign extrapyramidal side effects; agitated delirium of diverse causes; heatstroke; serotonin syndrome; stimulant toxicity; malignant hyperthermia associated with anesthesia; and withdrawal from dopamine agonists, sedatives, or alcohol. NMS may be indistinguishable from, and considered a drug-induced subtype of, malignant catatonia due to various causes (6).

The mainstay of treatment consists of early diagnosis, discontinuation of dopamine antagonists, and supportive medical care. Once antipsychotics are withheld, two-thirds of NMS cases resolve within one to two weeks, with an average duration of seven to 10 days. Patients may experience prolonged symptoms if long-acting injectable drugs are implicated, and occasionally, patients develop a prolonged residual catatonic and parkinsonian state that may respond to electroconvulsive therapy (ECT).

While some clinical reports suggest that benzodiazepines, dopamine agonists, dantrolene, and ECT can benefit patients with NMS, randomized, controlled trials comparing these agents with supportive care may not be feasible because NMS is rare, often self-limited after drug discontinuation, and heterogeneous in presentation, course, and outcome. These agents may be considered empirically in individual cases on the basis of targeted symptoms, severity, and duration of the episode.

After recovery, recurrences of NMS have been reported, but antipsychotic treatment can be reintroduced if necessary, provided conservative prescribing and monitoring guidelines are followed (3).

Additional information about the diagnosis and management of NMS is posted at the Neuroleptic Malignant Syndrome Information Service website.

1. Campbell EC, Caroff SN, Mann SC, Weinrieb RM, Berkowitz RM, Olson KN. Severe Drug Reactions. In: Levenson JL, Ferrando SJ, eds. Clinical Manual of Psychopharmacology in the Medically Ill. 2nd ed. Washington, D.C.: American Psychiatric Association Publishing; 2016:46-51.

2. Caroff SN, Campbell EC. Drug-Induced Extrapyramidal Syndromes: Implications for Contemporary Practice. The Psychiatric Clinics of North America. 2016;39(3):391-411.

3. Caroff SN. Neuroleptic Malignant Syndrome. In: Mann SC, Caroff SN, Keck PE Jr., Lazarus A., eds. Neuroleptic Malignant Syndrome and Related Conditions. 2nd ed. Washington, D.C.: American Psychiatric Press, Inc.; 2003:1-44.

4. Gurrera RJ, Caroff SN, Cohen A, et al. An International Consensus Study of Neuroleptic Malignant Syndrome Diagnostic Criteria Using the Delphi Method. The Journal of Clinical Psychiatry. 2011;72(9):1222-1228.

5. Martino G, Capasso M, Nasuti M, Bonanni L, Onofrj M, Thomas A. Dopamine Transporter Single-Photon Emission Computerized Tomography Supports Diagnosis of Akinetic Crisis of Parkinsonism and of Neuroleptic Malignant Syndrome. Medicine. 2015;94(13):e649.

6. Mann SC. Malignant Catatonia. In: Mann SC, Caroff SN, Keck PE Jr., Lazarus A., eds. Neuroleptic Malignant Syndrome and Related Conditions. Washington, D.C.: American Psychiatric Press, Inc.; 2003:121-143.