Antipsychotics: The Essentials Module 4: Adverse Effects Neuroleptic Malignant Syndrome Flavio Guzmán, MD

Outline Neuroleptic Malignant syndrome Epidemiology Associated drugs Risk Factors Clinical Manifestations Pathophysiology Differential Diagnosis Management

“ NMS is an acute disorder of thermoregulation and neuromotor control carrying a mortality rate of about 21% when untreated” Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

NMS - Epidemiology Estimates of incidence were once around 3% Recent statistics suggest incidence of 0.01 -0.02% The syndrome has been described in all age groups (most are young adults) Strawn JR, Keck PE, Jr., Caroff SN. Neuroleptic malignant syndrome. The American Journal of Psychiatry 2007;164:870-6.

NMS - Associated Drugs Dopamine antagonists Antipsychotics FGA High potency Low potency SGA Antiemetics E Wijdicks (2011). Neuroleptic Malignant Syndrome In: Michael J Aminoff. (Ed.), UpToDate. http://uptodate.com

NMS - Risk Factors Dehydration is present in about 92 % of patients ( risk factor or early complication?) Concomitant lithium use Use of high potency agents Long-acting injections High antipsychotic dose (not dose dependent) E Wijdicks (2011). Neuroleptic Malignant Syndrome In: Michael J Aminoff. (Ed.), UpToDate. http://uptodate.com

NMS - Clinical Manifestations Hyperthermia Higher than 38°C, even higher than 40°C Rigidity Typical: “lead pipe rigidity” Mental Status Changes Agitated delirium with confusion Autonomic Instability Tachycardia, tachypnea, labile or high BP NMS E Wijdicks (2011). Neuroleptic Malignant Syndrome In: Michael J Aminoff. (Ed.), UpToDate. http://uptodate.com

Lab Testing Serum CK: More than 1,000 UI (has high as 100,000 UI) Not specific for NMS Degree of elevation correlates w/ disease severity and prognosis Other abnormalities Leukocytosis Electrolyte abnormalities E Wijdicks (2011). Neuroleptic Malignant Syndrome In: Michael J Aminoff. (Ed.), UpToDate. http://uptodate.com

NMS - Pathophysiology Unknown Dopamine antagonism might be involved Hypothalamus Nigrostriatal pathway: Rigidity Hypothalamus: Hyperthermia Frontal lobe / Mesocortical blockade : altered mental status Strawn JR, Keck PE, Jr., Caroff SN. Neuroleptic malignant syndrome. The American Journal of Psychiatry 2007;164:870-6.

NMS – Differential Diagnosis Related Disorders Serotonin Syndrome Malignant Catatonia Unrelated Disorders Heatstroke CNS infections (Viral Encephalitis) E Wijdicks (2011). Neuroleptic Malignant Syndrome In: Michael J Aminoff. (Ed.), UpToDate. http://uptodate.com

Management of NMS General Specific agents (limited evidence) ECT Stop causative agent Supportive care Specific agents (limited evidence) Dantrolene Bromocriptine Amantadine ECT Strawn JR, Keck PE, Jr., Caroff SN. Neuroleptic malignant syndrome. The American Journal of Psychiatry 2007;164:870-6.

Key Points NMS is a potentially life-threatening complication of antipsychotic drug use. Treatment with high potency FGAs at high doses increases risk. Clinical manifestations include: mental status changes, rigidity, hyperthermia and autonomic instability. Serum CK levels greater than 1000 IU/L are suggestive of NMS. If NMS is suspected, antipsychotics should be discontinued immediately.

References and Further Reading Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010. Strawn JR, Keck PE, Jr., Caroff SN. Neuroleptic malignant syndrome. The American Journal of Psychiatry 2007;164:870-6. E Wijdicks (2011). Neuroleptic Malignant Syndrome In: Michael J Aminoff. (Ed.), UpToDate. http://uptodate.com