Serotonin Syndrome and Neuroleptic Malignant Syndrome: A New Review

I saw a new review about distinguishing, diagnosing and treating serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) [1]. I remember Paul Perry, the lead author, because he was one of the principal teachers of the psychopharmacology course during my residency in psychiatry at Iowa.

SS results from too much serotonin, often because of serotonergic drug polypharmacy, and it can be life-threatening. I’ve seen this several times in my career as a consulting psychiatrist and a co-attending on our Medical-Psychiatry Unit. The occurrence rate is unknown, often because it is unrecognized. NMS is an idiosyncratic adverse reaction to dopamine antagonists, which include other drugs in addition to antipsychotics. It can occur as well with abrupt withdrawal of dopaminergic agents used to treat Huntington’s disease and Parkinson’s disease.  It is also potentially life-threatening. NMS is rare, with a frequency estimates ranging from 0.07% to 2.2%. Both SS and NMS can be marked by delirium.

The most convincing explanation for the mechanism of SS, according to Perry and Wilborn is excessive serotonin in the central nervous system (CNS). The pathophysiology of NMS is not well understood but could involve CNS dopaminergic hypofunction or peripheral sympathetic autonomic nervous system hyperactivity.

SS can present clinically as mental status changes ranging from mood lability to frank delirium, sweating, tachycardia, labile blood pressure, shivering tremor, drooling, mydriasis, and myoclonic jerks as well as hyperreflexia, hyperthermia. Seizures can occur. Rhabdomyolysis can occur in about 27% of cases.

NMS patients tend to have 4 major clinical presentations including “lead pipe” muscle rigidity, hyperpyrexia, mental status changes (often delirium and catatonia), and autonomic instability. The muscle rigidity often leads to very high elevations in CK enzyme. Diagnostic confusion between SS and NMS often results because SS can be marked by some of the same features as NMS.

However, a lab profile including low serum iron, proteinuria, elevated CK, LDH, AST, and high white blood cell count occurs in over 75% of NMS cases. So the lab data can be critically important in distinguishing SS from NMS.

Moreover, marked muscular rigidity is more typical of NMS while any form of myoclonus suggests SS. Nausea and vomiting along with diarrhea are more suggestive of SS than NMS.

Treatment for SS is removing the offending serotonergic agents and support measures. Treatment for NMS also includes stopping the offending drugs and providing supportive care. Pharmacologic management preferred for NMS is Dantrolene, a skeletal muscle relaxant or Bromocriptine, a dopamine agonist.

Electroconvulsive therapy (ECT) has been recommended for severe NMS in which there’s a high risk of complications, catatonia, and dysphoria with psychotic symptoms. I have personally attended several cases over the years in which ECT was emergently applied, occasionally in the intensive care unit.

Many thanks to Paul Perry and his co-author Courtney Wilborn for this timely, excellent review.

1. Perry, P. J. and C. A. Wilborn (2012). “Serotonin syndrome vs neuroleptic malignant syndrome: A contrast of causes, diagnoses, and management.” Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists 24(2): 155-162.
BACKGROUND: Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are uncommon but potentially life-threatening adverse reactions associated with psychotropic medications. Polypharmacy and the similar presentation of SS and NMS make diagnosis of the 2 syndromes problematic. METHODS: A MEDLINE search was performed for the period 1960 to 2011 for case reports, review articles, and studies pertaining to SS and NMS. RESULTS: The majority of available literature on SS and NMS consists of case reports, case-control studies, and retrospective reviews. In addition, diagnostic criteria have been developed to aid in the diagnosis and management of SS and NMS. CONCLUSIONS: SS presents as mental status changes, autonomic nervous system disturbances, neurologic manifestations, and hyperthermia. Similarly, NMS presents as muscle rigidity, hyperpyrexia, mental status changes, and autonomic instability. However, the clinical laboratory profile of elevations in creatine kinase, liver function tests (lactate dehydrogenase, aspartate transaminase), and white blood cell count, coupled with a low serum iron level, distinguishes NMS from SS among patients taking neuroleptic and serotonin agonist medications simultaneously. For both SS and NMS, immediate discontinuation of the causative agent is the primary treatment, along with supportive care. For NMS, dantrolene is the most effective evidence-based drug treatment whereas there are no evidence-based drug treatments for SS. A 2-week washout of neuroleptic medication minimizes the chance of recurrence.