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The Edge: Serotonin Syndrome, Neuroleptic Malignant Syndrome, and Malignant Hyperthermia

The Edge is a new monthly column from FlightBridgeED that will feature top providers sharing current trends in critical care and prehospital medicine. In this installment FlightBridgeED's Dr. Jeff Jarvis explores serotonin syndrome and related conditions. 

Have you ever had a patient with altered mental status, perhaps some myoclonus and even fever, whom you were pretty sure had some type of toxicology issue going on but just weren’t sure what it might be? Perhaps you see they’re on an antidepressant or an antipsychotic. Maybe you even remember something about serotonin syndrome or neuroleptic malignant syndrome but can’t for the life of you remember which is which. 

If so, you’re not alone. These syndromes can be hard to tell apart at first glance. Throw in overdoses of monoamine oxidase inhibitor (MAOI) medications or even malignant hyperthermia, and things can get very confusing. A basic understanding of the relevant physiology and pharmacology will help us see what they have in common and, more important, how we can tell them apart. 

Serotonin Syndrome 

Let’s start with serotonin syndrome (SS). Selective serotonin reuptake inhibitors (SSRIs) are a common class of medications often prescribed for treatment of depression, anxiety, or compulsive disorders. As a class these drugs are typically much safer than the tricyclic antidepressants and monoamine oxidase inhibitors used prior to introduction of the SSRIs. SSRIs work by inhibiting the reabsorption of serotonin at the 5HT receptor on the presynaptic end bulb in the brain. This increase in the concentration of serotonin in the synapse is associated with improved mood and decreased anxiety.1

As a quick reminder of how synaptic transmission occurs, neurotransmitters like serotonin are created and stored in the presynaptic end of a neuron. As the result of a signal being sent down the neuron, the neurotransmitter is released and diffuses across the gap, or synapse, between the two neurons. They bind with receptors on the postsynaptic neuron, which causes the signal to continue on its merry way down the neuron to its ultimate target. The receptor then releases the neurotransmitter back into the synapse. Depending on the specific neurotransmitter, it can sometimes be broken down by enzymes that live near the receptors, inactivating it, or sucked up by the presynaptic neuron for recycling.2 

Common SSRIs include citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). There are also drugs that block the reuptake of serotonin in addition to other neurotransmitters, including dopamine and norepinephrine (bupropion/Wellbutrin).3 Other medications have more complicated mechanisms but can also lead to increased serotonin levels. These include duloxetine (Cymbalta), mirtazapine (Remeron), trazodone, and venlafaxine (Effexor). 

The other way to increase the amount of serotonin in the synapse is by inhibiting the breakdown of serotonin molecules. This is how monoamine oxidase inhibitors (MAOIs) work, although they also inhibit the breakdown of epinephrine and norepinephrine. The bottom line is that SSRIs and MAOIs lead to an increase in serotonin. Too much serotonin can lead to serotonin syndrome.

The hallmarks of serotonin syndrome include clonus, agitation/confusion, hypertension, tachycardia, and sometimes hyperthermia.4 There also needs to be some plausible serotonin-increasing medication. This can be seen with an increased dose or the addition of another serotonin-increasing medication (like another SSRI or MAOI). It is probably helpful to remember there are all sorts of unregulated herbs and spices out there that increase serotonin levels; St. John’s wort is the classic example.5 

The Hunter Serotonin Toxicity Criteria provides a useful cognitive diagnostic pathway for serotonin syndrome.6 It starts with the presence of a serotonergic agent. If a patient has spontaneous clonus, SS is present. If not, inducible or ocular clonus plus either agitation or diaphoresis indicates SS. Next, if there is tremor and hyperreflexia, that’s also SS. Finally, if there is hyperreflexia and fever and inducible or ocular clonus, that is SS. There are some great YouTube videos that have some nice demonstrations of these exam findings (links in sidebar).

Treatment of serotonin syndrome is focused on symptom management until the drugs can be metabolized.7 Most of these patients will be agitated with clonus. Benzodiazepines are the hallmark of treatment. Patients can be hyperthermic and easily become dehydrated, so fluids are warranted, particularly when tachycardic or hypotensive.

Monoamine oxidase inhibitor overdose can cause a similar presentation to serotonin syndrome.8 MAOI overdose typically looks like a sympathomimetic syndrome: hypertension, tachycardia, dehydration, diaphoresis, and agitation. Treatment is similar to serotonin syndrome, at least for the agitation. Profound hypertension associated with end-organ damage, if present, will also be treated. 

Problems With Antipsychotics

Now let’s switch from serotonin syndrome and other adverse events from antidepressants to the problems we see with antipsychotics. Antipsychotics come in two broad classes: typical and atypical. Both work by blocking dopamine D2 receptors in various places in the brain.9 The desired effect of this is a decrease in dopamine activity that leads to improvement in the “positive” symptoms of psychosis: hallucinations, agitation, and disordered thinking. 

Unfortunately, there are also D2 receptors in areas of the brain that help regulate movement by altering the balance between dopamine and acetylcholine (ACH). Blocking dopamine effects allows a predominance of ACH, leading to motor excitation. This manifests as extrapyramidal symptoms (EPS).10

The typical antipsychotics include low-potency drugs like prochlorperazine (Compazine), chlorpromazine (Thorazine), and high-potency ones like haloperidol (Haldol) and droperidol (Inapsine). These agents get the antipsychotic effects but are also more likely to get the negative EPS side effects. Atypical agents like olanzapine (Zyprexa) and ziprasidone (Geodon) give the same antipsychotic effect but with fewer side effects. These are less likely to cause EPS and typically less sedating. These atypicals can also help with the negative symptoms of psychosis like flat affect, social withdrawal, and lack of motivation. 

One of the more helpful side effects of these antidopaminergic agents, particularly the typicals, is suppression of dopamine in the chemotactic trigger zone, the place responsible for nausea. That’s why prochlorperazine, haloperidol, and droperidol are all effective antinausea medications. They can also be very effective for headaches. Droperidol is particularly helpful for nausea, agitation, and headache.11–22 It is why droperidol is such a useful agent for EMS and emergency medicine. Unfortunately, the FDA placed a “black box” warning on it, effectively removing it from practice. Sadly, there is good evidence this black box warning was unwarranted and the drug is safe.16,23–25

One of the primary side effects of antipsychotics, most common with the typical antipsychotics, is EPS. These can be divided into acute and chronic types. The acute ones are akathisia and dystonia. Akathisia is a subjective sense of restlessness and anxiety. It makes people feel very uncomfortable, like they can’t sit still or are coming out of their skin. Dystonias are involuntary movements, spasms, or tics. The chronic EPS is tardive dyskinesia. This is usually a result of long-term use of antipsychotics. These are quick, involuntary movements like lip smacking, blinking, chewing, and tongue movements. These can sometimes be permanent. 

EPS comes from an imbalance between dopamine and acetylcholine. The decrease in dopamine and relative increase in acetylcholine effects causes the motor movements. Treatment for acute EPS is with anticholinergics like diphenhydramine or benztropine (Cogentin).

Neuroleptic Malignant Syndrome, Malignant Hyperthermia 

Neuroleptic malignant syndrome (NMS) is a drug reaction. The word neuroleptic can be a bit confusing. Basically it’s the old word for antipsychotic. Think of NMS as an adverse reaction to antipsychotics. It usually comes on within the first month of antipsychotic use but can be seen after a dose increase. It is more common with the high-potency typical agents like haloperidol. It is pretty uncommon after a single administration; we’re really talking about patients who are taking these as outpatients. The cardinal features of neuroleptic malignant syndrome are altered mental status, autonomic nervous system instability, and hyperthermia.26 So…agitation, confusion, tachycardia, and fever—things we could also see with serotonin syndrome. This is why it can get confusing. Treatment of NMS is symptomatic: cooling, benzodiazepines, fluids, and bromocriptine.

Here are the key factors that can help us differentiate serotonin syndrome from neuroleptic malignant syndrome. 

  • First, look at the drug. If it is a serotonergic or a MAOI, think serotonin syndrome. If it is an antipsychotic, think NMS. 
  • If the symptoms came on rapidly (within a few hours), think serotonin syndrome. If they came on gradually, over days to weeks, think NMS.
  • Fever, agitation/confusion, tachycardia, and muscle rigidity are almost universally present with NMS but can be present in varying degrees with serotonin syndrome. 
  • Hyperreflexia or clonus is common in serotonin syndrome but unusual in NMS.

The last syndrome that sometimes gets lumped in with serotonin syndrome and NMS is malignant hyperthermia, likely because all three can present with fever. Malignant hyperthermia is a reaction to inhaled anesthetics or succinylcholine and presents with hyperthermia and muscle rigidity. It is treated with fluids, cooling, removal of the offending medication, and dantrolene.

Conclusion

By understanding the underlying physiology and pharmacology, we can usually sort out toxic syndromes such as serotonin syndrome, neuroleptic malignant syndrome, and malignant hyperthermia and provide appropriate stabilizing treatment.   

References

1. Bandelow B, Reitt M, Rover C, et al. Efficacy of treatments for anxiety disorders: a meta-analysis. Int Clin Psychopharmacol, 2015 Jul; 30(4): 183–92.

2. Hall JE, Hall ME. Guyton and Hall Textbook of Medical Physiology, 14th ed. Philadelphia, PA: Elsevier, 2020.

3. Katzung BG, Kruidering-Hall M, Trevor AJ. Antidepressants. New York, NY: McGraw-Hill Education, 2019.

4. Jurek L, Nourredine M, Megarbane B, et al. [The serotonin syndrome: An updated literature review]. Rev Med Interne, 2019; 40: 98–104.

5. St John’s wort and depression: slight efficacy at best, many drug interactions. Prescrire Int, 2004; 13: 187–92.

6. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM, 2003; 96: 635–42.

7. Stork CM. Serotonin Reuptake Inhibitors and Atypical Antidepressants. In: Nelson LS, Howland MA, Lewin NA, et al. Goldfrank’s Toxicologic Emergencies, 10th ed. New York, NY: McGraw-Hill Education, 2019.

8. Manini AF. Monoamine Oxidase Inhibitors. In: Nelson LS, Howland MA, Lewin NA, et al. Goldfrank’s Toxicologic Emergencies, 10th ed. New York, NY: McGraw-Hill Education, 2019.

9. DeBattista C. Antipsychotic Agents & Lithium. In: Katzung BG. Basic & Clinical Pharmacology. New York, NY: McGraw-Hill Education, 2017.

10. Pokorna O, Samelson-Jones E. Psychosis. In: Feldman MD, Christensen JF, Satterfield JM, Laponis R. Behavioral Medicine: A Guide for Clinical Practice, 5th ed. New York, NY: McGraw-Hill Education, 2019.

11. Page CB, Parker LE, Rashford SJ, Isoardi KZ, Isbister GK. A Prospective Study of the Safety and Effectiveness of Droperidol in Children for Prehospital Acute Behavioral Disturbance. Prehosp Emerg Care, 2019; 23: 519–26.

12. Page CB, Parker LE, Rashford SJ, Bosley E, Isoardi KZ, Williamson FE, Isbister GK. A Prospective Before and After Study of Droperidol for Prehospital Acute Behavioral Disturbance. Prehosp Emerg Care, 2018; 22: 713–21.

13. Khokhar MA, Rathbone J. Droperidol for psychosis-induced aggression or agitation. Cochrane Database Syst Rev, 2016; 12: CD002830.

14. Calver L, Drinkwater V, Gupta R, Page CB, Isbister GK. Droperidol v. haloperidol for sedation of aggressive behaviour in acute mental health: randomised controlled trial. Br J Psychiatry, 2015; 206: 223–8.

15. Isbister GK, Calver LA, Page CB, et al. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med, 2010 Oct; 56(4): 392–401.

16. Colwell CB. Managing the acutely agitated patient. Why Denver brought back the forgotten agent droperidol. EMS World, 2010; 39(7): 18–9.

17. Szwak K, Sacchetti A. Droperidol use in pediatric emergency department patients. Pediatr Emerg Care, 2010; 26: 248–50.

18. Silberstein SD, Young WB, Mendizabal JE, Rothrock JF, Alam AS. Acute migraine treatment with droperidol: A randomized, double-blind, placebo-controlled trial. Neurology, 2003; 60: 315–21.

19. Richman PB, Allegra J, Eskin B, et al. A randomized clinical trial to assess the efficacy of intramuscular droperidol for the treatment of acute migraine headache. Am J Emerg Med, 2002; 20: 39–42.

20. Hick JL, Mahoney BD, Lappe M. Prehospital sedation with intramuscular droperidol: a one-year pilot. Prehosp Emerg Care, 2001; 5: 391–94.

21. Miner JR, Fish SJ, Smith SW, Biros MH. Droperidol vs. prochlorperazine for benign headaches in the emergency department. Acad Emerg Med, 2001; 8: 873–9.

22. Thomas Jr. H, Schwartz E, Petrilli R. Droperidol versus haloperidol for chemical restraint of agitated and combative patients. Ann Emerg Med, 1992; 21: 407–13.

23. Newman DH. Training the Mind, and the FDA, on Droperidol. Ann Emerg Med, 2015; 66: 243–5.

24. Calver L, Page CB, Downes MA, et al. The Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department. Ann Emerg Med, 2015; 66: 230–8.

25. Horowitz BZ, Bizovi K, Moreno R. Droperidol—behind the black box warning. Acad Emerg Med, 2002; 9: 615–8.

26. Juurlink D. Antipsychotics. In: Nelson LS, Howland MA, Lewin NA, et al. Goldfrank’s Toxicologic Emergencies, 10th ed. New York, NY: McGraw-Hill Education, 2019. 

 

Serotonin Syndrome: What It Looks Like

 

Differentiating Features of Serotonin Syndrome and Neuroleptic Malignant Syndrome

Feature Serotonin Syndrome Nerol. Malig. Synd.
Antidopaminergic (antipsychotic) No Yes
Serotonergic (antidepressant)  Yes No
Onset of symptoms Minutes to hours Days to weeks
Hyperthermia, AMS, muscle rigidity Variable Almost universal
Hyperreflexia, myoclonus Usually Not so much
Treatment Benzodiazepines Bromocriptine
Resolution of symptoms 24–48 hrs. for complete resolution Days to weeks

 —Source: Rosen’s Emergency Medicine: Concepts and Clinical Practice, 7th edition, table 149-6

Jeffrey L. Jarvis, MD, MS, EMT-P, FACEP, FAEMS, is chief medical officer for FlightBridgeED and cohost of the FlightBridgeED EMS Lighthouse Project Podcast. He is EMS medical director for Williamson County EMS and Marble Falls Area EMS and is an EM physician at Baylor Scott & White Hospital in Round Rock, Tex.

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