1. JAMI FOREBACK, MD., PhD. ANNE DOHRENWEND, PhD. Mclaren Regional Medical Center/ Michigan State University College of Human Medicine Serotonin Syndrome

2. Objectives To identify signs and symptoms of Serotonin Syndrome (SS) To identify risks associated with particular medications To clarify management

3. Why should you care? Difficult to assess due to poor awareness and underdiagnosis Occurs in 14 to 16% of those who overdose on SSRIs Mortality of severe SS is 2-12% In 2005, the Toxic Exposure Surveillance System reported 48,279 incidences of exposure to SSRIs that caused toxic effects in 8,585 persons, resulting in 118 deaths

4. Definitions Serotonin  A neurotransmitter in the CNS, gut and other systems Serotonin Syndrome  A life-threatening adverse drug reaction that results from therapeutic drug use, intentional self-poisoning, or inadvertent interactions between drugs. Serotonin Toxicity or Excess  A spectrum of signs and symptoms resulting from excess serotonin  Serotonin syndrome exists at the extreme end of the severity spectrum

5. Key Features of Serotonin Toxicity Predictable consequence of excess serotonin Produces a spectrum of clinical findings Symptoms range from barely perceptible to lethal

6. Drugs Associated with SS SSRIs and SNRIs Monoamine oxidase inhibitors (MAOIs) Tricyclic antidepressants Opiate analgesics Over-the-counter cough medicines Antibiotics Weight loss meds Antiemetics Antimigraine agents Drugs of abuse Herbal products Other common meds: tramadol, buspirone, trazadone

7. Caveat Serotonin syndrome is a predictable consequence of excess serotonin, however…..

8. Caveat Serotonin syndrome is a predictable consequence of excess serotonin, however….. it has been reported to result from a single, therapeutic dose of an SSRI.

9. Mechanisms of Drug Interactions and SS Overdose of one or more serotonergic agents

10. Mechanisms of Drug Interactions and SS Overdose of one or more serotonergic agents Addition of inhibitors of cytochrome isoforms to therapeutic SSRI regimens

11. Mechanisms of Drug Interactions and SS Overdose of one or more serotonergic agents Addition of inhibitors of cytochrome isoforms to therapeutic SSRI regimens Adding serotonergic agents within 5 wks of discontinuation of fluoxetine

12. Drug Interaction and SS Inhibitors of monoamine oxidase are associated with severe SS, especially if used in combination with:  meperidine (Demerol)  dextromethorphan (Robitussin)  SSRIs  MDMA (Ecstasy)

13. Signs and Symptoms Vital signs:  Tachycardia  Hypertension  Hyperthermia General exam:  Akathisia (restlessness/need to move)  Shivering  Diaphoresis (sweating) with normal skin color  Anxiety

14. Signs and Symptoms HEENT exam  Mydriasis (enlarged pupils)  Dry oral mucosa GI exam  Hyperactive bowel sounds  +/- diarrhea

15. Signs and Symptoms Neurologic exam  Hyperreflexia (lower > upper extremities)  Clonus (elicited, spontaneous, ocular)  Muscle rigidity

16. YouTube - Ankle clonus

17. Symptom Onset Usually Rapid  Within minutes of change in medication or self-poisoning (60% of pts present within 6 hrs of medicine change or overdose) Mild cases  May present with sub-acute or chronic symptoms

18. Mild Presentation Afebrile Tachycardia Shivering Diaphoresis Mydriasis

19. Moderate Presentation Abnormal vital signs  Tachycardia  Hypertension  Hyperthermia with core temp of 40 C Physical Exam  Mydriasis, diaphoresis and normal skin color, hyperactive bowel sounds  Hyperreflexia and clonus, greater in lower extremities, and horizontal ocular clonus

20. Moderate Presentation (continued) Mental Changes  Mild agitation  Hypervigilance  Slightly pressured speech  May startle easily

21. Severe Presentation Physical Changes (all of above, plus)  Hypertension  Tachycardia that may deteriorate into shock  Agitated delirium  Muscular rigidity and hypertonicity, greater in lower extremities  Muscle hyperactivity with core temp greater than 41.1 C in life-threatening cases

22. Severe Presentation (continued) Lab findings  Metabolic acidosis  Rhabdomyolysis  Elevated serum aminotransferase and creatinine  Disseminated intravascular coagulopathy  Many of these abnormalities arise from poorly treated hyperthermia

23. Diagnosis is based on:  History of medications, over the counter drugs, illicit substances, dietary supplements  Evolution (timing) of symptoms  Finding of tremor, clonus, or akathisia

24. Diagnosis Clonus (inducible, spontaneous or ocular) is the most important finding in establishing the diagnosis of SS

25. Be Aware Muscle rigidity may mask the highly distinguishing findings of clonus and hyperflexia and thus, cloud the diagnosis of SS

26. Hunter Serotonin Toxicity Criteria

27. Presence of any of the following in the setting of a recent serotonergic agent:  Spontaneous clonus

28. Hunter Serotonin Toxicity Criteria Presence of any of the following in the setting of recent serotonergic agent:  Spontaneous clonus  Inducible clonus and either agitation or diaphoresis

29. Hunter Serotonin Toxicity Criteria Presence of any of the following in the setting of recent serotonergic agent:  Spontaneous clonus  Inducible clonus and either agitation or diaphoresis  Ocular clonus and either agitation or diaphoresis

30. Hunter Serotonin Toxicity Criteria Presence of any of the following in the setting of recent serotonergic agent:  Spontaneous clonus  Inducible clonus and either agitation or diaphoresis  Ocular clonus and either agitation or diaphoresis  Muscle rigidity, temp >38 C & either ocular or inducible clonus

31. Hunter Serotonin Toxicity Criteria Presence of any of the following in the setting of recent serotonergic agent:  Spontaneous clonus  Inducible clonus and either agitation or diaphoresis  Ocular clonus and either agitation or diaphoresis  Muscle rigidity, temp >38 C & either ocular or inducible clonus  Tremor and hyperreflexia

32. Differential Diagnosis Anticholinergic poisoning Malignant hyperthermia Neuroleptic malignant syndrome

33. Differential Diagnosis Anticholinergic poisoning  H/o Parkinson’s drugs, antihistamines, antipsychotics, TCAs, antispasmotics  normal reflexes, decreased BS Malignant hyperthermia  H/o exposure to inhaled anesthetic Neuroleptic malignant syndrome  H/o exposure to antipsychotic meds, slow onset, bradykinesia

34. Management Removal of precipitating drugs Provision of supportive care Control of agitation Administration of 5-HT2a Antagonists Control of autonomic instability Control of hyperthermia Recovery within 24hrs; longer if initiating drug(s) have long half-life or active metabolites

35. Management - depends on severity Mild: benzodiazepines, supportive care Moderate: control cardiac and thermal abnormalities and consider 5HT2a antagonists Severe or temp over 41.1 C: as above with immediate sedation, pharmacologic paralysis, and intubation

36. Use of Benzodiazepines Necessary, regardless of severity  They blunt hyperadrenergic component of the SS  They replace physical restraints, which are contraindicated:  May increase mortality  Increase lactic acidosis  Worsen hyperthermia

37. Use of 5-HT2a Antagonists Cyproheptadine is recommended  Tabs may be crushed and administered by nasogastric tube Olanzapine, and other atypical antipsychotic agents with 5-HT2a antagonist activity, may be beneficial Chlorpromazine is sometimes used as a parenteral agent (given IM)

38. Medications to Avoid Chlorpromazine should not be administered to a patient with hypotension or the neuroleptic malignant syndrome, or it may exacerbate findings Don’t Use  Propranolol, bromocriptine, dantrolene  Bromocriptine implicated in the development of SS

39. Control of BP Hypotension: treat with low dose, direct-acting sympathomimetic amines  Norepinephrine, phenylephrine, epinephrine Hypertension: treat with short-acting agents  Nitroprusside, esmolol

40. Use of Nondepolarizing Agents If temp above 41.1 C, induce paralysis with  Vecuronium, followed by intubation and ventilation Avoid premature termination of neuromuscular paralysis  associated with a recrudescence of hyperthermia No antipyretic agents

41. Pitfalls Misdiagnosis Failure to react quickly Adverse effects of pharmacologic therapy

42. Last Thoughts Utilize medical toxicologists, clinical pharmacology, and/or poison control to assist you in identifying proserotonergic agents and drug interactions Always consider the risk of SS  When the patient is on many medications  When using multidrug regimens to treat depression  When first starting an SSRI or increasing the dose

43. References Ables A, Nagubilli R. Prevention, diagnosis and management of Serotonin Syndrome. American Family Physician 2010;81(9):1139-1142. Frank C. Recognition and treatment of serotonin syndrome. Canadian Family Physician 2008;54:988- 992. Boyer E, Shannon M. The serotonin syndrome. New England Journal of Medicine 2005;352(11):1112- 1120.

44. References Dunkley E, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Q J Med 2003;96: 635- 642.