1. Serotonin syndrome: A literature review of therapeutic options? Rob Hall MD, PGY4 FRCPC Emergency Medicine Nov 8, 2003

2. Case: I just want to die 45yo male OD on paxil, gravol, ibuprofen tonight Smoked some crack Recent abstinence from EtOH Headache, fever X 1week HR125 sinus BP 165/105 Temp 38.0 RR20, sats 95% C/S normal Agitation Pupils 6 mm Hyperreflexic, clonus Tremulous Very diaphoretic Neck stiff No bowel sounds

3. Case Questions Is this serotonin syndrome? What is the differential dx? What tests should be done? What are the main treatments of serotonin syndrome? Is there any evidence for the use of cyproheptidine?

4. What is Serotonin? Neurotransmitter Mood, personality, sleep, sex, motor, temp, pain functions Very complex 14 receptors Excitatory and inhibitory functions

5. What is Serotonin Syndrome? Serotonin syndrome is a constellation of findings related to excessive stimulation of serotonin receptors and is manifested by cognitive, autonomic, and neuromuscular abnormalities

6. CAN you diagnosis serotonin syndrome? C COGNITIVE CHANGES: Agitation, confusion, euphoria, insomnia, hypomania, hallucinations A AUTONOMIC CHANGES: Tachycardia, HTN, fever, diaphoresis, mydriasis, arrythmias, tachypnea N NEUROMUSCULAR CHANGES: Tremor, hyperreflexia, clonus, ataxia, incoordination, seizures

7. Sternbach ’ s Criteria Addition or increased dose of a known serotonergic agent At least three of the C.A.N. criteria Other etiologies excluded –Withdrawl, sympathomimetics, anticholinergics, CNS infections, neuroleptic malignant syndrome No neuroleptics that have been started or increased prior to the onset of symptoms

8. What causes serotonin syndrome? SSRIs SNRIs MAOIs Cocaine Amphetamines LSD Lithium Wellbutrin And many more!!

9. How is Seritonin Syndrome Managed? Supportive Care Temperature control Benzodiazepines Fluids Other therapies –Cyprohepatadine –Beta – blockers –Chlorpromazine –Dantrolene

10. What is Cyproheptadine? Antihistamine with anticholinergic and antiserotonergic properties Blocks 5HT1a and 5HT2 receptors Used as antihistamine or for appetite stimulant in anorexia Recommended dosage: 4 mg po tid No intravenous formulation

11. Does Cyproheptadine work? Nisijima. Brain Research 2001 –Rat model of serotonin syndrome –Gave rats an MAOI + serotonin precursor –All died in 90 min untreated –Looked at different drug treatments

12. Does Cyproheptadine work? Nisijima. Brain Research 2001 DRUGDEATHS Cyproheptadine 5 mg/kg5/5 Cyproheptadine 10 mg/kg0/5 Dantrolene 20 mg/kg6/6 Propranolol 10 mg/kg5/5 Chlorpromazine 20 mg/kg6/6 Chlorpromazine 40 mg/kg0/5

13. Does Cyproheptadine work? Isbister. Ann Pharm. 2001 –“ We have used cyproheptadine in 62 patients with moderate seritonin syndrome with success ” –No specific data reported

14. Does Cyproheptadine work? Lappin. NEJM 1994 –Case report –Seritonin syndrome of moderate severity –Symptoms subsided 30 min after a 4 mg po dose –Dose repeated in 3hrs for recurrence of symptoms

15. Does Cyproheptadine work? Baigel. Eur Acad Anaesth 2003 –Case report –Severe serotonin syndrome –Cyproheptadine 8 mg po –Level of consciousness promptly improved, hypertonia resolved, temperature normalized

16. Does Cyproheptadine work? Gillman. J Clinical Psychopharmacology –Case report –Moderate serotonin syndrome –Treated with cyproheptadine 8 mg po with no effect, repeat dose at 8 hours with no effect –Chlorpromazine 50 mg im and symptoms improved steadily over next 2hrs

17. Does Cyproheptadine work? McDaniel. Ann Pharmacoltherapy 2001. –Case series of 4 patients –All mild to moderate serotonin syndromes –Dosing: 8 mg po and repeat q8hr –Responses seen within hours –No serious side – effects noted (some anticholinergic effects)

18. Does Cyproheptadine work? Graudins. J Emerg Med 1998 –Case series of 5 patients –Generally moderate severities –Initial dose 4-8mg po –A few got subsequent doses of 4 mg –Responses seen within 1-2 hours –No serious complicated reported

19. Does Cyproheptadine work? Maybe VERY little literature Appears effective Appears safe Probably not much down side to trying

20. ? Other treatments for Serotonin Syndrome Chlorpromazine –One case report: Gillmann J Clin Psychopharmacology Propranolol –One case report: Guze. J Clinical Pharmacol 1986 Dantrolene –Drew a blank_______________

21. The End …