Serotonin syndrome:

A literature review of therapeutic options?

Rob Hall MD, PGY4FRCPC Emergency Medicine

Nov 8, 2003

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

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?

What is Serotonin?

• Neurotransmitter• Mood, personality,

sleep, sex, motor, temp, pain functions

• Very complex• 14 receptors• Excitatory and

inhibitory functions

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

CAN you diagnosis serotonin syndrome?

CCOGNITIVE CHANGES: Agitation, confusion, euphoria, insomnia, hypomania, hallucinations

AAUTONOMIC CHANGES:Tachycardia, HTN, fever, diaphoresis, mydriasis, arrythmias, tachypnea

NNEUROMUSCULAR CHANGES:Tremor, hyperreflexia, clonus, ataxia, incoordination, seizures

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

What causes serotonin syndrome?

• SSRIs• SNRIs• MAOIs• Cocaine• Amphetamines• LSD• Lithium• Wellbutrin• And many

more!!

How is Seritonin Syndrome Managed?

• Supportive Care• Temperature control• Benzodiazepines• Fluids• Other therapies

– Cyprohepatadine– Beta – blockers– Chlorpromazine– Dantrolene

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

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

Does Cyproheptadine work? Nisijima. Brain Research 2001

DRUG DEATHS

Cyproheptadine 5 mg/kg 5/5

Cyproheptadine 10 mg/kg 0/5

Dantrolene 20 mg/kg 6/6

Propranolol 10 mg/kg 5/5

Chlorpromazine 20 mg/kg 6/6

Chlorpromazine 40 mg/kg 0/5

Does Cyproheptadine work?

• Isbister. Ann Pharm. 2001– “We have used cyproheptadine in 62

patients with moderate seritonin syndrome with success”

– No specific data reported

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

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

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

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)

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

Does Cyproheptadine work?

•Maybe•VERY little literature

• Appears effective• Appears safe• Probably not much down side to

trying

? 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_______________

The End…