• 
• 

Three Part Question

[In adult patients presenting with severe serotonin syndrome], is [cyproheptadine better than a placebo] at [reducing patient mortality]?

Clinical Scenario

A 30 year old male is brought to the emergency department following the ingestion of MDMA on a night out. He presents with a temperature of 40°C, rigidity and aggression. Following chemical restraint by diazepam, he is diagnosed with serotonin syndrome. As a your team attempt to manage his hyperkalaemic state, his temperature continues to rise and you consider whether or not administering cyproheptadine would reduce the risk of patient mortality.

Search Strategy

30/06/17
Cochrane Library:
• Serotonin syndrome
• Cyproheptadine

Ovid: Medline 1946- june week 4 2017
(exp Serotonin Syndrome/ OR serotonin toxicity.mp. OR exp N-Methyl-3,4-methylenedioxyamphetamine/ Or mdma.mp. OR ecstasy.mp. OR ssri overdose.mp. OR ssri toxicity.mp.) AND exp cyproheptadine/

Ovid: Embase 1974 – June 29 2017
(exp Serotonin Syndrome/ OR serotonin toxicity.mp. OR N-Methyl-3,4-methylenedioxyamphetamine.mp. Or mdma.mp. OR ecstasy.mp. OR ssri overdose.mp. OR ssri toxicity.mp.) AND exp cyproheptadine/
LIMIT “human”, “English language” and “Abstract”

Search Outcome

Cochrane: 0 results.
Medline: 5 results, none relevant to the BET.
Embase: 23 results, 4 relevant to BET.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
P.K. Gillman 1999 UK	Six patients presenting with symptoms that fit what appears to be the Sternbach criteria of serotonin syndrome.	Systematic Review	“Good” response to cypro-heptadine.	1/6 patients had a “good” response to cyproheptadine. This patient had “moderate” symptoms.	Seems to utilise what is now an outdated set of criteria for serotonin syndrome. Degree of symptom severity has been arbitrarily defined. Response to drug is only an estimate and poorly defined. Three cases are described as “probable” serotonin syndrome. Review contains only case reports/series.
			“Moderate“ response to cypro-heptadine.	2/6 patients had a “moderate” response to cyproheptadine. One of these had “mild” symptoms, the other “moderate”.
			“Poor” response to cypro-heptadine.	2/6 patients had a “poor” response to cyproheptadine. One of these had “mild” symptoms, the other “moderate”.
			No response to cypro-heptadine.	1/6 patients had no response to cyproheptadine. This patient had “moderate” symptoms.
W.W. McDaniel 2001 USA	Four patients diagnosed with serotonin syndrome.	Case Series	Resolution of symptoms and prevention of patient mortality.	All patients survived, with symptoms resolving after a number of days receiving 8mg cyproheptadine TDS.	Only a case-series.
A. Graudins et al 1998 Australia	Five patients presenting with signs and symptoms consistent with serotonin syndrome.	Case Series	Resolution of symptoms and prevention of patient mortality.	Three patients had fully resolved symptoms following a single 8mg dose of cyproheptadine. One patient required a further 4mg dose. The last patient recovered following three doses of 4mg at eight hour intervals.	Only a case-series.
S. Prakash et al 2016 India	Three patients that fit the Hunter criteria for serotonin syndrome treated with cyproheptadine.	Case Series	Resolution of symptoms and prevention of patient mortality.	All patients fully recovered over a number of days, following various doses of cyproheptadine.	Only a case-series.

Comment(s)

Despite widespread recommendations from prominent sources, relatively few studies have documented cyproheptadine's action upon serotonin syndrome and those that are present rely on case reports for evidence. However, from the literature that is available, cyproheptadine appears to be efficacious. What isn't apparent from the above table is that the medicine is available for oral use alone, making administration of the treatment an obstacle in these very acute, sometimes combative, patients.

Clinical Bottom Line

From the evidence available, cyproheptadine is both a safe and effective treatment for serotonin syndrome.

References

1. P. Gillman Serotonin Syndrome: Early Management with Cyproheptadine The Annals of Pharmacotherapy 2001; 35(7-8), pp.870-873
2. McDaniel, W. Serotonin Syndrome: Early Management with Cyproheptadine The Annals of Pharmacotherapy, 2001; 35(7-8), pp.870-873
3. Graudins, A., Stearman, A. and Chan, B. Treatment of the serotonin syndrome with cyproheptadine. The Journal of Emergency Medicine 1998; 16(4), pp.615-619
4. Prakash, S., Makwana, P., Rathore, C. and Dave, A. Serotonin syndrome presenting as febrile encephalopathy with CSF pleocytosis: a report of three cases Neurological Sciences 2016; 37(9), pp.1561-1564