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Three Part Question

[In adult patients presenting with severe serotonin syndrome], is [chlorpromazine or olanzapine 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 multiple ecstasy pills on a night out. He initially presents with a temperature of 40°C, impaired consciousness and muscle rigidity. He is diagnosed with serotonin syndrome, sedated with benzodiazepines and treated with ice packs. However, his temperature continues to rise. You consider whether olanzapine or chlorpromazine would be beneficial for the patient.

Search Strategy

03/07/17
Ovid: Medline 1946 to June Week 4 2017
• (exp serotonin syndrome/ OR serotonin toxicity) AND (olanzapine.mp. OR chlorpromazine.mp.)

Ovid: Embase 1974 – 2017 week 27
LIMIT: English, Human, Abstracts only
• (exp serotonin syndrome/ OR serotonin toxicity) AND (exp olanzapine/)
• (exp serotonin syndrome/ OR serotonin toxicity) AND (exp chlorpromazine/)

04/07/2017
Cochrane (four separate searches):
• Serotonin syndrome
• Serotonin toxicity
• Olanzapine
• Chlorpromazine

Search Outcome

Medline: 0 articles found.
Embase: 7 articles, 5 relevant to our search.
Cochrane: 0 articles found.
Five total papers relevant to the 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	Patients presenting with symptoms that fit the clinical criteria for serotonin syndrome.	Patients presenting with symptoms that fit the clinical criteria for serotonin syndrome.	“Good” response to chlorpro-mazine.	“Good” response to chlorpro-mazine.	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 chlorpro-mazine.	3/13 patients had a “moderate” response to chlorpromazine. 1/3 had severe, 1/3 had moderate and 1/3 had mild symptoms prior to treatment.
			“Poor” response to chlorpro-mazine.	3/13 patients had a “poor” response to chlorpromazine. 3/3 had severe symptoms prior to treatment.
B.S. Chan et al 1998 Australia	Patient identified as having serotonin syndrome via the Sternbach criteria.	Case Report	Resolution of symptoms and prevention of mortality.	Patient’s condition improved “significantly” following treatment of diazepam and chlorpromazine and was later discharged.	Only a case report. Unclear whether improvement was due to the benzodiazepine or chlorpromazine. Utilises a now outdated method for defining serotonin syndrome.
K. Feychting et al 2012 Sweden	Patient presenting with apparent serotonin syndrome following the ingestion of 3g of Venlafaxine.	Case Report	Resolution of symptoms and prevention of mortality.	Patient’s condition “improved dramatically” following sublingual administration of olanzapine 5mg.	Only a case report. No mention of other therapies used following the diagnosis of serotonin syndrome
L. Timmerman et al 2009 The Netherlands	Patient diagnosed as “delirum or serotonin syndrome” and treated as serotonin syndrome.	Case report	Resolution of symptoms and prevention of mortality.	Patient responded with complete remission following 24 hours of treated with olanzapine 5mg 2 dd.	Only a case report. Diagnosis of serotonin syndrome unclear, presenting only with psychiatric symptoms.
R.J. Daniels 1998 Australia	Patient diagnosed with serotonin syndrome following overdose of venlafaxine.	Case report	Resolution of symptoms and prevention of mortality.	Patient recovered completely following chlorpromazine, midazolam and cooling therapy.	Only a case report.

Comment(s)

Despite recommendations from prominent sources, chlorpromazine, a 5-HT receptor antagonist, is documented remarkably little as a treatment for serotonin syndrome. It has also been recorded to cause cardiovascular collapse even at therapeutic doses. Nevertheless, the literature that is available would indicate that chlorpromazine is both safe and effective at managing serotonin syndrome, though further studies are needed. Olanzapine, known to have 5-HT receptor antagonistic properties, has been scarcely recorded in its use versus the aforementioned condition, though it has proven to be effective in animal models. Its sublingual route could be beneficial in these critically unwell patients, but only case reports are available to support this medication.

Clinical Bottom Line

The literature indicates that chlorpromazine is safe and effective in the treatment of serotonin syndrome; little exists to support the same for olanzapine.

References

1. P. Gillman The serotonin syndrome and its treatment Journal of Psychopharmacology 1999; 13(1), pp.100-109
2. B.S. Chan, A. Graudins, I.M. Whyte, A.H. Dawson, G. Braitberg, G.G. Duggen Serotonin syndrome resulting from drug interactions The Medical Journal Of Australia 1998; 169(10), pp.523-5
3. K. Feychting, B. Jonsson, G. Sjöberg Successful Treatment of Serotonin Syndrome with Sublingual Olanzapine Clinical Toxicology 2012; 50(4), pp.323
4. Timmerman, L. and Hoek-Mensink, A. Opiates and SSRI's: risk for serotonin syndrome. European Neuropsychopharmacology 2009; 19(Suppl. 3), pp.S252-S253
5. Daniels, R. Serotonin syndrome due to venlafaxine overdose Emergency Medicine Journal 1998; 15(5), pp.333-334