Cyprohepta-doubts? Determining the Role of Cyproheptadine in Serotonin Syndrome

Take Home Points 

• Supportive care, such as benzodiazepines for sedation, is sufficient for most cases of serotonin syndrome. Paralysis via neuromuscular blockade may be necessary in severe cases.
• Evidence for benefit from cyproheptadine is extremely limited.
• Call the Utah Poison Control Center at 1-800-222-1222 at any time, 24/7, for assistance in managing serotonin syndrome and considerations for cyproheptadine administration.

Serotonin Syndrome

• Serotonin syndrome (or serotonin toxicity) is caused by a substantial increase in synaptic serotonin (5-HT), resulting in mild manifestations such as akathisia, increased gastrointestinal activity, and tremors, to more severe and life-threatening presentations such as sustained muscular hypertonicity, hyperthermia, seizures, and hallucinations. ¹
• There are 14 5-HT receptor subtypes that have been identified thus far²; however, overstimulation of 5-HT_1A and/or 5-HT_2A receptors are associated with development of serotonin syndrome. The most severe manifestations (rigidity, hyperthermia, hallucinations) are mediated by 5-HT_2A receptors.
• Both 5-HT_1A and 5-HT_2A have different affinities for serotonin and comodulate each other’s activity, making it difficult to generate a succinct pathophysiologic model.²
• Serotonergic medications are commonly used for a number of psychiatric conditions, including depression, anxiety, and eating disorders. Serotonergic agents possess varying degrees of serotonin receptor agonism, and toxicity depends on the quantity ingested. Serotonin syndrome may be attributable to a large ingestion of a single serotonergic agent, as well as combined ingestion of several serotonergic agents.³
• The diagnosis of serotonin syndrome is based on clinical findings, takes pertinent history into account, and is reliant on the exclusion of other diagnoses.^1,4,5,8 There are no laboratory tests that confirm the diagnosis.
• Although there is not one universally accepted set of criteria for the diagnosis, most definitions of serotonin syndrome require the presence of at least one symptom from each class within the classic triad of mental status changes (e.g., agitation, delirium, seizures), autonomic hyperactivity (e.g., diaphoresis, flushing, hyperthermia, tachycardia), and neuromuscular abnormalities (e.g., inducible and/or spontaneous clonus, tremors, hyperreflexia).^1,4,5,8
• Management of serotonin syndrome involves: 
  
  • Discontinuation of serotonergic agents
  • Gastrointestinal decontamination, such as administration of activated charcoal to prevent further absorption of the drug in patients presenting soon after ingestion
  • Supportive care (e.g., stabilization of airway, breathing, circulation); treatment of seizures, agitation with benzodiazepines, and active cooling measures for hyperthermia. 
• Benzodiazepines are the drug of choice for most mild and severe manifestations of serotonin syndrome.

Cyproheptadine

• Cyproheptadine is currently only FDA-approved for allergic conditions such as perennial and seasonal allergic rhinitis, vasomotor rhinitis, and allergic conjunctivitis. It is a potent antihistamine that competes at H1-receptor sites, with additional serotonin antagonist properties used for the off-label treatment of serotonin syndrome. The mechanism of action of cyproheptadine in serotonin syndrome is nonspecific serotonin antagonism at 5-HT_1A and 5-HT_2A receptors.² This prevents serotonin from binding at these receptor sites and thus mitigates the sequelae of serotonin syndrome. 

Cyproheptadine Efficacy

• Historically, cyproheptadine has been utilized to counteract serotonergic effects based on animal models and clinical experience.^2-5
• However, there is a larger body of evidence that suggests that cyproheptadine is not more effective or beneficial than supportive care alone in the management of rigidity, hyperthermia, and agitation in serotonin syndrome, and symptom duration does not appear to shorten despite its use.^2,3,5,6
• A 2020 systematic review of cyproheptadine use in serotonin syndrome aimed to provide a clinical update on the available evidence.² Out of 151 case reports, 148 (98%) were classified as Level D (very low) quality of evidence, and 3 were classified as Level C (low) quality of evidence. A large portion of cases were described as nothing more than firsthand experiences, providing poor grounds for a compelling recommendation.²
• Additionally, many of the systematic reviews conducted over the last 10 years have not reported strong recommendations for cyproheptadine use and consider it as an adjunct for patients who continue to experience symptoms despite adequate supportive care.

Cyproheptadine Indications

• Cyproheptadine currently does not have FDA approval for the treatment of serotonin syndrome.
• Cyproheptadine should be considered adjunctive treatment and is not a replacement for adequate sedation with GABA-ergic agents. Most cases of serotonin syndrome resolve with supportive care measures alone. If considering cyproheptadine, it should be given as soon as possible (see “Cyproheptadine Dosing” below).
• Since most mild cases of serotonin syndrome produce non-life-threatening symptoms, it is possible to treat those patients who respond to an initial dose of cyproheptadine at home.⁷ Mild toxicity with bothersome neuromuscular findings (tremor, clonus) who could otherwise be managed as an outpatient should be warned of the symptoms of serotonin syndrome and advised to return for re-evaluation if a recurrence occurs.
•  Call the Utah Poison Control Center to discuss indications for a specific patient.

Cyproheptadine Safety ³

• Cyproheptadine has been shown to exhibit anticholinergic effects; as a result, there may be the potential to exacerbate altered mental status due to these properties.¹ 
• An 11-year retrospective review of cyproheptadine use in serotonin syndrome reported to the California Poison Control Center revealed that of the 68 patients that received cyproheptadine,  53% of patients experienced some kind of adverse drug event. The three most common adverse drug events were tachycardia (32, 19.1%), sedation (13, 16.2%), hyperthermia (5, 7.4%), and delirium (5, 7.4%). Other adverse drug events presented as minor manifestations of an anticholinergic toxidrome (e.g., urinary retention). 
• There was no significant association between cyproheptadine administration and serious medical outcomes or hospitalization; however, patients receiving cyproheptadine were more likely to be admitted to an intensive care unit than those not.

Cyproheptadine Dosing ³

• Cyproheptadine dosing schemes and symptom response appear to be highly variable. A majority of case reports initiate at 8 mg with a maintenance dose of 8 mg every 8 hours. For pediatric patients, 0.25 mg/kg/day, divided TID (max daily dose of 12 mg), is recommended.
• Cyproheptadine is only available as an oral formulation. If aspiration is a concern, this can be crushed and given via nasogastric tube.
• The Lange Clinical Manual recommends an initial dose of 4 to 12 mg orally, followed by 4 mg every 1 to 4 hours as needed until symptoms resolve (max of 32 mg per day).⁴
• Goldfrank’s Toxicologic Emergencies recommends an initial dose of 12 mg followed by 2 mg every 2 hours until symptoms resolve.⁸
• Some patients appear to have a quick response to a 4 mg dose, while others do not respond to doses up to 16 mg. Case reports of patients who responded to a 4 mg dose typically had no hyperthermia and only mild to moderate manifestations of serotonin toxicity.⁸
• Since true symptoms of serotonin syndrome often resolve within 24 hours after cessation of the identified agent(s) and supportive care measures, the duration of treatment usually should not exceed this time period.

Lab Ordering and Pitfalls

• Specific labs to assess levels of serotonergic medications are not likely to provide any benefit.
• Perform ECG to rule out conduction system poisoning that affects the QRS or the QTc intervals. It is crucial that all patients get an ECG with serotonin syndrome, especially in the setting of known/suspected bupropion, venlafaxine, or citalopram overdose. 
• CBC, electrolytes, Mg, CK, glucose, CT head, and/or lumbar puncture may aid in the diagnosis of patients with altered mental status determined not to be due to the serotoninergic toxidrome.
• If the patient had severe agitation and/or muscle rigidity, check serum electrolytes and creatinine kinase (CK) level to evaluate for possible rhabdomyolysis.
• Check acetaminophen, aspirin, and ethanol levels in self-harm attempt settings.

Call the Utah Poison Control Center at 1-800-222-1222 at any time, 24/7, for assistance managing known or suspected serotonin syndrome.

References

1. Boyer EW, Shannon M. The serotonin syndrome [published correction appears in N Engl J Med. 2007 Jun 7;356(23):2437] [published correction appears in N Engl J Med. 2009 Oct 22;361(17):1714]. N Engl J Med. 2005;352(11):1112-1120. doi:10.1056/NEJMra041867.
2. Jacobs, Elizabeth & Akers, Katherine & Vohra, Varun & King, Andrew. (2020). Cyproheptadine for Serotonin Toxicity: an Updated Systematic Review and Grading of Evidence. Current Emergency and Hospital Medicine Reports. 8. 10.1007/s40138-020-00222-5.
3. Nguyen H, Pan A, Smollin C, Cantrell LF, Kearney T. An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California Poison Control System. J Clin Pharm Ther. 2019;44(2):327-334. doi:10.1111/jcpt.12796.
4. Benowitz NL. ANTIDEPRESSANTS, GENERAL (NONCYCLIC). In: Olson KR, Anderson IB, Benowitz NL, Blanc PD, Clark RF, Kearney TE, Kim-Katz SY, Wu AB. eds. Poisoning & Drug Overdose, 7e. McGraw-Hill Education; 2018. Accessed May 04, 2024. https://accessmedicine-mhmedical-com.ezproxy.lib.utah.edu/content.aspx?bookid=2284&sectionid=248383439.
5. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med. 1998;16(4):615-619. doi:10.1016/s0736-4679(98)00057-2.
6. Isbister GK. Comment: serotonin syndrome, mydriasis, and cyproheptadine. Ann Pharmacother. 2001;35(12):1672-1673. doi:10.1345/aph.16185b.
7. Horowitz BZ, Mullins ME. Cyproheptadine for serotonin syndrome in an accidental pediatric sertraline ingestion. Pediatr Emerg Care. 1999;15(5):325-327. doi:10.1097/00006565-199910000-00006.
8. Serotonin Reuptake Inhibitors and Atypical Antidepressants | Goldfrank’s Toxicologic Emergencies, 11e | AccessPharmacy | McGraw Hill Medical. Accessed May 4, 2024. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2569&sectionid=210272449