Nausea and Vomiting Associated With Selective Serotonin Reuptake Inhibitors

Incidence, Mechanisms and Management

Summary

Nausea and vomiting are common adverse effects of therapeutic drugs. Such symptoms are more often due to CNS effects than to direct toxic effects on the gastrointestinal tract (GIT). Drugs may cross the blood-brain barrier and activate the chemoreceptor trigger zone in the brainstem, which contains cells that are responsive to cholinergic, dopaminergic and serotonergic stimulation.

Selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are effective and well tolerated in the treatment of major affective disorders, but their usefulness is sometimes limited by adverse effects, particularly gastrointestinal effects. SSRIs exert their beneficial effects in depressive syndromes by increasing brain serotonin levels. They also increase serotonin levels in other tissues, particularly the GIT, which contains 90% of the body’s store of serotonin and large numbers of serotonin-responsive cells. Increased serotonergic neurotransmission causes anorexia, nausea, vomiting and diarrhoea in other settings, such as carcinoid syndrome, so gastrointestinal adverse effects are not unexpected with drugs that increase tissue serotonin levels. SSRI-induced nausea and vomiting are probably due to effects on the GIT as well as on the CNS.

There are complex interactions between serotonin receptor subtypes. Drugs antagonising one receptor subtype may act as agonists at another receptor. The pharmacotherapy of SSRI-induced nausea and vomiting requires an understanding of the actions and interactions of these receptors and their agonists/antagonists. The most effective drug for the treatment of SSRI-related adverse effects on the GIT is ondansetron, a serotonin 5-HT3 receptor antagonist that blocks the effects of serotonin in the brain and GIT. However, this drug has a high acquisition cost. Thus, the drug of choice may be cisapride which, although a weak 5-HT3 receptor antagonist, has the potential to reduce or abolish SSRI-induced nausea. Many patients with mild adverse effects will not require specific pharmacotherapy, as the nausea tends to abate with prolonged treatment with SSRIs because of gradual desensitisation of 5-HT3 receptors.

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References

  1. 1.

    Bhandari P, Bingham S, Andrews PL. The neuropharmacology of loperamide-induced emesis in the ferret: the role of the area postrema, vagus, opiate and 5-HT3 receptors. Neuropharmacology 1992; 31: 735–42

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Bhargava KP, Dixit KS, Palit G. Nature of histamine receptors in the emetic chemoreceptor trigger zone. Br J Pharmacol 1976; 57: 211–3

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Cubeddu LX, Hoffman IS, Fuenmayor NT, et al. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med 1990; 322: 810–6

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Miller AD, Leslie RA. The area postrema and vomiting. Front Neuroendocrinol 1994; 15: 301–20

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Hawthorn J, Andrews PL, Ang VT, et al. Differential release of vasopressin and oxytocin in response to abdominal vagal afferent stimulation or apomorphine in the ferret. Brain Res 1988; 438: 193–8

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Lee M, Feldman M. Nausea and vomiting. In: Sleisenger MH, Fordtran JS, editors. Gastrointestinal disease: pathophysiology/diagnosis/management. 5th ed. Philadelphia (PA): WB Saunders, 1993: 509–19

    Google Scholar 

  7. 7.

    Andrews PLR, Hawthorn J. The neurophysiology of vomiting. Baillieres Clin Gastroenterol 1988; 2: 141–68

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Monthly index of medical specialities. 20th ed. London: Haymarket Medical Publications Ltd, 1996

  9. 9.

    Brymer C, Winograd CH. Fluoxetine in elderly patients: is there cause for concern? J Am Geriatr Soc 1992; 40: 902–5

    PubMed  CAS  Google Scholar 

  10. 10.

    Wong DT, Reid LR, Threlkeld PG. Suppression of food intake in rats by fluoxetine: comparison of enantiomers and effects of serotonin antagonists. Pharmacol Biochem Behav 1988; 31: 475–9

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Wagner W, Zaborny BA, Gray TE. Fluvoxamine: a review of its safety profile in world-wide studies. Int Clin Psychopharmacol 1994; 9: 223–7

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Bergeron R, Blier P. Cisapride for the treatment of nausea produced by selective serotonin reuptake inhibitors. Am J Psychiatry 1994; 151: 1084–6

    PubMed  CAS  Google Scholar 

  13. 13.

    Levine LR, Enas GC, Thompson WL, et al. Use of fluoxetine, a selective serotonin-uptake inhibitor, in the treatment of obesity: a dose-response study. Int J Obes 1989; 13: 635–45

    PubMed  CAS  Google Scholar 

  14. 14.

    Russell JL. Relatively low doses of cisapride in the treatment of nausea in patients treated with venlafaxine for treatment-refractory depression. J Clin Psychopharmacol 1996; 16: 35–7

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Fritze J, Lanczik M. Pharmacokinetic interactions between carbamazepine and fluvoxamine [abstract]. Pharmacopsychiatry 1993; 26: 153

    Google Scholar 

  16. 16.

    WHO Drug Information 1994; 8: 156

  17. 17.

    Zelwer A. Fluoxetine-tricyclic combinations. Aust NZ J Psychiatry 1993; 27: 350–2

    CAS  Google Scholar 

  18. 18.

    Sporer KA. The serotonin syndrome: implicated drugs, pathophysiology and management. Drug Saf 1995; 13: 94–104

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Power BM, Hackett LP, Dusci LJ, et al. Antidepressant toxicity and the need for identification and concentration monitoring in overdose. Clin Pharmacokinet 1995; 29: 154–71

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Bodner RA, Lynch T, Lewis L, et al. Serotonin syndrome. Neurology 1995; 45: 219–23

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Shader RI. Question the experts. J Clin Psychopharmacol 1993; 13: 79

    Article  Google Scholar 

  22. 22.

    Hoyer D, Martin GR. Classification and nomenclature of 5-HT receptors: a comment on current issues. Behav Brain Res 1996; 73: 263–8

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Tonini M, Candura SM, Messori E, et al. Therapeutic potential of drugs with mixed 5-HT4 agonist/5-HT3 antagonist action in the control of emesis. Pharmacol Res 1995; 31: 257–60

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Talley NJ. 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. Aliment Pharmacol Ther 1992; 6: 273–89

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Costali B, Naylor RJ. 5-hydroxytryptamine: new receptors and novel drugs for gastrointestinal motor disorders. Scand J Gastroenterol 1990; 25: 769–87

    Article  Google Scholar 

  26. 26.

    Bradley PB, Engel G, Feniuk W, et al. Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacology 1986; 25: 563–76

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Ng WW, Jing J, Hyman PE, et al. Effect of 5-hydroxytryptamine and its antagonists on colonic smooth muscle of the rabbit. Dig Dis Sci 1991; 36: 168–73

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Baez M, Yu L, Cohen ML. Pharmacological and molecular evidence that the contractile response to serotonin in rat stomach fundus is not mediated by activation of the 5-hydroxytryptamine 1C receptor. Mol Pharmacol 1990; 38: 31–7

    PubMed  CAS  Google Scholar 

  29. 29.

    Gore S, Gilmore IT, Haigh CG, et al. Colonic transit in man is slowed by ondansetron (GR 38032F), a selective 5-hydroxytryptamine receptor (type 3) antagonist. Aliment Pharmacol Ther 1990; 4: 139–44

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Talley NJ, Phillips SF, Haddad A, et al. GR 38032F (ondansetron), a selective 5-HT3 receptor antagonist, slows colonic transit in healthy man. Dig Dis Sci 1990; 35: 477–80

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Allan SG. The 5HT3 antagonists: new generation antiemetics. Curr Ther 1993; 34: 15–8

    Google Scholar 

  32. 32.

    Gyermek L. 5-HT3 receptors: pharmacologic and therapeutic aspects. J Clin Pharmacol 1995; 35: 845–55

    PubMed  CAS  Google Scholar 

  33. 33.

    Oxford AW, Bell JA, Kilpatrick GJ, et al. Ondansetron and related 5-HT3 antagonists: recent advances. Prog Med Chem 1992; 29: 239–70

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Blier P, Bouchard C. Functional characterization of a 5-HT3 receptor which modulates the release of 5-HT in the guinea pig brain. Br J Pharmacol 1993; 108: 13–22

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Nemeth PR, Gullikson GW. Gastrointestinal motility stimulating drugs and 5-HT receptors on myenteric neurons. Eur J Pharmacol 1989; 166: 387–91

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Goyal RK, Hirano I. The enteric nervous system. N Engl J Med 1996; 334: 1106–15

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Andrews PLR, Rapeport WG, Sanger GJ. Neuropharmacology of emesis induced by anti-cancer therapy. Trends Pharmacol Sci 1988; 9: 334–41

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Maxton DG, Morris J, Whorwell PJ. Selective 5-hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia? Aliment Pharmacol Ther 1996; 10: 595–9

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Barr LC, Goodman WK, Price LH. Physical symptoms associated with paroxetine discontinuation [letter]. Am J Psychiatry 1994; 151: 289

    PubMed  CAS  Google Scholar 

  40. 40.

    Phillips SD. A possible paroxetine withdrawal syndrome. Am J Psychiatry 1995; 152: 645–6

    PubMed  CAS  Google Scholar 

  41. 41.

    Brown SGA, Prentice DA. Ondansetron in the treatment of theophylline overdose [letter]. Med J Aust 1992; 156: 512

    PubMed  CAS  Google Scholar 

  42. 42.

    Roberts JR, Carney S, Boyle SM, et al. Ondansetron quells drug-resistant emesis in theophylline poisoning. Am J Emerg Med 1993; 11: 609–10

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Dones I, Servello D, Ferrazza C, et al. Ondansetron as a treatment of intrathecal baclofen overdose: a case report [abstract]. J Neurology 1995; 242 Suppl. 2: 94

    Google Scholar 

  44. 44.

    Bailey J, Potokar J, Nutt D. Can the GI disturbance produced by SSRIs be attenuated by a 5HT3 antagonist [abstract]? Neuropsychopharmacology 1994; 10 Suppl. Pt 2: 220

    Google Scholar 

  45. 45.

    Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia [letter]. N Engl J Med 1996; 335: 290–1

    PubMed  Article  CAS  Google Scholar 

Download references

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Correspondence to Dr Philip G. McManis.

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McManis, P.G., Talley, N.J. Nausea and Vomiting Associated With Selective Serotonin Reuptake Inhibitors. CNS Drugs 8, 394–401 (1997). https://doi.org/10.2165/00023210-199708050-00005

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Keywords

  • Fluoxetine
  • Ondansetron
  • Fluvoxamine
  • Cisapride
  • Gastrointestinal Adverse Effect