Skip to main content
SpringerLink
Log in

Serotonin Syndrome

Incidence, Symptoms and Treatment

  • Review Articles
  • Adverse Effects
  • Published:
CNS Drugs Aims and scope Submit manuscript

Summary

In animals, the occurrence of a behavioural syndrome consisting of hyperactivity, stereotyped movements and increased body temperature can be induced by monoamine oxidase inhibitors (MAOIs), the serotonin (5-hydroxytryptamine; 5-HT) precursor, tryptophan, and serotonin reuptake inhibitors, alone or in combination. Most of these manifestations can be specifically blocked by pretreatment with an inhibitor of serotonin synthesis.

The associated symptoms of myoclonus, diarrhoea, confusion, hypomania, agitation, hyperreflexia, shivering, incoordination, fever and diaphoresis can occur in patients treated with serotonergic agents. This constitutes the ‘serotonin syndrome’. Cases of the serotonin syndrome were reported after treatments with tryptophan, MAOIs, serotonin reuptake inhibitors and tricyclic antidepressants, alone or in combination. In some cases, the serotonin syndrome corresponds to a toxic reaction induced by a combination of serotonergic agents at high dosages. In other cases, a toxic and potentially fatal interaction can occur between MAOIs, tricyclic agents and selective serotonin reuptake inhibitors (SSRIs) given at therapeutic dosages.

The serotonin syndrome also provides a heuristic model of the putative mode of action of antidepressants. Serotonin-related symptoms are the physical and objective expression of an antidepressant-induced increase in serotonin neurotransmission.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991; 148: 705–13

    PubMed  CAS  Google Scholar 

  2. Leonard BE. Neurochemistry: a psychiatric perspective. In: Dinan TG, editor. Principles and practice of biological psychiatry. London: Clinical Neuroscience Publishers, 1990: 1–50

    Google Scholar 

  3. Meltzer H, Lowry MT. The serotonin hypothesis of depression. In: Meltzer HY, editor. Psychopharmacology: the third generation of progress. New York: Raven Press, 1987: 513–26

    Google Scholar 

  4. Power AC, Cowen PJ. Fluoxetine and suicidal behaviour. Some clinical and theoretical aspects of a controversy. Br J Psychiatry 1992; 161: 735–41

    Article  PubMed  CAS  Google Scholar 

  5. Mann JJ, Stanley M, McBride PA, et al. Increased serotonin and beta-adrenergic binding in frontal cortex of suicide victims. Arch Gen Psychiatry 1986; 43: 954–9

    Article  PubMed  CAS  Google Scholar 

  6. Meltzer H. Serotonergic dysfunction in depression. Br J Psychiatry 1989; 155 Suppl 8.: 25–31

    Google Scholar 

  7. Meltzer H, Perline R, Tricon BJ, et al. Effects of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. Arch Gen Psychiatry 1984; 41: 391–402

    Article  PubMed  CAS  Google Scholar 

  8. Price LH, Charney DS, Delgado PL, et al. Effects of desipramine and fluvoxamine treatment on the prolactin response to tryptophan. Arch Gen Psychiatry 1989; 46: 625–31

    Article  PubMed  CAS  Google Scholar 

  9. Lee MA, Nash JF, Barnes M, et al. Inhibitory effect of ritanserin on the 5-hydroxytryptophan medicated cortisol ACTH and prolactin secretion in humans. Psychopharmacology 1991; 103: 258–64

    Article  PubMed  CAS  Google Scholar 

  10. Celada P, Dolera M, Alvarez E, et al. Effect of acute and chronic treatment with fluvoxamine on extracellular and platelet serotonin in the blood of major depressive patients. Relationship to clinical improvement. J Affect Disord 1992; 25: 243–50

    Article  PubMed  CAS  Google Scholar 

  11. Kremer HPH, Goekoop JG, Van Kempen GMJ. Clinical use of the determination of serotonin in whole blood. J Clin Psychopharmacol 1990; 10_(2): 83–7

    Article  Google Scholar 

  12. Lejoyeux M, Daveloose D, Mazière JC, et al. A spin label study of the membrane effect of various psychoactive drugs in human erythrocytes. Life Sci 1993; 52: 7–11

    Article  Google Scholar 

  13. Grahame-Smith DG. Studies in vivo of the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-Tryptophan. J Neurochem 1971; 18: 1053–66

    Article  PubMed  CAS  Google Scholar 

  14. Maley E, Wozniak KM. Interactions of a non-selective monoamine oxidase inhibitor, phenelzine, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake. J Psychiatr Res 1984; 8: 173–89

    Google Scholar 

  15. Gerson SC, Baldessarini RJL. Motor effects of serotonin in the central nervous system. Life Sci 1980; 27: 1435–51

    Article  PubMed  CAS  Google Scholar 

  16. Hunsinger RN, Wilson MC. A comparison of the fenfluramine-induced serotonergic syndrome in rats subacutely treated with either saline or d-amphetamine. Pharmacol Res Comm 1984; 16: 579–88

    Article  CAS  Google Scholar 

  17. Deakin JFW, Green AR. The effects of putative 5-hydroxy-tryptamine antagonists on the behaviour produced by administration of tranylcypromine and L-dopa to rats. Br J Pharmacol 1978; 64: 210–9

    Article  Google Scholar 

  18. Lucki I, Nobel MS, Frazer A. Differential actions of serotonin antagonists on two behavioural models of serotonin receptor activation in the rat. J Pharmacol Exp Ther 1984; 1: 133–9

    Google Scholar 

  19. Cowen PJ. Serotonin receptor subtypes: implication for psychopharmacology. Br J Psychiatry 1991; 159 Suppl. 12: 7–14

    Google Scholar 

  20. Glennon RA, Darmani NA, Martin BR. Multiple populations of serotonin receptors may modulate the behavioural effects of serotoninergic agents. Life Sci 1991; 48: 2493–8

    Article  PubMed  CAS  Google Scholar 

  21. Smith B, Prockop DJ. Central-nervous-system effects of ingestion of L-tryptophan by normal subjects. N Engl J Med 1962; 267: 1338–41

    Article  PubMed  CAS  Google Scholar 

  22. Baloh RW, Dietz J, Spooner JW. Myoclonus and ocular oscillations induced by L-Tryptophan. Ann Neurol 1982; 11: 95–7

    Article  PubMed  CAS  Google Scholar 

  23. Guze BH, Baxter Jr LR. The serotonin syndrome: case responsive to propranolol [letter]. J Clin Psychopharmacol 1986; 6: 119–20

    Article  PubMed  CAS  Google Scholar 

  24. Kline SS, Mauro LS, Scala-Barnett DM, et al. Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharmacol 1989; 8: 510–4

    CAS  Google Scholar 

  25. Levy AB, Bucher P, Votolato N. Myoclonus, hyperreflexia and diaphoresis in a patient on phenelzine-tryptophan combination treatment. Can J Psychiatry 1985; 30: 434–6

    PubMed  CAS  Google Scholar 

  26. Pope Jr HG, Jonas JM, Hudson JI, et al. Toxic reactions to the combination of monoamine oxidase inhibitors and tryptophan. Am J Psychiatry 1985; 42: 491–2

    Google Scholar 

  27. Price WA, Zimmer B, Kucas P. Serotonin syndrome: a case report. Clin Pharmacol 1986; 26: 77–8

    CAS  Google Scholar 

  28. Thomas JM, Rubin EH. Case report of a toxic reaction from a combination of tryptophan and phenelzine. Am J Psychiatry 1984; 141: 281–3

    PubMed  CAS  Google Scholar 

  29. Glassman A, Platman SR. Potentiation of a monoamine oxidase inhibitor by tryptophan. Psychiatry Res 1969; 7: 83–8

    Article  CAS  Google Scholar 

  30. Feighner JP, Boyer WF, Tyler DL. Adverse consequences of fluoxetine-MAOI combination therapy. J Clin Psychiatry 1990; 51: 222–5

    PubMed  CAS  Google Scholar 

  31. Sternbach H. Danger of MAOI therapy after fluoxetine withdrawal [letter]. Lancet 1988; 2: 850

    Article  PubMed  CAS  Google Scholar 

  32. Bhatara V, Bandettini F. Serotonin syndrome and drug interaction. Clin Pharmacol Ther 1993; 54(2): 230

    Article  PubMed  CAS  Google Scholar 

  33. Bhatara V, Bandettini F. A possible interaction between sertraline and tranylcypromine. Clin Pharm 1993; 12: 222–5

    PubMed  CAS  Google Scholar 

  34. Nierenberg DW, Semprebon M. The central nervous system serotonin syndrome. Clin Pharmacol Ther 1993; 53(1): 84–8

    Article  PubMed  CAS  Google Scholar 

  35. Spigset O, Mjorn-Dal T. Serotonin syndrome caused by a moclobemide-clomipramine interaction. BMJ 1993; 306: 248

    Article  PubMed  CAS  Google Scholar 

  36. Neuvonen PJ, Pohjota-Sintonen S, Tacka U, et al. Five fatal cases of serotonin syndromes after moclobemide-citalopram or moclobemide-clomipramine overdoses. Lancet 1993: 342: 1419

    Article  PubMed  CAS  Google Scholar 

  37. Lenzi A, Raffaelli S, Marazziti D. Serotonin syndrome-like symptoms in a patient with obsessive-compulsive disorder, following inappropriate increase in fluvoxamine dosage. Pharmacopsychiatry 1993; 26(3): 100–1

    Article  PubMed  CAS  Google Scholar 

  38. Steiner W, Fontaine R. Toxic reaction following the combined administration of fluoxetine and L-tryptophan: five case reports. Biol Psychiatry 1986; 21: 1067–71

    Article  PubMed  CAS  Google Scholar 

  39. Goldberg RJ, Huk M. Serotonin syndrome from trazodone and buspirone [letter]. Psychosomatics 1992; 2: 235

    Article  Google Scholar 

  40. Rosenblatt JE, Rosenblatt NC. How long a hiatus between discontinuing fluoxetine and beginning sertraline [abstract]. Curr Affect 111 1992; 11: 2

    Google Scholar 

  41. Dursun SM, Mathew VM, Reveley MA. Toxic serotonin syndrome after fluoxetine plus carbamazepine. Lancet 1993; 342: 442–3

    Article  PubMed  CAS  Google Scholar 

  42. Beaumont G. Drug interaction with clomipramine (Anafranil). J Int Med Res 1973 1: 480–4

    Google Scholar 

  43. Insel TR, Roy BF, Cohen RM, et al. Possible development of the serotonin syndrome in man. Am J Psychiatry 1982; 139: 954–95

    PubMed  CAS  Google Scholar 

  44. White K, Simpson G. Combined MAOI-tricyclic antidepressant treatment: a reevaluation. J Clin Psychopharmacol 1981; 1: 264–81

    Article  PubMed  CAS  Google Scholar 

  45. Lejoyeux M, Fineyre F, Adès J. The serotonin syndrome. Am J Psychiatry 1992; 149(10): 1410

    PubMed  CAS  Google Scholar 

  46. Sandyk R. L-Dopa-induced ‘serotonin syndrome’ in a parkinsonian patient on bromocriptine [letter]. J Clin Psychopharmacol 1986; 6: 194–5

    Article  PubMed  CAS  Google Scholar 

  47. De Castro RM. Antidepressants and myoclonus: a case report. J Clin Psychiatry 1985; 46(7): 284–7

    Google Scholar 

  48. Garvey MJ, Tollefson GD. Occurrence of myoclonus in patients treated with tricyclic antidepressants. Arch Gen Psychiatry 1987; 44: 269–72

    Article  PubMed  CAS  Google Scholar 

  49. Lejoyeux M, Rouillon F, Adès J, et al. Neural symptoms induced by tricyclic antidepressants: phenomenology and pathophysiology. Acta Psychiatr Scand 1992; 85: 249–56

    Article  PubMed  CAS  Google Scholar 

  50. Rouillon F, Lejoyeux M, Filteau MJ. Unwanted effects of long-term treatment of depression. In: Montgomery S, Rouillon F, editors, vol 3. Chichester: John Wiley & Sons, 1992: 81–111

    Google Scholar 

  51. Jacobs BL. Motor activity and the brain serotonin system. In: Fahn S, Marsden CD, Van Woert MH, editors. Advances in neurology: myoclonus, vol 43. New York: Raven Press, 1986: 481–92

    Google Scholar 

  52. Naquet R, Meldrum BS. Myoclonus induced by intermittent light stimulation in the baboon: neurophysiological and neuropharmacological approaches. In: Fahn S, Marsden CD, Van Woert MH, editors. Advances in neurology: myoclonus, vol 43. New York: Raven Press, 1986: 611–27

    Google Scholar 

  53. Chadwick D, Hallet M, Jenner P, et al. Treatment of post-hypoxic action myoclonus: implications for the pathophysiology of the disorder In: Fahn S, Marsden CD, Van Woert MH, editors. Advances in neurology: myoclonus, vol 43. New York: Raven Press, 1986: 183–90

    Google Scholar 

  54. Growdon JH, Young RR, Shahan BT. 5-Hydroxytryptophan in the treatment of several different syndromes in which myoclonus is prominent. Neurology 1976; 26: 1135–40

    Article  PubMed  CAS  Google Scholar 

  55. Darcourt G, Fadeuilhe A, Lavagna J, et al. Trois cas de myoclonies d’action au cours de traitements par l’imipramine et l’amitriptyline. Rev Neurol 1970; 122: 141–2

    PubMed  CAS  Google Scholar 

  56. Noble J, Matthew H. Acute poisoning by tricyclic antidepressants: clinical features and management of 100 patients. Clin Toxicol 1969; 2: 403–21

    Article  Google Scholar 

  57. Burks JS, Walker JE, Rumack BH. Tricyclic antidepressant poisoning: reversal of coma, choreathetosis, and myoclonus by physostigmine. JAMA 1974; 230: 1405–7

    Article  PubMed  CAS  Google Scholar 

  58. Lippman S, Tucker D. A second report of tricyclic-induced myoclonus. Am J Psychiatry 1977; 134: 585–6

    Google Scholar 

  59. Koller WC, Musa MN. Amitriptyline-induced abnormal movements. Neurology 1985; 35: 1086

    Article  PubMed  CAS  Google Scholar 

  60. Klerman G, Cole J. Clinical pharmacology of imipramine and related antidepressant compounds. Pharmacol Rev 1965; 17: 101–4

    PubMed  CAS  Google Scholar 

  61. Kronfol Z, Greden JF, Zis AP. Imipramine-induced tremor: effects of a beta-adrenergic blocking agent. J Clin Psychiatry 1983; 44 225–6

    PubMed  CAS  Google Scholar 

  62. Dickey W, Morrow JI. Drug-induced neurological disorders. Prog Neurobiol 1990; 34: 331–42

    Article  PubMed  CAS  Google Scholar 

  63. Christie P. Experience with imipramine (Tofranil) in geriatrics. Acta Psychiatr Neurol Scand 1961; 37 Suppl. 162: 118–20

    Google Scholar 

  64. Delay J, Deniker P. Efficacy of Tofranil in the treatment of various types of depression. Can Psychiatr Assoc J 1959; Suppl. 4: S100–12

    Google Scholar 

  65. Davies RK, Tucker GJ, Harrow M, et al. Confusional episodes and antidepressant medication. Am J Psychiatry 1971; 128: 95–9

    PubMed  CAS  Google Scholar 

  66. Livingston RL, Zucker DK, Isenberg K, et al. Tricyclic antidepressants and delirium. J Clin Psychiatry 1983; 44: 173–6

    PubMed  CAS  Google Scholar 

  67. Preskorn SH, Jerkovich GS. Central nervous system toxicity of tricyclic antidepressants: phenomenology, course, risk factors, and role of therapeutic drug monitoring. J Clin Psychopharmacol 1990; 10: 88–95

    Article  PubMed  CAS  Google Scholar 

  68. Meyers BS, Mei-Tal V Psychiatric reactions during tricyclic treatment of the elderly reconsidered. J Clin Psychopharmacol 1983; 3: 2–6

    Article  PubMed  CAS  Google Scholar 

  69. Stokes PE. Fluoxetine: a five-year review. Clin Ther 1993; 15: 216–43

    PubMed  CAS  Google Scholar 

  70. Lejoyeux M, Adès J, Rouillon F. Prospective evaluation of the ‘serotonin syndrome’ in depressed patients treated with clomipramine. Eur Neuropsychopharmacol 1992; 2: 300–1

    Article  Google Scholar 

  71. McTavish D, Benfield P. Clomipramine: an overview of its pharmacological properties. Drugs 1990; 39: 136–53

    Article  PubMed  CAS  Google Scholar 

  72. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd rev. ed. Washington, DC: American Psychiatric Association, 1987

    Google Scholar 

  73. Montgomery SA, Åsberg M. A new depression rating scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–9

    Article  PubMed  CAS  Google Scholar 

  74. Åsberg M, Cronholm B, Sjöqvist F, et al. Correlation of subjective side effects with plasma concentrations of nortriptyline. BMJ 1971; 3: 331–4

    Article  PubMed  Google Scholar 

  75. Lejoyeux M, Rouillon F, Adès J. Prospective evaluation of the serotonin syndrome in depressed inpatients treated with clomipramine. Acta Psychiatr Scand 1993; 88(5): 369–71

    Article  PubMed  CAS  Google Scholar 

  76. Lippman S, Moskovitz R, O’Tuama L. Tricyclic-induced myoclonus. Am J Psychiatry 1977; 134: 90–1

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Hôpital Louis Mourier, Colombes, 92700, France

    Michel Lejoyeux, Jean Adès & Frédéric Rouillon

Authors
  1. Michel Lejoyeux
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jean Adès
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frédéric Rouillon
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lejoyeux, M., Adès, J. & Rouillon, F. Serotonin Syndrome. CNS Drugs 2, 132–143 (1994). https://doi.org/10.2165/00023210-199402020-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-199402020-00006

Keywords

Search

Navigation