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Serotonin syndrome

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Introduction

  • Cause: exposure to one or more serotonergic drugs. In dogs usually due to ingestion of 5-hydroxytryptophan (5-HTP) supplement or overdose of a selective serotonin reuptake inhibitor (SSRI).
  • Signs: typically altered mental status, autonomic dysfunction and neuromuscular excitation.
  • Diagnosis: based on history and clinical signs.
  • Treatment: supportive, with decontamination, sedation, cooling and use of a serotonin antagonist, if required.
  • Prognosis: depends on the severity of signs which can vary from insignificant to potentially fatal.

Pathogenesis

Etiology

  • Serotonin syndrome is caused by a drug-induced excess of serotonin in the central nervous system (CNS).
  • It can occur when two serotonergic drugs are given together (in therapeutic dosage or overdose), following ingestion of a single agent.
  • Most cases in dogs are due to ingestion a human medicine such as 5-hydroxytryptophan (5-HTP) (an over-the-counter serotonin precursor) or a SSRI Therapeutics: behavior modifiers, whereas in humans it usually occurs with a combination of two or more serotonergic drugs.
  • There is no correlation between the dose ingested and severity or duration of clinical signs.

Predisposing factors

General

  • Exposure to one or more serotonergic drugs.

Pathophysiology

  • Serotonin (5-hydroxytryptamine) is a neurotransmitter with multiple effects.
  • Serotonin receptors are divided into several groups, each further divided into sub-types. In humans severe or life-threatening effects seem to result only from stimulation of 5-HT2 receptors.
  • Serotonin is found primarily in the gastrointestinal tract, the CNS and platelets. It is metabolized by monoamine oxidase in the liver.
  • Serotonin modulates attention, mood, appetite, and sleep as well as some cognitive functions, and modulation of serotonin is a common mechanism of action for many antidepressants.
  • Serotonin excess results in overstimulation of serotonin receptors and produces CNS, gastrointestinal and neuromuscular effects.
  • 5-hydroxytryptophan is a serotonin precursor. It is rapidly absorbed and crosses the blood brain barrier. It is rapidly converted to serotonin.
  • In humans the following drugs have been associated with moderate to severe serotonin toxicity:
    • Monoamine oxidase inhibitors, eg phenelzine, tranylcypromine, moclobemide, selegiline, linezolid, methylene blue.
    • Serotonin releasing agents:
      • Sibutramine, amphetamine, methylphenidate, phentermine, lisdexamfetamine.
      • Synthetic stimulants, eg 3,4-methylenedioxymethamphetamine/MDMA/ecstasy, cathinones.
      • Selective serotonin reuptake inhibitors (SSRIs), eg fluoxetine Fluoxetine hydrochloride, fluvoxamine, paroxetine, citalopram, escitalopram.
      • Serotonin-noradrenaline reuptake inhibitors (SNRIs), eg venlafaxine, duloxetine.
      • Tricyclic antidepressants, eg clomipramine Clomipramine hydrochloride, imipramine.
      • Opioid analgesics, eg pethidine Pethidine, tramadol Tramadol, fentanyl Fentanyl (parenteral).
      • Herbal St John’s wort (Hypericum perforatum) Herbal medicine: remedies.
      • Garcinia cambogia supplement.

Timecourse

  • Onset of serotonin syndrome in dogs can occur within a few minutes to a few hours after ingestion of a serotonergic drug.
  • Duration of signs is generally 4-72 hours; recovery usually occurs within 24-36 hours.

Epidemiology

  • There is little information on incidence of serotonin syndrome in veterinary medicine.
  • In 313 cases of SSRI toxicosis in in dogs 4 (1.3%) developed signs associated with serotonin syndrome, involving citalopram, fluoxetine (2 cases) and paroxetine.
  • In two studies of 21 and 65 dogs with 5-hydroxytryptophan ingestion, 7 remained well, 5 died (5.8%), 3 were euthanized (3.4%) and 71 recovered (82.6%).

Diagnosis

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Treatment

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Prevention

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Outcomes

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Further Reading

Publications

Refereed Papers

  • Recent references from PubMed and VetMedResource.
  • Kekla E, Bates N, Rawson-Harris P (2019) 5-Hydroxytryptophan (5-HTP) exposure in 65 dogs [abstract]. Clin Toxicol 57 (6), 529.
  • Ortolani J M, Bellis T J, Griego M D (2018) Xylitol toxicosis and serotonin-like syndrome occurring simultaneously in a dog secondary to ingestion of Natrol 5-HTP Fast Dissolve Tablets. Clin Case Rep 7 (1), 5-10 PubMed.
  • Hopkins J, Pardo M, Bischoff K (2017) Serotonin syndrome from 5-hydroxytryptophan supplement ingestion in a 9-month-old Labrador retriever. J Med Toxicol 13 (2), 183-186 PubMed.
  • Kawano T, Takahashi T, Kaminaga S, Kadono T, Yamanaka D, Iwata H, Eguchi S, Yokoyama M (2015) A comparison of midazolam and dexmedetomidine for the recovery of serotonin syndrome in rats. J Anesth 29, 631-634 PubMed.
  • Rushton WF, Charlton NP (2014) Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother 48 (12), 1651-1654 PubMed.
  • Dagtekin O, Marcus H, Müller C, Böttiger BW, Spöhr F (2011) Lipid therapy for serotonin syndrome after intoxication with venlafaxine, lamotrigine and diazepam. Minerva Anestesiol 77 (1), 93-95 PubMed.
  • Shioda K, Nisijima K, Yoshino T, Kato S (2010) Mirtazapine abolishes hyperthermia in an animal model of serotonin syndrome. Neurosci Lett 482, 216-219 PubMed.
  • Mohammad-Zadeh L F, Moses L, Gwaltney-Brant S M (2008) Serotonin: a review. J Vet Pharmacol Ther 31 (3), 187-99 PubMed.
  • Boyer E W, Shannon M (2005) The serotonin syndrome. N Engl J Med 352, (11), 1112-1120 PubMed.
  • Gwaltney-Brant S M, Albretsen J C, Khan S A (2000) 5-Hydroxytryptophan toxicosis in dogs: 21 cases (1989-1999). J Am Vet Med Assoc 216 (12),1937-1940 PubMed.

Other sources of information

  • Selman J, Millard H T (2021) Recognizing and treating serotonin syndrome. dvm360.com March, pp 45-47.
  • Simon L V, Keenaghan M (2021) Serotonin Syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing PubMed.
  • Shokry I M (2020) Preventing serotonin syndrome: Factors you need to know. Veterinary Practice News. Posted 15 June 2020. Available from: https://www.veterinarypracticenews.com/preventing-serotonin-syndrome-factors-you-need-to-know/ (accessed 14 April 2021).
  • Almgren C M, Lee J A (2013) Serotonin syndrome. Clinician’s Brief October, pp 11-16.

Organisation(s)

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