With the preponderance of serotonin-associated medications prescribed for both people and animals, veterinarians must know the potential for toxicity in their patients.
Orawan / stock.adobe.com
Serotonin, also called 5-hydroxytryptamine, is a neurotransmitter produced in the body. Among its diverse effects are vasoconstriction, bronchoconstriction, intestinal peristalsis, and altered platelet aggregation.1,2 Serotonin is also associated with mood alterations, aggression, thermoregulation, sleep, vomiting, and pain perception.2 Serotonin syndrome can be a life-threatening condition in which excess stimulation of serotonergic receptors in the nervous system leads to mentation changes, autonomic dysfunction, and neuromuscular abnormalities.
In humans, serotonin syndrome often results from concurrent administration of 2 serotonergic drugs. In veterinary medicine, it is reported most commonly following accidental ingestion of human prescription medications.3,4 However, as public awareness has increased regarding the beneficial effects of serotonin-associated medications in treating psychiatric disorders, veterinarians are prescribing these medications more frequently, especially for treatment of separation anxiety, behavior modification, cognitive dysfunction, feline inappropriate elimination, and storm phobia. Veterinarians must be knowledgeable regarding the clinical effects of these medications and their associated contraindications, which could lead to serotonin syndrome.
This article discusses common serotonergic drugs and their effects, as well as treatment and prognosis in patients with serotonin syndrome.
Serotonin syndrome is typically diagnosed based on a history of ingestion of a serotonergic drug and subsequent appropriate clinical signs. Clinical signs can develop in as little as an hour with an overdose, and potentially several days later if ingestion was secondary to synergism/ interaction. If no history of ingestion has been reported yet serotonin syndrome is suspected, urine, blood, and gastric contents can be submitted to a toxicology laboratory and empirical therapy should be instituted while awaiting results.5
Because there are multiple classes of serotonergic drugs, clinical signs of serotonin toxicity are diverse, and the clinician must be astute. Despite this varied potential for clinical signs, most patients will have gastrointestinal (GI) and neurologic clinical signs similar to those in humans. Serotonin toxicity in animals is characterized by autonomic hyperactivity (diarrhea, mydriasis, and tachycardia), neuromuscular signs (hyperreflexia, myoclonus, tremors, and rigidity), and altered mental status. Systemic hypertension or hypotension, pulmonary hypertension, vomiting, anorexia, hyperthermia, restlessness, ataxia, and seizures are also well-documented clinical signs of the condition in animals.1
The drugs most often implicated in serotonin syndrome include serotonin precursors, serotonin metabolism inhibitors, serotonin releasing agents, serotonin reuptake inhibitors, and serotonin receptor agonists.3 Antidepressants and attention-deficit/hyperactivity disorder (ADHD) medications, both serotonergic agents, were among the top 10 reported intoxications to the Pet Poison Control Hotline in 2018.6
Tricyclic antidepressants (TCAs), including trazodone, mirtazapine, and amitriptyline, block the reuptake of serotonin and norepinephrine in presynaptic terminals. TCAs are thought to have a narrow margin of safety, with a toxic dose of about 15 mg/kg. Of 456 cases reported to the Pet Poison Control Hotline between 1985 and 1999, the most common adverse effects of TCA ingestion included hyperexcitability and vomiting followed by ataxia, lethargy, and muscle tremors.7,8 Bradycardia and other arrhythmias were noted in severe cases, and death was reported in more than 7% of cases. It is essential to educate pet owners about the risk for serotonin syndrome when prescribing trazodone concurrently with other serotonergic drugs, such as fluoxetine for behavior modification or tramadol for pain control.8
Tramadol is frequently used in veterinary patients for its opiate-like agonist activities, but it also inhibits reuptake of serotonin and norepinephrine. Serotonin syndrome has been described in veterinary medicine with accidental tramadol overdoses in dogs and cats.2,9 Tramadol and trazodone are also commonly prescribed simultaneously, especially in postoperative patients. Although there are no reports of serotonin toxicity when these drugs are used in combination at their therapeutic doses, clinicians should be well aware of potential adverse effects associated with overdoses or use in older, debilitated patients.
Selective serotonin reuptake inhibitors (SSRIs), such as sertraline (Zoloft), fluoxetine (Prozac, Reconcile [PRN Pharmacal]), and citalopram (Celexa), are antidepressant medications that decrease the ability of platelets to uptake serotonin.10 They are considered safer than other serotonergic drugs, with a minimum reported lethal dose over 100 mg/kg in dogs and 50 mg/kg in cats.11
Although the majority of dogs reported to have ingested SSRIs in 1 study had no clinical signs, approximately 25% displayed lethargy, neurologic abnormalities (mydriasis, ataxia, depression, seizures, hyperesthesia), GI upset, tachycardia, respiratory difficulty, and/or hyperthermia. No study dogs died, but many received prompt and appropriate treatment.1,2 In a 2013 study of 33 cats that ingested SSRIs, 24% developed clinical signs, including sedation and GI upset12; 1 cat developed more severe clinical signs that included hyperthermia, neurologic abnormalities, and cardiovascular abnormalities.12 The remainder of cats were asymptomatic, and all cats survived to discharge.12
Monoamine oxidase inhibitors (MAOIs), such as selegiline (Anipryl [Zoetis], Eldepryl) and tranylcypromine are antidepressants that work by inhibiting serotonin metabolism. Selegiline is an MAO‐B inhibitor that is prescribed for canine cognitive dysfunction and treatment of hyperadrenocorticism. Signs of toxicity, such as restlessness, ataxia, disorientation, seizures, tachypnea, and tremors, are most commonly reported when MAOIs are combined with other drugs such as SSRIs and/or TCAs.13 The lethal dose of MAOIs for dogs and cats is not published, but the human toxic dose is reported to be 2 mg/kg.14
Serotonin releasing agents, such as amphetamines in ADHD medication (Adderall, Ritalin, Vyvanse), were the ninth most frequently reported intoxication.6 Clinical signs can include those seen commonly with other serotonergic drugs, in addition to agitation. Other illicit serotonin releasing drugs that may induce serotonin syndrome include cocaine and ecstasy, as well as lysergic acid diethylamide,and lithium (used to treat bipolar disorder), which stimulate serotonin receptors.3,15
Theserotonin precursortryptophan, which is converted to serotonin rapidly in the GI tract after ingestion, can be the main ingredient in over-the-counter dietary supplements. Similarly, neurologic and GI signs are seen most commonly in intoxications. Reported clinical signs include primarily neurologic and GI signs. Neurologic signs consisted of mydriasis, transient blindness, depression, disorientation, hyperesthesia, hyperreflexia, tremors, ataxia, paresis, seizures, and coma. GI signs included vomiting, diarrhea, abdominal pain, ptyalism, flatulence, and abdominal distension. In this report, 7 of 21 dogs developed hyperthermia, and 3 died. The minimum toxic dose was 23.6 mg/kg.16
Treatment of serotonin syndrome consists of prompt decontamination and aggressive supportive care. Decontamination in clinically normal animals is necessary either via emesis (apomorphine at 0.02-0.06 mg/kg intravenously [IV] or intramuscularly [IM]) or gastric lavage, followed by administration of activated charcoal. Activated charcoal (2 g/kg by mouth [PO]) should be administered every 6 hours in TCA ingestions and ingestions of other medications that undergo enterohepatic recirculation. A cathartic, such as sorbitol, could be administered with the first dose; however, cathartics with magnesium should be avoided in TCA ingestions due to decreased GI motility and risk of magnesium toxicosis.7 Due to the risk of aspiration pneumonia, decontamination methods should be avoided in animals with severe clinical signs.
The intensity of supportive therapy depends on the amount ingested and severity of clinical signs. Animals with GI signs should be treated with antinausea medication such as maropitant (1 mg/kg IV or subcutaneously [SC]) and gastroprotectants such as omeprazole (1 mg/kg PO twice daily) or pantoprazole (1 mg/kg IV twice daily ). Animals with neurologic signs (agitation, tremors, seizures) should be treated with methocarbamol (44 mg/kg IV initially, up to 330 mg/kg total or 132 mg/kg/day PO divided into 2 or 3 doses), diazepam (0.25-1 mg/kg IV as a bolus or 0.25-1 mg/kg/h as a constant-rate infusion [CRI]), or phenobarbital (2-20 mg/kg IV).17-19 Severely hyperthermic animals should be supported by active cooling measures such as evaporative cooling (soaking patient with cool water and directing a fan at them), cold water enemas, and room temperature IV fluid therapy.
Because hyperthermia results from excessive muscle activity, general anesthesia, neuromuscular paralysis (with atracurium at a loading dose of 0.2-0.5 mg/kg IV, then a CRI of 3-9 µg/kg/min), and mechanical ventilation may be considered for severe cases.3,4 Fluid diuresis is not necessary as serotonergic drugs are highly protein bound, but crystalloid fluid therapy is recommended for cardiovascular and renal support, even in patients that are not hyperthermic.5 IV lipid emulsion therapy has been described in human case reports but has not proven to be effective in veterinary species.20
Patients should be monitored for autonomic instability with electrocardiography and blood pressure monitoring. Hypotension should be treated with direct-acting sympathomimetics such as norepinephrine (start at 0.1 µg/kg/min IV and titrate to desired effect).21 Indirect-acting hypotensive medications such as dopamine should not be used due to altered metabolism.3 Hypertension and tachycardia can be present secondary to excessive catecholamine release in MAOI overdoses and should be treated with a short-acting beta-blocker such as esmolol (200-500 µg/kg IV followed by 25-100 µg/kg/min) or nitroprusside (0.5-3 µg/kg/min IV).3,22,23
The use of serotonin receptor antagonists such as chlorpromazine (0.2-0.5 mg/kg IV, IM, or SC every 6 hours) or cyproheptadine (1.1 mg/kg in dogs and 2-4 mg in cats PO every 4-6 hours) may prevent the onset and severity of clinical signs associated with serotonin syndrome.24-26 In rat models, cyproheptadine showed to be more effective, but both drugs prevented death in animals that had ingested higher doses of serotonergic medications.27
Prognosis in patients with serotonin syndrome ranges from good to guarded based on severity of clinical signs, amount ingested, concurrent medications, time to treatment initiation, and type of treatment. For patients receiving aggressive and expeditious treatment, most clinical signs will resolve within 36 hours.
Serotonin syndrome most commonly results from overdoses of serotonergic drugs such as serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors.
Jamie Selman, DVM, is a rotating small animal medicine and surgery intern at BluePearl Specialty and Emergency Pet Hospital in Overland Park, Kansas. She hopes to become a board-certified emergency and critical care specialist and is particularly interested in initial stabilization of trauma patients, sepsis, and transfusion medicine.
Heather Towle Millard, DVM, MS, DACVS-SA, is staff surgeon at BluePearl Specialty and Emergency Pet Hospital in Overland Park, Kansas. With more than 15 years of experience, Millard’s veterinary expertise includes advanced soft tissue surgery, oncologic surgery, and general orthopedic surgery. She enjoys mentoring passionate, energetic, and determined young doctors and being part of their journey to success.
References
1. Mohammad-Zadeh LF, Moses L, Gwaltney-Brant SM. Serotonin: a review. 2008;31(3):187-199. doi:10.1111/j.1365-2885.2008.00944.x
2. Thomas DE, Lee JA, Hovda LR. Retrospective evaluation of toxicosis from selective serotonin reuptake inhibitor antidepressants: 313 dogs (2005-2010). J Vet Emerg Crit Care (San Antonio). 2012;22(6):674-681. doi:10.1111/j.1476-4431.2012.00805.x
3. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120. doi:10.1056/NEJMra041867.
4. Isbister GK, Buckley NA. The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment. Clin Neuropharmacol. 2005;28(5):205-214. doi:10.1097/01.wnf.0000177642.89888.85
5. Reineke EL. Serotonin syndrome. In: Silverstein DC, Hopper K, eds. Small Animal Critical Care Medicine,2nd ed. Saunders/Elsevier;2015:414-418.
6. Flint C. The usual suspects: Top 10 toxins poisonous to pets. dvm360®. July 7, 2018. Accessed January 25, 2021. https://www.dvm360.com/view/usual-suspects-top-10-toxins-poisonous-pets
7. Johnson LR. Tricyclic antidepressant toxicosis. Vet Clin North Am Small Anim Pract. 1990;20(2):393-403. doi:10.1016/s0195-5616(90)50034-0
8. Shioda K, Nisijima K, Yoshino T, Kato S. Extracellular serotonin, dopamine and glutamate levels are elevated in the hypothalamus in a serotonin syndrome animal model induced by tranylcypromine and fluoxetine. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(4):633-640. doi:10.1016/j.pnpbp.2004.01.013
9. Indrawirawan Y, McAlees T. Tramadol toxicity in a cat: case report and literature review of seretonin syndrome. J Feline Med Surg. 2014;16(7):572-528. doi:10.1177/1098612X14539088
10. Chu A, Wadhwa R. Selective serotonin reuptake inhibitors. [Updated 2020 Nov 7]. In: StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK554406/
11. Dunkley EJC, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Q J Med. 2003;96:635-642. doi:10.1093/qjmed/hcg109
12. Pugh CM, Sweeney JT, Bloch CP, Lee JA, Johnson JA, Hovda LR. Selective serotonin reuptake inhibitor (SSRI) toxicosis in cats: 33 cases (2004-2010). J Vet Emerg Crit Care (San Antonio). 2013;23(5):565-570. doi:10.1111/vec.12091
13. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth. 2005;95(4):434-441. doi:10.1093/bja/aei210
14. Brent J. Monoamine oxidase inhibitors and the serotonin syndrome. In: Haddad LM, Shannon MW, Winchester JF, eds. Clinical Management of Poisoning and Drug Overdose. Saunders; 1998.
15. Thomas EK, Drobatz KJ, Mandell DC. Presumptive cocaine toxicosis in 19 dogs: 2004-2012. J Vet Emerg Crit Care(San Antonio). 2014;24(2):201-207. doi:10.1111/vec.12159
16. Gwaltney-Brant SM, Albretsen JC, Khan SA. 5-Hydroxytryptophan toxicosis in dogs: 21 cases (1989-1999). J Am Vet Med Assoc. 2000;216(12):1937-1940. doi:10.2460/javma.2000.216.1937
17. Plumb DC: Diazepam. In: Plumb’s Veterinary Drug Handbook. Wiley-Blackwell; 2015.
18. Plumb DC: Methocarbamol. In: Plumb’s Veterinary Drug Handbook. Wiley-Blackwell; 2015.
19. Plumb DC: Phenobarbitol. In: Plumb’s Veterinary Drug Handbook. Wiley-Blackwell; 2015
20. Dagtekin O, Marcus H, Müller C, Böttiger BW, Spöhr F. Lipid therapy for serotonin syndrome after intoxication with venlafaxine, lamotrigine and diazepam. Minerva Anestesiol. 2011;77(1):93-95.
21. Plumb DC: Norepinephrine. In: Plumb’s Veterinary Drug Handbook. Wiley-Blackwell; 2015.
22. Plumb DC: Esmolol. In: Plumb’s Veterinary Drug Handbook. Wiley-Blackwell; 2015.
23. Plumb DC: Sodium nitroprusside. In: Plumb’s Veterinary Drug Handbook. Wiley-Blackwell; 2015.
24. Mills KC. Serotonin syndrome. A clinical update. Crit Care Clin. 1997;13(4):763-783. doi:10.1016/s0749-0704(05)70368-7
25. Plumb DC: Chlorpromazine. In: Plumb’s Veterinary Drug Handbook. Wiley-Blackwell; 2015. Wiley-Blackwell.
26. Plumb DC: Cyproheptadine. In: Plumb’s Veterinary Drug Handbook. Wiley-Blackwell; 2008. Wiley-Blackwell. Pages 240-241.
27. Nisijima K, Yoshino T, Yui K, Katoh S. Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res. 2001;890(1):23-31. doi:10.1016/s0006-8993(00)03020-1
