Prompt and appropriate treatment is key to treating this life-threatening condition.
Serotonin, also called 5-hydroxytryptamine, is a neurotransmitter produced in the body. It has diverse bodily effects including, but not limited to, vasoconstriction, bronchoconstriction, intestinal peristalsis, and altered platelet aggregation. It is also associated with mood alterations, aggression, thermoregulation, sleep, vomiting, and pain perception. 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 after concurrent administration of two serotonergic drugs. In veterinary medicine, serotonin syndrome is most commonly reported to occur secondary to accidental ingestion of human prescription medications. However, as awareness has increased in humans regarding the beneficial effects of serotonin-associated medications to treat psychiatric disorders, veterinarians are using 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 inadvertent serotonin syndrome.
In this brief review, common serotonergic drugs and their effects will be discussed, followed by a discussion regarding treatment and prognosis.
Diagnosis of Serotonin Syndrome
Serotonin syndrome is typically diagnosed with 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 and if serotonin syndrome is suspected, urine, blood, and gastric contents can be submitted to a toxicology laboratory and empirical therapy should be instituted while pending results.
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 and neurologic clinical signs similar to humans. Mohammad-Zadeh et al. describes serotonin toxicity in animals that 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 been well-documented clinical signs of serotonin syndrome in animals.
Specific Clinical Effects of Common Serotonergic Drugs
The drugs most often implicated in serotonin syndrome include serotonin precursors, serotonin metabolism inhibitors, serotonin-releasing agents, serotonin reuptake inhibitors, and serotonin receptor agonists. Anti-depressant medications and ADHD drugs, both serotonergic agents, were in the top 10 reported intoxications to the Pet Poison Control Hotline in 2018.
Tricyclic antidepressants (TCAs) including trazadone, mirtazapine, and amitriptyline, block the reuptake of serotonin and norepinephrine in presynaptic terminals. TCAs are considered to have a narrow margin of safety, with a toxic dose of approximately 15 mg/kg. Out of 456 cases from 1985-1999 reported to the Pet Poison Control Hotline, the most common side effects of TCA ingestion included hyperexcitability and vomiting followed by ataxia, lethargy, and muscle tremors. Bradycardia and other arrhythmias were noted in severe cases, and death was reported in over 7% of cases. It is essential to educate owners of the risk of serotonin syndrome when prescribing trazodone concurrently with other serotonergic drugs, such as fluoxetine for behavior modification or tramadol for pain control.
Tramadol is used frequently in veterinary patients for its opiate-like agonist activities, but it also inhibits re-uptake of serotonin and norepinephrine. Serotonin syndrome has been described in veterinary medicine with accidental tramadol overdoses in dogs and cats. Tramadol and trazodone are also commonly prescribed simultaneously, especially in post-operative 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 side effects associated with overdoses or in older, debilitated patients.
Selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft), fluoxetine (Prozac or Reconcile), and citalopram (Celexa), are anti-depressant medications that decrease the ability for platelets to uptake serotonin. They are considered to be safer than other serotonergic drugs, with a minimum lethal dose reported to be over 100 mg/kg in dogs and 50 mg/kg in cats. While the majority of dogs reported to have ingested SSRIs had no clinical signs in one study, approximately 25% of dogs displayed lethargy, neurologic abnormalities (mydriasis, ataxia, depression, seizures, hyperesthesia), gastrointestinal upset, tachycardia, respiratory difficulty, and/or hyperthermia. No dogs were reported to have died, however many dogs in the study received prompt and appropriate treatment.
Monoamine oxidase inhibitors (MAOs), such as selegiline (Anipryl, Eldepryl) and tranylcypromine are anti-depressants that work by inhibiting serotonin metabolism. Selegiline (Anipryl) is a 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 MOAs are combined with other drugs such as SSRIs and/or TCAs. The lethal dose of MOAs for dogs and cats is not published, but the human toxic dose is considered to be 2 mg/kg.
Serotonin releasing agents such as amphetamines in the form of ADHD medication (Adderall, Ritalin, Vyvance), was the ninth most reported intoxication to the Pet Poison Hotline in 2018. The toxic doses between drugs vary but clinical signs are expected to develop at approximately 1 mg/kg ingested. Clinical signs can include those seen commonly with other serotonergic drugs, in addition to agitation. Other illicit drugs that may induce serotonin syndrome include the serotonin-releasing agents cocaine and ecstasy, as well as LSD (lysergic acid diethylamid) and lithium (used to treat bipolar disorder) which stimulate serotonin receptors.
The serotonin precursor Tryptophan, 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 gastrointestinal signs are seen most commonly in intoxications. Clinical signs reported by Gwaltney-Brant et al included primarily neurologic and gastrointestinal signs. Neurologic clinical signs consisted of mydriasis, transient blindness, depression, disorientation, hyperesthesia, hyperreflexia, tremors, ataxia, paresis, seizures, and coma. Gastrointestinal clinical signs consisted of vomiting, diarrhea, abdominal pain, ptyalism, flatulence, and bloat (abdominal distension). In this report, 7/21 dogs developed hyperthermia, and 3/21 dogs died. The minimum toxic dose in one study was 23.6 mg/kg.
Treatment and Prognosis
Treatment 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 IV or IM) or gastric lavage, followed by administration of activated charcoal. Activated charcoal (2 g/kg PO) should be administered every 6 hours in TCA ingestions and other ingestions of 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. Due to the risk of aspiration pneumonia, these methods of decontamination 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 gastrointestinal signs should be treated with anti-nausea medication such as maropitant (1 mg/kg IV or SC) and gastroprotectants such as omeprazole (1 mg/kg PO q12) or pantoprazole (1 mg/kg IV q12). 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 dosages), diazepam (0.25-1 mg/kg IV as a bolus or 0.25-1 mg/kg/hr as a CRI), or phenobarbital (2-20 mg/kg IV). 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 is a result of 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 mcg/kg/min), and mechanical ventilation may be considered for severe cases. Fluid diuresis is not necessary as serotonergic drugs are highly protein bound, however crystalloid fluid therapy is recommended for cardiovascular and renal support, even if the patient is not hyperthermic. Intravenous lipid emulsion therapy has been described in human case reports but has not proven to be effective in our veterinary species.
Patients should be monitored for autonomic instability with ECG and blood pressure monitoring. Hypotension should be treated with direct-acting sympathomimetics such as norepinephrine (start at 0.1 mcg/kg/min IV and titrate to desired effect). Indirect-acting hypotensive medications such as dopamine should not be used due to altered metabolism. 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 mcg/kg IV followed by 25-100 mcg/kg/min or nitroprusside (0.5-3 mcg/kg/min IV).
The usage of serotonin receptor antagonists such as chlorpromazine (0.2-0.5 mg/kg IV, IM, or SC q6) or cyproheptadine (1.1 mg/kg in dogs and 2-4 mg/kg in cats PO q4-6) may prevent the onset and severity of clinical signs associated with serotonin syndrome. In rat models, cyproheptadine has been shown to be more effective, but both drugs prevented death in animals that had ingested higher dosages of serotonergic medications.
Prognosis ranges from good to guarded based on severity of clinical signs, amount ingested, concurrent medications, time until treatment initiation, and type of treatment. For those patients receiving aggressive and expeditious treatment, most clinical signs will resolve within 36 hours.
This article originally appeared on the website DVM360.