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Veterinarian Technician February 2012 (Vol 33, No 2)

Inside Behavior: Serotonin Syndrome: When Good Drugs Are Used Badly

by Melissa M. Spooner, LVT, BS, KPA-CTP

    The specialized field of veterinary behavior is slowly becoming more prevalent. Because of increasing knowledge of behavioral medicine and the proliferation of board-certified veterinary behaviorists, more pets may be treated with antianxiety and antidepressant medications (anxiolytics) such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). These drugs are often prescribed to manage canine and feline chronic or acute anxiety, fear, stereotypic behaviors, vigilance, and reactivity.


    Reactivity—aggressive displays toward arousing stimuli
    Stereotypic behavior—a persistent, repetitive behavior that appears to serve no purpose11
    Vigilance—intense focus

    Like other fields in veterinary medicine, animal behavior is exploring new medications, revisiting old ones, and/or considering alternative therapies. This has led to drug reactions when SSRIs, monoamine oxidase inhibitors (MAOIs), or TCAs are combined with other medications, supplements, or foods that may cause excess serotonergic activity. These reactions can be very dangerous and even deadly.1 Overdose of a serotonin-based drug or use of a combination of two or more SSRIs, MAOIs, or TCAs may result in a toxicosis commonly called serotonin syndrome. Understanding the interactions between the drugs, nutritional supplements, and foods that may be problematic can help veterinarians diagnose serotonin syndrome.

    Selective Serotonin Reuptake Inhibitors

    SSRIs selectively block reuptake of serotonin by presynaptic neurons, increasing the serotonin level in the synapses. The SSRI fluoxetine has been used most commonly for treating canine behavior problems, particularly separation anxiety; however, this drug has also been used off label for various other problems. Although fluoxetine is likely the most well known SSRI, at least seven other SSRIs are prescribed in human and veterinary medicine; paroxetine and sertraline are gaining popularity.

    Tricyclic Antidepressants

    TCAs may be used to treat many problems for which SSRIs are also prescribed; however, the route of action of TCAs is slightly different than that of SSRIs. TCAs block reuptake of norepinephrine, dopamine, and serotonin by the presynaptic terminal, increasing the neurotransmitter level in synapses. Clomipramine is a well-known TCA; other TCAs include amitriptyline, imipramine, and doxepin.

    Monoamine Oxidase Inhibitors

    MAOIs have been used in human medicine since the 1950s. These drugs work by blocking the chemicals that break down serotonin and norepinephrine. The MAOIs phenelzine and tranylcypromine are typically used only in human medicine. The well-known MAOI selegiline is commonly used to treat canine cognitive dysfunction, which affects dogs much like dementia or Alzheimer disease affects people. Selegiline is the only MAOI approved to treat a behavioral condition in dogs. Several other MAOIs (e.g., amitraz) are used in veterinary medicine, but not specifically for behavioral conditions. Amitraz is used for treating and preventing tick infestation, so it is found in dips, topical preventives, and tick collars. MAOIs must be used with caution: while they can be very beneficial in several types of applications, they can be especially dangerous when used with certain foods, medications, and over-the-counter supplements.

    Alternative Medicine

    The increasing desire to treat medical issues using natural remedies and alternative medicine has slowly crossed over from human medicine to veterinary medicine. Several nutritional supplements, and even foods, may play a role in serotonin syndrome.


    Serotonin syndrome—also known as serotonin toxicity or iatrogenic serotonin toxidrome2—has been described as a continuum of serotonergic effects mediated by the intrasynaptic serotonin level.3 Serotonin syndrome has been documented in monkeys, rats, rabbits, dogs, and humans.4 Although the exact mechanisms by which excess serotonin causes serotonin syndrome are not fully understood, the clinical signs of toxicosis are generally acute and are categorized as follows5:

    • Autonomic hyperactivity—diaphoresis, diarrhea, fever, hypertension, mydriasis, tachycardia, and tachypnea

    • Neuromuscular signs—hyperreflexia, myoclonus, hyperthermia, rigidity, seizures, tremors, and pyramidal rigidity

    • Altered mental status—agitation, confusion, and excitement

    Serotonin syndrome can occur in several ways, such as drug overdose. For example, the average dose of clomipramine is 1 to 2 mg/kg PO q24h. Toxic doses in humans starting at 15 mg/kg have been reported, causing symptoms such as cardiac arrhythmias. Lethal doses of clomipramine have been reported to start at 100 mg/kg.6 Because the various drugs that can cause serotonin syndrome may differ greatly, clinicians should research the individual dosing recommendations and toxic levels. The ASPCA Animal Poison Control Center is an excellent resource. If toxicosis is suspected, it is important to obtain accurate information regarding how much medication was ingested so that appropriate actions can be taken and an accurate prognosis can be given. The most serious cases of serotonin syndrome involve drug combinations, specifically serotonergic agents. Serotonin syndrome due to combination of an MAOI with either an SSRI or a TCA is generally the most difficult to treat and can be deadly.6

    Other drug classes can also pose problems. For example, tramadol—an opioid analgesic with a weak serotonin reuptake inhibiting effect—combined with fluoxetine or any other SSRI can increase the risk for seizures. Metoclopramide—a dopamine receptor antagonist that is used as an antiemetic—combined with an SSRI is associated with a mildly increased risk for seizures.7

    Nutritional supplements can also be problematic. For example, ingestion of tryptophan while receiving selegiline, fluoxetine, or clomipramine can increase the risk for serotonin syndrome. Tryptophan is common in over-the-counter behavior supplements, so clients may inadvertently give it to their pets without their veterinarian’s knowledge. Clients should be alerted to this potential risk so that it can be avoided. The use of S-adenosylmethionine—a supplement commonly used for mental, liver, and joint support—should also be avoided with serotonergic agents. Foods that are high in tyramine (e.g., aged cheese, dried meats/fish, soy) should not be fed to pets undergoing behavior medication therapy.2


    The standard treatment protocol for serotonin syndrome consists of decontamination (if indicated), discontinuation of all serotonergic medications, administration of a serotonin antagonist, and supportive care.8 While a diagnosis of serotonin syndrome is being considered, it is important to determine exactly how much time has elapsed since ingestion of the toxic substance(s). Whether to proceed with decontamination depends on the amount of time that has passed. Decontamination should be performed only within the first 30 minutes (although one source6 suggests within 2 hours) after consumption of the toxic substance(s); otherwise, emesis, gastric lavage, or administration of adsorbents (e.g., activated charcoal) may not be helpful because the substance is no longer in the stomach.4 This guideline is based on the rapid onset of serotonergic agents, which are likely to have been absorbed after 30 minutes. Any food, medications, and supplements that have serotonergic effects should be discontinued immediately; depending on the circumstances, administration of these substances may resume once the patient is stable. To help stabilize the patient, supportive care and reversal agents should be a primary part of the treatment plan. Patient care involves treating the signs as they arise. For example, if dyspnea develops, the patient may benefit from flow-by oxygen or, in more serious cases, tracheal intubation. If seizures, tremors, or hyperactivity develops, diazepam or phenothiazine can be prescribed. If hyperthermia develops, the patient can be cooled slowly to normal body temperature. Lastly, cyproheptadine—a serotonin antagonist—should be administered.9


    The primary way to prevent serotonin syndrome is to avoid using (1) drug combinations that facilitate serotonin activity or (2) excessive amounts of a single serotonergic drug.8 Veterinary technicians can play an important role in preventing serotonin syndrome. By working with clients, we can obtain a complete behavior and medical history and report it to the veterinarian.10 Clients should be encouraged to list all medications (including over-the-counter medications) and supplements (including nutraceuticals) that the patient is, or was recently, receiving, including the dosage of the product and when it was started and last given. This list should be updated anytime medications or supplements are introduced or discontinued, their dosages are altered, or the patient is seen at the hospital. If possible, an alert should be placed in the patient’s digital and paper records. Fluorescent stickers are an inexpensive but effective method of alerting veterinary staff that the patient is receiving a medication that may interact with other medications. All medications should be stored in tamperproof containers that are inaccessible to the pet. (Several behavior medications are made to be highly palatable, so they can be tempting to pets.)

    A solid understanding of basic pharmacology (i.e., the various drug categories and the medications within each) could prevent a fatal toxicosis. In addition, tools such as the “Interactions Checker” at Drugs.com can be used to check for interactions between any number of medications, many of which are used in veterinary medicine; users are alerted to the possibility of toxicosis and whether it could be mild, moderate, or severe. Veterinary staff should know the appropriate start and stop times when a patient’s medication is replaced with one from a different drug category. For example, when a patient is being treated with an SSRI, such as fluoxetine, and the veterinarian decides to replace it with an MAOI, such as selegiline, there should be a 5-week minimum waiting period between administration of the two drugs; when an MAOI is replaced with an SSRI or a TCA, the ideal waiting period is at least 2 weeks.8 If the veterinarian decides to combine medications to optimize results (i.e., polypharmacy), clients should be made aware of the possible adverse effects and should ideally sign an informed consent form that provides all the pertinent information and acknowledges that they understand the purpose and risk of the prescribed medication.


    There is still much to be learned about serotonin syndrome. Reported cases of it in dogs are uncommon, but proactively understanding the risk of this toxicosis could help prevent it.

    The author’s credentials (KPA-CTP) stand for "Karen Pryor Academy Certified Training Partner."

    1. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352(11):1112-1120.

    2. Carroll GL. Serotonin syndrome: when good drugs adversely interact with analgesics and anesthetics (presentation). AVMA Conf 2011.

    3. Gillman PK. A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biol Psychiatry 2006;59:1046-1051.

    4. Crowell-Davis SL, Murray T. Veterinary Psychopharmacology. Ames, IA: Wiley-Blackwell; 2005.

    5. Crowell-Davis SL. Some facts behind psychotropic medications. Proc Am Vet Med Assoc 2010.

    6. Wismer T. Antidepressant drug overdoses in dogs. Vet Med 2000;95(7):520-525.

    7. Drugs.com. Interactions checker. www.drugs.com/vet. Accessed November 2011.

    8. Crowell-Davis SL, Poggiagliolmi S. Understanding behavior: serotonin syndrome. Compend Contin Educ Vet 2008;30(9):490-493.

    9. Gwaltney-Brandt S. Serotonin syndrome. Veterinary Information Network (VIN) 2011.

    10. Shaw J. Understanding common psychopharmacologic drugs used in canine patients. Vet Tech 2008;29(8):464-469.

    11. Crowell-Davis SL. Understanding behavior: stereotypic behavior and compulsive disorder. Compend Contin Educ Vet 2008;30(6):249.

    References »

    NEXT: Tech Tips (Feb. 2012)


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