Serotonin Syndrome
PROFILE
Serotonin (5-hydroxytryptamine [5-HT]) is a biogenic amine naturally present in the body and stored primarily in the presynaptic nerve terminals of the CNS, enterochromaffin cells, and platelets.
Serotonin functions in neurotransmission, intestinal motility, regulation of vasomotor tone and blood pressure, and platelet aggregation.
Systemic levels in the circulation are normally low
Related Article: Drug Interactions in Polypharmacy
Definition
Serotonin syndrome (SS) is a spectrum of clinical signs caused by the effects of elevated serotonin levels.
Ingestion of certain medications—at therapeutic (eg, adverse effect) or toxic doses—can result in SS (see Medications & Supplements That May Cause Serotonin Syndrome, and the handout, Agents Implicated in Serotonin Syndrome).
Systems
SS can affect multiple body systems to varying degrees, depending on medication and dose ingested (see Table, above).
Tryptophan is converted to 5-hydroxytryptophan (5-HTP) and then to serotonin.
Accidental poisoning from ingestion of holistic supplements containing 5-HTP can result in significant SS.
In humans, SS often occurs with coingestion of ≥2 drugs that alter serotonin metabolism via different mechanisms (eg, selective serotonin reuptake inhibitors [SSRIs], monoamine oxidase inhibitors [MAOIs]), although overdose of single agents has also been reported.1-3
In veterinary medicine, most SS cases result from accidental ingestion or overdose of 1 drug.
Depending on patient size and drug involved, ≥1 pill may be required to initiate clinical signs.
Genetic Implications
Individual variation or deficiencies in intrinsic monoamine oxidase and cytochrome P450 enzymes may affect drug sensitivity.
Specific implications for veterinary patients are unknown.
Related Article: Medical Management of Behavioral Problems
Incidence & Prevalence
Prevalence of SS in humans and other animals has increased over 10–15 years with increased use of antidepressants (particularly SSRI and selective norepinephrine reuptake inhibitor [SNRI] antidepressants).2
Geographic Distribution
There is no known specific geographic distribution associated with SS.
Signalment
Any species or breed may be affected.
Animal poison control helplines are most commonly contacted for SS in dogs, cats, birds, ferrets, and potbellied pigs (in order of decreasing frequency).4
Crossbreed dogs and Labrador retrievers were overpresented in one study.5
No sex or age predilections have been noted.
Causes
The most common causes of SS include excessive ingestion of SSRIs; SNRIs; tricyclic antidepressants (TCAs); MAOIs; and dietary supplements containing tryptophan, 5-HTP, and other herbal supplements.
Risk Factors
Risk for SS is increased in patients with underlying cardiovascular or metabolic (eg, hepatic or renal impairment) conditions, primary or secondary hypertension, and seizure disorders.
Some neonatal and geriatric patients may be at increased risk.
Pathophysiology
SS is caused by any substance or mechanism that increases serotonin levels in the CNS.
To date, four major mechanisms by which these agents increase serotonin in the CNS have been identified:
Serotonin metabolism inhibited (eg, MAOIs, isoniazid)
Reuptake of serotonin by presynaptic nerve terminals (eg, SSRIs, SNRIs, TCAs) inhibited
Serotonin precursor and serotonin agonist (eg, tryptophan, 5-HTP, other herbals) use increased
Release of stored serotonin from presynaptic nerves (eg, amphetamines; 3,4-methylenedioxy-n-methylamphetamines [eg, ecstasy]; cocaine) increased
History
A thorough patient history should include:
Clinical signs
Signalment
Vaccination status
Heartworm prevention
Exposure to trauma or infectious agents
Underlying conditions
Current and recent medications and supplements (including herbal)
Exposure history (eg, what, when, how much [dose strength, tablet number])
Emetic agents used at home (if any)
Owner medications
Physical Examination
A thorough, systematic examination should include assessment of vital signs with emphasis on the CNS and cardiovascular system.
Clinical Signs
Signs of SS can vary with the toxicant ingested, ingested dose, time to decontamination, and underlying patient health (see Table).
Level of concern, onset of signs, and duration of action can vary, depending on whether the drug is rapid onset, extended release, or sustained release.
With most rapid-onset drugs, signs may be observed as early as 30 minutes–2 hours postingestion.
With extended- or sustained-release formulations, signs may develop within 2–6 hours (rarely out to 12 hours) postexposure.
SS can be seen at therapeutic doses and overdoses of veterinary-prescribed medications
With low doses (ie, low levels of toxicosis) or adverse effects from drugs, mild signs (eg, GI and CNS signs) are common.
At higher doses, SS signs may include more serious GI upset and CNS signs, as well as cardio-pulmonary signs.
Untreated, SS can result in death.
DIAGNOSIS
Definitive Diagnosis
Over-the-counter urine drug tests may detect some (not all) agents suspected of causing SS.
These tests can produce false-negative and false-positive results and do not undergo strict laboratory standards.
Urine, blood, and stomach contents can be tested through a human or veterinary diagnostic laboratory, but testing may be cost-prohibitive, and results probably will not be available in time to benefit treatment.
Serum levels do not often correlate consistently with clinical signs.
Differential Diagnosis
Other exposures or toxicants that can result in similar signs include:
Illicit drugs
Sleep medications (eg, zolpidem, zopiclone, zaleplon)
Wild mushrooms
Tremorogenic mycotoxins (eg, compost, moldy food)
Atypical antipsychotics (SS vs neuroleptic malignant syndrome)
Opioids or opiates
Sympathomimetics
Anticholinergics
Insecticides (eg, carbamates, organophosphates)
Rodenticides (eg, zinc phosphide, bromethalin, strychnine)
Infectious diseases
Metabolic causes
Molluscicides (eg, metaldehyde)
TREATMENT
There is no specific antidote for SS.
Treatment is supportive and symptomatic, aimed at controlling GI, CNS, and cardiovascular signs and regulating body temperature.
Depending on when the toxicant was ingested, treatment may consist of decontamination measures followed by monitoring for clinical signs.
Decontamination (eg, emesis induction, administration of activated charcoal) should only be performed in the following situations:
In dogs only: At-home emesis induction can be performed safely with hydrogen peroxide only with recent ingestion (<15–30 min) in asymptomatic patients.
In cats: Immediate veterinary attention for appropriate emesis induction with xylazine should be performed in asymptomatic patients with recent ingestion (<1 hour); no at-home emetic agents are recommended.
At presentation, the decision regarding appropriate emesis induction should be based on whether the patient is asymptomatic and whether the benefit outweighs risk for aspiration.
See Suggested Reading for more on decontamination.
Inpatient or Outpatient
Asymptomatic patients should be monitored for 12 hours postexposure.
Because clinical signs may change abruptly, symptomatic patients should be monitored closely as inpatients.
After clinical signs have resolved (typically within 12–24 hours, rarely 48–72 hours in severe cases), the patient can be discharged.
Medical
GI Support
Antiemetic therapy (eg, maropitant 1 mg/kg SC q24h) should be administered after emesis or gastric lavage and before activated charcoal.
Activated charcoal with sorbitol should be administered.
Benefits of charcoal administration over aspiration risk should be considered in symptomatic patients.
Repeat doses without sorbitol can be provided for sustained- or extended-release drug exposures, TCAs, and drugs that undergo enterohepatic recirculation.
Fluid Therapy
IV fluids (standard crystalloids) at 1.5–2 times maintenance dose may provide adequate hydration and renal perfusion.
Diuresis typically does not enhance excretion of these drugs.
What to Monitor
Baseline renal values, blood glucose, and electrolytes in symptomatic patients
CNS and cardiovascular signs
Heart rate, respiratory rate, blood pressure, and body temperature
Continuous electrocardiographic monitoring if cardiac abnormalities develop
Symptomatic Supportive Care
Cooling measures for body temperature >106°F should be stopped once temperature is 103.5°F.
Antipyretics are not recommended.
Sensory stimuli should be minimized (if possible): no bright lights, loud noise, or sudden movements.
Cyproheptadine (5-HT2A serotonin receptor antagonist) can be used for SS, hyperesthesia, hyperreflexia, and vocalization.
May be used with sedation
Neurologic Support & Sedation
Sedatives may be used as needed for CNS excitation.
The goal is to calm the patient without causing excessive sedation.
Muscle relaxants (eg, methocarbamol) may be used for muscle fasciculation or tremors.
Anticonvulsants may be given for seizures.
Benzodiazepines (eg, diazepam, midazolam) are not generally recommended.
May increase CNS excitation
Medications
Agitation
Acepromazine at 0.05–0.1 mg/kg IV, IM, or SC
Chlorpromazine at 0.5–1 mg/kg slow IV or IM
Some serotonin receptor antagonist activity
SS
Cyproheptadine
Dogs: 1.1 mg/kg PO or PR q4–8h
Cats: 2–4 mg PO or PR q4–8h as needed
Tremors
Methocarbamol at 55–220 mg/kg slow IV to effect
Note risk for CNS/respiratory depression with high doses.
Seizures
Phenobarbital at 4–16 mg/kg IV as needed
Propofol at 2–6 mg/kg IV or 0.1–0.6 mg/kg/min CRI
Can decrease dose by 25% if acepromazine or chlorpromazine has been administered
General anesthesia
Arrhythmias
In tachycardic patients (dogs, >180 bpm; cats, >220–240 bpm) not responsive to sedation, use of β-blockers may be necessary.
Propranolol
0.02–0.06 mg/kg slow IV
Dogs: 0.1–0.2 mg/kg PO q8h
Cats: 2.5–10 mg total dose PO q8–12h
In bradycardic patients (dogs, <50–60 bpm; cats, <120 bpm), blood pressure should be checked immediately to monitor for reflex bradycardia secondary to severe hypertension.
Antihypertensives as needed (systolic blood pressure >180 mm Hg)
If patient is normotensive and bradycardic, treat with atropine at 0.01–0.02 mg/kg IM or IV
Antihypertensive (eg, nitroprusside) can be considered for hypertensive patients (systolic blood pressure >180–190 mm Hg).
Heart rate and blood pressure should be checked before administering any cardiac drugs; monitoring should be attentive and frequent.
Contraindications
Based on human extrapolations, benzodiazepines should be avoided, as they may increase CNS excitation.
S-adenosylmethionine (SAMe) may increase serotonergic effects.
Magnesium-containing cathartics in TCA exposures
Decreased GI motility may increase serum magnesium levels.
Precautions & Interactions
Drugs that may exacerbate signs of SS (eg, tramadol, SSRI antidepressants, MAOIs, ketoconazole, cimetidine, amitraz) should be avoided.
FOLLOW-UP
Patient Monitoring
During monitoring, any signs should be addressed symptomatically.
Symptomatic patients should be monitored closely until signs resolve.
Complications
Complications include rhabdomyolysis, myoglobinuria, disseminated intravascular coagulation (DIC), renal hypoxia/failure, and respiratory/CNS depression, any of which can lead to death.
Future Follow-up
Depending on the toxicant ingested, baseline biochemical evaluation may need to be performed then rechecked within days of hospital discharge
In General
Relative Cost
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Prognosis
Prognosis for SS is generally good unless severe signs (eg, arrhythmias, seizures, hyperthermia, DIC) occur.
Signs are potentially more severe with ingestion of TCAs and MAOIs.
Prevention
Owners should be counseled on the importance of keeping prescription medications, drugs, and herbal supplements out of reach.
Anecdotally, cats seem to preferentially ingest venlafaxine hydrochloride (Effexor XR, effexorxr.com) more often than most other medications; extra caution is advised
DIC = disseminated intravascular coagulation, MAOI = monoamine oxidase inhibitor, NMDA = N-methyl-d-aspartate, SNRI = selective norepinephrine reuptake inhibitor, SS = serotonin syndrome, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant
COLLEEN M. ALMGREN, DVM, PhD, is a staff veterinarian at Pet Poison Helpline in Minnesota. Her experience includes small and large animal clinical practice, laboratory animal medicine, pathology, and toxicology, her primary focus. Dr. Almgren has worked at ASPCA Animal Poison Control Center and has been published in scientific and veterinary medicine journals. She earned her DVM from University of Illinois and completed a pathology residency and PhD at The Ohio State University.
JUSTINE A. LEE, DVM, DACVECC, DABT, is CEO and founder of VetGirl, a subscription-based podcast service offering RACE-approved continuing education (CE). Dr. Lee graduated from Cornell University and completed her internship at Angell. She also completed an emergency fellowship and residency at University of Pennsylvania. Dr. Lee is double-boarded in both emergency critical care and toxicology. In 2011, she was named the NAVC Conference Small Animal Speaker of the Year, and she is passionate about delivering clinically relevant CE.