Serotonin is a broadly distributed central and peripheral nervous system neurotransmitter, and modulation has various clinical effects ranging from facilitating sleep to combating nausea.1 Trazodone, a medication registered for use in human patients in the United States, modifies serotonin concentrations. It is considered unique among the SSRI drugs because it has dose-dependent serotonin antagonist and agonist (as an SSRI) properties.2,3 At lower doses, the antagonist properties predominate and result in hypnosis, thereby enhancing sleep in people. As the dose is increased, the SSRI effects predominate, and the drug has anxiolytic, antiobsessive, and antidepressant actions.2–5 In people, the effects of trazodone are attributed to both the parent drug and the active metabolite m-CPP.6,7 Although, to our knowledge, this metabolite has not been studied in other species, the parent compound trazodone has gained popularity for the treatment of anxiety disorders in dogs as well as for calming dogs requiring confinement after surgical procedures in both hospital and home environments.8,9
To the best of the authors’ knowledge, there are no reports describing the pharmacology of trazodone or m-CPP in horses. Given its pharmacological profile in people and in dogs, the drug is likely to have use as a behavioral modifier in horses. If behavioral effects similar to those observed in other species occur in horses, trazodone has the potential to be used as a calming medication in a variety of circumstances. Knowledge of the pharmacodynamic profile of the drug is essential to further identifying potential beneficial and adverse effects. Characterization of the pharmacokinetic profile of trazodone and m-CPP (if the metabolite is produced in horses) would additionally facilitate detection in the event of its inappropriate use to modulate performance in sport horses. The objective of the study reported here was to measure concentrations of trazodone and m-CPP in plasma and urine after administration of trazodone to healthy exercised horses and to concurrently assess selected physiologic and behavioral effects of the drug in this species.
Supported by the Center for Equine Health at the University of California-Davis.
The authors declare that there were no conflicts of interest.
The authors thank Dan McKemie, Kelsey Seminoff, Alexandria White, Stacy Steinmetz, and Sandy Yim for technical Assistance.
Area under the curve
Liquid chromatography–tandem mass spectrometry
Limit of quantitation
Time to maximum plasma concentration
Selective serotonin reuptake inhibitor
Angiocatheter, Becton Dickinson, Franklin Lakes, NJ.
Trazodone HCl, Sigma-Aldrich Corp, St Louis, Mo.
Equine Senior, Purina Animal Nutrition LLC, Shoreview, Minn.
Becton Dickinson, Franklin Lakes, NJ.
Phenix Research Products, Chandler, NC.
d6-trazodone, Cerilliant, Round Rock, Tex.
d8-mCPP, Cerilliant, Round Rock, Tex.
TSQ Vantage, Thermo Scientific, San Jose, Calif.
Thermo Scientific, San Jose, Calif.
1100 series, Agilent Technologies, Palo Alto, Calif.
ACE 3 C18 column, Mac-Mod Analytical, Chadds Ford, Penn.
Xcaliber Quan Browser, version 3.1, Thermo Scientific, San Jose, Calif.
β-glucuronidase, Sigma-Aldrich Corp, St Louis, Mo.
CleanScreen DAU, United Chemical Technologies, Bristol, Penn.
Phoenix WinNonlin, version 6.3, Pharsight Corp, Cary, NC.
Forrest Medical, East Syracuse, NY.
Stata/IC, version 13.1, StataCorp LP, Tex.
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Scoring system for assessment of behavior following IV (1.5 mg/kg) or oral (4 mg/kg) administration of a single dose of trazodone to 6 healthy adult Thoroughbred horses enrolled in a training fitness program.
|Behavior||1||Appears bright and alert, behavior and responsiveness deemed normal|
|2||Appears aware of observer presence (either sees or reacts to voice) and is alert and responsive|
|3||Appears quiet in the stall (eg, standing, recumbent, or sleeping) and minimally responsive to observer presence or voice call but other normal behaviors are apparent|
|4||Appears sedated (either standing or recumbent) and does not respond to observer presence or voice call|
|5||Appears agitated, hyperexcitable, hypersensitive, or aggressive (alone or in combination)|
|Ear position||1||Forward and erect; horse may move ears around as if listening|
|2||Relaxed and in a lateral position|
|3||Relaxed and back|
|4||Pinned back; not relaxed|
|Response to foreign object||1||Easy to place object in the horse's mouth; 1 person can complete|
|2||Placed but with minor restraint; 1 person can complete|
|3||More restraint required or needs 2 people to place object|
|4||Unable to place object|
|Ambulation in and out of stall||1||Jumps the pole|
|2||Clears the pole with all 4 feet|
|3||Hits the pole with 1 or 2 feet|
|4||Hits the pole with 3 or 4 feet|
|5||Unable to walk over the pole|
|Response to sound||1||No response|
|2||Slight or barely perceptible response (eg, ear movement)|
|3||Mild response (eg, head raises calmly)|
|4||Moderate response (eg, lifts head up briskly, ears pricked)|
|5||Dramatic response (eg, horse alert and in motion or whinnying)|
Response to sound was assessed by partially filling a plastic gallon jug with pebbles and shaking it approximately 1.5 m away from the horse as described previously.12 Ability to ambulate in an out of the stall was assessed by walking the horse over a wooden pole (10 cm high × 10 cm wide and approx 1.2 m long) placed on the ground at the entrance of the stall. A plastic 60-cm3 syringe was used to assess the reaction to placement of a foreign object in the mouth.