Serotonin and norepinephrine reuptake inhibitors: Choosing the right drug (Proceedings)


A practical guide to choosing the right serotonin and norepinephrine reuptake inhibitors


  • SRI-Serotonin Reuptake Inhibitor

  • SSRI-Selective Serotonin Reuptake Inhibitor

  • SNRI-Serotonin and Norepinephrine Reuptake Inhibitor

  • TCA-Tricyclic Antidepressant (a family of SNRI's)

Cost: Old vs. new

  • New SSRI's and SNRI's are typically very expensive

  • We usually use the older ones in veterinary medicine because of cost issues


  • Inhibition of serotonin reuptake. This increases serotonergic neurotransmission by allowing serotonin molecules to act for extended periods of time.


  • 5-HT reuptake inhibition

  • NE reuptake inhibition

  • Chronic administration causes decreased numbers of β-adrenoceptors and serotonin receptors, as well as altered function of various serotonin receptors.

TCA's also

  • α-1 adrenergic antagonism

  • Anticholinergic

  • Antihistaminic

Uses in dogs and cats

  • Anxiety and disorders motivated by anxiety, e.g. urine marking

  • Aggression

  • Compulsive Disorder, e.g. tail-chasing, lick granuloma


  • Side Effects: Sedation, Anorexia, Gastrointestinal signs, Anxiety, Irritability, Insomnia, Aggression, Decreased libido

  • Slow onset of action

  • Metabolized in liver

  • Excreted through kidneys

  • Reduce dose in patients with hepatic or kidney impairment

  • May have 1-4 week latency to effect

  • Long t1/2

  • Use cautiously with patients with diabetes mellitus (may decrease blood glucose)

  • Use cautiously in patients with a history of seizures

  • DO NOT use in combination with a MAOI


  • DOGS: 0.5-1.0 mg/kg q24h

  • Has been used to treat canine acral lick dermatitis

Fluoxetine hydrochloride

  • DOGS: 1.0-2.0 mg/kg q24h

  • CATS 0.5-1.5 mg/kg q24h


  • CATS: 0.5-1.0 mg/kg

  • DOGS: 0.5-1.0 mg/kg


  • CATS: 0.5-1.0 mg/kg

  • DOGS: 0.5-4.0 mg/kg


  • Named after chemical structure

  • Use in animals as for SSRI's

Tertiary amines

  • Have two methyl groups at the end of their side chain.

  • More potent inhibition of 5-HT uptake

  • More potent α-adrenergic, cholinergic, and histaminergic receptor blockade

  • Significant sedative effects

  • Amitriptyline, Clomipramine, Doxepin, Imipramine

Secondary amines

  • One methyl group at the end of the side chain

  • More potent inhibition of NE reuptake

  • Desipramine, Nortriptyline

Biochemical activity

Effects - therapeutic

  • Norepinephrine

     o ↓General arousal

     o ↑Attention

     o ↓Mood reactivity

     o ↑Stress response modulation

  • Serotonin

     o Regulate mood states

     o ↓Fear responses

     o ↓↑Feeding behavior

     o ↓Stress response

     o ↓Impulsive behavior

Effects - α-adrenergic

  • Orthostatic hypotension

  • Sedation

  • Vasoconstriction

  • Smooth muscle contraction

Effects - cholinergic

  • Urinary retention

  • Dry mouth

  • Mydriasis

  • ↓Tear production

  • Impaired visual accommodation

  • Bronchodilation

Effects – anti-histaminic

  • Anti-pruritic effect

  • Sedation

  • Anti-ulcer activity

  • Weight gain

Cardiovascular effects: Much more profound in humans than in dogs and cats

Gastrointestinal effects

  • Vomiting

  • Diarrhea

  • Anorexia

  • Constipation

Behavioral Side effects

  • Sedation

  • Anxiety

  • Restlessness, agitation

  • Sleep disorders

  • Fatigue

  • Headache

  • Ataxia

Other effects

  • Lowered seizure threshold

  • Altered blood glucose levels

  • Bone marrow suppression

  • Bitter taste

     o Difficulty in medicating animals

     o Helps prevent overdosing

Dose management

  • 2 – 4 week latency to effect, sometimes longer

  • Give daily or b.i.d., not "as needed"

  • Stabilize for 1 – 2 months

  • Gradual withdrawal

  • Certain conditions require long-term treatment

  • Metabolized in liver

  • Cleared primarily through urine

  • DO NOT use in combination with a MAOI


  • DOGS 1-6 mg/kg q12-24 h

  • CATS 0.5-2.0 mg/kg q12-24 h


  • DOGS 1-3 mg/kg q12 hr

  • CATS 0.25-2.0 mg/kg q24h


  • DOGS 1.5-3.5 mg/kg q24h


  • CATS 0.5-1.0 mg/kg q12h

  • DOGS 3.0-5.0 mg/kg q8-12h


  • CATS 0.5-1.0 mg/kg q12-24h

  • DOGS 0.5-2.0 mg/kg q8-12h

  • Anti-enuretic effect

     o Canine submissive urination

     o Canine excitement-induced urination


  • CATS 0.5-2.0 mg/kg q12-24h

  • DOGS 1.0-2.0 mg/kg q12h

Serotonin syndrome

  • Mental changes

  • Neuromuscular changes

  • Autonomic changes

  • Usually mild and resolves in 24 to 72 hours

  • Can cause death

  • Mortality rate in humans of 11%

  • Especially likely if taking combinations that

     o Decrease serotonin metabolism: MAOI's

     o Inhibit serotonin uptake: SSRI's, TCA's

     o Serotonin receptor agonists: Buspirone


  • Discontinue all serotonergic medications

  • Benzodiazepines (diazepam or lorazepam) for myoclonus and hypothermia resulting from myoclonus. Clonazepam not effective.

  • Severe cases: cyproheptadine, methysergide, propranolol

  • Supportive treatment

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