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

Abbreviations

• 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

Action-SSRI's

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

Action-SNRI's

• 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

SSRI's

• 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

Citalopram

• 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

Paroxetine

• CATS: 0.5-1.0 mg/kg

• DOGS: 0.5-1.0 mg/kg

Sertraline

• CATS: 0.5-1.0 mg/kg

• DOGS: 0.5-4.0 mg/kg

TCA's

• 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

Amitriptyline

• DOGS 1-6 mg/kg q12-24 h

• CATS 0.5-2.0 mg/kg q12-24 h

Clomipramine

• DOGS 1-3 mg/kg q12 hr

• CATS 0.25-2.0 mg/kg q24h

Desipramine

• DOGS 1.5-3.5 mg/kg q24h

Doxepin

• CATS 0.5-1.0 mg/kg q12h

• DOGS 3.0-5.0 mg/kg q8-12h

Imipramine

• 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

Nortriptyline

• 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

Management

• 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