Serotonin and norepinephrine reuptake inhibitors to treat behavior problems (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 -adrenoceptors and serotonin receptors, as well as altered function of various serotonin receptors.

TCA's also

• -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

• May decrease seizure threshold, especially TCA's

• May alter blood glucose, especially SSRI's

• Slow onset of action

• Metabolized in liver

• Excreted through kidneys

• May have 1-4 week latency to effect

• Long t1/2

• DO NOT USE WITH MAOI's

SSRI's

Citalopram Hydrobromide

Dogs: 0.5-1.0 mg/kg q24h

Has been used to treat canine acral lick dermatitis

Fluoxetine Hydrochloride (Prozac®, Reconcile™)

DOGS: 1.0-2.0 mg/kg q24h

CATS 0.5-1.5 mg/kg q24h

FDA approved for Separation Anxiety in Dogs

In an open trial of 65 dogs with psychogenic pruritis, acral lick granulomas, tail mutilation, separation anxiety and miscellaneous behavioral problems, onset of efficacy was 5 to 16 days

Fluoxetine in Cats (Pryor et al. 2001)

Cats treated with fluoxetine showed a significant decrease in spraying by the second week, and continued to exhibit a decreased frequency through the end of an 8 week study.

Paroxetine HCl Paxil®

CATS: 0.5-1.0 mg/kg

DOGS: 0.5-1.0 mg/kg

Uses in animals

• Published efficacy for

• Urine spraying and aggression in cats

• Generalized anxiety disorder in dogs

• Weaving in horses

Sertraline (Zoloft®)

CATS: 0.5-1.0 mg/kg

DOGS: 0.5-4.0 mg/kg

• Published efficacy for

• Acral lick dermatitis (ALD) in dogs

• Aggressiveness in lizards (Anolis carolinensis)

TCA's-Tricyclic Antidepressants

Named after chemical structure

Tertiary Amines

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

• More potent inhibition of 5-HT uptake

• More potent a-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

General arousal

Attention

Mood reactivity

Stress response modulation

Serotonin

Regulate mood states

Fear responses

Feeding behavior

Stress response

Impulsive behavior

Effects - a-Adrenergic

Orthostatic hypotension, Dizziness, Syncope, Sedation, Vasoconstriction, Smooth muscle contraction

Effects - Cholinergic

Urinary retention, Dry mouth, Dental pathology, Stomatitis, Mydriasis, Tear production, Impaired visual accommodation, Blurred vision, 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

• ECG Assessment in Dogs

• Research on cardiac function in dogs given amitriptyline and clomipramine

• No ECG changes between pre and post-treatment

• No differences between untreated and treated dogs

Bitter taste

• Difficulty in medicating animals

• Helps prevent overdosing

• Dose Management

o 2 – 4 week latency to effect, sometimes longer

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

o Stabilize for 1 – 2 months

o Gradual withdrawal

o Certain conditions require long-term treatment

Toxicity in Companion Animals

Illinois Animal Poison Information Center-456 calls (1985-1989)-> 7% fatality rate

• 15 mg/kg PO potentially fatal

TCA Toxicity

Treatment-No specific antidote, Emetics not indicated, Supportive care, Airway support, Gastric lavage, Activated charcoal, Diazepam for seizures, Na bicarbonate for acidosis, Physostigmine IV helps with CNS and cardiac toxic effects in humans

Amitriptyline (Elavil)

Dog 1-6 mg/kg q12-24 h

Cat 0.5-2.0 mg/kg q12-24 h

TCA with most potent H1 blockade

Significantly less effective than clomipramine for compulsive disorder (Overall and Dunham 2002)

Clomipramine (Anafranil, Clomicalm™)

Dog 1-3 mg/kg q12 hr

Cat 0.25-2.0 mg/kg q24h

FDA approved for Separation Anxiety in Dogs

Desipramine

Dog 1.5-3.5 mg/kg q24h

Doxepin (Sinequan)

Cat 0.5-1.0 mg/kg q12h

Dog 3.0-5.0 mg/kg q8-12h

Imipramine

Cat 0.5-1.0 mg/kg q12-24h

Dog 0.5-2.0 mg/kg q8-12h

• Anti-enuretic effect

• Canine submissive urination

• Canine excitement-induced urination

• Urinary incontinence (dogs and cats)

Nortriptyline (Pamelor®)

Cat 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

Crowell-Davis SL and Murray T 2006. Veterinary Psychopharmacology, Blackwell Publishing.