Serotonin reuptake inhibitors: pros and cons (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.Chronic administration causes decreased numbers of serotonin receptors, as well as altered function of various sertonin receptors.

Action-SNRI's

• 5-HT reuptake inhibition and NE reuptake inhibition

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

• TCA's also have a-1 adrenergic antagonism, are anticholinergic and 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

Ssri's

• Slow onset of action

• Give daily, not “as needed”

• Can require 4-8 weeks to take full effect

• Metabolized in liver

• Excreted through kidneys

• May have 1-4 week latency to effect

• Long t1/2

Citalopram hydrobromide

• DOGS: 0.5-1.0 mg/kg q24h

Fluoxetine hydrochloride (prozac®, reconcile™)

• DOGS: 1.0-2.0 mg/kg q24h

• CATS 0.5-1.5 mg/kg q24h

Contraindications

• Reduce dose with patients with hepatic or kidney impairment

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

• History of seizures

• Use cautiously with TCA                       

• DO NOT use with MAOI

Pharmacokinetics

• Well absorbed after oral administration

• Metabolized by cytochrome P450 enzyme system to norfluoxetine, which is active

• In dogs, the elimination half-life of fluoxetine is 6-7 hours

Half-life of norfluoxetine is about 2 days

• Reconcile™End of 8 weeks

• 73% of dogs on Reconcile showed improvement

• 51% of dogs on placebo showed improvement

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

Sertraline (zoloft®)

• CATS: 0.5-1.0 mg/kg

• DOGS: 0.5-4.0 mg/kg

Tca's: tricyclic antidepressants

• 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 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 Serotonin Decrease general arousal Regulate mood states Increase attention Decrease fear responses Decrease mood reactivity Decrease or increase feeding behavior Increase stress response modulation Decrease impulsive behavior

Effects - a-Adrenergic antagonism

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

Effects - anticholinergic

• 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

• Gastrointestinal Effects: Vomiting, Diarrhea, Anorexia,Constipation

• Behavioral: Anxiety, Restlessness, Agitation, Sleep disorders, Fatigue, Headache, Ataxia

• Other Effects: Lowered seizure threshold, Altered blood glucose levels,Bone marrow suppression

• Bitter taste→Difficulty in medicating animals-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

Pharmacokinetics

• Individual variation in metabolic rate

• “Poor metabolizers”

• Hepatic P450 enzymes

• Decreased renal clearance in human geriatric patients

• Clinical experience→Some dogs appear to be poor metabolizers

Drug interactions

• MAOIs, Anticholinergics, Sympathomimetics, Cardiac toxicity, Thyroid supplements, Anti-thyroid agents, Agranulocytosis

• Cytochrome P450 competition: Antidepressants, Antipsychotics, Psychostimulants

• Precautions: Glaucoma, Urinary retention, Cardiac disease, Thyroid disease, Seizure disorder, Adrenal tumors, Liver disease, Kidney disease, Pregnant female, Lactating female

Tca toxicity

• Narrow therapeutic index in humans

• 1 week supply for a dog could be fatal to a human

• Toxicity at 2-6 x normal clinical dose

• 5% human fatality rate for overdoses

Toxicity in Companion Animals

• Illinois Animal Poison Information Center: 456 calls (1985-1989)

• Accidental ingestion of TCAs

• > 7% fatality rate

• ³ 15 mg/kg PO potentially fatal

Treatment

• No specific antidote, Emetics not indicated except in first 30 minutes, 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

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

• Used effectively in cats for Idiopathic cystitis, Excessive vocalization in a cat, Psychogenic alopecia

Clomipramine (anafranil, clomicalm™)

• DOG                       1-3 mg/kg q12 hr

• CAT                        0.25-2.0 mg/kg q24h

Pharmacokinetics

• Most serotonin selective of the TCA's

• Metabolites: Desmethylclomipramine

• Higher concentration than parent compound in humans, but not in dogs

• Potent NE REuptake inhibitor

Comparative pharmacokinetics

• Clomipramine: Desmethylclomipramine concentration

• Dog 3:1

• Human 1:2.5

• May be reason adverse events more common in humans

• Desmethylclomipramine has stronger anticholinergic activity than clomipramine

• Most common side effects: Mild sedation, usually transient, Vomiting, Appetite changes

• Also mydriasis and urinary retention

Administration: Single or divided dose

• 2-4 mg/kg (total daily label dose)

• With or without food (administration with food may reduce incidence of emesis)

• In practice, I often go up to 6 mg/kg tdd

• In clinical trials for Separation Anxiety, 75% of dogs were considered improved by their owners after one month of dosing

Higher doses more effective than lower doses (Simpson 1997; King et al. 2000)

• I only use low dose (1 mg/kg b.i.d.) in geriatric patients or patients with mild compromise of liver or kidney function

• Stereotypies/Compulsive Disorder

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: In humans is used for depression and childhood enuresis

• Canine submissive urination, Canine excitement-induced urination, Urinary incontinence (dogs and cats)

• Mild OCD

Nortriptyline (pamelor®)

• CAT        0.5-2.0 mg/kg q12-24h

• DOG       1.0-2.0 mg/kg q12h