Mechanism of Action:

• Blocks SERT pre-synaptically; increases 5-HT in amygdala, prefrontal cortex, and hypothalamus
• Long-acting active metabolite: norfluoxetine (half-life 5–14 days in dogs, 7–9 days in cats)
• Requires 4–6 weeks to achieve full therapeutic effect due to receptor downregulation and neuroplasticity
• Has weak norepinephrine reuptake inhibition at higher doses; 5-HT2 receptor blockade properties

FDA Approval:

• Reconcile (Eli Lilly): FDA-approved for canine separation anxiety (2007); first veterinary-labeled behavioral drug in the United States
• Reconcile is flavored (beef) for palatability
• Generic fluoxetine capsules/tablets are commonly used off-label for all other indications

Indications in Dogs:

• Separation anxiety (FDA-approved): howling, destruction, elimination, panting when owner absent
• Generalized anxiety disorder
• Noise phobia (thunderstorm, fireworks) — as baseline maintenance; combine with situational anxiolytics (trazodone, clonidine, gabapentin)
• Canine compulsive disorder (OCD): tail chasing, flank sucking, repetitive pacing, acral lick dermatitis
• Interdog aggression and fear-based aggression
• Stereotypic behavior in working/sporting breeds

Indications in Cats:

• Inappropriate elimination (urine spraying, periuria): reduces marking behavior in 50–70% of cases
• Feline intercat aggression
• Compulsive behaviors: excessive grooming (psychogenic alopecia), repetitive vocalization
• Generalized anxiety and hypervigilance

Behavioral Medicine Principle:

• Systematic desensitization and counter-conditioning protocols
• Environmental enrichment
• Owner education (avoid punishment; use positive reinforcement)

Canine Dosing:

• Starting dose: 1 mg/kg PO once daily
• Therapeutic range: 1–2 mg/kg PO once daily
• Maximum dose: 2 mg/kg/day (doses above this increase adverse effect risk without additional benefit in most dogs)
• Reconcile formulation: 8 mg, 16 mg, 32 mg, and 64 mg scored tablets given once daily

Dose titration in dogs:

• Start at 1 mg/kg PO q24h for 4–6 weeks
• If partial response with acceptable tolerability: increase to 1.5–2 mg/kg PO q24h
• Allow 4–6 weeks at each dose before assessing response (due to neuroadaptation lag)

Feline Dosing:

• Starting dose: 0.5–1 mg/kg PO once daily (or 5 mg/cat/day in most average-sized cats)
• Therapeutic range: 0.5–1.5 mg/kg PO once daily
• Many cats respond at 5 mg PO q24h regardless of exact body weight
• Use liquid formulation (Prozac solution 20 mg/5 mL) or compounded chicken-flavored liquid for palatability

Titration in cats:

• Start at 5 mg/cat PO q24h; reassess in 4–6 weeks
• If insufficient response: increase to 7.5–10 mg/cat/day
• Some cats respond to every-other-day dosing if side effects limit daily use

Tablet Splitting and Compounding:

• Human 10 mg and 20 mg capsules can be used; split carefully or open capsule into food
• Compounded liquid formulations: convenient for cats; confirm concentration with pharmacy
• Chewable beef-flavored Reconcile tablets are preferred for dogs with pill refusal

Discontinuation Protocol:

• Taper over 4–6 weeks rather than abrupt discontinuation to avoid discontinuation syndrome (anxiety rebound, GI upset)
• Reduce by 25–50% per week during tapering

When to Expect Response:

• Initial behavioral changes: 2–4 weeks
• Full therapeutic effect: 6–8 weeks at therapeutic dose
• Inform owners of delayed onset to improve compliance
• If no response at 8 weeks at maximum dose: reassess diagnosis; consider combination therapy

Common Adverse Effects:

• GI effects (most common): Anorexia (10–20%), nausea, vomiting, diarrhea; typically transient in first 1–2 weeks
• Sedation or behavioral activation: Initial lethargy or paradoxical agitation/anxiety in first 1–2 weeks
• Urinary retention: Rare; reported in cats with prior lower urinary tract disease
• Weight changes: Mild weight loss in some dogs at higher doses
• Tremors or ataxia: Rare; if persistent, reduce dose

Adverse Effects Specific to Cats:

• Anorexia: Can be significant in cats; monitor closely in first 2 weeks
• Increased vocalization or agitation in some cats (switch to buspirone if this occurs)
• Hypersalivation or nausea after compounded liquid doses (formulation-related; try different flavoring)

High-risk combinations with fluoxetine:

• MAOIs: Amitraz (tick collar/dip), selegiline — CONTRAINDICATED; 14-day washout before/after fluoxetine
• Tramadol: Weak serotonin reuptake inhibitor; combination increases serotonin syndrome risk — use caution; consider alternative opioids (buprenorphine, methadone)
• Other SSRIs or SNRIs (sertraline, venlafaxine)
• Tryptophan supplements
• St. John's Wort
• Linezolid (antibiotic with MAOI activity)

Serotonin Syndrome Signs:

• Agitation, hyperthermia, tachycardia, hypertension
• Muscle tremors, clonus, hyperreflexia
• GI signs: vomiting, diarrhea
• In severe cases: rhabdomyolysis, seizures, respiratory failure

Management of Serotonin Syndrome:

• Discontinue fluoxetine and all serotonergic drugs immediately
• Cyproheptadine (5-HT2A antagonist): 1.1 mg/kg PO (crushed and given via syringe) q4–6h in dogs; 2–4 mg/cat PO q6–12h
• Supportive care: IV fluids, cooling, benzodiazepines for muscle tremors, ICU monitoring

Other Drug Interactions:

• Fluoxetine inhibits CYP2D6 and CYP3A4: increases plasma levels of diazepam, cyclosporine, certain opioids
• Phenobarbital may reduce fluoxetine levels via hepatic enzyme induction — may need dose adjustment
• NSAIDs: additive GI mucosal risk at higher fluoxetine doses