Mirtazapine

Tetracyclic antidepressant Noradrenergic and specific serotonergic antidepressant (NaSSA)

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Cat PO 1.88 mg/cat (or 0.5-1 mg/kg) every 24-48 hours q24h or q48h Duration: Variable; often used for weeks to months depending on condition
Notes: For appetite stimulation, lower doses are often effective. In renal insufficiency, extend interval to q48h.
Dog PO 0.5-1 mg/kg every 12-24 hours q12h or q24h Duration: Variable; often used for weeks to months
Notes: For anxiety, may be used at 0.5-1 mg/kg q12-24h. For appetite stimulation, lower doses may be sufficient.
Rabbit PO 0.5-1 mg/kg every 24 hours q24h Duration: Variable
Notes: Use with caution; limited studies.

Clinical Indications & Species Uses

General Indications
  • Appetite stimulation
  • Antiemetic (off-label)
  • Sedation (off-label)
Dog (Canine)
  • Appetite stimulation in chronic illness
  • Weight loss management
  • Anxiety disorders (off-label)
  • Nausea and vomiting (off-label)
Cat (Feline)
  • Appetite stimulation in chronic kidney disease
  • Appetite stimulation in cancer
  • Appetite stimulation in other chronic illnesses
  • Nausea and vomiting (off-label)
  • Behavioral disorders (off-label)
Rabbit & Small Mammals
  • Appetite stimulation (off-label)
Exotic & Other Species
  • Appetite stimulation in some exotic species (off-label)

Pharmacology & Mechanism of Action

Drug Class: Tetracyclic antidepressant | Pharmacological Group: Noradrenergic and specific serotonergic antidepressant (NaSSA)

Mechanism of Action: Mirtazapine acts as an antagonist at central presynaptic alpha-2 adrenergic receptors, which results in increased release of norepinephrine and serotonin. It also blocks 5-HT2 and 5-HT3 receptors, leading to enhanced serotonergic transmission at 5-HT1A receptors. Additionally, it has potent antihistaminic (H1) activity, which contributes to its sedative and appetite-stimulating effects. It also antagonizes 5-HT7 receptors, which may contribute to its antidepressant and sleep-promoting effects.

Pharmacodynamics: Mirtazapine enhances noradrenergic and serotonergic neurotransmission. Its antagonism of 5-HT2 and 5-HT3 receptors reduces the adverse effects associated with non-selective serotonin receptor activation (e.g., sexual dysfunction, nausea). The H1 antihistaminic effect causes sedation and increased appetite. In veterinary medicine, the appetite-stimulating effect is often the primary therapeutic goal, particularly in cats with chronic kidney disease or other conditions causing anorexia.

⚡ Pharmacokinetics Summary

Absorption: Mirtazapine is well absorbed after oral administration. In cats, absorption is rapid with peak plasma concentrations occurring within 1-2 hours. Food may slightly delay absorption but does not significantly affect overall bioavailability.
Distribution: Mirtazapine is widely distributed throughout the body. It is lipophilic and crosses the blood-brain barrier. The volume of distribution is large, and it is extensively bound to plasma proteins (approximately 85% in humans; similar in animals).
Metabolism: Mirtazapine is extensively metabolized in the liver via demethylation and hydroxylation, primarily by cytochrome P450 enzymes (CYP2D6, CYP1A2, and CYP3A4 in humans). In animals, similar pathways are presumed. The metabolites are mostly inactive or have reduced activity.
Excretion: Mirtazapine and its metabolites are excreted primarily in the urine (about 75%) and feces (about 15%). In cats, the elimination half-life is approximately 8-12 hours, but it can be prolonged in animals with hepatic or renal impairment.
Half-Life: Cats: 8-12 hours; Dogs: approximately 4-6 hours; Humans: 20-40 hours.
Bioavailability: Oral bioavailability is approximately 50% in humans; in cats, it is estimated to be around 60-70% due to first-pass metabolism.
Protein Binding: Approximately 85% (in humans; similar in animals).

Available Formulations & Strengths

Oral Tablet 3.75 mg, 7.5 mg, 15 mg, 30 mg, 45 mg (PO)
Oral Solution 15 mg/mL (compounded) (PO)
Transdermal Gel 5 mg/0.1 mL (compounded) (Topical (applied to inner ear pinna))

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to mirtazapine or any component
  • Concurrent use with MAO inhibitors (e.g., selegiline) - risk of serotonin syndrome
  • Severe hepatic impairment (use with caution)
  • Severe renal impairment (use with caution, adjust dose)
Warnings & Clinical Precautions:
  • Use with caution in animals with cardiovascular disease, as mirtazapine may cause hypotension or arrhythmias.
  • May cause sedation; monitor for excessive drowsiness.
  • In cats with chronic kidney disease, monitor for signs of serotonin syndrome (e.g., agitation, tremors, hyperthermia) especially when combined with other serotonergic drugs.
  • Use with caution in animals with seizure disorders; may lower seizure threshold.
  • Transdermal formulations may have variable absorption; monitor clinical response.
  • Safety in pregnant or lactating animals has not been established; use only when clearly needed.

Adverse Effects & Reactions

Common:

  • Sedation
  • Increased appetite
  • Weight gain
  • Vomiting (especially at higher doses)
  • Hypersalivation (in cats)
  • Hyperactivity or agitation (paradoxical)

Serious / Severe:

  • Serotonin syndrome (when combined with other serotonergic drugs)
  • Bone marrow suppression (rare)
  • Hepatotoxicity (rare)
  • Seizures (rare)
  • Cardiac arrhythmias (rare)

Rare:

  • Allergic reactions
  • Urinary retention
  • Hypotension
  • Priapism (in males)

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
MAO inhibitors (e.g., selegiline) Increased risk of serotonin syndrome (hyperthermia, agitation, tremors, seizures). High
Other serotonergic drugs (e.g., SSRIs, SNRIs, tramadol) Additive serotonergic effects, risk of serotonin syndrome. High
CNS depressants (e.g., opioids, benzodiazepines, phenobarbital) Additive sedation and respiratory depression. Moderate
Cytochrome P450 inhibitors (e.g., ketoconazole, cimetidine) May increase mirtazapine plasma concentrations. Moderate
Cytochrome P450 inducers (e.g., phenobarbital, rifampin) May decrease mirtazapine plasma concentrations. Moderate
Warfarin May increase anticoagulant effect; monitor coagulation. Moderate

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe sedation
  • Ataxia
  • Tachycardia
  • Hypotension
  • Agitation
  • Tremors
  • Seizures
  • Respiratory depression

Emergency Treatment Protocol: Treatment is symptomatic and supportive. Induce emesis if recent ingestion and animal is conscious. Administer activated charcoal to reduce absorption. Provide intravenous fluids, cardiovascular support, and respiratory support as needed. Monitor for serotonin syndrome and seizures; use benzodiazepines for seizures. There is no specific antidote.

Food Animal Withdrawal Times

Not approved for food animals; no withdrawal times established. Use in food animals is prohibited or requires extended withdrawal periods; consult regulatory authorities.

Storage, Handling & Regulatory Information

Storage Temperature: Store at controlled room temperature 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F).

Handling & Special Conditions: Protect from moisture. Keep in tightly closed container. Compounded formulations may have specific storage requirements; follow label instructions.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Approved for human use; not FDA-approved for veterinary use, but widely used in veterinary medicine as an extra-label drug.

Extra-Label (Off-Label) Use: In the US, extra-label use in food animals is prohibited under AMDUCA if an approved drug exists for that species/indication. Since mirtazapine is not approved for food animals, its use in food animals is not permitted. In companion animals, extra-label use is allowed under veterinary discretion.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Mirtazapine is commonly used in veterinary medicine as an appetite stimulant, particularly in cats with chronic kidney disease, cancer, or other chronic illnesses. It is also used off-label for nausea and anxiety. In cats, the transdermal formulation is popular for ease of administration, but oral administration is more reliable. Doses should be adjusted in renal or hepatic impairment. Monitor for sedation and gastrointestinal upset. Avoid concurrent use with serotonergic drugs to prevent serotonin syndrome. Clinical response may take several days to assess; if no improvement in appetite after 2-3 days, reassess the treatment plan.

References & Literature

  • 📚 Plumb's Veterinary Drug Handbook
  • 📚 Papich Veterinary Pharmacology and Therapeutics
  • 📚 Compendium of Veterinary Products (CVP)