Mirtazapine

Mirtazapine has become widely used in veterinary medicine due to its commonly recognized effects of appetite stimulation and weight gain.

CLINICAL APPLICATIONS

• Mirtazapine is an effective appetite stimulant in cats^1-5 and is used for nutritional support in both dogs and cats with acute and chronic illness. 

  • Mirtazapine has been demonstrated in placebo-controlled trials to result in appetite stimulation in normal cats and appetite stimulation, weight gain, and improved body condition in cats with chronic kidney disease (CKD).^3,4 

  • The drug’s mechanism of action is not fully understood but likely involves antagonism of the serotonin 2C (5HT_2c) receptor, which is known for its appetite-inhibition activity, as well as antagonism of the histamine 1 (H₁) receptor, which also plays a role in appetite regulation.^6,7 

• Mirtazapine has antiemetic properties due to its antagonism of the serotonin 3 (5HT₃) receptor and has been shown to decrease vomiting in cats with CKD.⁴ 

• Because of its superior receptor-binding affinity, there is some evidence that concurrent administration of mirtazapine with 5HT₃-receptor antagonists (eg, ondansetron) may decrease the efficacy of ondansetron in humans.⁸ 

  • Although evidence for this interaction is not available for cats and dogs, this phenomenon should be taken into account when choosing antiemetic and antinausea regimens.

• Mirtazapine appears anecdotally to have some appetite-stimulating properties in dogs, but no studies have been conducted to assess appetite in healthy or hyporexic dogs receiving this drug.^9,10 

• A prokinetic effect has been demonstrated in healthy dogs that received mirtazapine at 1.7-2.0 mg/kg PO once, resulting in improved gastric emptying and colonic motility.¹¹ 

  • The clinical utility of this prokinetic effect merits further investigation.

PHARMACOKINETICS & PHARMACODYNAMICS

• In cats, administering one-fourth of a 15-mg tablet (3.75 mg) every 3 days was initially recommended based on an early, mostly anecdotal, open clinical trial in which a dose was extrapolated from use in humans¹⁰; however, several studies have since helped determine a more appropriate starting dose for cats. 

• Mirtazapine is amenable to transdermal administration and has been demonstrated to achieve therapeutic serum concentrations in cats.^1,5 

  • Placebo-controlled pharmacodynamic studies have demonstrated that transdermal administration of mirtazapine results in increased appetite in normal cats and increased appetite and weight in cats with CKD.^1,5 

  • Transdermal mirtazapine obtained from compounding pharmacies can have high variability¹ among preparations and may not have the same stability and efficacy as that demonstrated in referenced studies.

• The pharmacokinetics of mirtazapine is affected by age and several disease states.

  • As compared with humans (half-life, 20-40 hours), the half-life of oral mirtazapine in young normal cats is relatively short (9.2 hours).

  • A repeat-dosing study demonstrated little drug accumulation with daily administration of 1.87 mg/cat in young cats^2,3; median peak serum concentrations were reached in one hour.

  • In contrast, the half-life of oral mirtazapine is prolonged in elderly cats (12.1 hours) and cats with CKD (15.2 hours) and/or liver disease (15.1 hours).<sup2,12 sup> 

    • This is similar to pharmacokinetics in humans in which kidney and/or liver disease prolong half-life by 25% to 30%.¹³

• In young healthy dogs, the half-life of mirtazapine is 6 hours, with peak serum concentration at 0.9 hours.⁹

ADMINISTRATION & DOSE INTERVAL

• The variable pharmacokinetics of mirtazapine should be taken into account when determining the dose interval.

• The suggested oral dose interval for cats is 1.87 mg/cat PO q24h in younger cats with normal organ function, q48h in cats with CKD, and q48-72h in cats with liver disease.^2,3,12  

  • A higher dose of 3.75 mg has been associated with increased side effects, typically without any greater efficacy for appetite stimulation.^3,14

    • Some cats may require titration up to this dose.^3,14 

• The suggested (anecdotal) dose interval for dogs is 0.6-1.0 mg/kg q12h. 

  • Studies evaluating dose interval in dogs with liver and/or kidney disease have not been conducted.⁹

SAFETY & ADVERSE EFFECTS

• Adverse effects in cats are dose-dependent and much more likely to occur at higher doses or with accidental administration of an entire 7.5- or 15-mg tablet.^3,14 

  • Adverse effects, which appear to be more common in cats than in dogs, most commonly include vocalization, agitation, vomiting, abnormal gait/ataxia, restlessness, tremors/trembling, hypersalivation, tachypnea, tachycardia, and lethargy.^3,14

  • With both the oral and transdermal formulations, the dose should be titrated to the lowest effective amount for appetite stimulation to minimize adverse effects.

• Subclinical reversible increases in liver enzymes (eg, marked increases in alanine transaminase [possibly idiosyncratic]) may occur as a result of mirtazapine administration; discontinuation of the drug is recommended in these patients.⁴ 

• Concurrent administration with selective serotonin reuptake inhibitors may increase serotonin syndrome-like adverse effects.¹³

CKD = chronic kidney disease