Mirtazapine

Mirtazapine

Jessica M. Quimby, DVM, PhD, DACVIM, The Ohio State University

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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 cats1-5 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 (5HT2c) receptor, which is known for its appetite-inhibition activity, as well as antagonism of the histame 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 cats2,3; 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).2,12 
      • 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

References

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