mirtazapine (Remeron)

Introduction

Tradename: Remeron

Indications

• treatment of major depression
  • may improve appetite in patients with major depression
  • especially good for anxiety, somatisation, sleep disturbance & in patients with Parkinson's disease
• intractable pruritus
• chronic tension headache
• anxiety associated with repetitive behaviors

* not useful for treatment of obstructive sleep apnea

Contraindications

• concurrent use of MAO inhibitor
  • separate by a 2 week washout

pregnancy category = c

safety in lactation = ?

Dosage

• Start 15 mg PO QHS
• Average effective dose: 15-45 mg/day
• Maximum: 45 mg/day

Tabs: 7.5, 15 & 30 mg.

Pharmacokinetics

• rapidly & completely absorbed following oral administration
• absorption not affected by food
• peak plasma levels reached 2 hours after oral dose
• absolute bioavailability is about 50%
• metabolized extensively by liver
  • demethylation & hydroxylation
  • glucuronide conjugation
  • cyt P450 2D6 & 1A2 catalyze formation of 8-OH metabolite
  • cyt P450 3A4 catalyzes formation of N-desmethyl & N-oxide metabolites
• protein binding 85%
• elimination 1/2life of 20-40 hours
  • the (-) enantiomer has a 1/2life twice that of the (+) enantiomer
  • mean t1/2 for females is 37 hours; 26 hours for males
  • elimination 1/2life of 13-34 hours in younger adults
  • elimination 1/2life of 31-39 hours in older adults
• metabolites eliminated in the urine (75%) & feces (15%)

elimination via liver

elimination via kidney

1/2life = 20-40 hours

protein binding = 85 %

Adverse effects

• common (> 10%)
  • increased appetite (15-20%) with weight gain
    • greatest weight gain among antidepressants
  • somnolence (sedation)
• less common (1-10%)
  • low anticholinergic effects
    • dry mouth
    • constipation
    • confusion
    • dizziness
  • abnormal thought & abnormal dreams
  • increased serum cholesterol & triglycerides
• uncommon (< 2%)
  • agranulocytosis (0.1%, 3 cases, all reversible)
  • tremor
  • dyspnea
  • urinary frequency
  • increased alanine transaminase (ALT) > 3-fold (2%)
  • nausea
• other
  • sedation at a lower dose of 7.5 mg/day is overcome at a higher dose of 15 mg/day
  • orthostatic hypotension
  • No sexual dysfunction
  • anxiety may occur upon discontinuation

Overdose: No specific antidotes for overdose.

• drug adverse effects of antidepressants
• drug adverse effects of psychotropic agents
• drug adverse effects of antihypertensive agents

Drug interactions

• drugs metabolized by or inhibiting cyt P450 2D6, 1A2, or 3A4 are expected to have some interaction
• diazepam has minimal effect on mirtazapine plasma levels, but effects on motor skills were additive
• alcohol had minimal effect on mirtazapine plasma levels, but effects on motor & cognitive skills were additive
• increased CNS depression with clonidine

• drug interaction(s) of benzodiazepines with antidepressants
• drug interaction(s) of antidepressants with benzodiazepines
• drug interaction(s) of NSAIDs with antidepressants
• drug interaction(s) of NSAIDs & antihypertensives

Mechanism of action

• central alpha-2 adrenergic receptor antagonist
• moderate peripheral alpha-1 adrenergic receptor antagonist
• potent antagonist of 5HT2 & 5HT3 receptors
  • no affinity for 5HT1a or 5HT1b receptors
• antagonist of histamine H1 receptor
• moderate antagonist of muscarinic receptors
• increases norepinephrine activity
• increases serotonin activity via alpha-1 heteroreceptors on serotoninergic neurons

More general terms

• alpha-2 adrenergic receptor antagonist
• atypical antidepressant

Additional terms

• cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2)
• cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6)
• cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4205