indication

For the treatment of major depressive disorder.

pharmacology

Mirtazapine, an antidepressant of the piperazinoazepine class, is a tetracyclic compound with an anxiolytic effect. Mirtazapine has fewer ADRs than tricyclic antidepressants and is better tolerated. Selective blockade of specific serotonin receptors by mirtazapine likey minimizes side effects typical of other antidepressants.

mechanism of action

Mirtazapine acts as an antagonist at central pre-synaptic alpha(2)-receptors, inhibiting negative feedback to the presynaptic nerve and causing an increase in NE release. Blockade of heteroreceptors, alpha(2)-receptors contained in serotenergic neurons, enhances the release of 5-HT, increasing the interactions between 5-HT and 5-HT₁ receptors and contributing to the anxiolytic effects of mirtazapine. Mirtazapine also acts as a weak antagonist at 5-HT₁ receptors and as a potent antagonist at 5-HT₂ (particularly subtypes 2A and 2C) and 5-HT₃ receptors. Blockade of these receptors may explain the lower incidence of adverse effects such as anxiety, insomnia, and nausea. Mirtazapine also exhibits significant antagonism at H1-receptors, resulting in sedation. Mirtazapine has no effects on the reuptake of either NE or 5-HT and has only minimal activity at dopaminergic and muscarinic receptors.

toxicity

Symptoms of overdose include disorientation, drowsiness, impaired memory, and tachycardia. LD50 is 600-720mg/kg (oral, mice) and 320-490mg/kg (oral, rat) [PMID: 10333982]

biotransformation

Mirtazapine is extensively metabolized by demethylation and hydroxylation followed by glucuronide conjugation. Cytochrome P450 2D6 and cytochrome P450 1A2 are involved in formation of the 8-hydroxy metabolite of mirtazapine, and cytochrome P450 3A4 is responsible for the formation of the N-desmethyl and N-oxide metabolites. Several metabolites possess pharmacological activity, but plasma levels are very low.

absorption

Rapid and complete, but, due to first-pass metabolism, absolute bioavailability is 50%.

half life

20-40 hours

route of elimination

This drug is known to be substantially excreted by the kidney (75%).

drug interactions

Clonidine: Possible hypertensive crisis

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Donepezil: Possible antagonism of action

Ethotoin: The hydantoins may reduce mirtazapine plasma concentrations and pharmacological effects

Fluvoxamine: Fluvoxamine may increase the therapeutic and adverse effects of mirtazapine.

Fosphenytoin: The hydantoins may reduce mirtazapine plasma concentrations and pharmacological effects

Galantamine: Possible antagonism of action

Isocarboxazid: Possible severe adverse reaction with this combination

Mephenytoin: The hydantoins may reduce mirtazapine plasma concentrations and pharmacological effects

Phenelzine: Possible severe adverse reaction with this combination

Phenytoin: The hydantoins may reduce mirtazapine plasma concentrations and pharmacological effects

Rasagiline: Possible severe adverse reaction with this combination

Rivastigmine: Possible antagonism of action

Telithromycin: Telithromycin may reduce clearance of Mirtazapine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Mirtazapine if Telithromycin is initiated, discontinued or dose changed.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Mirtazapine. Consider alternate therapy or monitor for therapeutic/adverse effects of Mirtazapine if Terbinafine is initiated, discontinued or dose changed.

Tramadol: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Tranylcypromine: The MAO inhibitor, Tranylcypromine, may increase the central neurotoxic effects of the Mirtazapine. These agents should not be administered within 14 days of each other.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Triprolidine: The CNS depressants, Triprolidine and Mirtazapine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of mirtazapine by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of mirtazapine if voriconazole is initiated, discontinued or dose changed.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and mirtazapine, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.