Mechanism of Action of Mirtazapine
Mirtazapine enhances noradrenergic and serotonergic neurotransmission by antagonizing central presynaptic α2-adrenergic autoreceptors and heteroreceptors, while simultaneously blocking postsynaptic 5-HT2 and 5-HT3 receptors, resulting in selective enhancement of 5-HT1 receptor-mediated serotonergic activity. 1
Primary Mechanism
Mirtazapine acts as an antagonist at presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors, which removes the brake on norepinephrine release from noradrenergic neurons 1, 2
This α2-receptor blockade occurs on both norepinephrine and serotonin presynaptic axons, leading to increased release of both neurotransmitters 2, 3
The drug has 10-fold higher affinity for central presynaptic α2-adrenoceptors than for central postsynaptic and peripheral α2-adrenoceptors, and 30-fold higher affinity for α2-adrenoceptors than for α1-adrenoceptors 3
Serotonergic Specificity
Mirtazapine potently blocks postsynaptic 5-HT2 and 5-HT3 receptors while having no significant affinity for 5-HT1A and 5-HT1B receptors 1, 2
This selective receptor blockade means that the increased serotonin release specifically stimulates 5-HT1 receptors, as the 5-HT2 and 5-HT3 pathways are blocked 3, 4
The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors, which is thought to provide antidepressant effects while avoiding serotonergic side effects 4
Dual Enhancement Pathway
Mirtazapine increases serotonergic cell-firing in the dorsal raphe through noradrenergic enhancement, as increased norepinephrine stimulates α1-adrenoceptors on serotonergic neurons 5
The drug blocks noradrenaline-mediated inhibition of hippocampal serotonin release (an α2-adrenoceptor-mediated effect), further increasing serotonin availability 5
This results in both direct and indirect enhancement of serotonergic transmission: direct through α2-heteroreceptor blockade on serotonin neurons, and indirect through increased noradrenergic stimulation of serotonergic cell bodies 3, 5
Additional Receptor Activity
Mirtazapine acts as an antagonist of histamine H1 receptors, which explains its prominent sedative effects 1, 3
The drug has antagonist activity at peripheral α1-adrenergic receptors, which may explain orthostatic hypotension 1
Mirtazapine has very weak affinity for muscarinic cholinergic receptors, resulting in minimal anticholinergic side effects compared to tricyclic antidepressants 4, 6
The drug does not inhibit serotonin reuptake, distinguishing it from SSRIs and making it mechanistically unique 3, 5
Clinical Classification
Mirtazapine is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA) based on its dual mechanism 5
It has also been described as a tetracyclic antidepressant with noradrenergic and specific serotonergic activity 7, 3
The mechanism differs fundamentally from tricyclic antidepressants (which block reuptake) and SSRIs (which selectively block serotonin reuptake only) 4, 6
Metabolic Considerations
Mirtazapine does not inhibit the reuptake of norepinephrine or serotonin; its effects are purely receptor-mediated 3, 5
The drug is extensively metabolized in the liver via demethylation and hydroxylation followed by glucuronide conjugation, with CYP2D6 and CYP1A2 involved in 8-hydroxy metabolite formation and CYP3A responsible for N-desmethyl and N-oxide metabolites 1
Unconjugated metabolites possess pharmacological activity but are present at very low plasma levels, with the desmethyl metabolite being less active than the parent compound 1, 4