What is the mechanism of action of mirtazapine in treating major depressive disorder?

Mechanism of Action of Mirtazapine

Primary Mechanism

Mirtazapine enhances both noradrenergic and serotonergic neurotransmission through antagonism of central presynaptic α2-adrenergic inhibitory auto-receptors and heteroreceptors, though the precise mechanism underlying its antidepressant efficacy remains unclear. 1

Detailed Pharmacodynamic Actions

Noradrenergic Enhancement

• Mirtazapine blocks central presynaptic α2-adrenergic auto-receptors and heteroreceptors, which removes inhibitory feedback on norepinephrine release, thereby increasing noradrenergic neurotransmission 1, 2
• The drug demonstrates 10-fold higher affinity for central presynaptic α2-adrenoceptors compared to peripheral α2-adrenoceptors 3

Serotonergic Enhancement

• Mirtazapine enhances serotonergic neurotransmission specifically through 5-HT1 receptor-mediated pathways while simultaneously blocking postsynaptic 5-HT2 and 5-HT3 receptors 1, 2
• The increased serotonin release is channeled through 5-HT1 receptors because mirtazapine directly antagonizes 5-HT2 and 5-HT3 receptors, preventing serotonin from acting at these sites 3
• Mirtazapine has no significant affinity for 5-HT1A and 5-HT1B receptors 1

Dual Mechanism Integration

• The enhancement of serotonergic transmission occurs through two complementary pathways: (1) stimulating the noradrenergic system's excitatory effect on serotonergic cell firing via α1-adrenoceptor activation, and (2) blocking the noradrenergic system's inhibitory effect on serotonin release via α2-adrenoceptor antagonism 3
• Mirtazapine does not inhibit serotonin or norepinephrine reuptake, distinguishing it from SSRIs and tricyclic antidepressants 2, 3

Additional Receptor Activities

Histamine and Other Receptors

• Mirtazapine acts as an antagonist at histamine H1 receptors, which explains its prominent sedative effects, particularly at lower doses 1, 2
• The drug antagonizes peripheral α1-adrenergic receptors, accounting for potential orthostatic hypotension 1
• Mirtazapine has very weak affinity for muscarinic cholinergic receptors, resulting in minimal anticholinergic side effects 2, 3

Clinical Implications of Mechanism

Rapid Onset of Action

• The dual enhancement of both noradrenergic and 5-HT1 receptor-mediated neurotransmission contributes to mirtazapine's statistically significantly faster onset of action compared to SSRIs like citalopram, fluoxetine, paroxetine, and sertraline 4, 5

Unique Side Effect Profile

• The specific blockade of 5-HT2 and 5-HT3 receptors prevents serotonin-related adverse effects commonly seen with SSRIs, including gastrointestinal disturbances and sexual dysfunction 2, 6
• Histamine H1 receptor antagonism produces transient somnolence and increased appetite, which are the most commonly reported adverse events and may be more prominent at lower doses 2, 6

Anxiolytic and Sleep Benefits

• The combination of 5-HT2 and 5-HT3 receptor blockade, along with H1 antagonism, contributes to mirtazapine's beneficial effects on anxiety symptoms and sleep disturbances that commonly accompany depression 5, 7