What is the mechanism of action of mirtazapine?

Mechanism of Action of Mirtazapine

Mirtazapine works primarily as an antagonist of central presynaptic α2-adrenergic auto- and heteroreceptors, which enhances both noradrenergic and serotonergic neurotransmission, while simultaneously blocking 5-HT2 and 5-HT3 receptors to create a specific serotonergic effect focused on 5-HT1A receptors. 1

Primary Pharmacological Actions

Mirtazapine's mechanism involves several distinct receptor interactions:

• α2-Adrenergic Antagonism:

  • Blocks presynaptic α2-adrenergic autoreceptors on noradrenergic neurons, increasing norepinephrine release 1, 2
  • Blocks α2-adrenergic heteroreceptors on serotonergic neurons, enhancing serotonin release 3
  • Has 10-fold higher affinity for central presynaptic α2-receptors than for postsynaptic receptors 4

• Serotonergic Effects:

  • Potent antagonist of postsynaptic 5-HT2 and 5-HT3 receptors 1, 3
  • Enhances 5-HT1A-mediated serotonergic transmission indirectly 3
  • Does not inhibit serotonin reuptake (unlike SSRIs) 4

• Other Receptor Activity:

  • Strong antagonist of histamine (H1) receptors, explaining its sedative effects 1
  • Antagonist of peripheral α1-adrenergic receptors, contributing to orthostatic hypotension 1
  • Antagonist of muscarinic receptors, but with lower affinity than TCAs 1, 4

Unique Aspects of Mirtazapine's Mechanism

Mirtazapine is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA) due to its unique dual mechanism 3:

1. It increases noradrenergic transmission directly through α2-autoreceptor blockade
2. It enhances serotonergic transmission through two mechanisms:
   • Blocking α2-heteroreceptors on serotonergic neurons
   • Enhancing stimulatory effect of norepinephrine on serotonergic cell firing (α1-adrenoceptor mediated) 4
3. It selectively enhances 5-HT1A-mediated serotonergic activity while blocking 5-HT2 and 5-HT3 receptors 3

Clinical Implications of Mechanism

The receptor profile of mirtazapine explains its clinical effects:

• Antidepressant Efficacy: Results from enhanced noradrenergic and 5-HT1A-mediated serotonergic transmission 2

• Anxiolytic Effects: Attributed to 5-HT2 and 5-HT3 receptor blockade 3

• Sleep Improvement: Due to potent H1 receptor antagonism and 5-HT2 receptor blockade 1, 3

• Side Effect Profile:

  • Sedation and increased appetite (54% and 17% respectively) due to H1 receptor antagonism 5, 1
  • Weight gain (10%) related to H1 blockade and increased appetite 5
  • Lower doses (7.5-15mg) are more sedating due to predominant H1 antagonism 5
  • Minimal sexual dysfunction compared to SSRIs due to different mechanism 6

Pharmacokinetic Considerations

• Bioavailability is approximately 50% 1
• Peak plasma concentrations reached within 2-3 hours 1, 4
• Extensively metabolized in the liver via CYP2D6, CYP1A2, and CYP3A4 1, 6
• Elimination half-life of 20-40 hours, allowing once-daily dosing 1, 2

Clinical Pitfalls and Considerations

• Lower doses (7.5-15mg) tend to be more sedating due to predominant H1 receptor antagonism, while higher doses (30-45mg) have more balanced noradrenergic and serotonergic effects 5
• Mirtazapine may cause rare but serious hematological effects such as agranulocytosis and neutropenia 5, 4
• Mirtazapine is not recommended as an appetite stimulant in persons with dementia due to uncertain benefits and potential harmful side effects 5
• Unlike SSRIs, mirtazapine does not directly block serotonin reuptake, which explains its different side effect profile 4, 6

Mirtazapine's unique mechanism of action distinguishes it from other antidepressants and explains its particular efficacy profile and side effect pattern, making it a valuable option for patients who cannot tolerate or do not respond to other antidepressant classes.