What is the mode of action of Mirtazapine (Remeron)?

From the Guidelines

Mirtazapine's mode of action is primarily characterized by its antagonism of presynaptic alpha-2 adrenergic receptors, increasing the release of norepinephrine and serotonin, and its blockade of certain serotonin receptors, which reduces side effects and enhances antidepressant effects. This unique mechanism of action is distinct from other antidepressants, such as SSRIs and SNRIs, and is supported by studies such as the one published in the Annals of Internal Medicine in 2008 1. The study highlights the efficacy of mirtazapine in treating depressive disorders, including its faster onset of action compared to other antidepressants like fluoxetine, paroxetine, or sertraline.

Some key points about mirtazapine's mode of action include:

• Antagonism of presynaptic alpha-2 adrenergic receptors, which increases the release of norepinephrine and serotonin
• Blockade of certain serotonin receptors (5-HT2A, 5-HT2C, and 5-HT3), which reduces side effects like sexual dysfunction, nausea, and anxiety
• Strong blockade of histamine H1 receptors, contributing to its sedative properties
• Minimal anticholinergic effects and no significant inhibition of the reuptake of serotonin, norepinephrine, or dopamine

The sedative effect of mirtazapine is most pronounced at lower doses (7.5-15mg) and becomes less prominent at higher therapeutic doses (30-45mg) where the noradrenergic effects become more dominant, as noted in the study 1. This unique pharmacological profile makes mirtazapine particularly useful for patients with depression accompanied by anxiety, insomnia, or poor appetite, as it can help improve sleep and stimulate appetite even before its full antidepressant effect develops.

From the FDA Drug Label

The mechanism of action of mirtazapine for the treatment of major depressive disorder, is unclear. However, its efficacy could be mediated through its activity as an antagonist at central presynaptic α2-adrenergic inhibitory auto-receptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.

Mirtazapine acts as an antagonist at α2-adrenergic inhibitory auto-receptors and heteroreceptors and as an antagonist at serotonin 5-HT2 and 5-HT3 receptors.

The mode of action of mirtazapine is not fully understood, but it is believed to be mediated through its activity as an:

• antagonist at central presynaptic α2-adrenergic inhibitory auto-receptors and heteroreceptors
• enhancer of central noradrenergic and serotonergic activity
• antagonist at serotonin 5-HT2 and 5-HT3 receptors 2

From the Research

Mode of Action

• Mirtazapine is a unique antidepressant that refines the specificity of effects on noradrenergic and serotonergic systems 3.
• It is an antagonist of presynaptic alpha 2-adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin (5-HT) presynaptic axons, plus is a potent antagonist of postsynaptic 5-HT2 and 5-HT3 receptors 3, 4.
• The net outcome of these effects is increased noradrenergic activity together with specific increased serotonergic activity, especially at 5-HT1A receptors 3, 5.
• Mirtazapine enhances noradrenergic and serotonergic neurotransmission via blockade of central α2-adrenergic auto- and heteroreceptors 4.
• The increased release of serotonin (5-hydroxytryptamine; 5-HT) stimulates serotonin 5-HT1 receptors because mirtazapine directly blocks 5-HT2 and 5-HT3 receptors 4.

Pharmacological Profile

• Mirtazapine has a high affinity for serotonin 5-HT2 and 5-HT3 receptors, central and peripheral histamine H1 receptors and a low affinity for 5-HT1, dopaminergic and muscarinic cholinergic receptors 4.
• The bioavailability of mirtazapine is approximately 50% 4.
• Peak plasma concentrations are reached within 2.2 to 3.1 hours after single oral doses of 15 to 75mg and are dose-dependent 4.
• Mirtazapine is extensively metabolised in the liver; up to 85% of the drug is eliminated in the urine (up to 4% as unchanged drug) and the remaining 15% is eliminated in the faeces 4.

Clinical Efficacy

• Mirtazapine produces clinical improvements significantly superior to those of placebo, similar to those of tricyclic antidepressants (TCAs) and possibly superior to those of trazodone 4.
• The antidepressant efficacy of mirtazapine was established in several placebo-controlled trials 5, 6, 7.
• Mirtazapine is effective in all levels of severity of depressive illness, as well as in a broad range of symptoms associated with depression 7.
• It seems to be safe and effective during long-term use 5.