From the Guidelines
Mirtazapine works as an antidepressant by increasing levels of norepinephrine and serotonin in the brain through a unique mechanism of action. This mechanism involves blocking certain receptors, including:
- Alpha-2 adrenergic receptors, which increases the release of norepinephrine and serotonin 1
- Certain serotonin receptors (5-HT2 and 5-HT3), which enhances the overall serotonergic effect
- It also has strong antihistamine effects, which contribute to its sedating properties The medication's efficacy and safety have been evaluated in various studies, including a meta-analysis of published RCTs and observational studies 1. Key points to consider when prescribing mirtazapine include:
- Typical dosing: 15 mg orally once daily at bedtime, potentially increasing to 30-45 mg based on response and tolerability
- Sedating effects: often help with sleep disturbances associated with depression
- Time to onset of action: usually takes 2-4 weeks to show full antidepressant effects
- Common side effects: increased appetite, weight gain, and drowsiness, which are generally more pronounced at lower doses due to the drug's higher affinity for histamine receptors at lower concentrations 1.
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 mechanism of action of mirtazapine is not fully understood, but it is thought 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
Mechanism of Action of Mirtazapine
The mechanism of action of mirtazapine involves:
- Antagonism of presynaptic alpha 2-adrenergic autoreceptors and heteroreceptors, leading to increased noradrenergic activity 3, 4, 5
- Blockade of postsynaptic 5-HT2 and 5-HT3 receptors, resulting in increased serotonergic activity, especially at 5-HT1A receptors 3, 4, 5
- Enhancement of 5-HT1A-mediated serotonergic transmission 4, 5
- Increased release of norepinephrine and serotonin due to the blockade of alpha2-adrenergic autoreceptors and heteroreceptors 4, 5
Key Features of Mirtazapine's Mechanism
- Mirtazapine does not inhibit serotonin reuptake, unlike selective serotonin reuptake inhibitors (SSRIs) 4, 5
- It has a high affinity for central and peripheral histamine H1 receptors, which may contribute to its sedative effects 4, 6
- Mirtazapine's mechanism of action is distinct from other antidepressants, such as tricyclic antidepressants (TCAs) and SSRIs 3, 4, 5
Effects on Neurotransmission
- Mirtazapine increases noradrenergic and serotonergic neurotransmission, which may contribute to its antidepressant effects 3, 4, 5
- The increased release of serotonin stimulates 5-HT1 receptors, which may also contribute to its antidepressant effects 4
- Mirtazapine's effects on the alpha1-adrenergic system, including increased responsiveness and binding, may also play a role in its mechanism of action 6