From the FDA Drug Label
The mechanism of action of mirtazapine tablets, as with other drugs effective in the treatment of major depressive disorder, is unknown. Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity These studies have shown that mirtazapine acts as an antagonist at central presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity.
The FDA drug label confirms that mirtazapine's α2-adrenergic antagonism leads to increased norepinephrine release. However, it does not directly address the effects of this increased norepinephrine release on volume expansion, pressure surges, or vascular integrity. Additionally, the label does not mention the stimulation of β1 receptors in the kidneys or the activation of the renin-angiotensin-aldosterone system leading to fluid retention and increased blood pressure 1.
From the Research
Mirtazapine's α2-adrenergic antagonism does increase norepinephrine release, but this does not typically lead to significant blood pressure elevation through the mechanisms described. While mirtazapine blocks presynaptic α2-adrenergic receptors, causing increased norepinephrine release in the central nervous system and periphery, this effect is generally modest and counterbalanced by other pharmacological properties of the medication, as noted in studies such as 2. Mirtazapine also blocks α1-adrenergic receptors, which actually reduces vasoconstriction and can prevent blood pressure increases. The medication does not directly stimulate β1 receptors in the kidneys in a clinically significant way, and activation of the renin-angiotensin-aldosterone system is not a major concern with this medication.
Some key points to consider:
- Mirtazapine's mechanism of action involves increasing noradrenergic and serotonergic neurotransmission via blockade of central α2-adrenergic auto- and heteroreceptors, as discussed in 3.
- The increased release of serotonin (5-hydroxytryptamine; 5-HT) stimulates serotonin 5-HT1 receptors because mirtazapine directly blocks 5-HT2 and 5-HT3 receptors, as explained in 4.
- In clinical practice, mirtazapine is generally considered to have a neutral effect on blood pressure compared to other antidepressants, with some patients even experiencing orthostatic hypotension rather than hypertension, as indicated by the lack of significant cardiovascular effects in studies like 5.
- Fluid retention can occur as a side effect but is typically related to other mechanisms, such as increased appetite and weight gain, which are common side effects of mirtazapine, as reported in 2.
For patients with cardiovascular concerns, regular blood pressure monitoring is recommended when starting mirtazapine, but significant hypertensive effects through the proposed mechanism are not commonly observed, suggesting that mirtazapine can be a viable option for patients with depression who also have cardiovascular issues, as supported by the findings in 2.