From the Guidelines
Mirtazapine works primarily by blocking alpha-2 adrenergic receptors, which increases norepinephrine and serotonin release, while also blocking certain serotonin receptors (5-HT2A, 5-HT2C, and 5-HT3) and histamine H1 receptors, and it typically takes 4-6 weeks to develop its full antidepressant benefits. This unique mechanism helps improve mood, anxiety, sleep, and appetite. Patients may notice some effects like improved sleep and appetite within the first 1-2 weeks of starting mirtazapine.
Key Points
- The medication should be taken consistently, usually once daily at bedtime due to its sedating effects, with typical starting doses of 15 mg that may be increased to 30-45 mg as needed 1.
- It's essential to continue taking mirtazapine even after feeling better, as stopping too soon can lead to relapse.
- Side effects may include drowsiness, increased appetite, weight gain, and dry mouth, with drowsiness being more pronounced at lower doses (15 mg) than at higher doses (30-45 mg) due to the medication's unique receptor binding profile.
- If considering discontinuation, this should be done gradually under medical supervision to avoid withdrawal symptoms.
Mechanism and Onset of Action
Mirtazapine's mechanism of action is distinct from other antidepressants, and its onset of action is faster than some other medications, such as fluoxetine, paroxetine, or sertraline 1. However, after 4 weeks, most response rates were similar.
Maintenance and Discontinuation
Four fair-quality trials demonstrated no substantial difference between fluoxetine and sertraline, fluvoxamine and sertraline, duloxetine and paroxetine, and trazodone and venlafaxine for maintaining response or remission of MDD 1. A meta-analysis of 31 randomized trials supports the continuation of antidepressant therapy to reduce the risk for relapse.
Adverse Effects
The most commonly reported adverse events were constipation, diarrhea, dizziness, headache, insomnia, nausea, sexual side effects, and somnolence 1. Nausea and vomiting were the most common reasons for discontinuation in efficacy studies. Although studies evaluating the risk for suicidality showed no differences between second-generation antidepressants, patients receiving SSRIs had an increased risk for nonfatal suicide attempts.
Clinical Considerations
When treating acute-phase MDD, the second-generation antidepressants did not significantly differ in efficacy, effectiveness, or quality of life 1. Mirtazapine had a significantly faster onset of action. Almost 38% of patients did not achieve a treatment response during 6 to 12 weeks of treatment with second-generation antidepressants and 54% did not achieve remission. Second-generation antidepressants did not differ in the rate of achieving remission.
Treatment of Depression with Accompanying Symptom Clusters
The evidence review evaluated the comparative effectiveness of second-generation antidepressants for treatment of depression associated with symptom clusters, such as anxiety, insomnia, and pain 1. Evidence from 6 fair-quality head-to-head trials comparing fluoxetine or paroxetine with sertraline, sertraline with bupropion, and sertraline with venlafaxine showed similar antidepressive efficacy for patients with MDD and anxiety symptoms.
Summary
In summary, when treating acute-phase MDD, the second-generation antidepressants did not significantly differ in efficacy, effectiveness, or quality of life 1. Mirtazapine had a significantly faster onset of action. Almost 38% of patients did not achieve a treatment response during 6 to 12 weeks of treatment with second-generation antidepressants and 54% did not achieve remission. Second-generation antidepressants did not differ in the rate of achieving remission.
From the FDA Drug Label
12.1 Mechanism of Action 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. 12.3 Pharmacokinetics Plasma levels of mirtazapine are linearly related to dose over a dose range of 15 to 80 mg (1. 78 times the maximum recommended dose). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio=1. 5). Mirtazapine has a half-life of about 20 to 40 hours following oral administration of mirtazapine tablets
The mechanism of action of mirtazapine is not entirely clear, but it is believed to be related to its activity as an antagonist at central presynaptic α2-adrenergic inhibitory auto-receptors and heteroreceptors, which enhances central noradrenergic and serotonergic activity.
- Onset of action: The drug reaches peak plasma concentrations within about 2 hours post-dose, and steady state plasma levels are attained within 5 days.
- Duration of action: Mirtazapine has a half-life of about 20 to 40 hours, which means it will take around 4-10 days for the drug to be completely eliminated from the system, but its effects may last as long as the drug is present in the system, which is approximately 5 half-lives, or around 8-20 days after the last dose, considering the range of half-life values 2.
From the Research
Mirtazapine Mechanism 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
- The net outcome of these effects is increased noradrenergic activity together with specific increased serotonergic activity, especially at 5-HT1A receptors 3
- Mirtazapine blocks central α2-adrenergic auto- and heteroreceptors, but has no effect on noradrenaline (norepinephrine) reuptake 4
Onset of Action and Duration
- Mirtazapine has an onset of clinical effect in 2-4 weeks similar to other antidepressants 3
- Sleep disturbances and anxiety symptoms may improve in the first week of treatment 3
- The mean elimination half-life of mirtazapine is approximately 20-40 hours, enabling once-daily bedtime dosing 3
- The bioavailability of mirtazapine is approximately 50%, with peak plasma concentrations reached within 2.2 to 3.1 hours after single oral doses 4
Efficacy and Tolerability
- 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
- Mirtazapine is generally well tolerated in patients with depression, with the most commonly reported adverse effects being somnolence, increased appetite, weight gain, and dizziness 5
- Mirtazapine may also be effective in the treatment of anxiety disorders, obsessive-compulsive disorder, and other psychiatric indications 6