Mirtazapine is an atypical antidepressant and is used primarily for the treatment of a major depressive disorder.[1][2] The drug has sedative, antiemetic, anxiolytic, and appetite stimulant effects, which explains its off-label use for the following conditions: insomnia, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, generalized anxiety disorder, social anxiety disorder, headaches, and migraines.[3] Most commonly, clinicians prescribe mirtazapine when individuals have not achieved success with initial pharmacological therapies for major depressive disorder, and they use it predominantly in depressed individuals with insomnia and/or individuals who are underweight.

Mirtazapine was first synthesized and written about in 1989. Mirtazapine first received approval for the treatment of a major depressive disorder in the Netherlands in 1994. It was finally FDA-approved in the United States in 1996 for the treatment of moderate and severe depression.

In 2010, the National Institute for Health and Care Excellence in the United Kingdom published a guideline for the treatment of depression, and this study also included a review of various antidepressants. Concerning mirtazapine, it stated that there was no difference between mirtazapine and other antidepressants currently in use on any efficacy measure, but mirtazapine had a higher chance of achieving remission in a statistical though not clinical setting. It also showed a statistical advantage over current SSRIs in terms of decreasing the symptoms of depression, but the finding was not clinically meaningful. However, the guideline still recommended generic SSRIs as the first-line treatment for depression as they were equally as effective as other antidepressants, but had a favorable risk-benefit ratio.[4]

A systemic review and network meta-analysis conducted in 2018 comparing the efficacy and acceptability of 21 different antidepressant drugs demonstrated mirtazapine as one of the most effective when compared to other antidepressants in head-to-head studies.[5]

Currently, the available evidence shows that mirtazapine is effective in all stages of severity of depressive illness and also for a broad range of symptoms that are associated with depression.

Mirtazapine is part of the group tetracyclic antidepressants (TeCA) that work by exerting antagonist effects on the central presynaptic alpha-2-adrenergic receptors, which causes an increased release of serotonin and norepinephrine. Mirtazapine is also sometimes called a noradrenergic and specific serotonergic antidepressant (NaSSA). Noradrenaline is known to have an activating effect on the sympathetic nervous system, and this could explain the general increase in activity and increased metabolism seen with mirtazapine. It also acts as a potent antagonist of H1 histamine receptors (producing a sedating, calming effect) and 5-HT2A, 5-HT2C, and 5-HT3 serotonin receptors. 

Mirtazapine's ability to antagonize 5-HTA, 5HT2C, and 5-HT3 receptors leads to the remaining serotonin concentration left to interact with the free 5-HT1 receptor. This interaction with the 5-HT1 receptor (particularly the 5-HT1A receptor) is what leads to antidepressant effects.

It has also demonstrated a moderate to weak antagonist effect on peripheral alpha1-adrenergic and muscarinic receptors. Unlike many other antidepressants, mirtazapine does not inhibit the reuptake of serotonin, dopamine, or norepinephrine. Unlike most TCAs, it shows weak or no activity as a blocker of sodium or calcium channels, or as an anticholinergic.[4][6]

Mirtazapine is rapidly absorbed and has an oral bioavailability of around 50%. About 85% of the drug is bound to plasma proteins in a reversible but nonspecific manner. Mirtazapine is metabolized in the liver by demethylation and then hydroxylation via the cytochrome P450 enzymes (more specifically CYP1A2, CYP2D6, and CYP3A4). One of its major metabolites is desmethylmirtazapine.[4]

There is no clear, established relationship between the plasma concentration of mirtazapine and its antidepressant effect, nor is there a known dose-effect relationship. The overall half-life of mirtazapine is approximately 20 to 40 hours. The drugs' elimination is around 15% in feces and the remaining 75% in urine.

The currently recommended starting dose for mirtazapine is 15 mg per day, which patients can take without regard to meals, administered as a single dose of an orally disintegrating tablet, preferably in the evening just before sleep because of the common sedative effect of mirtazapine. In controlled clinical trials to establish the efficacy of mirtazapine in the management of major depressive disorder, the most effective range was determined to be around 15 to 45 mg per day. Although the exact relationship between the dose of mirtazapine and the satisfactory response in the management of major depressive disorder remains yet to be adequately established, patients who did not respond to the initial 15 mg dose could benefit from dose increases to a maximum of around 45 mg per day. Because the elimination half-life is around 20 to 40 hours, changes in dose should not be made for at least 1 to 2 weeks, to allow for sufficient time for the assessment of the therapeutic response to the given dose.

In elderly patients and those with moderate to severe hepatic or renal impairment, the clearance of mirtazapine becomes significantly reduced. Therefore, the physician should be aware that the plasma mirtazapine levels could increase in these patient groups, and he should adjust the initial administered dose accordingly with close monitoring of the drug levels in the blood.

Mirtazapine has several significant side effects. The adverse effects which occur in greater than 10% of the people taking the drug include:

• Drowsiness (54%)
• Weight gain (12%)
• Xerostomia (25%)
• Increased serum cholesterol (15%)
• Constipation (13%)
• Increased appetite (17%)

In 2011, a Cochrane review found that when compared to other antidepressants, mirtazapine is more likely to cause sleepiness and weight gain, but less likely to cause tremors compared to tricyclic antidepressants, and far less likely to cause sexual dysfunction compared to SSRIs.[2] 

Some antidepressants, especially SSRIs, could paradoxically exacerbate depression, anxiety, and even cause suicidal ideation in some people. Despite having a sedating effect, mirtazapine is also one of the drugs capable of this, so it carries a black box label warning on its packaging of these potential effects.[3]

Sudden cessation of mirtazapine use could cause discontinuation syndrome in patients. Therefore a slow and gradual reduction in dose is recommended to minimize the symptoms of discontinuation syndrome. Sudden cessation of treatment could cause depression, panic attacks, tinnitus, restlessness, vertigo, decreased appetite, insomnia, nausea, vomiting, diarrhea, and sometimes hypomania or mania.[3][7]

Hypersensitivity or allergy to mirtazapine or any component of its formulation would preclude the use of the drug.

Do not give mirtazapine to any patient who is currently on MAO inhibitors. There should be a gap of at least 14 days between the discontinuation of an MAO inhibitor (intended to treat psychiatric disorders) and the initiation of therapy with mirtazapine. Conversely, the same amount of time (at least 14 days) should be allowed to pass after stopping mirtazapine and initiating MAO inhibitors for the treatment of psychiatric disorders. This delay is because of the increased risk of serotonin syndrome with concurrent use of both drugs.[7]

Do not give mirtazapine in any patient who is currently receiving intravenous methylene blue or linezolid because of an increased risk of serotonin syndrome.