Continuing Education Activity
Mirtazapine is an atypical antidepressant and is used primarily for the treatment of a major depressive disorder. The drug has sedative, antiemetic, anxiolytic, and appetite stimulant effects, which explains its off-label use for insomnia, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, generalized anxiety disorder, social anxiety disorder, headaches, and migraines. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of mirtazapine, pertinent for members of the interprofessional team in treating patients with fungal infections where it is of clinical value.
- Review the mechanism of action of mirtazapine.
- Identify the approved and off-label indications for mirtazapine.
- Summarize the adverse event profile of mirtazapine.
- Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from therapy with mirtazapine.
Mirtazapine is an atypical antidepressant and is used primarily for the treatment of a major depressive disorder. 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. 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 treating 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.
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.
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 associated with depression.
Mechanism of Action
Mirtazapine is part of the tetracyclic antidepressants (TeCA) group that works 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 lead 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.
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.
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. Drug 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 managing 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 managing 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 to assess 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 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.
Some antidepressants, especially SSRIs, could paradoxically exacerbate depression and anxiety and even cause suicidal ideation in some people. Despite having a sedating effect, mirtazapine is also one of the drugs capable of this adverse effect, so it carries a black box label warning on its packaging of these potential effects.
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.
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 therapy initiation with mirtazapine. Conversely, the same amount of time (at least 14 days) should be allowed to pass after stopping mirtazapine and initiating MAO inhibitors to treat psychiatric disorders. This delay is because of the increased risk of serotonin syndrome with concurrent use of both drugs.
Do not give mirtazapine to any patient currently receiving intravenous methylene blue or linezolid because of an increased risk of serotonin syndrome.
Patients undergoing treatment with mirtazapine require monitoring for the following:
- Agranulocytosis or severe neutropenia (such as stomatitis, sore throat, other possible signs of infection, or a low WBC)
- Renal function (elimination of mirtazapine from the body correlates with creatinine clearance)
- Hepatic function (the oral clearance of mirtazapine from the body was decreased by approximately 30% in patients with hepatic impairment as opposed to patients with normal hepatic function)
- Mental status for depression
- Signs/symptoms of serotonin syndrome
- Suicide ideation (especially at the initiation of therapy or when doses are decreased or increased)
- Social functioning
- Panic attacks
- Lipid profile and weight gain
Mirtazapine classifies as "pregnancy risk factor class C."
Although its metabolites are secreted into breast milk, adverse events have generally not been observed in breastfeeding individuals. One case report noted possible sedation and weight gain. Therefore, its use requires caution in breastfeeding women.
In the event of an overdose, mirtazapine is a relatively safe drug, although it is slightly more toxic than most of the SSRIs (except citalopram) in overdose cases. Unlike the tricyclic antidepressants, mirtazapine demonstrated no significant adverse cardiovascular effects at 7 to 22 times its maximum recommended dose. Case reports in which the patients overdosed with 30 to 50 times the prescribed dose described mirtazapine as relatively non-toxic compared to the tricyclic antidepressants.
So far, there are twelve reported fatalities attributed to overdose with mirtazapine. The reported fatal toxicity index (which is deaths per million prescriptions) for mirtazapine is 3.1 (95% CI), which is relatively similar to that observed with SSRIs.
Taking mirtazapine with other sedative drugs can severely increase the sedative effect. Mirtazapine has various drug interactions and should be used cautiously or not at all with many drugs. These include:
- St. John’s Wort
- Seizure medications: phenytoin, carbamazepine
- Migraine medications: sumatriptan, zolmitriptan, and others
- Medications for mood and thought disorders: lithium, other antidepressants, and antipsychotics
Enhancing Healthcare Team Outcomes
An interprofessional team consisting of the prescriber (MD, DO, NP, PA), nurse, and pharmacist, should actively manage patients on mirtazapine therapy. All team members should be aware that other drugs could interact with mirtazapine, including prescription drugs, vitamins, over-the-counter medicines, and herbal products. Therefore, the team must be mindful of the medications the patient is currently on before prescribing mirtazapine and provide care and use of the medication, minimizing risk. They also need to be alert to the medication's adverse effects and make appropriate dosing adjustments or change to a different agent if necessary. This team approach with result in greater therapeutic success in patients taking mirtazapine. [Level 5]