Continuing Education Activity

Mirtazapine is an atypical antidepressant and is used primarily for the treatment of a major depressive disorder. Mirtazapine is in a group of tetracyclic antidepressants (TeCA). Mirtazapine inhibits the central presynaptic alpha-2-adrenergic receptors, which causes an increased release of serotonin and norepinephrine. 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 interprofessional team members in treating patients with depression where it is of clinical value.

Objectives:

• Review the mechanism of action of mirtazapine.
• Identify the FDA-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 for patients who might benefit from therapy with mirtazapine.

Indications

Mirtazapine is an atypical antidepressant and is used primarily for the treatment of a major depressive disorder. Experts synthesized mirtazapine in 1989. Mirtazapine first received approval for treating a major depressive disorder in the Netherlands in 1994. It was finally FDA-approved in the United States in 1996 for treating moderate and severe depression. Mirtazapine is not approved by FDA for use in pediatric patients.[1][2][3]

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. Clinicians usually prescribe mirtazapine for major depressive disorder after using Selective serotonin reuptake inhibitors (SSRI). Mirtazapine is used predominantly in depressed patients with insomnia and/or underweight individuals.[4][5]

In 2010, the National Institute for Health and Care Excellence(NICE) in the United Kingdom published a guideline for treating depression, and this study also included a review of various antidepressants. NICE guidelines stated that mirtazapine is as efficacious as other antidepressants. Moreover, mirtazapine had a higher chance of remission in a statistical, though not clinical, setting. It also showed a statistical advantage over current SSRIs in decreasing the symptoms of depression, but the finding was not clinically meaningful. Therefore, the guideline recommended SSRIs as the first-line treatment for depression as they were equally as effective as other antidepressants but had a favorable risk-benefit ratio.[6]

A systemic review and network meta-analysis conducted in 2018 comparing the efficacy and acceptability of 21 antidepressant drugs demonstrated mirtazapine as one of the most effective compared to other antidepressants in head-to-head studies. The available evidence shows that mirtazapine is effective in all stages of severity of depressive illness and a broad range of symptoms associated with depression.[7]

A recent RCT evaluated mirtazapine for methamphetamine use disorder. In this study, mirtazapine reduced methamphetamine use and high-risk HIV behaviors, and the with benefits of the treatment extended after the treatment period.[8]

FDA-approved Indication

• Treatment of unipolar major depressive disorder (MDD)[9]

Off-label Clinical Uses

• Insomnia[10]
• Panic disorder[11]
• Prophylaxis of chronic tension-type headache[12]
• Social anxiety disorder[13]
• Post-traumatic Stress Disorder(in combination with SSRI)[14]
• fibromyalgia[1]

Mechanism of Action

Mirtazapine is a tetracyclic antidepressant drug (TeCA). Mirtazapine inhibits 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, explaining 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.[15]

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) 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 tricyclic antidepressants(TCA), it shows weak or no activity as a blocker of sodium or calcium channels or as an anticholinergic.[6][16]

Pharmacokinetics

Absorption: Mirtazapine is rapidly absorbed, and peak plasma concentrations are attained in 2 hours. The presence of food has a negligible effect on both the rate and extent of absorption and does not need a dose adjustment of mirtazapine. There is no clear, established relationship between the plasma concentration of mirtazapine and its antidepressant effect, nor is there a known dose-effect relationship.

Distribution: Mirtazapine has high plasma protein binding(85%) and is bound to plasma proteins in a reversible but nonspecific manner.

Metabolism: Mirtazapine is extensively metabolized in the liver by demethylation, hydroxylation, conjugation, and cytochrome P450 enzymes (CYP1A2, CYP2D6, and CYP3A4). One of its major metabolites is desmethylmirtazapine. 

Excretion: Mean elimination half-life of mirtazapine varies from 20 to 40 hours. Metabolites of mirtazapine are excreted primarily via urine 75% and feces(15%).[17]

Administration

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 oral 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 daily. However, 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 about 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.[6]

Sudden cessation of mirtazapine use could cause discontinuation syndrome in patients. Therefore, a slow and gradual reduction in dose is recommended to minimize discontinuation syndrome symptoms. Sudden cessation of treatment could cause depression, panic attacks, tinnitus, restlessness, vertigo, decreased appetite, insomnia, nausea, vomiting, diarrhea, and sometimes hypomania or mania.[4][18]

Specific Patient Population

Patients with Hepatic Impairment: Mirtazapine is extensively metabolized by the liver; hence clinicians should be cautious while prescribing mirtazapine in patients with moderate to severe hepatic impairment.

Patients with Renal Impairment: Clearance of mirtazapine is significantly reduced in renal disease; use with caution if GFR<40 mL/min/1.73 m.

Pregnancy Considerations: Mirtazapine is classified as a former FDA "pregnancy risk factor class C." The clinical implication is that mirtazapine should only be given to pregnant women if needed.[19] A recent nationwide survey in Denmark demonstrated that mirtazapine use in pregnancy is not associated with congenital malformations or adverse pregnancy outcomes.[20]

Breastfeeding Considerations: Clinical data suggest that maternal doses of up to 120 mg daily produce low levels of mirtazapine in milk and would not cause any adverse outcomes in breastfed infants, especially if the infant is older than two months in age. In addition, a safety scoring system finds mirtazapine use acceptable during breastfeeding. However, the case report noted possible sedation and weight gain with mirtazapine. Case reports noted possible sedation and weight gain with mirtazapine, and exclusively breastfed infants should be monitored for adverse drug reactions and adequate growth if mirtazapine is used during lactation.[21][22]

COVID-19 considerations: In an observational study involving 7230 patients, 345 patients received antidepressants. The study revealed that the use of antidepressants, including mirtazapine, was significantly associated with a reduced risk of intubation or death in hospitalized patients( p < 0.05).[23]

Adverse Effects

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%)
• Increase in appetite (17%)
• Sedation
• Thrombocytopenia[24]
• bone marrow suppression and neutropenia[25][26]
• hypertriglyceridemia[27]
• Acute pancreatitis(rare but life-threatening ADR)[28]
• A Cochrane review conducted in 2011 found that compared to other antidepressants, mirtazapine is more likely to cause drowsiness and weight gain but less likely to cause tremors and sexual dysfunction.[2] 
• Transient alterations of liver function tests and rare cases of acute liver injury[29]
• Mirtazapine can antagonize clonidine's hypotensive effect; hence caution is advised in patients with cardiovascular disorders[20]

Contraindications

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

• Avoid prescribing 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 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.[18]

• Avoid prescribing mirtazapine to any patient receiving intravenous methylene blue or linezolid because of an increased risk of serotonin syndrome.[30]

• Boxed warning-Mirtazapine can paradoxically exacerbate depression and anxiety and even cause suicidal ideation in some people. Closely monitor these patients.[4]

Monitoring

Patients undergoing treatment with mirtazapine require monitoring for the following:

Psychiatric Assessment

• Hamilton Depression Rating Scale (HAM-D) - Stratifies severity of depression[31]
• PHQ-9 (Patient Health Questionnaire-9) - Objectifies the degree of depression severity.[32]
• Columbia Suicide Severity Rating Scale - Suicide ideation (especially at the initiation of therapy or when doses are decreased or increased)[33]
• GAD-7 (General Anxiety Disorder-7)- Measures severity of anxiety.[34]

Medical Assessment

• Agranulocytosis or severe neutropenia (such as stomatitis, sore throat, other possible signs of infection, or a low WBC)
• Signs/symptoms of serotonin syndrome
• Lipid profile and weight gain.
• In elderly patients and patients with significant renal and hepatic impairment, clearance of mirtazapine is reduced. Therefore, clinicians should monitor renal and liver function and the drug levels in the blood.[6]

Toxicity

Taking mirtazapine with other sedative drugs can severely increase the sedative effect. In addition, mirtazapine has various drug interactions and should be used cautiously or is contraindicated. These include:

• Diazepam
• Tramadol
• Cimetidine
• Ketoconazole
• St. John’s wort
• Tryptophan
• Seizure medications: phenytoin, carbamazepine
• Migraine medications: sumatriptan, zolmitriptan
• Medications for mood and thought disorders: lithium, other antidepressants, and antipsychotics[6]

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 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 tricyclic antidepressants.[21][35] Few fatalities have been attributed to an overdose of mirtazapine. The reported fatal toxicity index (deaths per million prescriptions) for mirtazapine is 3.1 (95% CI), which is relatively similar to that observed with SSRIs. A study analyzed mirtazapine overdose in 267 patients. It concluded that tachycardia, mild hypertension, and mild CNS depression are associated with overdose, and the patients taking co-ingestants with mirtazapine had more severe toxicity.[36] 

Signs and symptoms associated with overdose also were associated with disorientation, drowsiness, and impaired memory. As discussed above, serious outcomes (including fatalities) may occur at doses higher than recommended, especially with mixed overdoses.[37] In case of overdose, clinicians should provide supportive treatment. It is important to note that there are no specific antidotes for mirtazapine. Contact Poison Control (1-800-222-1222) for the latest recommendations.[38]

Enhancing Healthcare Team Outcomes

Mirtazapine is an FDA-approved novel antidepressant with a unique mechanism of action used to treat major depressive disorders. Healthcare providers should be aware of the indications, mechanism of action, adverse reactions, and toxicity due to the unique pharmacology and adverse reaction profile of mirtazapine.

Typically psychiatrists initiate mirtazapine therapy for appropriate indications and play a crucial role in overall disease management. Clinicians (MDs, DOs, NPs, PAs) ensure timely follow-up and assess the response to therapy(e.g., PHQ-9). Pharmacists should ensure medication reconciliation and ensure proper dosing. In addition, multiple drug-drug interactions are associated with mirtazapine use, including prescription drugs, vitamins, over-the-counter medicines, and herbal products. Therefore pharmacists should report to the clinician/psychiatrist in case of drug interactions. Specialty-trained nurses should observe the patients for worsening symptoms of depression. Psychiatrist consultation is essential in the intentional overdose of mirtazapine. Additionally, board-certified psychologists can provide cognitive-behavioral therapy, interpersonal psychotherapy, and psychodynamic therapies for patients suffering from depression(American Psychological Association, 2021).[39]

Emergency department physicians play a vital role in mirtazapine toxicity and maintain circulation, airway, and breathing. Moreover, in an intentional overdose of mirtazapine or serotonin syndrome, psychiatrists and critical care physicians should work collaboratively to improve patient outcomes. In addition, clinicians should contact the poison control center if unknown ingestions are suspected, along with mirtazapine.

As illustrated above, multiple healthcare providers, including clinicians, specialists, pharmacists, and nurses, manage patients on mirtazapine therapy. Consequently, an interprofessional team approach that utilizes open communication between all team members and accurate record-keeping results in higher therapeutic success and better patient outcomes.[16][40] [Level 2]