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 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 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.[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. The Clinicians usually prescribe mirtazapine for major depressive disorder after using Selective serotonin reuptake inhibitors(SSRI).  They use it predominantly in depressed individuals 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 achieving 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 still 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 different 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]

FDA-approved Indication

• Treatment of unipolar major depressive disorder (MDD)[8]

Off Label Clinical Uses

• Insomnia[9]
• Panic disorder[10]
• Prophylaxis of chronic tension-type headache[11]
• Social anxiety disorder[12]
• Post-traumatic Stress Disorder(in combination with SSRI)[13]
• fibromyalgia[1] 

Mechanism of Action

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. 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.[14]

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 tricyclic antidepressants(TCA), it shows weak or no activity as a blocker of sodium or calcium channels or as an anticholinergic.[6][15]

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 (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.[16]

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 the 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.[6]

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.[6]

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.[4][17]

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[18]
• bone marrow suppression and neutropenia[19][20]
• hypertriglyceridemia[21]
• Acute pancreatitis(rare but life-threatening ADR)[22]
• Cochrane review conducted in 2011 found that when 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[23]

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.[17]

• Avoid prescribing mirtazapine to any patient currently receiving intravenous methylene blue or linezolid because of an increased risk of serotonin syndrome.[24]

• Black box label 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[25]
• PHQ-9 (Patient Health Questionnaire-9) - Objectifies degree of depression severity.[26]
• Columbia Suicide Severity Rating Scale - Suicide ideation (especially at the initiation of therapy or when doses are decreased or increased)[27]
• GAD-7 (General Anxiety Disorder-7)- Measures severity of anxiety.[28]

Medical Assessment

• 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)
• Signs/symptoms of serotonin syndrome
• Lipid profile and weight gain

Pregnancy Consideration

• Mirtazapine classifies as "pregnancy risk factor class C."
• The clinical implication is that mirtazapine should be given to pregnant women only if needed.[29]

Breastfeeding Implications

• Mirtazapine's metabolites are present in breast milk, but 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.[30][31]

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 use 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 the tricyclic antidepressants.[30][32]

So far, there are twelve reported fatalities attributed to overdose with 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. In addition, there were reports of mirtazapine overdose alone or in combination with other pharmacological agents in premarketing clinical studies.

Signs and symptoms reported in association with overdose included disorientation, drowsiness, impaired memory, and tachycardia. Based on postmarketing reports, serious outcomes (including fatalities) may occur at dosages higher than the recommended doses, especially with mixed overdoses.[33] It is important to note that there are no specific antidotes for mirtazapine. Contact Poison Control (1-800-222-1222) for the latest recommendations.[34]

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, there are multiple drug-drug interactions associated with mirtazapine use, including prescription drugs, vitamins, over-the-counter medicines, and herbal products. Therefore pharmacists should report back to the clinician/psychiatrist in case of drug interactions. Specialty trained nurses should observe the patients for worsening symptoms of depression. Psychiatrist consultation is important in the intentional overdose of mirtazapine.

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 consisting of clinicians (MDs, DOs, NPs, PAs), specialists, pharmacists, and nurses manage patients on mirtazapine therapy. Consequently, an interprofessional team approach results in higher therapeutic success and better patient outcomes.[15][35] [Level 2]