Mirtazapine

Article Author:
Talha Jilani
Article Editor:
Abdolreza Saadabadi
Updated:
10/9/2019 2:57:50 PM
PubMed Link:
Mirtazapine

Indications

Mirtazapine is an atypical antidepressant and is used primarily for the treatment of a major depressive disorder. [1][2] The drug was also found to have 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]

Mirtazapine was first synthesized and written about in 1989. Mirtazapine was first approved 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. With respect to mirtazapine, it stated that there was no difference between mirtazapine and other antidepressants currently in use on any efficacy measure, but mirtazapine had a greater 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 important. 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, available evidence demonstrates that mirtazapine is effective in all stages of severity of depressive illness, and also for a broad range of symptoms which are associated with depression.

Mechanism of Action

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. It has also demonstrated a moderate to weak antagonist effect on peripheral alpha1-adrenergic and muscarinic receptors. Unlike many other antidepressants, the reuptake of serotonin, dopamine or norepinephrine is not inhibited by mirtazapine. 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 found 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]

No clear relationship between the plasma concentration of mirtazapine and its antidepressant effect has been established, nor is there a known dose-effect relationship. The overall half-life of mirtazapine is approximately 20 to 40 hours. Around 15% is eliminated in feces and the remaining 75% in urine.

Administration

The currently recommended starting dose for mirtazapine is 15 mg per day, which can be administered without regard to meals. This is 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 has not been 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 is significantly reduced. Therefore, the physician should be aware that the plasma mirtazapine levels could be increased in these patient groups and he should adjust the initial administered dose accordingly with close monitoring of the drug levels in the blood.

Adverse Effects

Mirtazapine has several side effects which are significant. 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][3]

Contraindications

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 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 being treated with intravenous methylene blue or linezolid because of an increased risk of serotonin syndrome.

Monitoring

Patients undergoing treatment with mirtazapine should be monitored 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 is correlated with creatinine clearance) 
  • Hepatic function (the oral clearance of mirtazapine from the body was decreased by approximately 30% in patients with hepatic impairment 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)
  • Mania
  • Anxiety
  • Social functioning
  • Panic attacks
  • Lipid profile and weight gain

Mirtazapine is classified 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, it should cautiously be used in breastfeeding women. [7][8]

Toxicity

In the event of an overdose, mirtazapine is considered to be a relatively safe drug, although it is considered 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 nontoxic, compared to the tricyclic antidepressants. [8][9]

So far, twelve reported fatalities have been attributed to overdose with mirtazapine. The fatal toxicity index (which is deaths per million prescriptions) for mirtazapine is reported as 3.1 (95% CI), which is relatively similar to that observed with SSRIs.

Drug Interactions

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:

  • Diazepam
  • Tramadol
  • Cimetidine
  • Ketoconazole
  • St. John’s Wort
  • Tryptophan
  • Seizure medications- Phenytoin, Carbamazepine
  • Migraine medications- Sumatriptan, Zolmitriptan, and others
  • Medicine for mood disorders, and thought disorders: Lithium, other antidepressants, and antipsychotics

Enhancing Healthcare Team Outcomes

A multidisciplinary team consisting of the nurse, pharmacist, and prescriber should all be aware that other drugs could interact with mirtazapine, including prescription drugs, vitamins, over-the-counter medicines, and herbal products. Therefore, it is essential that the team is aware of the medications the patient is currently on before prescribing mirtazapine and provide care and use of the medication minimizing risk. [6]


References

[1] Ottman AA,Warner CB,Brown JN, The role of mirtazapine in patients with fibromyalgia: a systematic review. Rheumatology international. 2018 Dec     [PubMed PMID: 29860538]
[2] Watanabe N,Omori IM,Nakagawa A,Cipriani A,Barbui C,Churchill R,Furukawa TA, Mirtazapine versus other antidepressive agents for depression. The Cochrane database of systematic reviews. 2011 Dec 7     [PubMed PMID: 22161405]
[3] Nutt DJ, Tolerability and safety aspects of mirtazapine. Human psychopharmacology. 2002 Jun     [PubMed PMID: 12404669]
[4] Anttila SA,Leinonen EV, A review of the pharmacological and clinical profile of mirtazapine. CNS drug reviews. 2001 Fall     [PubMed PMID: 11607047]
[5] Wang SM,Han C,Bahk WM,Lee SJ,Patkar AA,Masand PS,Pae CU, Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review. Chonnam medical journal. 2018 May     [PubMed PMID: 29854675]
[6] Gorman JM, Mirtazapine: clinical overview. The Journal of clinical psychiatry. 1999     [PubMed PMID: 10446735]
[7] Buckley NA,McManus PR, Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ (Clinical research ed.). 2002 Dec 7     [PubMed PMID: 12468481]
[8] Holzbach R,Jahn H,Pajonk FG,Mähne C, Suicide attempts with mirtazapine overdose without complications. Biological psychiatry. 1998 Nov 1     [PubMed PMID: 9807651]
[9] Retz W,Maier S,Maris F,Rösler M, Non-fatal mirtazapine overdose. International clinical psychopharmacology. 1998 Nov     [PubMed PMID: 9861579]