Mirtazapine (Remeron)

Primer

Mirtazapine (Trade name: Remeron) is an antidepressant in the noradrenergic and specific serotonergic antidepressant (NaSSA) class. It has potent histaminergic blockade which gives it sedative and appetite stimulant properties. It is commonly used in the treatment of major depressive disorder and anxiety disorders.

Pharmacokinetics

Pharmacokinetics of Mirtazapine

Absorption Well absorbed in gastrointestinal tract (50% bioavailability)
Distribution 85% bound to protein
Metabolism Hepatic
Elimination Urine (75%), Feces (15%)
Peak plasma levels 2 hours (PO)
Half-life 20-40 hours*
* = Remember that since mirtazapine has a relatively long half-life, especially in females; consequently, it may take 1-2 weeks to reach steady state

Mirtazapine: Cytochrome P450 Metabolism

Substrate of (Metabolized by) 1A2, 2D6, 3A4
Induces -
Inhibits -

Pharmacodynamics

Mechanism of Action

  • Histamine (H1) receptor antagonism:
    • Causes the prominent sedation and weight gain effects of mirtazapine
  • Muscarinic (M1) receptor antagonism:
    • Causes moderate anticholinergic side effects (e.g. - dry mouth, constipation)
  • Alpha-1 (α1) receptor antagonism:
    • Causes a moderate blood pressure-lowering effect
  • Presynaptic alpha-2 (α2) receptor antagonism:
    • Antagonism of presynaptic α2-autoreceptors on noradrenergic (NA/NE) neurons leads to increased release of noradrenaline, and results in increased firing of postsynaptic serotonergic neurons
    • Antagonism of presynaptic α2-heteroreceptors on serotonergic (5-HT) neurons also inhibits negative feedback, which in turn leads to increased release of serotonin
    • These two actions cause the primary antidepressant effect
  • Serotonin (5-HT) receptor agonism and antagonism:
    • Agonism at 5-HT1
    • Antagonism at 5-HT2A, 5-HT2C, 5-HT3
      • 5-HT2A antagonism reverses sexual dysfunction and causes anxiolysis and sedation
      • 5-HT2C antagonism is linked to antidepressant effects, anxiolysis, sedation and increased appetite
      • 5-HT3 antagonism has significant anti-nausea effects[1]
    • Similar to venlafaxine, mirtazapine is more serotonergic at lower doses and more noradrenergic at higher doses

Low Dose vs. High Dose

Why Do Lower Doses of Mirtazapine Cause More Sedation?

Mirtazapine acts mainly on 3 receptors: histaminergic, noradrenergic, and serotonergic receptors. However, at low doses (e.g. - 7.5 mg), mirtazapine has a higher affinity to (and thus preferentially blocks) the histamine-1 receptor, compared to the other 2 receptors.[2][3] At higher doses, this antihistamine activity is offset by increased noradrenergic transmission, which reduces its sedating effects.[4][5] Although sedation is expected at low doses, it is usually most noticeable in the first few weeks of therapy and diminishes with continued treatment.[6]

Indications

Dosing

Dosing for Mirtazapine

Starting 7.5 mg to 15 mg qHS (start with 7.5mg in the elderly)
Titration Increase by 15 mg every 1-2 weeks
Maximum 45 mg qHS
Taper See Tapering/Switching Antidepressants

Formulations

  • Mirtazapine comes in oral formulation (PO) tablet, or a dissolvable tablet.

California Rocket Fuel

  • Combining venlafaxine with mirtazapine has been dubbed “California Rocket Fuel” by psychopharmacologist Stephen Stahl because of the multiple mechanisms of action on neurotransmitter systems.[8] The hypothesis is that mirtazapine increases both serotonin and norepinephrine via a different mechanism than SSRIs/SNRIs. This combination therapy was found to outperform parnate (tranylcypromine) in the landmark STAR*D trial.[9]
  • No formal randomized trials have been performed, so its evidence is largely based on expert opinion.[10] Smaller open-label trials have been done supporting its efficacy.[11][12][13][14][15]
  • The maximum dosage for this combination therapy is the same as the standard dose for each respective drug (i.e. - venlafaxine ER's maximum dose is 225mg daily (IR = 375mg daily), and mirtazapine's maximum dose is 45mg daily).

Monitoring

  • Individuals with a history of cardiovascular disease, family history of QT prolongation, or using other QT prolonging medication should have an ECG done.
  • If patient develops clinical evidence of infection, check CBC to assess for neutropenia/agranulocytosis
  • If patient develops clinical evidence of liver toxicity, check LFTs

Contraindications

Absolute

Drug-Drug Interactions

  • Mirtazapine has few significant drug-drug interactions, so this makes it useful as a combination antidepressant for use as an adjunctive treatment option.
  • Carbamazepine can reduce plasma levels of mirtazapine by up to 60% via induction of the cytochrome 3A4.

Side Effects

  • Sedation (>50% of adults)
  • Significant weight gain and increased appetite (30-40%)
  • Orthostatic hypotension, dizziness
  • Transient increases in liver enzymes (2%)
  • Anticholinergic effects including dry mouth, increased thirst, and constipation
  • Increase in plasma cholesterol, triglyceride levels
  • There is no bleeding risk with mirtazapine, unlike with SSRIs.
  • Antidepressant induced sexual dysfunction (18%), though lower than other antidepressants
  • Restless legs syndrome (estimated to be up to 28%)[16]

Why Does Mirtazapine Have So Little SSRI-type Side Effects?

SSRIs typically activate postsynaptic 5-HT2 and 5-HT3 receptors, which can cause anxiety, insomnia, nausea, and sexual dysfunction. Mirtazapine, however, is an antagonist of postsynaptic 5-HT2 and 5-HT3 receptors, which reduces anxiety and depressive symptoms while lacking the side effects typically found with 5-HT activation (like with SSRIs).[17]

Adverse Events

  • QTc prolongation
    • In rare cases, mirtazapine has been linked to QTc prolongation and Torsades de Pointes.[18]
  • Serotonin syndrome
  • Agranulocytosis (six case reports)[19]
    • Periodic CBC to rule out agranulocytosis is important, especially in the elderly. However, all patients recover after drug discontinuation.

Clinical Pearls

  • Mirtazapine reduces sleep latency and prolongs total sleep duration
  • Mirtazapine is best dosed as a nighttime medication in the evening due to its sedative properties
  • Less likely to cause hyponatremia, compared with other antidepressant classes like SSRIs.

Special Populations

Geriatric

  • Older adults have reduced clearance of mirtazapine, and thus typically require lower doses.

Pediatric

  • Mirtazapine has not received any indications for treatment in the pediatric population.

Obstetric and Fetal

  • No teratogenic effects in humans, but there may be an increased rate of spontaneous abortions and preterm births.[20]
  • Mirtazapine is secreted into breastmilk at low concentrations.

Medically Ill

  • Hepatic clearance decreased by 40% in patients with liver cirrhosis.[21]
  • Renal clearance reduced by 30 to 50% in patients with renal impairment.[22]

Resources

References

1) Kast, R. E., & Foley, K. F. (2007). Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5‐HT3 antagonists with good antinausea effects. European journal of cancer care, 16(4), 351-354.
2) Anttila, S. A., & Leinonen, E. V. (2001). A review of the pharmacological and clinical profile of mirtazapine. CNS drug reviews, 7(3), 249-264.
3) Kasper, S., Praschak-Rieder, N., Tauscher, J., & Wolf, R. (1997). A risk-benefit assessment of mirtazapine in the treatment of depression. Drug safety, 17(4), 251-264.
4) Kasper, S., Praschak-Rieder, N., Tauscher, J., & Wolf, R. (1997). A risk-benefit assessment of mirtazapine in the treatment of depression. Drug safety, 17(4), 251-264.
5) https://www.ncbi.nlm.nih.gov/pubmed/15902580
6) Radhakishun, F. S., van den Bos, J., van der Heijden, B. C., Roes, K. C., & O'hanlon, J. F. (2000). Mirtazapine effects on alertness and sleep in patients as recorded by interactive telecommunication during treatment with different dosing regimens. Journal of clinical psychopharmacology, 20(5), 531-537.
7) Kast, R. E., & Foley, K. F. (2007). Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5‐HT3 antagonists with good antinausea effects. European journal of cancer care, 16(4), 351-354.
8) Stahl's Essential Psychopharmacology, 2nd Edition, pg. 290
9) McGrath, P. J., Stewart, J. W., Fava, M., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., ... & Luther, J. F. (2006). Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR* D report. American Journal of Psychiatry, 163(9), 1531-1541.
10) Gándara, J., Agüera, L., Rojo, J. E., Ros, S., & Pedro, J. M. (2005). Use of antidepressant combinations: which, when and why? Results of a Spanish survey. Acta Psychiatrica Scandinavica, 112(s428), 32-35.
11) Hannan, N., Hamzah, Z., Akinpeloye, H. O., & Meagher, D. (2007). Venlafaxine—mirtazapine combination in the treatment of persistent depressive illness. Journal of Psychopharmacology, 21(2), 161-164.
12) PsychCentral: Combining Meds for Depression: The State of the Art
13) Malhi, G. S., Ng, F., & Berk, M. (2008). Dual–dual action? Combining venlafaxine and mirtazapine in the treatment of depression. Australian & New Zealand Journal of Psychiatry, 42(4), 346-349.
14) Silva, J., Mota, J., & Azevedo, P. (2016). California rocket fuel: And what about being a first line treatment?. European Psychiatry, 33, S684.
15) Pandarakalam, J. P. (2010). SNRI‐NaSSA combination therapy for treatment‐resistant depression. Progress in Neurology and Psychiatry, 14(1), 26-29.
16) Ağargün, M. Y., Kara, H., Özbek, H., Tombul, T., & Ozer, O. A. (2002). Restless legs syndrome induced by mirtazapine. The Journal of clinical psychiatry, 63(12), 18215.
17) Stimmel, G. L., Dopheide, J. A., & Stahl, S. M. (1997). Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 17(1), 10-21.
18) Jasiak, N. M., & Bostwick, J. R. (2014). Risk of QT/QTc prolongation among newer non-SSRI antidepressants. Annals of Pharmacotherapy, 48(12), 1620-1628.
19) Remeron (mirtazapine) product monograph
20) Djulus, J., Koren, G., Einarson, T. R., Wilton, L., Shakir, S., Diav-Citrin, O., ... & Einarson, A. (2006). Exposure to mirtazapine during pregnancy: a prospective, comparative study of birth outcomes. The Journal of clinical psychiatry, 67(8), 1280-1284.
21) Procyshyn, R. M., Bezchlibnyk-Butler, K. Z., & Jeffries, J. J. (Eds.). (2019). Clinical handbook of psychotropic drugs. Hogrefe Publishing.
22) Procyshyn, R. M., Bezchlibnyk-Butler, K. Z., & Jeffries, J. J. (Eds.). (2019). Clinical handbook of psychotropic drugs. Hogrefe Publishing.