Therapeutics

Mirtazapine

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Overview

Name: Mirtazapine
Synonyms: Remeron, esmirtazapine, Org 50081
Chemical Name: (±)-2-Methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)

Background

Mirtazapine is a tricyclic antidepressant. It inhibits central presynaptic α-2-adrenergic receptors, and increases the release of serotonin and norepinephrine. It produces sedation by antagonizing H1 histamine receptors. This drug is approved to treat major depressive disorder, and used off-label for insomnia, panic disorder, PTSE, anxiety, and headaches. Common side effects are sleepiness, dizziness, increased appetite, and weight gain. One study associated mirtazapine use in younger people with significantly increased mortality after one and five years, compared to other antidepressants (Coupland et al., 2018).

Between 2009 and 2014, mirtazapine was one of the most widely prescribed antidepressants for older people and those with dementia in Europe (Forns et al., 2019). However, in a placebo-controlled study of 218 people with Alzheimer’s dementia, the drug showed no efficacy for depression (Banerjee et al., 2011; Jul 2011 news). Mirtazapine also failed to improve nighttime sleep in a small study of 24 people with Alzheimer's disease, but caused more daytime sleepiness compared to placebo (Scoralick et al., 2016).

Secondary analyses of the depression trial data identified a possible benefit on neuropsychiatric symptoms, and improvement in caregivers’ experience (Banerjee et al., 2013; Romeo et al., 2013; Zuidersma et al., 2019).

Findings

In an open-label study in 16 Alzheimer’s patients with agitation, the Cohen Mansfield Agitation Inventory (CMAI) decreased by an average of 10 points after 12 weeks of mirtazapine at 15-30 mg per day. No significant side effects or cognitive deterioration were reported (Cakir and Kulaksizoglu, 2008).

From January 2017 to March 2020, the Study of Mirtazapine for Agitated Behaviors in Dementia (SYMBAD) evaluated 12 weeks treatment versus placebo in 204 people with Alzheimer’s. It enrolled patients from psychiatric outpatient services and nursing homes in the U.K., who had agitation that did not respond to nonpharmacological treatment. The study found no difference between drug and placebo in the primary outcome of the CMAI after 12 weeks, on an average dose of 30.5 mg per day. CMAI scores dropped by about 10 points in both groups by week six, and stayed below baseline in both at 12 weeks. The number of people with adverse events was similar between placebo and control, but there were seven deaths in the mirtazapine group compared to one in the placebo group, suggesting the possibility of higher mortality with mirtazapine use (Banerjee et al., 2021). The drug did not change the cost of health care, or caregiver burden, compared to placebo (Henderson et al., 2022).

A study of 52 Alzheimer’s patients in Iran is testing mirtazapine as an add-on to the antipsychotic medication quetiapine in people with aggression.

For details on studies of mirtazapine in dementia, see clinicaltrials.gov .

Last Updated: 13 Jan 2023

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References

News Citations

  1. A Paradigm Shift for Treating Depression in Alzheimer’s?

Paper Citations

  1. Cakir S, Kulaksizoglu IB. The efficacy of mirtazapine in agitated patients with Alzheimer's disease: A 12-week open-label pilot study. Neuropsychiatr Dis Treat. 2008 Oct;4(5):963-6. PubMed.
  2. Banerjee S, High J, Stirling S, Shepstone L, Swart AM, Telling T, Henderson C, Ballard C, Bentham P, Burns A, Farina N, Fox C, Francis P, Howard R, Knapp M, Leroi I, Livingston G, Nilforooshan R, Nurock S, O'Brien J, Price A, Thomas AJ, Tabet N. Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial. Lancet. 2021 Oct 23;398(10310):1487-1497. PubMed.
  3. Henderson C, Knapp M, Stirling S, Shepstone L, High J, Ballard C, Bentham P, Burns A, Farina N, Fox C, Fountain J, Francis P, Howard R, Leroi I, Livingston G, Nilforooshan R, Nurock S, O'Brien JT, Price A, Swart AM, Tabet N, Telling T, Thomas AJ, Banerjee S. Cost-effectiveness of mirtazapine for agitated behaviors in dementia: findings from a randomized controlled trial. Int Psychogeriatr. 2022 Oct;34(10):905-917. Epub 2022 Jul 19 PubMed.
  4. Coupland C, Hill T, Morriss R, Moore M, Arthur A, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in people aged 20-64 years: cohort study using a primary care database. BMC Med. 2018 Mar 8;16(1):36. PubMed.
  5. Forns J, Pottegård A, Reinders T, Poblador-Plou B, Morros R, Brandt L, Cainzos-Achirica M, Hellfritzsch M, Schink T, Prados-Torres A, Giner-Soriano M, Hägg D, Hallas J, Cortés J, Jacquot E, Deltour N, Perez-Gutthann S, Pladevall M, Reutfors J. Antidepressant use in Denmark, Germany, Spain, and Sweden between 2009 and 2014: Incidence and comorbidities of antidepressant initiators. J Affect Disord. 2019 Apr 15;249:242-252. Epub 2019 Feb 6 PubMed.
  6. Banerjee S, Hellier J, Dewey M, Romeo R, Ballard C, Baldwin R, Bentham P, Fox C, Holmes C, Katona C, Knapp M, Lawton C, Lindesay J, Livingston G, McCrae N, Moniz-Cook E, Murray J, Nurock S, Orrell M, O'Brien J, Poppe M, Thomas A, Walwyn R, Wilson K, Burns A. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet. 2011 Jul 30;378(9789):403-11. Epub 2011 Jul 19 PubMed.
  7. Scoralick FM, Louzada LL, Quintas JL, Naves JO, Camargos EF, Nóbrega OT. Mirtazapine does not improve sleep disorders in Alzheimer's disease: results from a double-blind, placebo-controlled pilot study. Psychogeriatrics. 2016 Jan 27; PubMed.
  8. Banerjee S, Hellier J, Romeo R, Dewey M, Knapp M, Ballard C, Baldwin R, Bentham P, Fox C, Holmes C, Katona C, Lawton C, Lindesay J, Livingston G, McCrae N, Moniz-Cook E, Murray J, Nurock S, Orrell M, O'brien J, Poppe M, Thomas A, Walwyn R, Wilson K, Burns A. Study of the use of antidepressants for depression in dementia: the HTA-SADD trial--a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine. Health Technol Assess. 2013 Feb;17(7):1-166. PubMed.
  9. Romeo R, Knapp M, Hellier J, Dewey M, Ballard C, Baldwin R, Bentham P, Burns A, Fox C, Holmes C, Katona C, Lawton C, Lindesay J, Livingston G, McCrae N, Moniz-Cook E, Murray J, Nurock S, O'Brien J, Poppe M, Thomas A, Walwyn R, Wilson K, Banerjee S. Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial. Br J Psychiatry. 2013 Feb;202:121-8. Epub 2012 Dec 20 PubMed.
  10. Zuidersma M, Chua KC, Hellier J, Voshaar RO, Banerjee S, HTA-SADD Investigator Group. Sertraline and Mirtazapine Versus Placebo in Subgroups of Depression in Dementia: Findings From the HTA-SADD Randomized Controlled Trial. Am J Geriatr Psychiatry. 2019 Sep;27(9):920-931. Epub 2019 Apr 6 PubMed.

External Citations

  1. study
  2. clinicaltrials.gov

Further Reading

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