Background   Patients referred to palliative care services often have between 3 and 7 distressing symptoms and may require multiple medications for effective symptom reduction (1). Due to its effects on multiple receptors, mirtazapine has the potential to target several common symptoms in serious illness with one medication. This Fast Fact provides an overview of the pharmacology and potential uses of mirtazapine in palliative care beyond its FDA indication as an antidepressant. 

Pharmacology    Mirtazapine is a tetracyclic antidepressant that antagonizes noradrenergic, histamine (H1), 5-HT2 and 5-HT3 receptors, thereby enhancing central norepinephrine and serotonergic transmission (2,3). It has a relatively high oral bioavailability (50%) for its medication class. It is absorbed relatively quickly reaching peak plasma concentrations within 2 hours and its absorption is not affected by food (3,4). The half-life is long and variable, between 20 to 40 hours, with the longest half-lives seen in elderly women.  Consequently, steady state levels of the medication may not be achieved for a week (4). Dose reductions are necessary in liver and renal failure, as it is metabolized in the liver mainly by the cytochrome (CYP) P450 isoenzymes and >75% is excreted in the urine (2,3).  

Utility in symptom management in Patients with serious illness: 

Mood disorders:  Mirtazapine has been shown to be effective in moderate-severe major depression at doses of 15 and 30 mg in short-term and long-term (up to 72 weeks) studies of otherwise healthy adults (8) and in adults with advanced cancer (9). It is not considered to be any more or less effective than other modern antidepressants, though it may have a faster onset of antidepressant action with reductions in affective symptoms described in just 1-2 weeks (10). Fast Fact #309 for more information on pharmacotherapy for depression.
Pruritus: In case reports, mirtazapine has been shown to be effective for chronic pruritus related to inflammatory skin disease, cancer, cholestasis, and renal failure at doses of 15-30 mg/day (5,6).
Anorexia: Mirtazapine is associated with short and long-term weight gain in otherwise healthy depressed children and adults likely due to appetite stimulation via effects on H1 and 5-HT2 receptors (7,8). This has led to an interest in using mirtazapine for anorexia related to cancer and other advanced illnesses. Results in controlled studies for this indication are mixed. In some studies, endpoints such as statistically significant weight gain (11), improved appetite (11), increased energy intake (12), and decreased proportion of sarcopenia (12) was observed in patients with advanced cancer taking 15 mg of mirtazapine vs placebo.  In other studies, 15 mg of nightly mirtazapine was found to have no benefit compared to placebo in improving subjective feelings of appetite in patients with advanced cancer (13)
Insomnia: Cancer patients have reported improvements in early, middle, and late insomnia scores over 6 weeks at doses of 7.5-15 mg/day (8,14). Its sedative effects are likely compromised at doses higher than 15 mg/day, as antihistamine activity may be offset by higher norepinephrine transmission (11,15). 
Nausea: Case reports of its antiemetic efficacy (assumed to be due to 5HT3 antagonism) in patients with hyperemesis gravidarum and postoperative nausea and vomiting suggest wider applicability. A small open-label study showed significant improvement in nausea in cancer patients but otherwise, evidence for a robust antiemetic effect in seriously ill populations is scant (16).  

Side effects   Dry mouth, dizziness, daytime sedation, and constipation are more commonly associated with mirtazapine compared with SSRIs (2,14,17). However, it may be less associated with sexual dysfunction (18). A QOL study in older cancer patients showed a relatively high drop-out rate (42%) after only 2 weeks due to somnolence, delirium, hallucinations, xerostomia, dizziness, and, fatigue. Of note, less than 10% of the patients in this study reported a significant improvement in their QOL (19). 

Drug Interactions   Mirtazapine has little inhibitory effects on CYP isoenzymes, has few drug-drug interactions, and is postulated to hardly affect the pharmacokinetics of co-administered medications (4,17). Caution should still be exerted when used along with medications known to increase the risk of serotonin syndrome (20,21).  

Dosing      Mirtazapine is available in generic form in 7.5 mg, 15 mg, 30 mg, and 45 mg oral tablets. It also comes as an orally disintegrating tablet for patients who cannot swallow or absorb enteric drugs. Starting dose varies based on the indication of use but is generally between 7.5 mg and 15 mg once daily or nightly.  Dosing can be doubled every 1-2 weeks up to a maximum of 45 mg/day. Mirtazapine is commonly dosed at night due to its sedating properties. 

Pediatrics   Mirtazapine has been evaluated in children aged 7 to 17 with depression, but it was not found to have a significant effect when compared to placebo (22).  It has not been well studied for off-label purposes in children.  

Cost varies based on dose and tablet type. The monthly cost for a generic 15 mg oral disintegrating tab is about $35 vs $15 for the regular generic tablet (23).  

Summary    Mirtazapine is an effective anti-depressant which targets multiple neurotransmitters and thereby may have potential in alleviating additional symptoms experienced by seriously ill patients. Side effects may limit its utility in a significant number of patients it is prescribed to. 

References 

1. Potter J, Hami F, Bryan T, Quigley C. Symptoms in 400 patients referred to palliative care services: prevalence and patterns. Palliative Medicine 2003;17:310-314. 
2. Anttila SAK, Leinonen EVJ. A Review of the Pharmacological and Clinical Profile of Mirtazapine. CNS Drug Reviews 2001;7:249-64. 
3. Davis MP, Dickerson ED, Pappagallo M, Benedetti C, Grauer PA, Lycan J. Mirtazepine: Heir apparent to amitriptyline? American Journal of Hospice and Palliative Medicine 2001;18:42-6. 
4. Timmer CJ, Ad Sitsen JM, delbressine LP. Clinical Pharmacokinetics of Mirtazapine. Clinical Pharmacokinetics 2000;38:461-74. 
5. Hundley JL, Yosipovitch G. Mirtazapine for reducing nocturnal itch in patients with chronic pruritus: a pilot study. Journal of the American Academy of Dermatology 2004;50:889-91. 
6. Davis MP, Frandsen JL, Walsh D, Andresen S, Taylor S. Mirtazapine for Pruritus. Journal of Pain and Symptom Management 2003;25:288-91. 
7. Fava M. Weight gain and antidepressants. J Clin Psychiatry 2000;61 Suppl 11:37-41. 
8. Fawcett J, Barkin RL. Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. Journal of Affective Disorders 1998;51:267-85. 
9. Thompson C.  Onset of action of antidepressants: results of different analyses. Hum Psychopharmacol. 2002: 17 Suppl 1: S27–32. 
10. Riechelmann RP, Burman D, Tannock IF, Rodin G, Zimmermann C. Phase II Trial of Mirtazapine for Cancer-Related Cachexia and Anorexia. American Journal of Hospice and Palliative Medicine 2010;27:106-10. 
11. Leonard SD, Karlamangla A. Dose-dependant sedating and stimulating effects of mirtazapine. Proceedings of UCLA health care 2015;Vol 19.  
12. Arrieta O, Cárdenas-Fernández D, Rodriguez-Mayoral O, et al. Mirtazapine as appetite stimulant in patients with non–small cell lung cancer and anorexia: a randomized clinical trial. JAMA oncology. 2024 Jan 11. 
13. Hunter CN, Abdel-Aal HH, Elsherief WA, et al.  Mirtazapine in cancer-associated anorexia and cachexia: a double-blind placebo-controlled randomized trial. Journal of Pain and Symptom Management 2021; 62(6):1207-1215. 
14. Economos G, Lovell N, Johnston A, et al.  What is the evidence for mirtazapine in treating cancer-related symptomatology? A systematic review.  Supportive Care in Cancer 2020; 28:1597-1606. 
15. Dolder CR, Nelson MH, Iler CA. The effects of mirtazapine on sleep in patients with major depressive disorder. Ann Clin Psychiatry 2012;24(3):215-224. 
16. Kim SW, Shin IS, Kim JM, et al. Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression. Psychiatry Clin Neurosci. 2008 Feb;62(1):75-83. 
17. Puzantian T. Mirtazapine, an antidepressant. American journal of health-system pharmacy 1998;55:44-9. 
18. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry, 62 (Suppl 3) (2001), pp. 10–21 
19. Davis MP,  Kirkova J, Lagman R, Walsh D, Karafa M. Intolerance to mirtazapine in advanced cancer. J Pain Symptom Manage. 2011 Sep;42(3):e4-7. 
20. Houlihan DJ. Serotonin Syndrome Resulting from Coadministration of Tramadol, Venlafaxine, and Mirtazapine. Ann Pharmacother 2004;38:411-3. 
21. Poeschla BD, Bartle P, Hansen KP. Serotonin syndrome associated with polypharmacy in the elderly. General Hospital Psychiatry 2011;33:301.e9-.e11. 
22. Cheung AH, Emslie GJ, Mayes TL. Review of the efficacy and safety of antidepressants in youth depression. J Child Psychol Psychiatry. 2005;46:735-754. 
23. Mirtazapine prices, coupons, and patient assistance programs.  Drugs.com 2024.  Available at https://drugs.com/price-guide/mirtazapine.  Last accessed 2/28/24.   

Author Affiliations:  Stanford University School of Medicine, Palo Alto, CA; Selayang Hospital, Ministry of Health, Malaysia.
Conflicts of Interest: none
Version History: Originally edited by Sean Marks MD; electronically published April 2016; reviewed and updated in February 2024.