Abstract
P
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 two hours and its absorption is not affected by food.3,4 The half-life is long and variable, between 20 and 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
Mood Disorders
Mirtazapine has been shown to be effective in moderate-severe major depression in short-term and long-term (up to 72 weeks) studies of otherwise healthy adults. 8 It is not considered to be any more or less effective than other modern antidepressants, although it may have a faster onset of antidepressant action with reductions in affective symptoms described in just one to two weeks. 9 Refer to 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 through 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. No well-designed studies have confirmed mirtazapine's effectiveness for this indication. A small open-label study demonstrated weight gain of >1 kg after four weeks of therapy in only 4 of 17 (24%) cancer patients. Secondary endpoints of improvements in appetite and health-related quality of life (QOL) were noted in only 24% and 6% of patients, respectively. 10
Insomnia
Cancer patients have reported improvements in early, middle, and late insomnia scores over six weeks at doses of 7.5–15 mg/day. 8 Its sedative effects are likely compromised at doses higher than 15 mg/day, as antihistamine activity may be offset by higher norepinephrine transmission.11,12
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. 13
Side Effects
Dry mouth, day-time sedation, and constipation are more commonly associated with mirtazapine compared with SSRIs.2,14 However, it may be less associated with sexual dysfunction. 15 A QOL study in older cancer patients showed a relatively high drop-out rate (42%) after only two weeks due to somnolence, delirium, hallucinations, xerostomia, nausea, fatigue, or insomnia. Of note, less than 10% of the patients in this study reported a significant improvement in their QOL. 16
Drug Interactions
Mirtazapine has little inhibitory effects on CYP isoenzymes, has few drug–drug interactions, and is postulated to hardly affect the pharmacokinetics of coadministered medications.4,14 Caution should still be exerted when used along with medications known to increase the risk of serotonin syndrome.17,18
Dosing
Mirtazapine is available in generic form in 7.5, 15, 30, 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 and 15 mg once daily or nightly. Dosing can be doubled every one to two 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 with placebo. 19 It has not been well studied for off-label purposes in children.
Cost
Cost varies based on dose and tablet type. The monthly cost for a generic 15 mg oral disintegrating tablet is about $60 versus $40 for the regular generic tablet. This makes mirtazapine slightly more expensive than citalopram, paroxetine, and sertraline, but less expensive than escitalopram or venlafaxine. 20
Summary
Mirtazapine is an effective antidepressant that targets multiple neurotransmitters and thereby may have potential in alleviating additional symptoms experienced by seriously ill patients. However, its known toxicity and lack of efficacy in improving QOL measurements in nondepressed seriously ill patients should make clinicians refrain from using it routinely for off-label purposes.
Footnotes
Acknowledgment
We thank the Director General of Health, Malaysia for the approval to publish this article.