Mechanism of effect
Mirtazapine is a tetracyclic antidepressant that works by its central presynaptic alpha2-adrenergic antagonist effects, which results in increased release of norepinephrine and serotonin. It is also a potent antagonist of 5-HT2 and 5-HT3 serotonin receptors and H1 histamine receptors and a moderate peripheral alpha1-adrenergic and muscarinic antagonist; it does not inhibit the reuptake of norepinephrine or serotonin
Pharmacokinetics
Onset of action:
Anxiety disorders (panic disorder): Initial effects may be observed within 2 weeks of treatment, with continued improvements through 4 to 6 weeks (WFSBP [Bandelow 2012]); some experts suggest up to 12 weeks of treatment may be necessary for response (BAP [Baldwin 2014]; Katzman 2014; WFSBP [Bandelow 2012]).
Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009).
Absorption: Rapid and complete.
Protein binding: ~85%.
Metabolism: Extensively hepatic via CYP1A2, 2D6, 3A4 and via demethylation and hydroxylation.
Bioavailability: ~50%.
Half-life elimination: ~20 to 40 hours; increased with renal or hepatic impairment.
Time to peak, serum: ~2 hours.
Excretion: Urine (75%) and feces (15%) as metabolites.
Drug indications
Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder (MDD)
Dosage
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Headache, chronic tension-type, prophylaxis (alternative agent) (off-label use): Oral: Initial: 15 mg once daily at bedtime; may increase after 1 week to 30 mg/day based on response and tolerability (Bendtsen 2004)
Major depressive disorder (unipolar): Oral: Initial: 15 mg once daily at bedtime; increase dose in 15 mg increments at intervals no less than every 1 to 2 weeks based on response and tolerability. Maximum dose: 45 mg/day (product labeling); however, doses up to 60 mg/day have been used in clinical trials (VA/DoD 2016; Watanabe 2011).
Panic disorder (alternative agent) (off-label use):
Note: As monotherapy or adjunctive therapy in patients nonresponsive to SSRIs.
Oral: Initial: 15 mg once daily at bedtime; may increase in increments of 15 mg at intervals of no less than 1 week based on response and tolerability, up to a usual maximum of 45 mg once daily (product labeling). Average doses in clinical trials were ~30 mg/day; doses up to 60 mg/day have been evaluated (Boshuisen 2001; Montañés-Rada 2005; Ribeiro 2001)
Drug contraindications
Hypersensitivity to mirtazapine or any component of the formulation; use of monoamine oxidase inhibitors (MAOIs) including linezolid or methylene blue IV (concurrently or within 14 days of stopping an MAOI)
Side effects
dry mouth , dizziness , Blurred vision , vertigo , Dyspnea , hypertriglyceridemia , Hyper-cholesteremia , urinary retention , increased appetite , difficulty urinating , skin rush , increased liver enzymes in the blood>10%:
Central nervous system: Drowsiness (54%)
Endocrine & metabolic: Weight gain (12%; weight gain of >7% reported in 8% of adults, 49% of pediatric patients), increased serum cholesterol (15%)
Gastrointestinal: Xerostomia (25%), increased appetite (17%), constipation (13%)
Interactions
Sibutramine , Cyclobenzaprine , Sodium Oxybate , Tapentadol , methylene blue , teriflunomide , rasagiline , Dolasetron , Palonosetron , vandetanib , Mefloquine , Dofetilide , Peginterferon alfa-2b , Lorcaserin , Desvenlafaxine , Halofantrine , Grepafloxacin , Dexfenfluramine , Levomilnacipran , tropisetron , Bepridil , bedaquiline , Cannabidiol , Blonanserin , BromazepamAlerts
Major psychiatric warnings:
• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Mirtazapine is not FDA approved for use in children.
Points of recommendation
- Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
- • It may take several weeks to see the full effects.
- • Do not stop taking this drug all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop this drug, you will want to slowly stop it as ordered by your doctor.
- • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this drug affects you.
- • Some people may have a higher chance of eye problems with this drug. Your doctor may want you to have an eye exam to see if you have a higher chance of these eye problems. Call your doctor right away if you have eye pain, change in eyesight, or swelling or redness in or around the eye.
- • Low white blood cell counts have rarely happened with this drug. This may lead to a higher chance of getting an infection. Tell your doctor if you have ever had a low white blood cell count. Call your doctor right away if you have signs of infection like fever, chills, or sore throat.
- • An unsafe heartbeat that is not normal (long QT on ECG) has happened with this drug. Sudden deaths have rarely happened in people taking this drug. Talk with the doctor.
- • This drug may cause high cholesterol and triglyceride levels. Talk with the doctor.
- • Have blood work checked as you have been told by the doctor. Talk with the doctor.
- • Avoid drinking alcohol while taking this drug.
- • Talk with your doctor before you use other drugs and natural products that slow your actions.
- • If you have phenylketonuria (PKU), talk with your doctor. Some products have phenylalanine.
- • If you are 65 or older, use this drug with care. You could have more side effects.
- • Tell your doctor if you are pregnant, plan on getting pregnant, or are breast-feeding. You will need to talk about the benefits and risks to you and the baby.
Pregnancy level
Mirtazapine crosses the placenta (Hatzidaki 2008).
A significant increase in major teratogenic effects has not been observed following exposure to mirtazapine during pregnancy; however, information is limited (Larsen 2015; MacQueen 2016).
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