JOURNAL ARTICLE
REVIEW

Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression

J Fawcett, R L Barkin
Journal of Affective Disorders 1998, 51 (3): 267-85
10333982
Mirtazapine is a presynaptic alpha-2 antagonist that has dual action by increasing noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors because mirtazapine is a postsynaptic serotonergic 5-HT2 and 5-HT3 antagonist. In addition, mirtazapine has only a weak affinity for 5-HT1 receptors and has very weak muscarinic anticholinergic and histamine (H1) antagonist properties. As a consequence of its unique pharmacodynamic properties, mirtazapine is an effective, safe and well-tolerated addition to the antidepressant armamentarium. Mirtazapine is well absorbed from the gastrointestinal tract following oral administration, and it is extensively metabolized in the liver to four metabolites via demethylation and hydroxylation, followed by glucuronide conjugation. The unconjugated desmethyl metabolite is pharmacologically less active than the parent compound. Mirtazapine lacks auto-induction of hepatic isoenzymes. Although mirtazapine is a substrate of P450 isoenzymes 1A2, 2D6 and 3A4, in vitro studies show that it is not a potent inhibitor or inducer of any of these enzymes. Mirtazapine has been evaluated in a worldwide clinical development program involving approximately 4500 patients. Controlled clinical trials involving almost 2800 mirtazapine-treated patients have demonstrated the compound to be effective for the treatment of moderate-to-serve major depression. Mirtazapine was consistently superior to placebo, and equivalent in efficacy to the tricyclic antidepressants amitriptyline, doxepin and clomipramine, but with an improved tolerability profile. Mirtazapine has shown a rapid onset of action in patients with predominantly severe depressive illness in a comparative study against fluoxetine. Mirtazapine has a unique tolerability profile, since the specific postsynaptic 5-HT2 and 5-HT3 receptor blockade of mirtazapine provides early antidepressant effects without causing unwanted serotonin-related side-effects. Transient somnolence, hyperphagia and weight gain are the most commonly reported adverse events, which may be attributed to the antihistaminic (H1) activity of mirtazapine at low doses. Somnolence, the most commonly reported side-effect, appears to be less frequent at higher dosages. Mirtazapine also demonstrates important anxiolytic and sleep-improving effects, which may be related to its pharmacodynamic properties. In addition, mirtazapine does not appear to be associated with sexual dysfunction. Mirtazapine has shown no significant cardiovascular adverse effects at multiples of 7 to 22 times the maximum recommended dose. Mirtazapine is a unique addition to the antidepressant armamentarium as first-line therapy in patients with major depression and symptoms of anxiety/agitation or anxiety/somatization or complaints of insomnia and as a useful alternative in depressed patients who do not adequately respond to or are intolerant of tricyclic antidepressants or serotonin-specific reuptake inhibitors.

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