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

Mirtazapine is a presynaptic alpha-2 antagonist that has dual action by inc reasing noradrenergic and serotonergic neurotransmission. The enhancement o f serotonergic neurotransmission is specifically mediated via 5-HT1 recepto rs because mirtazapine is a postsynaptic serotonergic 5-HT2 and 5-HT3 antag onist. In addition, mirtazapine has only a weak affinity for 5-HT1 receptor s and has very weak muscarinic anticholinergic and histamine (H-1) antagoni st properties. As a consequence of its unique pharmacodynamic properties, m irtazapine is an effective, safe and well-tolerated addition to the antidep ressant armamentarium. Mirtazapine is well absorbed from the gastrointestinal tract following oral administration, and it is extensively metabolized in the liver to four met abolites via demethylation and hydroxylation, followed by glucuronide conju gation. The unconjugated desmethyl metabolite is pharmacologically less act ive than the parent compound. Mirtazapine lacks auto-induction of hepatic i soenzymes, 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-severe major depression. Mir tazapine was consistently superior to placebo, and equivalent in efficacy t o the tricyclic antidepressants amitriptyline, doxepin and clomipramine, bu t with an improved tolerability profile. Mirtazapine has shown a rapid onse t of action in patients with predominantly severe depressive illness in a c omparative study against fluoxetine. Mirtazapine has a unique tolerability profile, since the specific postsynap tic 5-HT2 and 5-HT3 receptor blockade of mirtazapine provides early antidep ressant effects without causing unwanted serotonin-related side-effects. Tr ansient somnolence, hyperphagia and weight gain are the most commonly repor ted adverse events, which may be attributed to the antihistaminic (H-1) act ivity of mirtazapine at low doses. Somnolence, the most commonly reported s ide-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 time s the maximum recommended dose. Mirtazapine is a unique addition to the ant idepressant armamentarium as first-line therapy in patients with major depr ession and symptoms of anxiety/agitation or anxiety/somatization or complai nts of insomnia and as a useful alternative in depressed patients who do no t adequately respond to or are intolerant serotonin-specific reuptake inhib itors. (C) 1998 Elsevier Science B.V. All rights reserved.