Mirtazapine : A Review of its Pharmacology and Therapeutic Potential in the Management of Major Depression.

SYNOPSIS: Mirtazapine is a tetracyclic antidepressant with a novel mechanism of action; it increases noradrenergic and serotonergic neurotransmission via blockade of central α2-adrenergic auto- and heteroreceptors. The increased release of serotonin (5-hydroxytryptamine; 5-HT) stimulates serotonin 5-HT1 receptors because mirtazapine directly blocks 5-HT2 and 5-HT3 receptors. The enhancement of both noradrenergic- and 5-HT1 receptor-mediated neurotransmission is thought to be responsible for the antidepressant activity of mirtazapine. In short term (5 to 6 weeks) clinical trials in patients with depression. mirtazapine produces clinical improvements significantly superior to those of placebo, similar to those of tricyclic antidepressants (TCAs) [amitriptyline, clomipramine and doxepin] and possibly superior to those of trazodone. Short term clinical tolerability data suggest that mirtazapine produces fewer anticholinergic-, adrenergic- and serotonergic-related adverse events than TCAs. In rare cases, mirtazapine, in common with many antidepressants, was associated with potentially serious changes in haematological parameters (e.g. agranulocytosis and neutropenia). The drug appears to be safe in overdose and possesses a very low propensity for inducing seizures. Comparisons with other classes of antidepressants are needed to determine the relative position of mirtazapine in clinical practice. However, preliminary data indicate that mirtazapine, with its novel mechanism of action, is a promising addition to currently available options for the treatment of depression. PHARMACODYNAMIC PROPERTIES: In vitro neurochemical studies have demonstrated that mirtazapine blocks central α2-adrenergic auto- and heteroreceptors, but has no effect on noradrenaline (norepinephrine) reuptake. The affinity of the drug was 10-fold higher for central presynaptic α2-adrenoceptors than for central postsynaptic and peripheral α2-adrenoceptors, and 30-fold higher for α2-adrenoceptors than for α1-adrenoceptors. Microdialysis and neurophysiological experiments as well as behavioural studies performed in rats support the α2-adrenoceptor antagonist properties of mirtazapine. Receptor binding studies have shown that mirtazapine has a high affinity for serotonin 5-HT2 and 5-HT3 receptors, central and peripheral histamine H1 receptors and a low affinity for 5-HT1, dopaminergic and muscarinic cholinergic receptors. Its activity at serotonin receptor subtypes has been confirmed in animal behaviour models. Mirtazapine activates 5-HT1 receptor-mediated serotonergic neurotransmission by enhancing the stimulatory effect of the noradrenergic system on serotonergic cell firing (an α1-adrenoceptor-mediated effect) as well as antagonising the inhibitory effect of the noradrenergic system on serotonin release (an α2-adrenoceptor-mediated effect). Electrophysiological experiments have demonstrated that mirtazapine enhances serotonergic transmission through blockade of presynaptic α2-adrenoceptors. The drug does not inhibit serotonin reuptake. PHARMACOKINETIC PROPERTIES: The bioavailability of mirtazapine is approximately 50%. Peak plasma concentrations are reached within 2.2 to 3.1 hours after single oral doses of 15 to 75mg and are dose-dependent. Mirtazapine is extensively metabolised in the liver; up to 85% of the drug is eliminated in the urine (up to 4% as unchanged drug) and the remaining 15% is eliminated in the faeces. The mean elimination half-life of mirtazapine is approximately 22 hours, making it suitable for once-daily administration. THERAPEUTIC POTENTIAL: In randomised double-blind comparative trials including patients with major depression, short term (5 to 6 weeks) therapy with mirtazapine was significantly more effective than placebo, as effective as amitriptyline, clomipramine and doxepin, and at least as effective as trazodone. Results from a meta-analysis of 5 comparative trials in which 60% of patients were hospitalised with severe depression [mean baseline 17-item Hamilton Depression Rating Scale (HAMD) score ≥25] revealed no significant differences between mirtazapine and amitriptyline. The responder rates (≥50% decrease in HAMD score from baseline) at 6 weeks and study end-point were 70 and 61 %, respectively, for mirtazapine and 73 and 64%, respectively, for amitriptyline. In a comparative trial in older outpatients (mean age 61 to 63 years), reductions in rating scale scores of depression and the percentage of responders tended to be higher in mirtazapine than in trazodone recipients. TOLERABILITY: The tolerability profile of mirtazapine is based on results from short term (5 to 6 weeks) comparisons with placebo and other antidepressants; no longer term data are available. Drowsiness (23 vs 14%), excessive sedation (19 vs 5%), dry mouth (25 vs 16%), increased appetite (11 vs 2%) and bodyweight gain (10 vs 1%) occurred significantly more frequently with mirtazapine in placebo-controlled trials. Analysis of blood pressure, heart rate and symptoms of sexual dysfunction indicated no significant differences between mirtazapine and placebo recipients. In a meta-analysis, mirtazapine appeared to be better tolerated than amitriptyline, with significantly fewer patients experiencing anticholinergic (dry mouth, constipation, and abnormal accommodation and vision), cardiac (palpitations and tachycardia) and neurological (tremor and vertigo) adverse events. Mirtazapine was at least as well tolerated as clomipramine, doxepin and trazodone in comparative trials and appeared to be associated with slightly lower incidences of anticholinergic and neurological adverse events than these drugs. Clinical trial and postmarketing surveillance data suggest that mirtazapine has a very low potential for inducing seizures. Excessive but transient somnolence was the only symptom noted in 10 patients taking an overdose (up to 315mg) of mirtazapine. Mirtazapine is infrequently associated with clinically relevant changes in laboratory parameters. Granulocytopenia and elevated alanine aminotransferase levels have been reported; most were mild in severity and returned to normal values with continued administration of mirtazapine. Elevated cholesterol levels (mean 3 to 4%) have also been reported. DOSAGE AND ADMINISTRATION: The recommended starting dosage of mirtazapine is 15 mg/day for 4 days, then 30 mg/day for 10 days. If effective, the drug should be continued unchanged at this dosage or, in patients assessed as insufficiently improved, the daily dosage may be further increased to 45 mg/day. In patients with hepatic or renal insufficiency, careful dosage titration as well as regular and close monitoring for adverse events is recommended. Concomitant use of mirtazapine and diazepam or alcohol (ethanol) may also impair cognitive and/or motor performance.