Mirtazapine: An Antidepressant with Noradrenergic and Specific Serotonergic Effects

Mirtazapine is a unique antidepressant that refines the specificity of effects on noradrenergic and serotonergic systems. It is an antagonist of presynaptic α 2 ‐adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin (5‐HT) presynaptic axons, plus is a potent antagonist of postsynaptic 5‐HT 2 and 5‐HT 3 receptors. The net outcome of these effects is increased noradrenergic activity together with specific increased serotonergic activity, especially at 5‐HT 1A receptors. This mechanism of action maintains equivalent antidepressant efficacy but minimizes many of the adverse effects common to both tricyclic antidepressants and selective serotonin reuptake inhibitors. Mirtazapine has an onset of clinical effect in 2–4 weeks similar to other antidepressants, although sleep disturbances and anxiety symptoms may improve in the first week of treatment. It has minimal cardiovascular and anticholinergic effects, and essentially lacks serotonergic effects such as gastrointestinal symptoms, insomnia, and sexual dysfunction. Sedation, increased appetite, and weight gain are more common with mirtazapine than with placebo. An elimination half‐life of 20–40 hours enables once‐daily bedtime dosing. The recommended initial dosage is 15 mg once/day at bedtime, with an effective daily dosage range of 15–45 mg. Cases of overdose of up to 975 mg caused significant sedation but no cardiovascular or respiratory effects or seizures.