Why Do Lower Doses of Mirtazapine Cause More Sedation?
Mirtazapine acts mainly on 3 receptors: histaminergic, noradrenergic, and serotonergic receptors. However, at low doses (e.g. - 7.5 mg), mirtazapine has a higher affinity to (and thus preferentially blocks) the histamine-1 receptor, compared to the other 2 receptors. At higher doses, this antihistamine activity is offset by increased noradrenergic transmission, which reduces its sedating effects. Although sedation is expected at low doses, it is usually most noticeable in the first few weeks of therapy and diminishes with continued treatment.