Mirtazapine’s likely antidepressant action is due to antagonism of the presynaptic alpha-2 adrenergic receptors. This should allow for the greater release of serotonin and norepinephrine.

However, mirtazapine’s most potent activity is antagonism of histamine-1 receptors (thus, the sedation). At higher doses, mirtazapine also blocks 5HT2A, 5-HT2C, and 5-HT3 receptors. Antagonism of alpha-2 receptors actually comes last with increasing dosage.

Interestingly, agonism of 5-HT2A, 5-HT2C, and 5-HT3 receptors may be related to the adverse effects of SSRIs: sleep disturbance (5-HT2A), anxiety and weight gain (5-HT2C), and nausea/loose stools/vomiting (5-HT3). Therefore, the antagonist effects of mirtazapine at these sites may mitigate some of the adverse effects of the SSRIs.

With information from: Imipramine, Mirtazapine, and Nefazodone: Multiple Targets. Sheldon H Preskorn, MD. Journal of Practical Psychiatry and Behavioral Health, March 2000, 97-102.