The thing about mirtazapine
So I always get confused about the details of mirtazapine’s mechanisms of action. I’m not sure what my mental block is. Time to review.
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.