Mirtazapine has a unique mechanism of action. It inhibits norepinephrine α2 auto- and hetero-receptors (shown present on a norepinephrine and a serotonin neuron). The inhibition of the α2 auto-receptors results in an increase in NE neurotransmission from the norepinephrine neurons (1). Interestingly, the inhibition of the α2 hetero-receptors also causes an increase in 5-HT neurotransmission from the serotonergic neurons (2).

Thus, this one receptor has two effects: a down regulation of post-synaptic norepinephrine receptors (3) and a down-regulation of non-antagonized post-synaptic serotonin receptors (4). Note that mirtazapine is also an antagonist for the 5HT2A&C and 5HT3 receptors, which potentially could lead to enhanced antidepressant activity (5HT2 receptors) and decreased risk of GI side effects (5HT3 receptors).


Mirtazepine’s main mechanism of antidepressant action is the same as the SSRI’s and tricyclics. 


The increased presence of noradrenaline in the synapse leads to stimulation of dendritic norepinephrine hetero-receptors on the serotonin neuron. 


Based on mechanism of action, mirtazepine should cause less nausea than SSRI’s.