Venlafaxine is a compound that is structurally unrelated to other antidepressants.12 Like the TCAs, venlafaxine inhibits the neuronal uptake of both serotonin and norepinepherine. Venlafaxine has dose-dependent, sequential effects on the uptake pumps for serotonin and then norepinephrine.. At 75 mg/day, venlafaxine is predominantly a serotonin reuptake inhibitor (SRI) like the SSRIs. At 375 mg/day, it produces comparable norepinephrine uptake inhibition to an NSRI such as desipramine.13
Mirtazapine is the most recently released of these four and is the first a2-antagonist marketed as an antidepressant.14 Mirtazapine's unique mechanism of action does not involve enzyme inhibition or blockade of neurotransmitter reuptake. Mirtazapine increases the release of norepinepherine from central noradrenergic neurons by blocking the presynaptic inhibitory alpha-2 autoreceptors. It spares the alpha-1 postsynaptic receptor and therefore results in net increase noradrenergic transmission. As a second presynaptic receptor blocking function, mirtazapine blocks the inhibitory alpha-2 heteroreceptors located on serotonergic neurons, resulting in increase release of serotonin. Postsynaptically, mirtazapine has low affinity for the 5-HT1A receptor, thus allowing serotonin released into the synapse to bind to and stimulate this receptor. However, it blocks postsynaptic 5-HT2 and 5-HT3 receptors. Stimulation of the 5-HT2 receptor is thought to be responsible for the serotonergic side effects of insomnia, agitation, and sexual dysfunction seen with the SSRI's and 5-HT3 receptor stimulation is thought to mediate nausea seen with these agents.15, 16, 17 Therefore, mirtazapine's receptor blocking profile prevents the side-effects seen with nonselective activation of serotonin receptors which occurs with pure reuptake blockers.
