This chapter reviews the actions of antidepressant drugs that work as alpha 2 antagonists (i.e., mirtazapine) or as serotonin antagonist/reuptake inhibitors (SARIs) (i.e., trazodone and nefazodone). The focus is on the unique characteristics of alpha 2 antagonism and SARIs, both of which are second-line treatment options. The aim is to familiarize the reader with these various options for treating depression.

SSRI: selective serotonin reuptake inhibitors. NDRI: norepinephrine dopamine reuptake inhibitors. SNRI: serotonin norepinephrine reuptake inhibitors. SDA: serotonin dopamine antagonists. α 2 antagonist: alpha 2 antagonists. NRI: selective norepinephrine reuptake inhibitors. TCA: tricyclic antidepressants. SARI: serotonin 2A antagonist/reuptake inhibitors. MAOI: monoamine oxidase inhibitors. 5HT1A: serotonin 1A partial agonists. BZ: benzodiazepines. DPA: dopamine partial agonists. MTHF: L-5-methyl-tetrahydrofolate. T3/T4: thyroid hormone. ECT: electroconvulsive therapy. IPT: interper-sonal therapy. VNS: vagus nerve stimulation.

Mirtazapine's antagonist actions at 5HT2A and 2C receptors also results in increased release of dopamine and norepinephrine, and these 5HT2A and 5HT2C antagonist actions may also provide useful anxiolytic and antidepressant as well as sleep-restoring properties. In addition, mirtazapine is able to increase serotonin release without causing sexual dysfunction.

Due to its 5HT2A and 5HT2C antagonist properties, and thus its ability to disinhibit both NE and DA release (see Figs. 1.32 and 1.33), mirtazapine is further classified as a norepinephrine and dopamine disinhibitor (NDDI). 5HT3 antagonist action may reduce nausea, with H1 action potentially relieving insomnia and improving anxiety, but causing weight gain. So, this complex molecule is an NDDI (due to 5HT2A and 5HT2C antagonism), an SNDI (due to alpha 2 antagonism) plus a 5HT3 and H1 antagonist!