1. Serotonin-norepinephrine reuptake inhibitors—SNRIs bind both the serotonin and the norepinephrine transporters. The NET is structurally very similar to the 5-HT transporter. Like the serotonin transporter, it is a 12-transmembrane domain complex that allosterically binds norepinephrine. The NET also has a moderate affinity for dopamine.
Venlafaxine is a weak inhibitor of NET, whereas desvenlafaxine, duloxetine, milnacipran, and levomilnacipran are more balanced inhibitors of both SERT and NET. Nonetheless, the affinity of most SNRIs tends to be much greater for SERT than for NET. The SNRIs differ from the TCAs in that they lack the potent antihistamine, α-adrenergic blocking, and anticholinergic effects of the TCAs. As a result, the SNRIs tend to be favored over the TCAs in the treatment of MDD and pain syndromes because of their better tolerability.
2. Tricyclic antidepressants—The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine’s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effect initially, its metabolite, desipramine, then balances this effect with more NET inhibition.
Common adverse effects of the TCAs, including dry mouth and constipation, are attributable to the potent antimuscarinic effects of many of these drugs. The TCAs also tend to be potent antagonists of the histamine H1 receptor. TCAs such as doxepin are sometimes prescribed as hypnotics and used in treatments for pruritus because of their antihistamine properties. The blockade of α adrenoceptors can result in substantial orthostatic hypotension, particularly in older patients.
C. 5-HT Receptor Modulators
The principle action of both nefazodone and trazodone appears to be blockade of the 5-HT2A receptor. Inhibition of this receptor in both animal and human studies is associated with substantial antianxiety, antipsychotic, and antidepressant effects. Conversely, agonists of the 5-HT2A receptor, eg, lysergic acid (LSD) and mescaline, are often hallucinogenic and anxiogenic. The 5-HT2A receptor is a G protein-coupled receptor and is distributed throughout the neocortex.
Nefazodone is a weak inhibitor of both SERT and NET but is a potent antagonist of the postsynaptic 5-HT2A receptor, as are its metabolites. Trazodone is also a weak but selective inhibitor of SERT with little effect on NET. Its primary metabolite, m-cpp, is a potent 5-HT2 antagonist, and much of trazodone’s benefits as an antidepressant might be attributed to this effect. Trazodone also has weak-to-moderate presynaptic α-adrenergic–blocking properties and is a modest antagonist of the H1 receptor.
As described above, vortioxetine has multimodal effects on a variety of 5-HT receptors and is an allosteric inhibitor of SERT. It has no known direct activity on norepinephrine or dopamine receptors.
D. Tetracyclic and Unicyclic Antidepressants