As previously noted, all currently available antidepressants enhance monoamine neurotransmission by one of several mechanisms. The most common mechanism is inhibition of the activity of SERT, NET, or both monoamine transporters (Table 30–2). Antidepressants that inhibit SERT, NET, or both include the SSRIs and SNRIs (by definition) and the TCAs. Another mechanism for increasing the availability of monoamines is inhibition of their enzymatic degradation (by the MAOIs). Additional strategies for enhancing monoamine tone include binding presynaptic autoreceptors (mirtazapine) or specific postsynaptic receptors (5-HT2 antagonists and mirtazapine). Ultimately, the increased availability of monoamines for binding in the synaptic cleft results in a cascade of events that enhance the transcription of some proteins and the inhibition of others. It is the net production of these proteins, including BDNF, glucocorticoid receptors, β adrenoceptors, and other proteins, that appears to determine the benefits as well as the toxicity of a given agent.
A. Selective Serotonin Reuptake Inhibitors
The serotonin transporter (SERT) is a glycoprotein with 12 trans-membrane regions embedded in the axon terminal and cell body membranes of serotonergic neurons. When extracellular serotonin binds to receptors on the transporter, conformational changes occur in the transporter and serotonin, Na+, and Cl− are moved into the cell. Binding of intracellular K+ then results in the release of serotonin inside the cell and return of the transporter to its original conformation. SSRIs allosterically inhibit the transporter by binding the SERT receptor at a site other than the serotonin binding site. At therapeutic doses, about 80% of the activity of the transporter is inhibited. Functional polymorphisms exist for SERT that determine the activity of the transporter (Table 30–2).
SSRIs have modest effects on other neurotransmitters. Unlike TCAs and SNRIs, there is little evidence that SSRIs have prominent effects on β adrenoceptors or the norepinephrine transporter, NET. Binding to the serotonin transporter is associated with tonic
TABLE 30–2 Blocking effects of some antidepressant drugs on several receptors and transporters.
1 Vortioxetine is an agonist or partial agonist at 5-HT1A and 5-HT1B receptors, an antagonist at 5-HT3 and 5-HT7 receptors, and an inhibitor of SERT.
ACh M, acetylcholine muscarinic receptor; α1, alpha1-adrenoceptor; H1, histamine1 receptor; 5-HT2, serotonin 5-HT2 receptor; ND, no data found; NET, norepinephrine transporter; SERT, serotonin transporter. 0/+, minimal affinity; +, mild affinity; ++, moderate affinity; +++, high affinity.
inhibition of the dopamine system, although there is substantial interindividual variability in this effect. The SSRIs do not bind aggressively to histamine, muscarinic, or other receptors.
B. Drugs That Block Both Serotonin and Norepinephrine Transporters
A large number of antidepressants have mixed inhibitory effects on both serotonin and norepinephrine transporters. The newer agents in this class (venlafaxine and duloxetine) are termed SNRIs; those in the older group are termed TCAs on the basis of their structures.