R1 R1: = (CH2)3NCH3
Vortioxetine is a newer agent that acts as an antagonist of the 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist of the 5-HT1B receptor, and an agonist of the 5HT1A receptor. It also inhibits the serotonin transporter, but its actions are not primarily related to SERT inhibition and it is therefore not classified as an SSRI. Vortioxetine has demonstrated efficacy in major depression in a number of controlled clinical studies. In addition, vortioxetine is approved in Europe and the USA to treat cognitive dysfunction associated with depression.
D. Tetracyclic and Unicyclic Antidepressants
A number of antidepressants do not fit neatly into the other classes. Among these are bupropion, mirtazapine, amoxapine, vilazodone, and maprotiline (Figure 30–5). Bupropion has a unicyclic aminoketone structure. Its unique structure results in a different side-effect profile than most antidepressants (described below). Bupropion somewhat resembles amphetamine in chemical structure and, like the stimulant, has central nervous system (CNS) activating properties.
Mirtazapine was introduced in 1994 and, like bupropion, is one of the few antidepressants not commonly associated with
FIGURE 30–5 Structures of the tetracyclics, amoxapine, maprotiline, and mirtazapine and the unicyclic, bupropion.
sexual effects. It has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds.
Mirtazapine, amoxapine, and maprotiline have tetracyclic structures. Amoxapine is the N-demethylated metabolite of loxapine, an older antipsychotic drug. Amoxapine and maprotiline share structural similarities and side effects comparable to the TCAs. As a result, these tetracyclics are not commonly prescribed in current practice. Their primary use is in MDD that is unresponsive to other agents. Vilazodone has a multi-ring structure that allows it to bind potently to the serotonin transporter but minimally to the dopamine and norepinephrine transporter.
E. Monoamine Oxidase Inhibitors
Arguably the first modern class of antidepressants, monoamine oxidase inhibitors (MAOIs) were introduced in the 1950s but are now rarely used in clinical practice because of toxicity and potentially lethal food and drug interactions. Their primary use now is in the treatment of depression unresponsive to other antidepressants. However, MAOIs have also been used historically to treat anxiety states, including social anxiety and panic disorder. In addition, selegiline is used in the treatment of Parkinson’s disease (see Chapter 28).
Current MAOIs include the hydrazine derivatives phenelzine and isocarboxazid and the nonhydrazines tranylcypromine, selegiline, and moclobemide (the latter is not available in the USA). The hydrazines and tranylcypromine bind irreversibly and nonselectively with MAO-A and -B, whereas other MAOIs may have more selective or reversible properties. Some of the MAOIs such as tranylcypromine resemble amphetamine in chemical structure, whereas other MAOIs such as selegiline have amphetamine-like metabolites. As a result, these MAOIs tend to have substantial CNS-stimulating effects.
The antidepressants share several pharmacokinetic features (Table 30–1). Most have fairly rapid oral absorption, achieve peak plasma levels within 2–3 hours, are tightly bound to plasma proteins, undergo hepatic metabolism, and are renally cleared. However, even within classes, the pharmacokinetics of individual antidepressants varies considerably.
A. Selective Serotonin Reuptake Inhibitors