Antidepressants: Taxonomy and Relation to Mechanism of Action
There are several ways in which antidepressants are grouped. One is historically, in which antidepressants are roughly divided by the period in which they were introduced (e.g., such terms as “first-generation” antidepressants). Another is by chemical structure (e.g., “tricyclic antidepressants”). Alternatively, they are classi-fied by their presumed mechanism of action (“selective serotonin reuptake inhibitors”). In practice, a combination of these is used: thus, some TCAs, which primarily act through serotonin reuptake inhibition (e.g., clomipramine), are usually included with other TCAs rather than as a serotonin reuptake inhibitor, even though they could rightly claim membership in either category.
These are, historically, the first antidepressants, and were discov-ered primarily through serendipity. They include the monoamine antidepressants and the TCAs.
Historically, these are the first antidepressants discovered. How-ever, owing largely to their side effects, and dietary restrictions, they have rarely enjoyed popular use. They are all characterized by their unique mechanism: they inhibit the action of monoam-ine oxidase (MAO), the primary catabolic enzyme for the monoamines. The end result is an overall increase in available monoamines.
These medications all have a structural similarity in common. They are subdivided by the number of amine groups they pos-sess, and are usually referred to as either “tertiary” or “secondary” TCAs. Several are related by metabolism, thus the tertiary amines – amitriptyline and imipramine – are metabolized to the second-ary amines – nortriptyline and desipramine – respectively. They all act through reuptake inhibition, and are generally selective for the norepinephrine transporter; several, however, have equal or greater affinity for the serotonin transporter. Normally, excess monoam-ine is taken up through monoamine transporters into the neuron, where it can be stored, or, more often, catabolized by intracellular MAO. Reuptake inhibitors prevent this through inhibition of the transporter; the excess neurotransmitter remains in the synaptic space where it can bind with receptors. That this is the mechanism of action of these and many other antidepressants is reinforced by the fact that correlations have been demonstrated between trans-porter inhibition and clinical improvement in depressive symptoms (Hrdina et al., 1997). The TCAs were the drugs of choice for de-pression through the 1980s. Though very effective, their somewhat nonselective actions, acting on cholinergic, presynaptic adrenergic receptors, for example, resulted in a number of side effects.
These medications were developed using knowledge gained from the first-generation antidepressants. An effort was made to pro-duce medications that were more selective for certain actions. The primary benefit of such selectivity was a decrease in unin-tended side effects.
The SSRIs were first introduced in the late 1980s, and within a few years eclipsed the TCAs as the drugs of choice for depres-sion. As the name suggests, they all act through inhibition of the serotonin transporter. Though very similar, they have some sub-tle differences, mainly in terms of their half-life, their potency for reuptake inhibition, and their affinity for some other receptors.
These medications are not only the most popular antide-pressants, but also some of the most popular drugs of any type. The US sales data demonstrate that the SSRIs remain one of the most lucrative of drugs. In 2001, for example, the producer of ser-traline reported global sales of over $2 billion from the product.
Like the SSRIs, medications in this class share a similar mecha-nism with the SSRIs, but act on the norepinephrine transporter and have little affinity for the serotonin transporter. Reboxetine (currently available in Europe, and expected to be available soon in the USA) is an example of such a medication.
Sometimes referred to as “atypical antidepressants” several were introduced during the same period as the SSRIs. These include bupropion, which seems to exert primarily a dopaminergic ef-fect, and trazodone, which was structurally related to the TCAs but has a primary serotonergic mechanism. Nomifensine, which is not commercially available after international reports of severe hemolytic anemias were reported, would be in a class similar to bupropion.
The next generation of antidepressants involved various attempts to expand the potential of second-generation compounds. One important feature of this group is that many of them have multiple actions. In some cases, this involves actions on multiple neurotrans-mitters. In other cases, it involves multiple mechanisms of action. Though, in a way this may seem a return to the broader acting first-generation compounds, the attempt with these drugs is to maxi-mize the presumed “clinically relevant” effects of the drugs, while minimizing the less important (and potentially adverse) actions.
Medications in this class share a common mechanism with the SSRIs, but differ in that they have equal affinity for the nore-pinephrine and serotonin transporter. Currently, the only med-ications of this type available in the USA are venlafaxine and duloxetine. Other medications (available in other countries), such as milnacipran, have similar mechanisms of action. Though, like several of the TCAs, venlafaxine has multiple receptor effects, it is relatively free of the anticholinergic and antihistaminic side effects that are common with the TCAs.
These agents have multiple mechanisms of action, all of which appear to be of clinical importance. Nefazodone is an example of such an agent, with both serotonin (as well as norepinephrine) transporter inhibition as well as antagonism of 5-HT2A and alpha-1-receptors. Trazodone may be similar; however, its effects are somewhat less specific, and as a result, it resembles the TCAs in some respects.
Currently, the only agent in this class is mirtazapine. This agent is unique in that it appears to work primarily through receptor blockade, specifically through blockade of the alpha-2-autore-ceptors on presynaptic noradrenergic neurons, which enhances noradrenergic output. They may exert a similar effect toward autoreceptors on serotonin neurons. Antagonism of 5-HT2 and 5-HT3 receptors may also concentrate the effect of serotonin on
Most studies comparing antidepressants have not found sig-nificant differences in efficacy between agents. In general, studies comparing TCAs and SSRIs have shown equal efficacy, and meta-analyses of these studies have generally confirmed these findings (Anderson, 2000; Workman and Short, 1993). However, there have been some trends in this data, with TCAs showing, perhaps, greater efficacy in patients with severe depression (Perry, 1996).
Meta-analyses lend some support to the contention that drugs with multiple actions have a greater efficacy than those that are more highly selective. There is some suggestion that the antidepressants that are selective for norepinephrine and serotinin may be more effective than the SSRIs alone. Though these meta-analyses are compelling, the fact that improved efficacy has yet to be demonstrated by the “gold standard” of a placebo-controlled study likely explains why the third generation of antidepressants does not yet enjoy a reputation for improved efficacy. And, even if some of the newer drugs do show improved efficacy, the proposed reason for this – multiplicity of action – may not be correct. In fact, at least one meta-analysis investigating this hypothesis, in which multiple action drugs were compared with selective drugs, did not find a difference between the two (Freemantle et al., 2000). As such, our treatment recommendations, as outlined in the summary, make the assumption that the efficacy of antidepressants is approximately equal for all agents.