Mechanisms of Action All known antidepressants affect monoamine neurotransmis-

sion. MAOIs inhibit the activity of monoamine oxidase, resulting in a decrease in the breakdown of dopamine, serotonin, and norepinephrine in the synapse, thus increasing the amount of these neurotransmitters available for release and synaptic transmission. MAOIs are highly effective antidepressants and anxiolytics but are rarely used due to dietary restrictions that must be adhered to in order to avoid tyramine-induced hypertensive crises.

TCAs block presynaptic reuptake of norepinephrine and serotonin to various degrees. Several are related by metabolism, thus the tertiary amines amitriptyline and imipramine are metabolized to the secondary amines nortriptyline and desipramine respectively. All act through reuptake inhibition and are generally selective for the norepinephrine transporter; several, however, have equal or greater affinity for the serotonin transporter. The TCAs were the drugs of choice for depression through the 1980s. Though effective, their nonselective actions on cholinergic, histaminergic, and presynaptic adrenergic receptors resulted in a number of side effects.

SSRIs were first introduced in the late 1980s, and rapidly eclipsed the TCAs as the drugs of choice for depression. There are subtle differences between compounds, mainly in terms of their half-life, their potency for reuptake inhibition, and their affinity for some other receptors. As SSRIs more selectively affect reuptake, with few effects on the adrenergic, histaminergic, and cholinergic systems, side effects have been reduced.

ANTIDEPRESSANTS 43 The selective norepinephrine reuptake inhibitors (NRIs)

such as reboxetine (not available in the US) or atomoxetine share a similar mechanism with the SSRIs, but act on the norepinephrine transporter and have little affinity for the serotonin transporter.

Several other second-generation agents, sometimes referred to as “atypical antidepressants”, were introduced during the same period as the SSRIs. These include bupro- pion, which seems to exert primarily a dopaminergic effect, and trazodone, which is structurally related to the TCAs but has a primary serotonergic mechanism.

Of the serotonin receptors, 5-hydroxytryptamine type 1A appears most related to the therapeutic effects of antidepressants, and this receptor influences norepinephrine, dopamine, acetylcholine, neuropeptides, other serotonin receptors, and probably beta-receptor downregulation.

The so-called third-generation antidepressants include serotonin–norepinephrine reuptake inhibitors (SNRIs – venlafaxine, milnacipran and duloxetine), mixed serotonin antagonist/reuptake inhibitors (nefazodone and trazodone) and the mixed serotonin/noradrenaline antagonist mirtazapine. SNRIs have equal affinity for the norepinephrine and serotonin transporter. 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.

Mixed serotonin antagonist/reuptake inhibitors such as nefazodone have multiple mechanisms of action, with both serotonin (as well as norepinephrine) transporter inhibi-

tion as well as antagonism of 5-HT 2A and alpha- 1 -receptors. Trazodone is similar; however, its effects are somewhat less specific.

The mixed serotonin/noradrenaline antagonist mirtazapine is unique in that it appears to work primarily through specific receptor blockade of the alpha- 2 -autoreceptors on presynaptic noradrenergic neurons, enhancing noradrenergic output. This class may exert a similar effect toward autoreceptors on

serotonin neurons. Antagonism of 5-HT 2 and 5-HT 3 receptors may also concentrate the effect of serotonin on 5-HT 1A

44 HANDBOOK OF PSYCHIATRIC DRUGS

receptors. The antidepressants available in the US, their class, and relative costs are listed in Table 2-1.

Mechanisms of Action All known antidepressants affect monoamine neurotransmis-