The MAO inhibitors irreversibly bind to mitochondrial MAO, preventing oxidative deamination of the monoamines dopamine, norepinephrine, and serotonin. These bind to both forms of MAO (MAOA and MAOB) and include the drugs phenelzine, tranylcypromine, and isocarboxazid (Baldessarini 1996). These drugs also prevent hepatic breakdown of tyramine (a substance found in many foods such as aged cheese, red wine, and figs) by MAOB, which can precipitate a hypertensive crisis. A newer class of reversible, short-acting MAO inhibitors (e.g., moclobemide) are being investigated that are selective to MAOA, and thus do not have the same tyramine toxicity problems. Thus, the antidepressant effect of MAO inhibitors is believed to lie in their ability to increase available monoamines.
Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine.
Mirtazapine (Remeron) is a newer antidepressant that also blocks 5-HT reuptake, but additionally has antagonistic effects at adrenergic a2, 5-HT2, and 5-HT3 receptors (Stahl 1998). Mirtazapine appears to have indirect agonistic effects on 5-HT1A receptors, which may contribute to its antidepressant effect (Berendsen and Broekkamp 1997). Nefazodone, as well, has SSRI and 5-HT2 antagonist effects. The 5-HT2 antagonist effects of these antidepressants is believed to be responsible for their lower incidence of sexual side effects (Nutt 1997).
In addition to acute effects, chronic use of antidepressants causes chronic receptor adaptations. For example, venlafaxine blocks reuptake
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