Rational site-directed pharmacotherapy for major depressive disorder.

It is now accepted that major depressive disorder (MDD) is not a single pathophysiological entity. It is therefore not surprising that remission rates to a first antidepressant trial are low. In addition, antidepressants may target various neuronal elements for which there are gene polymorphisms, such as the serotonin (5-HT) reuptake transporter, which may modulate response. Acting on a single monoaminergic target, such as inhibiting the 5-HT transporter, may confer efficacy in MDD, but other targets may be used and/or combined in treatment-resistant patients. These include the blockade of norepinephrine transporters, monoamine oxidase, 5-HT(2A), 5-HT(1B) and 5-HT7 receptors, and the activation of 5-HT(1A) and dopamine 2 receptors. While antidepressants may have more than one of these properties, so do atypical antipsychotics. When using the latter medications, however, their regimens should be below those effective in treating psychosis to avoid dopamine 2 antagonism, which could be counter-productive in MDD. In some patients, combining medications from treatment initiation may also provide additional therapeutic benefits.