Neuropharmacology of antidepressants that modify central noradrenergic and serotonergic function: a short review

The first generation of antidepressants largely act as ‘dual’ action drugs in that they facilitate both noradrenergic and serotonergic activity either by blocking the reuptake of noradrenaline and serotonin (tricyclic antidepressants) or by inhibiting the catabolism of these amines (monoamine oxidase inhibitors). Largely as a consequence of their unacceptable side effects, these drugs have been partly replaced by the second generation drugs that showed selectivity of either the noradrenaline (viloxazine, maprotiline, reboxetine) or serotonin (fluoxetine, sertraline, etc.) transporter. While these second generation drugs have undoubted advantages in terms of their safety and tolerability, there is growing evidence that the efficacy of some of these selective uptake inhibitors (e.g. SSRIs) in the treatment of the more severe forms of depression is less than that of the TCAs. This has led to the view that ‘dual action’ antidepressants may offer superiority in the treatment of severe depression. Two groups of novel antidepressants have been developed to meet the need of combining increased efficacy with safety. These include the mixed amine reuptake inhibitors such as lofepramine, venlafaxine and milnacipran and the novel tetracyclic antidepressant mirtazepine that facilitates the functional activity of both noradrenaline and serotonin without affecting the reuptake sites.