Serotonin noradrenaline reuptake inhibitors: Logical evolution of antidepressant development

Although considerable progress has been made in improving the tolerability of antidepressant drugs, the classical tricyclic antidepressants (TCA) are still a standard for efficacy. The selective serotonin reuptake inhibitors (SSRI) are much better tolerated than the TCAs, but their antidepressant efficacy is, at best, equivalent and probably inferior to the TCA, clomipramine, in many situations. The introduction of the SSRIs naturally focussed both fundamental and clinical research effort on the role of serotonin (5-HT) in the pharmacogenesis and pharmacotherapy of depression. More recently the probable role of noradrenaline (NA) has been "rediscovered" and increasingly both 5-HT and NA dysfunctions are seen as fundamental to depressive illness. The therapeutic importance of this has been underlined by studies showing the increased antidepressant efficacy obtained when selective serotonergic drugs have been used in conjunction with selective noradrenergic drugs. The development of the new class of serotonin and noradrenaline reuptake inhibitors (SNRI) was a logical extension of these ideas. Compounds of this class, which currently comprises venlafaxine, milnacipran and duloxetine, act to inhibit the reuptake of both monoamines with no direct actions at postsynaptic receptors. Although, by definition all three SNRIs have actions on both 5-HT and NA neurotransmission, they do not all have equal potency for both transmitters. Venlafaxine has a 30-fold higher affinity for 5-HT than NA while duloxetine has a 10-fold selectivity for 5-HT. Only milnacipran is balanced between the two neurotransmitters with an approximately equal potency for the inhibition of reuptake of 5-HT and NA both in vitro and in vivo. At high doses venlafaxine and duloxetine appear to be superior to SSRIs but not at lower doses. Duloxetine is, however, not licensed in the EU at these higher doses. Milnacipran at usual doses appears more effective than SSRIs with efficacy which is similar to TCAs but with a lower side effect burden.