Brain noradrenaline and the mechanisms of action of antidepressant drugs.

The basic mechanisms of action of presently used antidepressant drugs are still far from understood. This review will address a few critical issues in this area, namely (i) putative mechanisms underlying the delay in onset of action of monoamine reuptake inhibitors and potential limitations to the efficacy of these drugs, (ii) the significance of stress-induced activation of the locus coeruleus noradrenergic system for the function of the mesolimbic reward system and the effect of chronic antidepressant treatment within this context and (iii) the interaction between brain noradrenaline and 5-hydroxytryptamine systems and its significance for antidepressant drug action. Recent preclinical and clinical research which suggest novel strategies to enhance antidepressant drug efficacy will also be discussed. From this review emerges the notion that facilitation of brain noradrenergic neurotransmission may represent a more fundamental means to achieve maximal response in major depression than hitherto understood.