Neurochemical aspects of depression: the past and the future?

The role of aberrant neurochemical substrates in the etiology of depression and the neurochemical mechanisms of antidepressant therapies have been the subjects of many hypotheses in the last 30 years. Pharmacological studies of early antidepressant drugs indicated that brain monoamines were significantly affected by these drugs and these led to the formulation of the biogenic amine hypothesis of depression. Although this hypothesis has been of heuristic value in the study of drug mechanisms and has provided a basis for screening drugs for antidepressant potential, deficiencies in it have become apparent. Neuroanatomical and neurochemical considerations favour the view that brain noradrenaline and serotonin systems may serve as bias adjusting systems for each other and numerous other neural systems. As a consequence of such a relationship, a primary defect in some other neural system would appear amplified in measurements of serotonin or noradrenaline. A possible site for this primary defect may be in membrane composition and function. Recent studies have found that typical and other antidepressant therapies have a pronounced effect on membrane lipids. Thus, in view of the important functions of membrane lipids and the fact that they have been linked to the initiation and development of a number of other disease processes, it is now suggested that consideration be given to them as playing primary causal roles in the etiology of depression and as a site of action for antidepressant drugs.