Beyond the monoamine hypothesis: The quest for an integrative etiology of depression and new therapeutic strategies

Understanding the pathogenesis of depression and the mechanism of action of clinically effective antidepressants are of considerable interest. Early clinical observations pointed to a decreased monoamine function, which has resulted in the "monoamine hypothesis" of depression. However, as helpful as this hypothesis was for the development of amine-based potent antidepressants, crucial discrepancies, e.g., delayed clinical onset of mood-enhancing effects and the lack of major mood alteration after monoamines depletion, made it rather unlikely that the cause of depression is a simple deficiency of central monoamines. Furthermore, in recent years a growing body of evidence highlighted the possibility that genome regulation, epigenetic modifications or alterations in differential neuronal cell type responsiveness could play a key role in the origin and development of mood disorders. Therefore, providing an integrative theory of the neurobiology of depression may help to explain some of the complexities of this disorder and discover novel pharmacological targets. On the basis of current knowledge we want to discuss an extended "monoamine hypothesis" and propose possible new fields/ideas/concepts which need to be explored for the development of more effective antidepressant treatments.