A MOLECULAR AND CELLULAR THEORY OF DEPRESSION

Recent studies have begun to characterize the actions of stress and an tidepressant treatments beyond the neurotransmitter and receptor level . This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monop hosphate system in specific brain regions, including the increased fun ction and expression of the transcription factor cyclic adenosine mono phosphate response element-binding protein, The activated cyclic adeno sine 3',5'-monophosphate system leads to the regulation of specific ta rget genes, including the increased expression of brain-derived neurot rophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by th e discovery that stress can decrease the expression of brain-derived n eurotrophic factor and lead to atrophy of these same populations of st ress-vulnerable hippocampal neurons. The possibility that the decrease d size and impaired function of these neurons may be involved in depre ssion is supported by recent clinical imaging studies, which demonstra te a decreased volume of certain brain structures, These findings cons titute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellula r mechanisms that decrease or increase, respectively, neurotrophic fac tors necessary for the survival and function of particular neurons. Th is hypothesis also explains how stress and other types of neuronal ins ult can lead to depression in vulnerable individuals and it outlines n ovel targets for the rational design of fundamentally new therapeutic agents.