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      A molecular and cellular theory of depression.

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          Abstract

          Recent studies have begun to characterize the actions of stress and antidepressant 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'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute 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 intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.

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          Author and article information

          Journal
          Arch Gen Psychiatry
          Archives of general psychiatry
          American Medical Association (AMA)
          0003-990X
          0003-990X
          Jul 1997
          : 54
          : 7
          Affiliations
          [1 ] Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, USA.
          Article
          10.1001/archpsyc.1997.01830190015002
          9236543
          e956fdc4-c5c4-4172-8ff5-3c1506e273ba
          History

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