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Sci. STKE, 23 March 2004
Vol. 2004, Issue 225, p. re5
[DOI: 10.1126/stke.2252004re5]


Life Stress, Genes, and Depression: Multiple Pathways Lead to Increased Risk and New Opportunities for Intervention

Dennis S. Charney1* and Husseini K. Manji2

1Chief, Mood and Anxiety Disorders Research Program, National Institute of Mental Health, 15K North Drive, Room 101, MSC 2670, Bethesda, MD 20892–2670, USA. E-mail: charneyd{at} Fax: (301) 594-9959.
2Chief, Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Building 49, Room B1EE16, 49 Convent Drive, MSC 4405, Bethesda, MD 20892–4405, USA. E-mail: manji{at} Fax: (301) 480-0123.

Abstract: Major depression is a common, severe, chronic, and often life-threatening illness. There is a growing appreciation that, far from being a disease with purely psychological manifestations, major depression is a systemic disease with deleterious effects on multiple organ systems. Stressful life events have a substantial causal association with depression, and there is now compelling evidence that even early life stress constitutes a major risk factor for the subsequent development of depression. The emerging evidence suggests that the combination of genetics, early life stress, and ongoing stress may ultimately determine individual responsiveness to stress and the vulnerability to psychiatric disorders, such as depression. It is likely that genetic factors and life stress contribute not only to neurochemical alterations, but also to the impairments of cellular plasticity and resilience observed in depression. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell plasticity and resilience are long-term targets for the actions of antidepressant agents. Agents capable of reversing the hypothesized impairments of cellular resilience, reductions in brain volume, and cell death or atrophy in depression have the potential of becoming new therapeutic classes of antidepressant drugs. Novel cellular targets include agents targeting neurotrophic pathways, glucocorticoid signaling, phosphodiesterase activity, and glutamatergic throughput. The future development of treatments that more directly target molecules in critical CNS (central nervous system) signaling pathways that regulate cellular plasticity thus hold promise as novel, improved long-term treatments for major depression.

*Corresponding author. E-mail: charneyd{at}

Citation: D. S. Charney, H. K. Manji, Life Stress, Genes, and Depression: Multiple Pathways Lead to Increased Risk and New Opportunities for Intervention. Sci. STKE 2004, re5 (2004).

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