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

Dennis S. Charney^1* 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}nih.gov. 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}nih.gov. Fax: (301) 480-0123.

Gloss: This STKE Review with 2 figures and 122 references concerns the interaction between stress, genetic factors, and vulnerability to depression. Evidence suggests that the combination of genetics, early life stress, and ongoing stress determine how an individual responds to stress and his vulnerability to psychiatric disorders, such as depression. It is likely that genetic factors and life stress contribute not only to alterations in various neurotransmitter systems, but also to the impairments of cellular plasticity and resilience that are observed in depression. Increased understanding of the specific cellular and neurochemical alterations that contribute to depression, and of the intracellular signaling pathways that underlie cellular plasticity and resilience, may lead to the identification of novel therapeutic targets and, therefore, to the development of novel antidepressant therapies.

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

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