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Even chromatin gets the blues

Nature Neuroscience volume 9, pages 465–466 (2006)Cite this article

Antidepressants take a few weeks to act, and their effects can extend for months after the drugs are discontinued. Tsankova et al. suggest a possible molecular basis for these effects, by showing that stress and the antidepressant imipramine induce modifications of chromatin to produce more or less repressive states for gene expression.

Major depressive disorder is the most common serious disorder of the brain, with a lifetime risk of 16.2% in the United States1. Accordingly, antidepressants are among the most widely prescribed of all drugs. Although existing antidepressant drugs have clear benefits, they have significant limitations in efficacy. An additional shortcoming is that, for unknown reasons, all antidepressants take a while (typically 2–4 weeks) before patients see any benefits, putting them at risk in the interim. Moreover, the beneficial effects of antidepressants may extend for months or years after the drugs are discontinued (usually after 4–6 months of treatment). In this issue, Tsankova et al.2 provide insights into the molecular basis behind the slow onset and persistence of beneficial effects and hint at possible new targets for antidepressant development. They report that imipramine, a tricyclic antidepressant, downregulates a protein called histone deactylase (HDAC)-5, which in turn alters the conformation of chromatin. This conformational change then correlates with the transcriptional activation of the brain-derived neurotrophic factor (Bdnf) gene, which has been previously linked to antidepressant action.

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Figure 1: Model for states of chromatin surrounding the BDNF promoter.

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  1. Department of Neurobiology, Harvard Medical School, Massachusetts Hall, Cambridge, 02138, Massachusetts, USA

    Steven E Hyman

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  1. Steven E Hyman
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Hyman, S. Even chromatin gets the blues. Nat Neurosci 9, 465–466 (2006). https://doi.org/10.1038/nn0406-465

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