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Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

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Abstract

Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.

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Figure 1: Heterogeneity of depression and influences on susceptibility to depression.

Marina Corral Spence/Nature Publishing Group

Figure 2: Chronic stress causes atrophy of neuronal processes and decreases synapse number.

Marina Corral Spence/Nature Publishing Group

Figure 3: The multiple heterogeneous signaling pathways that influence synapse formation and stability and that could contribute to loss of synapses in depression.

Marina Corral Spence/Nature Publishing Group

Figure 4: Mechanism of action of the fast-acting antidepressant ketamine in the mPFC.

Marina Corral Spence/Nature Publishing Group

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Acknowledgements

This work was supported by the US National Institute of Mental Health grants MH045481 (R.S.D.) and MH093897 (R.S.D.), the National Center for Advancing Translational Science grant 1UH2TR000960-01 (J.H.K.), the National Institute on Alcohol Abuse and Alcoholism grants P50AA12870 (J.H.K.) and M01RR00125 (J.H.K.), the Yale Center for Clinical Investigation grant UL1 RR024139 (J.H.K.), the state of Connecticut's Department of Mental Health and Addiction Services (DMHAS; to R.S.D., G.K.A., G.S. and J.H.K.), the Yale University School of Medicine (R.S.D. and J.H.K.), the Brain and Behavior Research Foundation (G.S.), the Pfeiffer Research Foundation (G.S. and J.H.K.) and the National Center for Posttraumatic Stress Disorder (R.S.D., G.S. and J.H.K.).

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Correspondence to Ronald S Duman.

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R.S.D. has served as a consultant for Pfizer, Eli Lilly and Company, Johnson and Johnson, Bristol-Myers Squibb, Lundbeck, Forest Laboratories, Taisho Pharmaceuticals, Sunovion Pharmaceuticals and Naurex. R.S.D. has also received research support from Eli Lilly and Company, Forest Laboratories, Taisho Pharmaceuticals, Sunovion Pharmaceuticals and Naurex. G.K.A. has no competing financial interests. G.S. has served as a consultant for Allergan, Alkermes, AstraZeneca, Avanier Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Hoffman La-Roche, Janssen, Merck and Company, Navigen, Naurex, Noven Pharmaceuticals, Servier Pharmaceuticals, Taisho Pharmaceuticals, Takeda, Teva and Vistagen Therapeutics. G.S. has also received additional research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Johnson and Johnson, Hoffman La-Roche, Merck and Company, Naurex and Servier over the last 24 months. Free medication was provided to G.S. for an NIH-sponsored study by Sanofi-Aventis. J.H.K. serves as a consultant for Amgen, AstraZeneca, Biogen, Biomedisyn, Forum Pharmaceuticals, Janssen Research and Development, Otsuka America, Sage Therapeutics, Sunovion and Takeda Industries. J.H.K. is on the scientific advisory board of Lohocla Research, Luc Therapeutics and Pfizer Pharmaceuticals and receives research support from Lohocla Research, Luc Therapeutics and Pfizer Pharmaceuticals. G.S. and J.H.K. hold shares in BioHaven Pharmaceuticals Holding Company and are co-inventors on a US patent (#8,778,979) held by Yale University.

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Duman, R., Aghajanian, G., Sanacora, G. et al. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22, 238–249 (2016). https://doi.org/10.1038/nm.4050

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