Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

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

Nature Medicine volume 22, pages 238–249 (2016)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Whiteford, H.A. et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382, 1575–1586 (2013).

    Article  PubMed  Google Scholar 

  2. Kessler, R.C. et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). J. Am. Med. Assoc. 289, 3095–3105 (2003).

    Article  Google Scholar 

  3. Trivedi, M.H. et al. STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am. J. Psychiatry 163, 28–40 (2006).

    Article  PubMed  Google Scholar 

  4. Walker, E.R., McGee, R.E. & Druss, B.G. Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis. JAMA Psychiatry 72, 334–341 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gaynes, B.N. et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr. Serv. 60, 1439–1445 (2009).

    Article  PubMed  Google Scholar 

  6. Russo, S.J., Murrough, J.W., Han, M.H., Charney, D.S. & Nestler, E.J. Neurobiology of resilience. Nat. Neurosci. 15, 1475–1484 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. MacQueen, G.M., Yucel, K., Taylor, V.H., Macdonald, K. & Joffe, R. Posterior hippocampal volumes are associated with remission rates in patients with major depressive disorder. Biol. Psychiatry 64, 880–883 (2008).

    Article  PubMed  Google Scholar 

  8. Savitz, J. & Drevets, W.C. Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide. Neurosci. Biobehav. Rev. 33, 699–771 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kang, H.J. et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat. Med. 18, 1413–1417 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Duman, R.S. & Aghajanian, G.K. Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68–72 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. McEwen, B.S., Eiland, L., Hunter, R.G. & Miller, M.M. Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology 62, 3–12 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Morrison, J.H. & Baxter, M.G. The aging cortical synapse: hallmarks and implications for cognitive decline. Nat. Rev. Neurosci. 13, 240–250 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Holtmaat, A. & Svoboda, K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat. Rev. Neurosci. 10, 647–658 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Kessels, H.W. & Malinow, R. Synaptic AMPA receptor plasticity and behavior. Neuron 61, 340–350 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yoshihara, Y., De Roo, M. & Muller, D. Dendritic spine formation and stabilization. Curr. Opin. Neurobiol. 19, 146–153 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Sanacora, G., Zarate, C.A., Krystal, J.H. & Manji, H.K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat. Rev. Drug Discov. 7, 426–437 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Popoli, M., Yan, Z., McEwen, B.S. & Sanacora, G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13, 22–37 (2012).

    Article  CAS  Google Scholar 

  18. Sun, H., Kennedy, P.J. & Nestler, E.J. Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology 38, 124–137 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Menke, A. & Binder, E.B. Epigenetic alterations in depression and antidepressant treatment. Dialogues Clin. Neurosci. 16, 395–404 (2014).

    PubMed  PubMed Central  Google Scholar 

  20. Weaver, I.C. et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847–854 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Krishnan, V. & Nestler, E.J. The molecular neurobiology of depression. Nature 455, 894–902 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Manji, H.K., Drevets, W.C. & Charney, D.S. The cellular neurobiology of depression. Nat. Med. 7, 541–547 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Nemeroff, C.B. & Owens, M.J. Treatment of mood disorders. Nat. Neurosci. 5, 1068–1070 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Liu, R.J. & Aghajanian, G.K. Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc. Natl. Acad. Sci. USA 105, 359–364 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Magariños, A.M. & McEwen, B.S. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience 69, 89–98 (1995).

    Article  PubMed  Google Scholar 

  26. Lowy, M.T., Wittenberg, L. & Yamamoto, B.K. Effect of acute stress on hippocampal glutamate levels and spectrin proteolysis in young and aged rats. J. Neurochem. 65, 268–274 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Moghaddam, B., Adams, B., Verma, A. & Daly, D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J. Neurosci. 17, 2921–2927 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang, T.Y., Labonté, B., Wen, X.L., Turecki, G. & Meaney, M.J. Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacology 38, 111–123 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Dunn, E.C. et al. Genetic determinants of depression: recent findings and future directions. Harv. Rev. Psychiatry 23, 1–18 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ota, K.T. et al. REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nat. Med. 20, 531–535 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hardingham, G.E. & Bading, H. Synaptic versus extrasynaptic NMDA receptor signaling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11, 682–696 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bocchio-Chiavetto, L. et al. Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. World J. Biol. Psychiatry 11, 763–773 (2010).

    Article  PubMed  Google Scholar 

  33. Duman, R.S. & Monteggia, L.M. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 1116–1127 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Dwivedi, Y. Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr. Dis. Treat. 5, 433–449 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Turner, C.A., Akil, H., Watson, S.J. & Evans, S.J. The fibroblast growth factor system and mood disorders. Biol. Psychiatry 59, 1128–1135 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Jourdi, H. et al. Positive AMPA receptor modulation rapidly stimulates BDNF release and increases dendritic mRNA translation. J. Neurosci. 29, 8688–8697 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen, H., Pandey, G.N. & Dwivedi, Y. Hippocampal cell proliferation regulation by repeated stress and antidepressants. Neuroreport 17, 863–867 (2006).

    Article  PubMed  Google Scholar 

  38. Liu, R. et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol. Psychiatry 71, 996–1005 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Liu, R.J. et al. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology 38, 2268–2277 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Magariños, A.M. et al. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus 21, 253–264 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Autry, A.E., Adachi, M., Cheng, P. & Monteggia, L.M. Gender-specific impact of brain-derived neurotrophic factor signaling on stress-induced depression-like behavior. Biol. Psychiatry 66, 84–90 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Duman, C.H., Schlesinger, L., Kodama, M., Russell, D.S. & Duman, R.S. A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment. Biol. Psychiatry 61, 661–670 (2007b).

  43. Gatt, J.M. et al. Interactions between BDNFVal66Met polymorphism and early-life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol. Psychiatry 14, 681–695 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Kaufman, J. et al. Brain-derived neurotrophic factor–5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol. Psychiatry 59, 673–680 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Kim, J.M. et al. Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders. Biol. Psychiatry 62, 423–428 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Hoeffer, C.A. & Klann, E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33, 67–75 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Lu, Y., Christian, K. & Lu, B. BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol. Learn. Mem. 89, 312–323 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Minichiello, L. TrkB signaling pathways in LTP and learning. Nat. Rev. Neurosci. 10, 850–860 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Watson, K. & Baar, K. mTOR and the health benefits of exercise. Semin. Cell Dev. Biol. 36, 130–139 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Feyissa, A.M., Chandran, A., Stockmeier, C.A. & Karolewicz, B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 70–75 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Jernigan, C.S. et al. The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 1774–1779 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–964 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Voleti, B. et al. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis and antidepressant behavioral responses. Biol. Psychiatry 74, 742–749 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Chandran, A. et al. Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress. Prog. Neuropsychopharmacol. Biol. Psychiatry 40, 240–245 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Li, N. et al. Glutamate N-methyl-d-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol. Psychiatry 69, 754–761 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bloch, M., Daly, R.C. & Rubinow, D.R. Endocrine factors in the etiology of postpartum depression. Compr. Psychiatry 44, 234–246 (2003).

    Article  PubMed  Google Scholar 

  57. Rubinow, D.R. & Girdler, S.S. Hormones, heart disease and health: individualized medicine versus throwing the baby out with the bathwater. Depress. Anxiety 28, E1–E15 (2011).

    Article  PubMed  Google Scholar 

  58. Borrow, A.P. & Cameron, N.M. Estrogenic mediation of serotonergic and neurotrophic systems: implications for female mood disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 54, 13–25 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Hughes, Z.A. et al. Estrogen receptor neurobiology and its potential for translation into broad-spectrum therapeutics for CNS disorders. Curr. Mol. Pharmacol. 2, 215–236 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Kangaspeska, S. et al. Transient cyclical methylation of promoter DNA. Nature 452, 112–115 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Licznerski, P. & Duman, R.S. Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression. Neuroscience 251, 33–50 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Karki, P., Smith, K., Johnson, J. Jr. & Lee, E. Astrocyte-derived growth factors and estrogen neuroprotection: role of transforming growth factor–α in estrogen-induced upregulation of glutamate transporters in astrocytes. Mol. Cell. Endocrinol. 389, 58–64 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Barouk, S. et al. 17β-estradiol increases astrocytic vascular endothelial growth factor (VEGF) in adult female rat hippocampus. Endocrinology 152, 1745–1751 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cavus, I. & Duman, R.S. Influence of estradiol, stress and 5-HT2A agonist treatment on brain-derived neurotrophic factor expression in female rats. Biol. Psychiatry 54, 59–69 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Kiss, A. et al. 17β-estradiol replacement in young, adult and middle-aged female ovariectomized rats promotes improvement of spatial reference memory and an antidepressant effect, and alters monoamines and BDNF levels in memory- and depression-related brain areas. Behav. Brain Res. 227, 100–108 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Scharfman, H.E. & MacLusky, N.J. The influence of gonadal hormones on neuronal excitability, seizures and epilepsy in the female. Epilepsia 47, 1423–1440 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hao, J. et al. Estrogen alters spine number and morphology in prefrontal cortex of aged female rhesus monkeys. J. Neurosci. 26, 2571–2578 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Shansky, R.M. & Morrison, J.H. Stress-induced dendritic remodeling in the medial prefrontal cortex: effects of circuit, hormones and rest. Brain Res. 1293, 108–113 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Woolley, C.S. & McEwen, B.S. Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J. Neurosci. 12, 2549–2554 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Fan, L. et al. Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal–regulated kinase and phosphatidylinositol 3-kinase activation. J. Neurosci. 30, 4390–4400 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Packard, M.G. & Teather, L.A. Intrahippocampal estradiol infusion enhances memory in ovariectomized rats. Neuroreport 8, 3009–3013 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Wei, J. et al. Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition. Mol. Psychiatry 19, 588–598 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Spencer, J.L., Waters, E.M., Milner, T.A., Lee, F.S. & McEwen, B.S. BDNF variant BDNFVal66Met interacts with estrous cycle in the control of hippocampal function. Proc. Natl. Acad. Sci. USA 107, 4395–4400 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Nilsson, S. & Gustafsson, J.A. Estrogen receptors: therapies targeted to receptor subtypes. Clin. Pharmacol. Ther. 89, 44–55 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Spencer, J.L. et al. Uncovering the mechanisms of estrogen effects on hippocampal function. Front. Neuroendocrinol. 29, 219–237 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Fortress, A.M., Fan, L., Orr, P.T., Zhao, Z. & Frick, K.M. Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus. Learn. Mem. 20, 147–155 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Fortress, A.M., Kim, J., Poole, R.L., Gould, T.J. & Frick, K.M. 17β-estradiol regulates histone alterations associated with memory consolidation and increases Bdnf promoter acetylation in middle-aged female mice. Learn. Mem. 21, 457–467 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Leone, T., Coast, E., Narayanan, S. & de Graft Aikins, A. Diabetes and depression comorbidity and socio-economic status in low- and middle-income countries (LMICs): a mapping of the evidence. Global. Health 8, 39 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Luppino, F.S. et al. Overweight, obesity and depression: a systematic review and meta-analysis of longitudinal studies. Arch. Gen. Psychiatry 67, 220–229 (2010).

    Article  PubMed  Google Scholar 

  80. Mansur, R.B., Brietzke, E. & McIntyre, R.S. Is there a 'metabolic-mood syndrome'? A review of the relationship between obesity and mood disorders. Neurosci. Biobehav. Rev. 52, 89–104 (2015).

    Article  PubMed  Google Scholar 

  81. van Dooren, F.E. et al. Depression and risk of mortality in people with diabetes mellitus: a systematic review and meta-analysis. PLoS One 8, e57058 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Vogelzangs, N. et al. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl. Psychiatry 2, e79 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Rethorst, C.D., Bernstein, I. & Trivedi, M.H. Inflammation, obesity and metabolic syndrome in depression: analysis of the 2009–2010 National Health and Nutrition Examination Survey (NHANES). J. Clin. Psychiatry 75, e1428–e1432 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Choi, J., Joseph, L. & Pilote, L. Obesity and C-reactive protein in various populations: a systematic review and meta-analysis. Obes. Rev. 14, 232–244 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. Pasquali, R. The hypothalamic-pituitary-adrenal axis and sex hormones in chronic stress and obesity: pathophysiological and clinical aspects. Ann. NY Acad. Sci. 1264, 20–35 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Moulton, C.D., Pickup, J.C. & Ismail, K. The link between depression and diabetes: the search for shared mechanisms. Lancet Diabetes Endocrinol. 3, 461–471 (2015).

    Article  PubMed  Google Scholar 

  87. Russo, S.J. & Nestler, E.J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609–625 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Volkow, N.D., Wang, G.J. & Baler, R.D. Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn. Sci. 15, 37–46 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Volkow, N.D., Wang, G.J., Fowler, J.S. & Telang, F. Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology. Phil. Trans. R. Soc. Lond. B 363, 3191–3200 (2008).

    Article  Google Scholar 

  90. Hendrickx, H., McEwen, B.S. & Ouderaa, Fv. Metabolism, mood and cognition in aging: the importance of lifestyle and dietary intervention. Neurobiol. Aging 26 (suppl. 1), 1–5 (2005).

    Article  PubMed  Google Scholar 

  91. Lu, X.Y., Kim, C.S., Frazer, A. & Zhang, W. Leptin: a potential novel antidepressant. Proc. Natl. Acad. Sci. USA 103, 1593–1598 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lutter, M. et al. The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat. Neurosci. 11, 752–753 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Spencer, S.J., Emmerzaal, T.L., Kozicz, T. & Andrews, Z.B. Ghrelin's role in the hypothalamic-pituitary-adrenal axis stress response: implications for mood disorders. Biol. Psychiatry 78, 19–27 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. We˛drychowicz, A., Zaja¸c, A., Pilecki, M., Kos´cielniak, B. & Tomasik, P.J. Peptides from adipose tissue in mental disorders. World J. Psychiatry 4, 103–111 (2014).

    Article  Google Scholar 

  95. Mayer, E.A., Knight, R., Mazmanian, S.K., Cryan, J.F. & Tillisch, K. Gut microbes and the brain: paradigm shift in neuroscience. J. Neurosci. 34, 15490–15496 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Petra, A.I. et al. Gut-microbiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation. Clin. Ther. 37, 984–995 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhou, L. & Foster, J.A. Psychobiotics and the gut-brain axis: in the pursuit of happiness. Neuropsychiatr. Dis. Treat. 11, 715–723 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Gardner, A. & Boles, R.G. Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective-spectrum disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 730–743 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Manji, H. et al. Impaired mitochondrial function in psychiatric disorders. Nat. Rev. Neurosci. 13, 293–307 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Abdallah, C.G. et al. Glutamate metabolism in major depressive disorder. Am. J. Psychiatry 171, 1320–1327 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Tabák, A.G., Akbaraly, T.N., Batty, G.D. & Kivimäki, M. Depression and type 2 diabetes: a causal association? Lancet Diabetes Endocrinol. 2, 236–245 (2014).

    Article  PubMed  Google Scholar 

  102. Kassi, E., Pervanidou, P., Kaltsas, G. & Chrousos, G. Metabolic syndrome: definitions and controversies. BMC Med. 9, 48 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Reaven, G.M. The metabolic syndrome: time to get off the merry-go-round? J. Intern. Med. 269, 127–136 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. Arnold, S.E. et al. High-fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiol. Dis. 67, 79–87 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Magariños, A.M. & McEwen, B.S. Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress. Proc. Natl. Acad. Sci. USA 97, 11056–11061 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Stranahan, A.M. et al. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 18, 1085–1088 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Markham, A. et al. Brain-derived neurotrophic factor–mediated effects on mitochondrial respiratory coupling and neuroprotection share the same molecular signaling pathways. Eur. J. Neurosci. 35, 366–374 (2012).

    Article  PubMed  Google Scholar 

  108. Marosi, K. & Mattson, M.P. BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol. Metab. 25, 89–98 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Schwartz, E. & Mobbs, C.V. Hypothalamic BDNF and obesity: found in translation. Nat. Med. 18, 496–497 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Unger, T.J., Calderon, G.A., Bradley, L.C., Sena-Esteves, M. & Rios, M. Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J. Neurosci. 27, 14265–14274 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kleinridders, A. et al. Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proc. Natl. Acad. Sci. USA 112, 3463–3468 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Agudelo, L.Z. et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159, 33–45 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Voss, M.W., Vivar, C., Kramer, A.F. & van Praag, H. Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn. Sci. 17, 525–544 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Dinan, T.G. Inflammatory markers in depression. Curr. Opin. Psychiatry 22, 32–36 (2009).

    Article  PubMed  Google Scholar 

  115. Iwata, M., Ota, K.T. & Duman, R.S. The inflammasome: pathways linking psychological stress, depression and systemic illnesses. Brain Behav. Immun. 31, 105–114 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Miller, A.H., Maletic, V. & Raison, C.L. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Raison, C.L., Capuron, L. & Miller, A.H. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 27, 24–31 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Howren, M.B., Lamkin, D.M. & Suls, J. Associations of depression with C-reactive protein, IL-1 and IL-6: a meta-analysis. Psychosom. Med. 71, 171–186 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Raison, C.L. & Miller, A.H. Malaise, melancholia and madness: the evolutionary legacy of an inflammatory bias. Brain Behav. Immun. 31, 1–8 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Iwata, M. et al. Psychological stress activates the inflammasome via release of ATP and stimulation of the P2X7 receptor. Biol. Psychiatry doi:10.1016/j.biopsych.2015.11.026 (8 December 2015).

  122. Boulanger, L.M. Immune proteins in brain development and synaptic plasticity. Neuron 64, 93–109 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Goshen, I. et al. A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 32, 1106–1115 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Khairova, R.A., Machado-Vieira, R., Du, J. & Manji, H.K. A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int. J. Neuropsychopharmacol. 12, 561–578 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Murray, C.A. & Lynch, M.A. Evidence that increased hippocampal expression of the cytokine interleukin-1β is a common trigger for age- and stress-induced impairments in long-term potentiation. J. Neurosci. 18, 2974–2981 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Stellwagen, D. & Malenka, R.C. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054–1059 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Paolicelli, R.C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Schafer, D.P. et al. Microglia sculpt postnatal neural circuits in an activity- and complement-dependent manner. Neuron 74, 691–705 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Stephan, A.H., Barres, B.A. & Stevens, B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369–389 (2012).

    Article  CAS  PubMed  Google Scholar 

  130. Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Raison, C.L. et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70, 31–41 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Castrén, E. & Hen, R. Neuronal plasticity and antidepressant actions. Trends Neurosci. 36, 259–267 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Krishnan, V. & Nestler, E.J. Linking molecules to mood: new insight into the biology of depression. Am. J. Psychiatry 167, 1305–1320 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Miller, B.R. & Hen, R. The current state of the neurogenic theory of depression and anxiety. Curr. Opin. Neurobiol. 30, 51–58 (2015).

    Article  CAS  PubMed  Google Scholar 

  135. Chen, Z.-Y. Genetic variant BDNFVal66Met polymorphism alters anxiety-related behavior. Science 314, 140–143 (2006b).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Duman, R.S. & Voleti, B. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci. 35, 47–56 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Yu, H. et al. Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J. Neurosci. 32, 4092–4101 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Jiang, B. et al. SKF83959 produces antidepressant effects in a chronic social-defeat stress model of depression through the BDNF-TrkB pathway. Int. J. Neuropsychopharmacol. 18, pyu096 (2015).

    PubMed Central  Google Scholar 

  139. Abbott, C.C. et al. Hippocampal structural and functional changes associated with electroconvulsive therapy response. Transl. Psychiatry 4, e483 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Dukart, J. et al. Electroconvulsive therapy–induced brain plasticity determines therapeutic outcome in mood disorders. Proc. Natl. Acad. Sci. USA 111, 1156–1161 (2014).

    Article  CAS  PubMed  Google Scholar 

  141. Bath, K.G. et al. BDNFVal66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity. Neuropsychopharmacology 37, 1297–1304 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Karpova, N.N. et al. Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science 334, 1731–1734 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Maya Vetencourt, J.F. et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320, 385–388 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Ampuero, E. et al. Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex. Neuroscience 169, 98–108 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Bessa, J. et al. Hippocampal neurogenesis induced by antidepressant drugs: an epiphenomenon in their mood-improving actions. Mol. Psychiatry 14, 739 (2009).

    Article  CAS  Google Scholar 

  146. Magariños, A.M. & McEwen, B.S. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors. Neuroscience 69, 83–88 (1995a).

    Article  PubMed  Google Scholar 

  147. Castrén, E. Is mood chemistry? Nat. Rev. Neurosci. 6, 241–246 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. Berman, R.M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Diazgranados, N. et al. A randomized add-on trial of an N-methyl-d-aspartate antagonist in treatment-resistant bipolar depression. Arch. Gen. Psychiatry 67, 793–802 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zarate, C.A. Jr. et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864 (2006).

    Article  CAS  PubMed  Google Scholar 

  151. DiazGranados, N. et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-d-aspartate antagonist in patients with treatment-resistant major depressive disorder. J. Clin. Psychiatry 71, 1605–1611 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Price, R.B., Nock, M.K., Charney, D.S. & Mathew, S.J. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol. Psychiatry 66, 522–526 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Drevets, W.C. & Furey, M.L. Replication of scopolamine's antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol. Psychiatry 67, 432–438 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. DeWilde, K.E., Levitch, C.F., Murrough, J.W., Mathew, S.J. & Iosifescu, D.V. The promise of ketamine for treatment-resistant depression: current evidence and future directions. Ann. NY Acad. Sci. 1345, 47–58 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Sanacora, G. & Schatzberg, A.F. Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? Neuropsychopharmacology 40, 1307 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Miller, O.H. et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. eLife 3, e03581 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Paul, R.K. et al. (R,S)-ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase mammalian target of rapamycin function. Anesthesiology 121, 149–159 (2014).

    Article  CAS  PubMed  Google Scholar 

  158. Zhou, W. et al. Ketamine-induced antidepressant effects are associated with AMPA receptor–mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur. Psychiatry 29, 419–423 (2014).

    Article  CAS  PubMed  Google Scholar 

  159. Liu, R.J., Ota, K.T., Dutheil, S., Duman, R.S. & Aghajanian, G.K. Ketamine strengthens CRF-activated amygdala inputs to basal dendrites in mPFC layer V pyramidal cells in the prelimbic but not the infralimbic subregion, a key suppressor of stress responses. Neuropsychopharmacology 40, 2066–2075 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Maeng, S. et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of α-amino-3-hydroxy-5-methylisoxazole-4–propionic acid receptors. Biol. Psychiatry 63, 349–352 (2008).

    Article  CAS  PubMed  Google Scholar 

  161. Homayoun, H. & Moghaddam, B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J. Neurosci. 27, 11496–11500 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Stone, J.M. et al. Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology. Mol. Psychiatry 17, 664–665 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Takei, N. et al. Brain-derived neurotrophic factor induces mammalian target of rapamycin–dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J. Neurosci. 24, 9760–9769 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Autry, A.E. et al. NMDA receptor blockade at rest triggers rapid behavioral antidepressant responses. Nature 475, 91–95 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Liu, R.J. et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol. Psychiatry 71, 996–1005 (2012).

    Article  CAS  PubMed  Google Scholar 

  166. Gass, N. et al. Sub-anesthetic ketamine modulates intrinsic BOLD connectivity within the hippocampal-prefrontal circuit in the rat. Neuropsychopharmacology 39, 895–906 (2014).

    Article  CAS  PubMed  Google Scholar 

  167. Murrough, J.W. et al. Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl. Psychiatry 5, e509 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Preskorn, S. et al. A placebo-controlled trial of the NR2B subunit–specific NMDA antagonist CP-101,606 plus paroxetine for treatment-resistant depression (TRD). (115th Annual Meeting of the American Psychological Association) (American Psychological Association, Washington, D.C., 2007).

  169. Sanacora, G. et al. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol. Psychiatry 19, 978–985 (2014).

    Article  CAS  PubMed  Google Scholar 

  170. Arai, A.C. & Kessler, M. Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior. Curr. Drug Targets 8, 583–602 (2007).

    Article  CAS  PubMed  Google Scholar 

  171. Pilc, A., Chaki, S., Nowak, G. & Witkin, J.M. Mood disorders: regulation by metabotropic glutamate receptors. Biochem. Pharmacol. 75, 997–1006 (2008).

    Article  CAS  PubMed  Google Scholar 

  172. Duric, V. et al. A negative regulator of MAP kinase causes depressive behavior. Nat. Med. 16, 1328–1332 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Navarria, A. et al. Rapid antidepressant actions of scopolamine: role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors. Neurobiol. Dis. 82, 254–261 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Witkin, J.M. et al. M1 and M2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine. J. Pharmacol. Exp. Ther. 351, 448–456 (2014).

    Article  CAS  PubMed  Google Scholar 

  175. Luoni, A., Macchi, F., Papp, M., Molteni, R. & Riva, M.A. Lurasidone exerts antidepressant properties in the chronic mild-stress model through the regulation of synaptic and neuroplastic mechanisms in the rat prefrontal cortex. Int. J. Neuropsychopharmacol. 18, pyu061 (2015).

    Article  CAS  PubMed Central  Google Scholar 

  176. Osborn, M. et al. Antidepressant-like effects of erythropoietin: a focus on behavioral and hippocampal processes. PLoS One 8, e72813 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Pałucha-Poniewiera, A., Szewczyk, B. & Pilc, A. Activation of the mTOR signaling pathway in the antidepressant-like activity of the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082 in the FST in rats. Neuropharmacology 82, 59–68 (2014).

    Article  CAS  PubMed  Google Scholar 

  178. Zhong, P. et al. Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology 39, 1763–1776 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Sullivan, P.F., Neale, M.C. & Kendler, K.S. Genetic epidemiology of major depression: review and meta-analysis. Am. J. Psychiatry 157, 1552–1562 (2000).

    Article  CAS  PubMed  Google Scholar 

  180. López-León, S. et al. Meta-analyses of genetic studies on major depressive disorder. Mol. Psychiatry 13, 772–785 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Levinson, D.F. et al. Genetic studies of major depressive disorder: why are there no genome-wide association study findings and what can we do about it? Biol. Psychiatry 76, 510–512 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat. Neurosci. 18, 199–209 (2015).

  183. Kaufman, J. et al. Social supports and serotonin transporter gene moderate depression in maltreated children. Proc. Natl. Acad. Sci. USA 101, 17316–17321 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Nestler, E.J. Epigenetic mechanisms of depression. JAMA Psychiatry 71, 454–456 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Dias, B.G., Maddox, S.A., Klengel, T. & Ressler, K.J. Epigenetic mechanisms underlying learning and the inheritance of learned behaviors. Trends Neurosci. 38, 96–107 (2015).

    Article  CAS  PubMed  Google Scholar 

  186. Wallis, J.D. Cross-species studies of orbitofrontal cortex and value-based decision-making. Nat. Neurosci. 15, 13–19 (2012).

    Article  CAS  Google Scholar 

  187. Carmichael, S.T. & Price, J.L. Sensory and premotor connections of the orbital and medial prefrontal cortex of macaque monkeys. J. Comp. Neurol. 363, 642–664 (1995).

    Article  CAS  PubMed  Google Scholar 

  188. Haber, S.N., Kunishio, K., Mizobuchi, M. & Lynd-Balta, E. The orbital and medial prefrontal circuit through the primate basal ganglia. J. Neurosci. 15, 4851–4867 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Ongür, D., Ferry, A.T. & Price, J.L. Architectonic subdivision of the human orbital and medial prefrontal cortex. J. Comp. Neurol. 460, 425–449 (2003).

    Article  PubMed  Google Scholar 

  190. Price, J.L. & Drevets, W.C. Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192–216 (2010).

    Article  PubMed  Google Scholar 

  191. Phillips, M.L., Ladouceur, C.D. & Drevets, W.C. A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder. Mol. Psychiatry 13 829, 833–857 (2008).

    Article  Google Scholar 

  192. Vertes, R.P. Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 51, 32–58 (2004).

    Article  CAS  PubMed  Google Scholar 

  193. Patton, M.H., Bizup, B.T. & Grace, A.A. The infralimbic cortex bidirectionally modulates mesolimbic dopamine neuron activity via distinct neural pathways. J. Neurosci. 33, 16865–16873 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Phillips, M.L. et al. Identifying predictors, moderators and mediators of antidepressant response in major depressive disorder: neuroimaging approaches. Am. J. Psychiatry 172, 124–138 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Pizzagalli, D.A. Depression, stress and anhedonia: toward a synthesis and integrated model. Annu. Rev. Clin. Psychol. 10, 393–423 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Ronald S Duman, George K Aghajanian, Gerard Sanacora & John H Krystal

  2. Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Ronald S Duman, George K Aghajanian, Gerard Sanacora & John H Krystal

Authors
  1. Ronald S Duman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George K Aghajanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gerard Sanacora
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John H Krystal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ronald S Duman.

Ethics declarations

Competing interests

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4050

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing