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Structural neural plasticity evoked by rapid-acting antidepressant interventions

Nature Reviews Neuroscience volume 26, pages 101–114 (2025)Cite this article

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A Publisher Correction to this article was published on 12 December 2024

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Abstract

A feature in the pathophysiology of major depressive disorder (MDD), a mood disorder, is the impairment of excitatory synapses in the prefrontal cortex. Intriguingly, different types of treatment with fairly rapid antidepressant effects (within days or a few weeks), such as ketamine, electroconvulsive therapy and non-invasive neurostimulation, seem to converge on enhancement of neural plasticity. However, the forms and mechanisms of plasticity that link antidepressant interventions to the restoration of excitatory synaptic function are still unknown. In this Review, we highlight preclinical research from the past 15 years showing that ketamine and psychedelic drugs can trigger the growth of dendritic spines in cortical pyramidal neurons. We compare the longitudinal effects of various psychoactive drugs on neuronal rewiring, and we highlight rapid onset and sustained time course as notable characteristics for putative rapid-acting antidepressant drugs. Furthermore, we consider gaps in the current understanding of drug-evoked in vivo structural plasticity. We also discuss the prospects of using synaptic remodelling to understand other antidepressant interventions, such as repetitive transcranial magnetic stimulation. Finally, we conclude that structural neural plasticity can provide unique insights into the neurobiological actions of psychoactive drugs and antidepressant interventions.

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Fig. 1: Imaging dendritic spines in vivo.
Fig. 2: Effects of different psychoactive drugs on apical dendritic spines of cortical pyramidal neurons in mice.
Fig. 3: The life cycle of a dendritic spine.
Fig. 4: Time courses of antidepressant intervention-evoked structural neural plasticity in rodents and therapeutic onset in humans.

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Acknowledgements

The authors thank N. Savalia (Yale University, New Haven, CT, USA) for the feedback and L.-X. Shao (Cornell University, Ithaca, NY, USA) for the help with making the figures. The authors acknowledge the support of National Institutes of Health (NIH) grants R01MH121848, R01MH128217 and R01MH137047 (A.C.K.), One Mind–COMPASS Rising Star Award (A.C.K.), NIH training grant T32NS041228 (C. Liao), NIH training grant T32GM152349 (A.N.D.), NIH grants MH123154, MH118451 and MH109685 (C. Liston), NIH grant DA047851 (C. Liston), and grants from One Mind, Hartwell Foundation, Rita Allen Foundation, Klingenstein-Simons Foundation Fund, Brain and Behaviour Research Foundation, Hope for Depression Research Foundation, and Pritzker Neuropsychiatric Disorders Research Consortium (C. Liston).

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  1. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA

    Clara Liao, Cassandra Wojtasiewicz & Alex C. Kwan

  2. Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, USA

    Clara Liao

  3. Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA

    Alisha N. Dua, Conor Liston & Alex C. Kwan

  4. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA

    Conor Liston

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All authors researched data for the article and contributed substantially to the discussion of the content. C. Liao and A.C.K. wrote the article. All authors reviewed the manuscript before submission.

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A.C.K. has been a scientific adviser or consultant for Boehringer Ingelheim, Empyrean Neuroscience, Freedom Biosciences, and Psylo. A.C.K. has received research support from Intra-Cellular Therapies. C. Liston has served as a scientific adviser or consultant for Brainify.AI, Compass Pathways, Delix Therapeutics, and Magnus Medical. The other authors report no competing interests.

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Liao, C., Dua, A.N., Wojtasiewicz, C. et al. Structural neural plasticity evoked by rapid-acting antidepressant interventions. Nat. Rev. Neurosci. 26, 101–114 (2025). https://doi.org/10.1038/s41583-024-00876-0

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