Cortical inhibition, facilitation and plasticity in late-life depression: effects of venlafaxine pharmacotherapy

Cortical inhibition, facilitation and plasticity in late-life depression: effects of venlafaxine pharmacotherapy

J Psychiatry Neurosci 2021;46(1):E88-E96 | PDF | Appendix

Jennifer I. Lissemore, MSc; Benoit H. Mulsant, MD; Tarek K. Rajji, MD; Jordan F. Karp, MD; Charles F. Reynolds III, MD; Eric J. Lenze, MD; Jonathan Downar, MD, PhD; Robert Chen, MBBChir, MSc; Zafiris J. Daskalakis, MD, PhD; Daniel M. Blumberger, MD

Background: Late-life depression is often associated with non-response or relapse following conventional antidepressant treatment. The pathophysiology of late-life depression likely involves a complex interplay between aging and depression, and may include abnormalities in cortical inhibition and plasticity. However, the extent to which these cortical processes are modifiable by antidepressant pharmacotherapy is unknown.

Methods: Sixty-eight patients with late-life depression received 12 weeks of treatment with open-label venlafaxine, a serotonin-norepinephrine reuptake inhibitor (≤ 300 mg/d). We combined transcranial magnetic stimulation of the left motor cortex with electromyography recordings from the right hand to measure cortical inhibition using contralateral cortical silent period and paired-pulse short-interval intracortical inhibition paradigms; cortical facilitation using a paired-pulse intracortical facilitation paradigm; and short-term cortical plasticity using a paired associative stimulation paradigm. All measures were collected at baseline, 1 week into treatment (n = 23) and after approximately 12 weeks of treatment.

Results: Venlafaxine did not significantly alter cortical inhibition, facilitation or plasticity after 1 or 12 weeks of treatment. Improvements in depressive symptoms during treatment were not associated with changes in cortical physiology.

Limitations: The results presented here are specific to the motor cortex. Future work should investigate whether these findings extend to cortical areas more closely associated with depression, such as the dorsolateral prefrontal cortex.

Conclusion: These findings suggest that antidepressant treatment with venlafaxine does not exert meaningful changes in motor cortical inhibition or plasticity in late-life depression. The absence of changes in motor cortical physiology, alongside improvements in depressive symptoms, suggests that age-related changes may play a role in previously identified abnormalities in motor cortical processes in late-life depression, and that venlafaxine treatment does not target these abnormalities.


Submitted Jan. 3, 2020; Revised May 30, 2020; Accepted Jun. 18, 2020; Early-released Oct. 29, 2020

Affiliations: From the Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Ont., Canada (Lissemore, Rajji, Daskalakis, Blumberger); the Department of Psychiatry, University of Toronto, Toronto, Ont., Canada (Lissemore, Mulsant, Rajji, Downar, Daskalakis, Blumberger); the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont., Canada (Mulsant, Rajji, Daskalakis, Blumberger); the Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA (Karp, Reynolds); the Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA (Lenze); the MRI-Guided rTMS Clinic and Krembil Research Institute, University Health Network, Toronto, Ont., Canada (Downar); and the Division of Neurology, Department of Medicine, University of Toronto and Krembil Research Institute Toronto, Ont., Canada (Chen).

Funding: This work was directly supported by NIMH grant NIH R34MH101365.

Competing interests: B. Mulsant reports non-financial support from Capital Solution Design LLC, HAPPYneuron, Bristol-Myers Squibb and Eli Lilly; grants from Brain Canada, the Patient-Centered Outcomes Research Institute (PCORI), the Canadian Institutes of Health Research (CIHR), the National Institutes of Health (NIH) and the Centre for Addiction and Mental Health (CAMH) Foundation; and other support from General Electric. T. Rajji has received research support from Brain Canada, the Brain and Behavior Research Foundation, the BrightFocus Foundation, the Canada Foundation for Innovation, a Canada Research Chair, CIHR, the Centre for Aging and Brain Health Innovation, NIH, the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation and the Weston Brain Institute; in-kind equipment support for an investigator-initiated study from Magstim; and in-kind research accounts from Scientific Brain Training Pro. J. Karp is a scientific advisor to NightWare and received medication supplies for investigator-initiated trials from Pfizer and Indivior and honoraria for development and presentation of a webinar (disease-state, not product-focused) from Otsuka. C. Reynolds III reports grants from the NIH during the conduct of the study; grants from the NIH, the PCORI, the Center for Medicare and Medicaid Services, the American Foundation for Suicide Prevention, the Brain and Behavior Research Foundation and the Commonwealth of Pennsylvania outside the submitted work; and non-financial support from Bristol Meyers Squib and Pfizer, outside the submitted work. E. Lenze received research support from the National Institute on Aging, the National Center for Complementary and Integrative Health, the National Institute of Mental Health (NIMH), the Office of Behavioral and Social Sciences Research, the United States Food and Drug Administration, PCORI, the McKnight Brain Research Foundation, the Taylor Family Institute for Innovative Psychiatric Research, the Barnes Jewish Foundation, Takeda, Acadia Alkermes, Aptinyx and Lundbeck; and consulting fees from Janssen and Jazz Pharmaceuticals. J. Downar reports grants from the Arrell Family Foundation, the Buchan Family Foundation, Brain Canada, the Canadian Biomarker Integration Network in Depression, CIHR, the Klarman Family Foundation, NIMH, the Ontario Brain Institute and the Weston Family Foundation; and other support from ANT Neuro, BrainCheck, Restorative Brain Clinics and TMS Neuro Solutions, all outside the submitted work. R. Chen received honoraria from Allergan, Merz and Ipsen. Z. Daskalakis reports non-financial support from Brainsway Inc; non-financial support from Magventure Inc; grants from the Ontario Mental Health Foundation, CIHR, NIMH, the Temerty Family, the Grant Family, the CAMH Foundation and the Campbell Institute, all outside the submitted work. D. Blumberger has received research support from CIHR, NIMH, Brain Canada and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute; received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd; is the site principal investigator for one sponsor-initiated study for Brainsway Ltd.; receives in-kind equipment support from Magventure for investigator-initiated research; and received medication supplies for an investigator-initiated trial from Indivior. No other competing interests were declared.

Contributors: B. Mulsant, T. Rajji, C. Reynolds III, E. Lenze, Z. Daskalakis and D. Blumberger designed the study. J. Lissemore, B. Mulsant, J. Karp, E. Lenze, Z. Daskalakis and D. Blumberger acquired the data, which J. Lissemore, B. Mulsant, T. Rajji, C. Reynolds III, E. Lenze, J. Downar, R. Chen, Z. Daskalakis and D. Blumberger analyzed. J. Lissemore, E. Lenze and D. Blumberger wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

DOI: 10.1503/jpn.200001

Correspondence to: D.M. Blumberger, Temerty Centre for Therapeutic Brain Intervention, Department of Psychiatry, University of Toronto, 1001 Queen St. W., Unit 4, Room 115, Toronto, ON M6J 1H4; daniel.blumberger@camh.ca