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Placebo stimulates neuroplasticity in depression: implications for clinical practice and research

  • Seymour, Jeremy1
  • Mathers, Nigel2
  • 1 Retired Consultant Psychiatrist, Rotherham Doncaster and South Humber NHS Trust, Rotherham , (United Kingdom)
  • 2 Emeritus Professor, Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield , (United Kingdom)
Published Article
Frontiers in Psychiatry
Frontiers Media SA
Publication Date
Jan 10, 2024
DOI: 10.3389/fpsyt.2023.1301143
  • Psychiatry
  • Hypothesis and Theory


Neither psychological nor neuroscientific investigations have been able to fully explain the paradox that placebo is designed to be inert in randomized controlled trials (RCTs), yet appears to be effective in evaluations of clinical interventions in all fields of medicine and alternative medicine. This article develops the Neuroplasticity Placebo Theory, which posits that neuroplasticity in fronto-limbic areas is the unifying factor in placebo response (seen in RCTs) and placebo effect (seen in clinical interventions) where it is not intended to be inert. Depression is the disorder that has the highest placebo response of any medical condition and has the greatest potential for understanding how placebos work: recent developments in understanding of the pathophysiology of depression suggest that fronto-limbic areas are sensitized in depression which is associated with a particularly strong placebo phenomenon. An innovative linkage is made between diverse areas of the psychology and the translational psychiatry literature to provide supportive evidence for the Neuroplasticity Placebo Theory. This is underpinned by neuro-radiological evidence of fronto-limbic change in the placebo arm of antidepressant trials. If placebo stimulates neuroplasticity in fronto-limbic areas in conditions other than depression - and results in a partially active treatment in other areas of medicine - there are far reaching consequences for the day-to-day use of placebo in clinical practice, the future design of RCTs in all clinical conditions, and existing unwarranted assertions about the efficacy of antidepressant medications. If fronto-limbic neuroplasticity is the common denominator in designating placebo as a partially active treatment, the terms placebo effect and placebo response should be replaced by the single term “placebo treatment.”

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