Rapid-acting and neuromodulatory interventions for treatment-resistant OCD: clinical implications in stress reduction

Obsessive-compulsive disorder (OCD) is a highly debilitating and often chronic condition. A large percentage of patients do not respond to first-line treatments with selective serotonin reuptake inhibitors (SSRIs) or cognitive behavioral therapy (CBT), underscoring the need for novel therapeutic approaches. In this context, promising innovative treatments have recently emerged for OCD; these include pharmacological options such as ketamine and psilocybin—which may exert rapid-acting effects—as well as neuromodulatory treatments such as repetitive transcranial magnetic stimulation (rTMS) and deep brain stimulation (DBS).

In addition, growing evidence links early life stress with neuroinflammatory pathways and dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in OCD, opening novel treatment targets. While preliminary clinical trials of novel rapid-acting substances in OCD are encouraging, results are mixed and evidence of repeated dosing is scarce. This narrative review synthesizes current evidence on rapid-acting and neuromodulatory treatments for OCD, with a particular focus on stress-related mechanisms, offering new therapeutic possibilities as well as avenues for future research.

This research was supported in part by the Austrian Science Fund (FWF; 10.55776/KLP7307523) and in part by the Intramural Research Program of the National Institutes of Health (NIH; ZIAMH002927). The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S.

Department of Health and Human Services. The author(s) declared that financial support was received for this work and/or its publication. Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria Johan Saelens, Franziska Stadler, Victoria Forschauer & Christoph Kraus Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA Dr.

Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2 R,6 R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2 R,6 R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorder. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. After leaving the NIMH, and since beginning employment at the Medical University of Vienna, Dr.

Kraus has received honoraria from LivaNova, Pfizer, Johnson & Johnson and AbbVie. Baldermann receives research support from Else-Kroener-Fresenius Foundation (Germany) and Fraunhofer Society (Germany), received personal honoraria for lectures from Arcana (Germany), and is a consultant for Boston Scientific (USA), Inomed (Germany), and Brainlab (Germany). All other authors have no conflict of interest to disclose, financial or otherwise.