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The why, when, where, how, and so what of so-called rapidly acting antidepressants

Neuropsychopharmacology volume 49, pages 189–196 (2024)Cite this article

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Abstract

Developing antidepressants that are not only more effective but are rapidly acting is the Holy Grail for psychiatry. We review multiple issues that arise in determining rapid responses in antidepressant trials. The current status of purportedly rapid acting agents is first reviewed. Then, a number of key questions/issues are addressed: Is there a unifying definition for rapid response across studies? Should rapid response criteria be based on required measurable effects on overall improvement? On specific symptoms such as psychomotor retardation, depressed mood, or anhedonia? In associated symptoms such as anxiety or insomnia? When should onset be considered rapid—by Day 3? Day7? Day 14? If there is a rapid response, for how long should the effects be maintained? Is maintenance of effect dependent on continuing the medication? Is rapid response associated with specific mechanisms of action? Do the mechanisms of action suggest possible risk for drug abuse? How important is rapid response really in an often chronic or recurrent depressive disorder? In which types of patients could rapid response be particularly important? What are the study design issues that need to be considered for assessing rapid response, including: selection of specific types of depressed patients, multiple doses of drug studied, designation of primary and secondary outcome measures, specific time points at which to determine efficacy, requirements for demonstrating durability, etc. A framework for approaching this complex area is developed for both researchers and clinicians.

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Funding

Funding

AFS has received funding from the NIMH, Pritzker Neuropsychotic Disorders Research Consortium and the American Foundation for Suicide Prevention. SJM is supported through the use of resources and facilities at the Michael E. Debakey VA Medical Center, Houston, Texas and receives support from The Menninger Clinic.

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Authors and Affiliations

  1. Kenneth T. Norris, Jr., Professor of Psychiatry and Behavioral Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Alan F. Schatzberg

  2. Marjorie Bintliff Johnson and Raleigh White Johnson, Jr. Chair for Research in Psychiatry, Menninger Department of Psychiatry and Behavioral Science, Baylor College of Medicine, Houston, TX, USA

    Sanjay J. Mathew

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AFS and SJM contributed equally to the conception of the paper and drafting and reviewing it. They agree to be accountable for all aspects of the work in ensuring any questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Alan F. Schatzberg.

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Competing interests

AFS has served as a consultant to Alto Neuroscience, ANeurotech, Compass, Magnus, NeuraWell, Parexel, Sage and Signant. He holds equity in Alto Neuroscience, Corcept, Delpor, Madrigal, Magnus, Seattle Genetics, Titan and Xhale. SJM has served as a consultant to Almatica Pharma, Axsome Therapeutics, Biohaven, BioXcel Therapeutics, Boehringer-Ingelheim, Clexio Biosciences, COMPASS Pathways, Delix Therapeutics, Douglas Pharmaceuticals, Eleusis, EMA Wellness, Engrail Therapeutics, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, Signant Health, Sunovion, and XW Pharma. He has received research support from Boehringer-Ingelheim, Merck, Neurocrine, and Sage Therapeutics.

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Schatzberg, A.F., Mathew, S.J. The why, when, where, how, and so what of so-called rapidly acting antidepressants. Neuropsychopharmacol. 49, 189–196 (2024). https://doi.org/10.1038/s41386-023-01647-8

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