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Randomized trial of ketamine masked by surgical anesthesia in patients with depression

Nature Mental Health volume 1, pages 876–886 (2023)Cite this article

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Abstract

Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. Here we present a single-center, parallel-arm, triple-masked, randomized, placebo-controlled trial assessing the antidepressant efficacy of intravenous ketamine masked by surgical anesthesia (ClinicalTrials.gov, NCT03861988). Adult patients (N = 40) with major depressive disorder who were scheduled for routine surgery were randomized to a single infusion of ketamine (0.5 mg kg−1) or placebo (saline) during usual anesthesia. All participants, investigators and direct-patient-care staff were masked to treatment allocation. The primary outcome was depression severity measured by the Montgomery–Åsberg Depression Rating Scale at 1, 2 and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received. A mixed-effects model showed no evidence of effect of treatment assignment on the primary outcome (−5.82, 95% confidence interval −13.3 to 1.64, P = 0.13). Of all participants, 36.8% guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. In conclusion, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in patients with moderate-to-severe depression using surgical anesthesia. Although this masking strategy is impractical for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment to minimize participant-expectancy bias.

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Fig. 1: CONSORT flow diagram.
Fig. 2: Depression severity, masking assessment and other outcomes.

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Data availability

De-identified participant data, data dictionaries, the study protocol and the statistical analysis plan are available at https://osf.io/zdkr8/ (https://doi.org/10.17605/OSF.IO/ZDKR8). All participants have consented to sharing de-identified data with outside entities for scientific research purposes.

Code availability

R code used for data analysis is publicly available at https://osf.io/zdkr8/ (https://doi.org/10.17605/OSF.IO/ZDKR8).

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Acknowledgements

This work was supported by a grant awarded to B.D.H. by the Society for Neuroscience in Anesthesiology and Critical Care. T.R.L. received salary support through a T32 grant from the NIH National Institute on Drug Abuse (3T32DA035165-02S1). The funding bodies supporting this study had no influence on the conduct of the trial, analysis of the data, or reporting of the results. We acknowledge K. Pfaff (medical student, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA) and R. Thordstein (Lund University, Lund, Sweden) for assistance with contacting patients and V. Ramachandran (Stanford University School of Medicine, Stanford, CA, USA) for implementing the PHQ-2 survey into the Anesthesia Preoperative Evaluation Clinic electronic workflow at Stanford. Statistical support was provided by Data Studio (Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA), which is supported by the National Center For Advancing Translational Sciences of the National Institutes of Health under award number UL1TR003142. Screening and outcomes data were entered into Stanford REDCap (version 13.4.10), a secure online data-capture platform (http://redcap.stanford.edu) developed and operated by the Stanford Medicine Research IT team. The REDCap platform services at Stanford are subsidized by (1) the Stanford School of Medicine Research Office and (2) the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant UL1 TR001085.

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Authors and Affiliations

  1. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Theresa R. Lii, Ashleigh E. Smith, Josephine R. Flohr, Robin L. Okada, Cynthia A. Nyongesa & Boris D. Heifets

  2. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA

    Lisa J. Cianfichi

  3. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Laura M. Hack, Alan F. Schatzberg & Boris D. Heifets

  4. Sierra Pacific Mental Illness Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Laura M. Hack

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Contributions

T.R.L. and B.D.H. designed the trial. T.R.L. analyzed the data and wrote the first draft of the paper. A.E.S., J.R.F., R.L.O., C.A.N. and L.J.C. performed the trial and collected the data. L.M.H. and A.F.S. provided content expertise and advice on trial design. The overall trial was overseen by B.D.H. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Corresponding author

Correspondence to Boris D. Heifets.

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Competing interests

B.D.H. is on the scientific advisory boards of Osmind and Journey Clinical and is a consultant to Clairvoyant Therapeutics and Vine Ventures. A.F.S. has served as a consultant to Alto Neuroscience, ANeurotech, Compass, Magnus, NeuraWell, Parexal, Sage and Signant. He holds equity in Alto Neuroscience, Corcept, Delpor, Madrigal, Magnus, Seattle Genetics, Titan and Xhale. These interests had no role in the present trial. The other authors declare no competing interests.

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Nature Mental Health thanks Gerard Sanacora and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Depression ratings reanalyzed according to patient guess.

On day 14, the final day of patient assessments, patients were asked the following questions: “What treatment do you think you received?” MADRS scores were reanalyzed according to their guess, irrespective of their true group allocation. Mean and standard deviation (SD) MADRS scores are shown using the alternate grouping: “Ketamine”, n = 17; “Placebo”, n = 10; “I don’t know”, n = 11.

Extended Data Table 1 Depression Outcomes
Full size table
Extended Data Table 2 Average Daily Inpatient Opioid Use
Full size table

Supplementary information

Supplementary Information

Clinical trial protocols, statistical analysis plans and summary of protocol amendments.

Reporting Summary

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Lii, T.R., Smith, A.E., Flohr, J.R. et al. Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nat. Mental Health 1, 876–886 (2023). https://doi.org/10.1038/s44220-023-00140-x

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