New Treatments for Depression

Depression Treatments: Ketamine, Propofol, Nitrous Oxide, Psychedelics, and Transcranial Magnetic Stimulation. What Is the Evidence?

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By Stuart M Caplen, MD

In 2020, an estimated 8.4% of the US adult population (21 million adults) and 12% of the U.S. population aged 12 to 17 (2.9 million adolescents) had at least one major depressive episode. Depression with severe impairment is defined by a two week or more period of depressed mood or loss of interest or pleasure in daily activities, with many associated symptoms such as problems with sleeping, eating, energy, concentration, or self-worth.[1]

Depression is typically treated with a combination of antidepressants and psychotherapy. However, only 40 to 70% of depressed patients respond to these treatments, and about 10% to 30% of patients with a major depressive disorder develop severe treatment resistant depression (TRD).[2] In the past, electroconvulsive therapy (ECT) was used as the main treatment when other methods had failed. Recently, other modalities such as ketamine, propofol, nitrous oxide, psychedelics, and transcranial magnetic stimulation have been evaluated as alternative treatments for severe TRD to avoid the potentially severe side effects of ECT. This article will look at how successful those modalities are in treating TRD, and the level of scientific evidence for their usefulness.

  • Ketamine

  • Propofol

  • Nitrous Oxide

  • Psychedelics

  • Transcranial Magnetic Stimulation

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Stuart M. Caplen, MD, FACEP, MSM

Dr. Caplen is a retired emergency medicine physician and former emergency department medical director, who also has a Master of Science in Health Care Management degree, and green belt certification in Lean/Six Sigma.


[1] Major Depression. National Institute of Mental Health. Last Updated: January 2022. Retrieved from:

[2] Jaffe, D.H., Rive, B. & Denee, T.R. The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry 19, 247 (2019). Retrieved from:

[3] Carboni Ezio C et al. Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success? Frontiers in Neuroscience. 30 April 2021. Retrieved from:

[4] Berman R et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry. 47, 351–354. 2000. Retrieved from:

[5] Mickey BJ, White AT, Arp AM, et al. Propofol for Treatment-Resistant Depression: A Pilot Study. Int J Neuropsychopharmacology. 2018;21(12):1079-1089. Retrieved from:

[6] Passie T et al. Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers. European Neuropsychopharmacology, Volume 44, Pages 92-104. 2021. Retrieved from:

[7] Wei, Y., Chang, L., and Hashimoto, K. A historical review of antidepressant effects of ketamine and its enantiomers. Pharmacol. Biochem. Behav. 190:172870. 2020. Retrieved from:

[8] Singh JB et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol. Psychiatry 80, 424–431. 2016. Retrieved from:

[9] Canuso CM. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am. J. Psychiatry 175, 620–630. 2018. Retrieved from:

[10] Sapkota A, Khurshid H, Qureshi IA, et al. Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review. Cureus. 2021;13(8):e17352. 2021 Aug 21. Retrieved from:

[11] Capuzzi E, Caldiroli A, Capellazzi M, et al. Long-Term Efficacy of Intranasal Esketamine in Treatment-Resistant Major Depression: A Systematic Review. Int J Mol Sci. 2021;22(17):9338. 2021 Aug 28. Retrieved from:

[12] Dean R et al. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database of Systematic Reviews. 12 September 2021. Retrieved from:

[13] Walsh Z et al. Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. BJPsych. 23 December 2021. Retrieved from:

[14] Mickey BJ, White AT, Arp AM, et al. Propofol for Treatment-Resistant Depression: A Pilot Study. Int J Neuropsychopharmacology. 2018;21(12):1079-1089. Retrieved from:

[15] Nagele P et al. Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial, Biological Psychiatry, Volume 78, Issue 1, Pages 10-18. 2015. Retrieved from:

[16] Nagele P et al. A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression. Science Translational Medicine Vol 13, Issue 597. 9 Jun 2021. Retrieved from:

[17] Carhart-Harris RL et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences Feb 2012, 109 (6) 2138-2143. Retrieved from:

[18] Kuypers KPC. The therapeutic potential of microdosing psychedelics in depression. Therapeutic Advances in Psychopharmacology. January 2020. Retrieved from:

[19] Nutt D, Carhart-Harris R. The Current Status of Psychedelics in Psychiatry. JAMA Psychiatry. 2021;78(2):121–122. Retrieved from:

[20] Romeo B, Karila L, Martelli C, Benyamina A. Efficacy of psychedelic treatments on depressive symptoms: A meta-analysis. Journal of Psychopharmacology. 2020;34(10):1079-1085. Retrieved from:

[21] Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial [published correction appears in JAMA Psychiatry. 2021 Feb 10. Retrieved from: JAMA Psychiatry. 2021;78(5):481-489.

[22] Carhart-Harris R et al. Trial of Psilocybin versus Escitalopram for Depression. NEJM, 384:1402-1411. April 15, 2021. Retrieved from:

[23] Sonmez AI, Camsari DD, Nandakumar AL, et al. Accelerated TMS for Depression: A systematic review and meta-analysis. Psychiatry Res. 2019;273:770-781. Retrieved from:

[24] Connolly KR et al. Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: results observed with the first 100 consecutive cases of depression at an academic medical center. J Clin Psychiatry. 2012 Apr;73(4):e567-73. Retrieved from:

[25] Nash J. Attractive Therapy: Magnetic Brain Stimulation Gaining Favor as Treatment for Depression. Scientific American. August 30, 2010. Retrieved from:

[26] Stultz DJ et al. Transcranial Magnetic Stimulation (TMS) Safety with Respect to Seizures: A Literature Review. Neuropsychiatric Disease and Treatment Volume 16:2989-3000. December 2020. Retrieved from:

[27] Brunoni AR, Chaimani A, Moffa AH, et al. Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes: A Systematic Review With Network Meta-analysis. JAMA Psychiatry. 2017;74(2):143–152. Retrieved from:

[28] Watts V. New TMS Device Reduces Depression Symptoms. Psychiatric News, American Psychiatric Association, 4 Sep 2015. Retrieved from:

[29] Novey W. Are all rTMS machines equal? New research suggests there may be clinically significant differences. Ment Illn. 2019;11(1):8125. Published 2019 Jun 11. Retrieved from:

[30] John P. O’Reardon JP et al. Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial. Biological Psychiatry, Volume 62, Issue 11, 2007, Pages 1208-1216. Retrieved from:

[31] George MS, Lisanby SH, Avery D, et al. Daily Left Prefrontal Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder: A Sham-Controlled Randomized Trial. Arch Gen Psychiatry. 2010;67(5):507–516. Retrieved from:

[32] Rodriguez‐Martin JL et al. Transcranial magnetic stimulation for treating depression. Cochrane Database Syst Rev. 2002. Retrieved from:

[33] Couturier JL. Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci Mar 2005, 30 (2) 83-90. Retrieved from:

[34] Robert M Berman RM et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biological Psychiatry, Volume 47, Issue 4 Pages 332-337. 2000. Retrieved from:

[35] Martin JLR et al. Repetitive transcranial magnetic stimulation for the treatment of depressionThe British Journal of Psychiatry , Volume 182 , Issue 6 , June 2003 , pp. 480 – 491. Retrieved from:

[36] Berlim, M., Van den Eynde, F., Tovar-Perdomo, S., & Daskalakis, Z. (2014). Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: A systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychological Medicine, 44(2), 225-239. Retrieved from:

[37] Holtzheimer PE, Russo J, Avery DH. A meta-analysis of repetitive transcranial magnetic stimulation in the treatment of depression. 2001. In: Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995. Retrieved from:

[38] Magnezi R, Aminov E, Shmuel D, Dreifuss M, Dannon P. Comparison between neurostimulation techniques repetitive transcranial magnetic stimulation vs electroconvulsive therapy for the treatment of resistant depression: patient preference and cost-effectiveness. Patient Prefer Adherence. 2016;10:1481-1487. Published 2016 Aug 4. Retrieved from:

[39] Ren J et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: A systematic review and meta-analysis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 51, 2014, Pages 181-189. Retrieved from:


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