April 27, 2022

The Evidence Base: Two Ketamine Studies to Become Familiar with Now

Written by

L. Alison McInnes, MD, MS

Beyond the development of new mental health treatments, research is a fundamental influence on payers to increase coverage for therapies – and for politicians who campaign for increased treatment access and reduced stigma. Peer-reviewed articles help unify practice standards so patients receive the best possible care, and ensure that clinicians have the best information to help protect against potential legal challenges.

It’s critical for your clinical practice to stay current with the newest research literature, but it can be hard to keep up. The Evidence Base aims to help clinicians follow the developments that advance evidence-based mental health practices. 

Recently, two noteworthy research papers caught our attention at Osmind. The first centers on the safety of ketamine in community practice. The second paper focuses on ketamine drug interactions. Both are summarized below.

1) The safety of ketamine in community practice

Post-marketing safety concerns with esketamine: a disproportionality analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System. Psychother Psychosom. 2021;90:41–8. Gastaldon C. Raschi E, Kane JM, Barbui C, Schoretsanitis G. 

While this paper is behind a paywall, it is highly relevant to clinicians and demonstrates the importance of real world evidence. Clinical trials enroll a relatively small number of carefully screened patients. Real world evidence furthers the preliminary understanding gained from clinical trials, to establish the safety and efficacy of treatment interventions in the general population. 

The Gastaldon et al. article describes safety/tolerability concerns emerging with esketamine administration in real-world populations. A preliminary analysis of data obtained by the United States Food and Drug Administration Adverse Event Reporting System (FAERS) suggests there are discrepancies in the safety/tolerability profiles of esketamine between clinical trials and real-world care settings. 

  • The reporting odds ratio for suicidal ideation was 24.03 (95% confidence interval 18.72–30.84), and female patients were more likely to experience serious adverse events compared with male patients (χ2 = 125.29, p < 0.001).
  • Patients with serious adverse events were more likely to be receiving antidepressant polypharmacy (χ2 = 9.08, p = 0.003), weighed more than those with non-serious adverse events (p = 0.043), and the frequency of serious adverse events was higher in patients receiving 84 mg of esketamine compared with those receiving 56 mg (χ2 = 5.79, p = 0.016). 

The takeaway: Polypharmacy, comorbid medical conditions, female gender and higher dosing were all associated with more adverse outcomes in community patients receiving esketamine. 

2) Interactions between ketamine and psychiatric medications

Pharmacodynamic Interactions Between Ketamine and Psychiatric Medications Used in the Treatment of Depression: A Systematic ReviewInt J Neuropsychopharmacol. 2021 Oct 23;24(10):808-831. doi: 10.1093/ijnp/pyab039. PMID: 34170315; PMCID: PMC8538895. Veraart JKE, Smith-Apeldoorn SY, Bakker IM, Visser BAE, Kamphuis J, Schoevers RA, Touw DJ.

  • This paper states that benzodiazepines were repeatedly shown to reduce the duration of ketamine’s antidepressant effect. However, here we’ll note benzodiazepines did not appear to attenuate the antidepressant effects of esketamine if prohibited within 8 hours before or after dosing.1
  • Three studies found that the effects of ketamine in healthy controls were attenuated by pretreatment with lamotrigine 300 mg. However, four studies did not confirm the interaction. The only study to assess the effects of pretreatment with 300 mg of lamotrigine in patients with treatment resistant depression did not confirm an inhibitory effect on antidepressant response. 
  • For the monoamine oxidase-inhibitor tranylcypromine, case reports showed no relevant changes in vital signs during concurrent esketamine use. A small case series suggests that ketamine responders may go on to do well with selegiline.2
  • No significant interactions between lithium and ketamine were reported. One paper indicated an interaction between ketamine and haloperidol, while two other studies did not. 
  • Four papers investigated risperidone, including three neuroimaging studies showing an attenuating effect of risperidone on ketamine-induced brain perfusion changes. One paper reported no effect of olanzapine on ketamine’s acute psychotomimetic effects.

The takeaway: Benzodiazepines reduce the effects of ketamine’s antidepressant effects. Avoid administration of benzodiazepines within 8 hours before or after esketamine administration. There is insufficient evidence to support lowering or skipping lamotrigine dosing prior to ketamine administration at this time.

About Dr. Alison McInnes

Dr. Alison McInnes is Vice President, Medical Affairs at Osmind. She is a nationally recognized expert in psychiatry and mood and anxiety disorders, having specialized in treating refractory disease for over a decade. She is an expert in ketamine treatment and psychedelic medicine. McInnes founded and served as Medical Director for Kaiser Permanente's ketamine infusion therapy program for a number of years, and was previously an Associate Professor of Psychiatry at Mount Sinai School of Medicine for 8 years where she ran a lab in psychiatric genetics. She was also an adjunct clinical professor at UCSF.

Dr. McInnes is regularly invited to speak at national and international conferences and consults for biopharmaceutical companies working at the cutting edge of neuropsychiatry. She is a member of the American Society of Ketamine Physicians, Psychotherapists and Practitioners (ASKP3) Certification Governance Commission, which is an autonomous governing body that oversees the development, implementation, and management of a certification program for clinicians offering ketamine therapy. In her current clinical practice, she focuses on treatment-resistant mood disorders and complex cases.

Dr. McInnes received Bachelor’s and Master’s degrees from Stanford University and her MD from Columbia University. She completed residency at UCSF and research at the VA Research Fellowship and Howard Hughes Physician Research Fellowship in Psychiatric Genetics at UCSF.

Get the latest in your inbox

Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.

Share this

Related Blog Posts



We’re Hiring!



Get the latest in your inbox

Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.

If you, or someone you know, is in crisis or needs immediate assistance, please call 911 immediately. To talk to someone now, please call the National Suicide Prevention Lifeline at 1-800-273-8255.

Osmind Inc. © 2023 All Rights Reserved.