USE OF KETAMINE FOR DEPRESSION IN SPECIAL POPULATIONS

Replicated randomized controlled clinical trials (RCTs) have demonstrated rapid and robust antidepressant effects with ketamine for treatment resistant depression (TRD). Safety and tolerability of ketamine infused at 0.5-1 mg/kg over 40 minutes has been established in RCTs and real world effectiveness (RWE) studies, however, many RCTs excluded more complex patient presentations raising questions about the safety and effectiveness of ketamine in these specific subgroups that have been under represented in clinical trials. The present session will review existing evidence and present original data from our group evaluating the clinical utility and safety of ketamine for TRD in older adults, medically ill patients near end of life, patients with comorbid borderline personality disorder (BPD) and bipolar disorder. In all of these subgroups, we observed comparable antidepressant effectiveness, however, this presentation will focus specifically on safety and tolerability in these groups. Older Adults: In an RWE study (NCT04209296), we treated fifty-three older adults (Mage = 67, SD = 6; 57% female [n = 30]) with an acute course of 4 ketamine infusions. Thirty-six participants (69%) experienced treatment-emergent hypertension during at least 1 infusion, and 10 (19%) required intervention with an antihypertensive. Drowsiness was the most commonly reported adverse event (50% of infusions; n = 73). End of Life: We conducted a single-arm, open-label phase II trial in participants with advanced cancer with moderate to severe MDD received three flexible doses of intranasal (IN) ketamine (50−150 mg) over a one-week period (NCT03410446). Mean MADRS scores decreased significantly from baseline (mean MADRS of 31, standard deviation 7.6) to Day 8 (11 +/− 7.4) with an overall decrease of 20 points (p < 0.001). Common adverse effects included fatigue, dissociation, nausea, dysgeusia and headaches; almost all adverse effects were mild and transient, resolving within 2 h of each ketamine dose with one dropout related to adverse effects (negative dissociative episode). TRD with comorbid BPD: In a TRD population with comorbid BPD (N=100; n=50 BPD-positive compared with n=50 BPD-negative), an acute course of 4 ketamine infusions was administered (NCT04209296). Both BPD-positive and BPD-negative groups improved significantly on the QIDS-SR16, QIDS-SR16 suicide ideation item, anxiety, and functionality scales with large effect sizes. There was no significant difference between groups with regards to side effects or drop out. No treatment-emergent suicidality was observed. There was a trend for greater dissociative symptoms during infusions that did not reach statistical significance. Treatment Resistant Bipolar Depression (TRBD): We conducted a randomized, midazolam-controlled clinical trial in 69 TRBD patients receiving an acute course of 4 ketamine or 4 midazolam infusions over 2-weeks (NCT05004896). Safety and tolerability were comparable to previous studies in major depressive disorder (MDD). We closely monitored for any treatment emergent mania, hypomania or psychosis on a daily basis during the trial. No evidence of treatment emergent mania or psychosis were observed in either arm, however, 1 participant in each arm developed mixed features, suggesting of a 2-3% risk of treatment emergent mixed features with ketamine or midazolam. This estimate aligns with previous RWE studies and single dose ketamine trials in bipolar disorder, suggesting risk of mania or hypomania is relatively low. Taken together, the safety and tolerability of ketamine in more complex patient populations appears promising with comparable side effects as observed in MDD RCTs that often excluded these individuals.

References

Kevork Danayan, Noah Chisamore, Nelson B. Rodrigues, Joshua D. Di Vincenzo, Shakila Meshkat, Zoe Doyle, Rodrigo Mansur, Lee Phan, Farhan Fancy, Edmond Chau, Aniqa Tabassum, Kevin Kratiuk, Anil Arekapudi, Kayla M. Teopiz, Roger S. McIntyre, Joshua D. Rosenblat, Real world effectiveness of repeated ketamine infusions for treatment-resistant depression with comorbid borderline personality disorder, Psychiatry Research, Volume 323, 2023, 115133, https://doi.org/10.1016/j.psychres.2023.115133. Orly Lipsitz, Joshua D. Di Vincenzo, Nelson B. Rodrigues, Danielle S. Cha, Yena Lee, David Greenberg, Kayla M. Teopiz, Roger C. Ho, Bing Cao, Kangguang Lin, Mehala Subramaniapillai, Alastair J. Flint, Kevin Kratiuk, Roger S. McIntyre, Joshua D. Rosenblat, Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series, The American Journal of Geriatric Psychiatry, Volume 29, Issue 9, 2021, Pages 899-913, https://doi.org/10.1016/j.jagp.2020.12.032.