While esketamine, the S-isomer of ketamine, is approved by the FDA for treatment-resistant depression and major depressive disorder with suicidality, IV ketamine—a mixture of R- and S-isomers—remains off-label for this indication. In a position paper, the American College of Clinical Pharmacy expressed concern about the inherent unfavorable risk-benefit profile of off-label ketamine. Therefore, it is important to have real-world data to help address some of these concerns.

The investigators conducted a retrospective analysis of deidentified data of patients with depression who received IV ketamine between 2016 and 2020 at one of 178 community clinic-based practices in 40 states in the U.S. The purpose of this study was to quantify treatment responses to IV ketamine using data from an online platform and results of Patient Health Questionnaire-9 (PHQ-9).

The response on the PHQ-9 was defined as a 50% or greater decrease in total PHQ-9 score from pretreatment status. Remission occurred if the PHQ-9 score decreased to less than 5. The presence of suicidal ideations (SI) was assessed by a score of 1 or more on line item 9 of the PHQ-9 (i.e., "Thoughts that you would be better off dead or of hurting yourself"). PHQ-9 scores of 0 to 9 were rated as no or mild depression, 10 to 14 as moderate depression, 15 to 19 as moderately severe depression, and 20 to 27 as severe depression. Induction consisted of a series of four to eight infusions administered over the course of 7 to 28 days with the additional stipulation that each infusion be labeled as an induction infusion in the software. A Kaplan-Meier curve was utilized to assess the durability of response after induction and before the initiation of maintenance infusions.

To be included in the study, patients had to have received four to eight infusions of IV ketamine for induction within a 7- to 28-day period; a baseline PHQ-9 had to be conducted within 1 month prior to induction; and the post-induction PHQ-9 had to be reported 14 to 31 days after the final induction infusion and prior to any maintenance infusion.

Of the 9,016 patients within the database, 537 met the inclusion criteria and underwent further analysis. The response rate to IV ketamine induction was 53.6% and was associated with a Cohen's d effect size of 1.5, indicating a large effect size. The remission rate was 28.9%. Despite these positive results, however, 8.4% of patients who completed the induction phase experienced an increase in PHQ-9 scores.

A drop in PHQ-9 scores was a function of baseline scores such that patients with higher baseline PHQ-9 scores needed to have larger reductions than patients with lower baseline scores to achieve responder status.

Among the 356 patients with suicidal ideations prior to induction, there was complete resolution in 42.7% following induction with IV ketamine. About 3% of those who completed induction experienced an increase in suicidal ideation and an increase in overall PHQ-9 scores, whereas another 3% also had an increase in suicidal ideation but without an increase in PHQ-9 scores.

Of those who achieved responder status, 78.3% retained responder status 28 days after induction and 59.9% still were responding 56 days post induction.

While this study sheds a positive light on IV ketamine, pharmacists should also be cognizant of the limitations of this study, which included that those who completed induction represented only 15.3% of patients since this is the group who had both pre- and post-PHQ-9 data available; data were lacking on demographics, past medical history, substance use, chronicity of condition, number of failed treatments, previous use of electroconvulsive therapy or transcranial magnetic stimulation, current medications, number of patients enrolled in psychotherapy, and dosage; and enrollment may have been subject to economic and racial selection bias since IV medication is typically not covered by insurance.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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