A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings

This retrospective analysis (n=537) assessed the effectiveness of intravenous ketamine therapy in community-based practices i.e real-world care settings. Over half of the participants showed a response at 14-31 days post-infusion and 28.9% remitted while 73% exhibited a reduction in suicidal ideation. However, remission status was weakly inversely correlated with depression severity.

Abstract

“Background: Outcomes of ketamine intravenous therapy (KIT) for depression in real-world care settings have been minimally evaluated. We set out to quantify treatment response to KIT in a large sample of patients from community-based practices.

Methods: We retrospectively analyzed 9016 depression patients who received KIT between 2016 and 2020 at one of 178 community practices across the United States. Depression symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9). The induction phase of KIT was defined to be a series of 4–8 infusions administered over 7 to 28 days.

Results: Among the 537 patients who underwent induction and had sufficient data, 53.6% of patients showed a response (≥ 50% reduction in PHQ-9 score) at 14–31 days post-induction and 28.9% remitted (PHQ-9 score drop to < 5). The effect size was d = 1.5. Among patients with baseline suicidal ideation (SI), 73.0% exhibited a reduction in SI. A subset (8.4%) of patients experienced an increase in depressive symptoms after induction while 6.0% of patients reported increased SI. The response rate was uniform across 4 levels of baseline depression severity. However, more severe illness was weakly correlated with a greater drop in scores while remission status was weakly inversely correlated with depression severity. Kaplan-Meier analyses showed that a patient who responds to KIT induction has approximately 80% probability of sustaining response at 4 weeks and approximately 60% probability at 8 weeks, even without maintenance infusions.

Conclusion: KIT can elicit a robust antidepressant response in community clinics; however, a small percentage of patients worsened.”

Authors: L. Alison McInnes, Jimmy J. Qian, Rishab S. Gargeya, Charles DeBattista & Borris Heifets

Notes

Given the legal status surrounding ketamine, it is widely available as an ‘off-label’ treatment for a range of mental health disorders. As a result, numerous clinics exist across the globe offering ketamine-assisted therapy for the treatment of mental disorders like depression and anxiety. While many clinical trials have taken place to prove the effectiveness of using ketamine to treat the aforementioned disorders, little attention has been paid to how these clinical research findings have translated into real-world practices.

The present study sought to address this research gap by analysing the data from depressed patients who received ketamine-infusion therapy (KIT) at community-based practices in the U.S. from 2016-2020. Care providers used the Patient Health Questionnaire (PHQ-9) to assess depressive symptoms. Patients received 4-8 ketamine infusions over 7 to 28 days.

The real-world findings:

• 537 patients who had undergone induction had sufficient data and were included in the final analysis.
• 53.6% of these patients showed a response (≥ 50% reduction in PHQ-9 score) at 14–31 days post-induction and 28.9% remitted (PHQ-9 score drop to < 5) (115/537 patients remitted).
• The overall effect size was large as measured using Cohen’s d, yielding an effect size of 1.5 (d=1.5).
• Among the patients with suicidal ideation (SI), 73% had a reduction in SI.
• Negative effects inlcuded a subset (8.4%) of patients experienced an increase in depressive symptoms after induction while 6.0% of patients reported increased SI.

The present study is the largest published analysis to date that examines the effectiveness of a standard KIT induction protocol in depressed patients treated at community clinics across the U.S i.e a real-world setting. The findings of the study are roughly in line with that of previously reported results in the clinical setting. The authors do acknowledge some limitations to their findings. For example, unblinded clinicians who want to see their patients improve as well as the patients themselves who paid for KIT expecting positive outcomes may have positively skewed results. Furthermore, it was not assessed if patients were ketamine naive.

Overall, the present paper is one of the first to address the effectiveness of ketamine-assisted therapy in a real-world setting. As other psychedelic-assisted therapies become available, similar studies will be needed to assess how treatment protocols designed in the clinical setting can translate into real-world practices. In an ideal world, these protocols and therapies should directly translate into therapeutic outcomes observed during research. Therefore, studies will be needed to determine if this is true.

Summary

We evaluated the treatment response of ketamine intravenous therapy for depression in community-based practices.

1. Introduction

Ketamine intravenous therapy (KIT) is a rapid and effective treatment for depression. Most efficacy data reflects responses to single infusions of ketamine administered to patients at academic medical centers.

Ketamine clinics have opened across the United States offering a variety of infusion regimens, but detailed time course data using standardized clinical instruments is still largely lacking.

A ketamine induction regimen involves a series of closely spaced infusions over a two-week period, followed by maintenance KIT at variable intervals. Prospective studies have found antidepressant response and remission rates to be similar to those observed after single ketamine infusions, though repeated infusions may offer enhanced therapeutic benefit.

Here, we report outcomes on 9016 de-identified real-world outpatients with symptoms of depression who received ketamine infusion therapy (KIT) between 2016 and 2020 at 178 independent community ketamine practices across the United States.

2.1. Sample

We analyzed de-identified data from 9016 patients who received KIT for depression at one of 178 private practice community clinics between January 1, 2016 and December 30, 2020. The clinics used a measurement-based care software platform and sent text messages to patients’ cell phones with reminders to complete the PHQ-9.

2.2. Clinical procedures

178 independent community practices used the measurement-based care software to code ketamine infusions for depression. The most common adjunctive medications were given for hypertension, nausea, and anxiety, and patients were generally expected to pay out-of-pocket for the infusions.

2.3. Outcomes and variables

The PHQ-9 was used as the primary measure of depression symptoms. Induction was defined as a series of 4 – 8 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. The baseline PHQ-9 was required one month prior to induction, and the post-induction PHQ-9 was required 14 – 31 days after the final induction infusion.

2.4. Statistical analysis

The Chi-Square Test of Independence, Cohen’s d statistic, point biserial correlation test, and Kaplan-Meier curve were used to analyze the data. A p-value of 0.05 was considered significant.

3.1. Subject characteristics

Our dataset of 9016 patients included 537 patients who received KIT induction consisting of 4 to 8 infusions within a 7 – 28 day period. 56.9% of patients completed their induction within 14 days, consistent with previously published induction schemata.

We evaluated the extent to which patients in our analysis may have differed from the overall population by comparing the distribution of baseline PHQ-9 scores in these respective groups. We found that the mean and median baseline PHQ-9 scores for patients who failed to complete the induction were similar to those of patients who completed it. We examined a subset of 374 patients who dropped out before infusion 4 and found that their baseline PHQ-9 score was statistically different from the baseline score of the n = 537 population, but that the difference was not clinically meaningful.

Patients who did not diligently fill out surveys could not be represented in the analysis of treatment response calculation, but the mean PHQ-9 score 14 – 31 days after induction was similar for all 381 patients who received 6 induction infusions.

3.2. Depression outcomes for KIT induction

All post-induction outcomes were quantified 14 – 31 days after the final induction infusion. A subset of patients (8.4%) experienced an increase in PHQ-9 score during induction, but the likelihood of worsening showed a negligible negative correlation with baseline PHQ-9 severity.

We examined the relationship between baseline depression severity and response to KIT induction. Patients with higher baseline scores had larger reductions in PHQ-9 score than patients with lower baseline scores to achieve responder status.

The likelihood of remission was negatively correlated with the baseline levels of severity, and more severe illness was weakly inversely correlated with the likelihood of remission.

3.3. SI in KIT induction

Within the n = 537 cohort, 66.3% of patients had baseline SI to some degree, and 73.0% of patients with baseline SI reported an improvement in SI after KIT induction. Furthermore, 42.7% of patients who had baseline SI prior to induction exhibited no more SI at the end of induction.

3.4. Durability of response to induction

We performed a Kaplan-Meier analysis to estimate the probability of relapse over time for patients who either responded or remitted after induction. The probability of retaining responder status was 78.3% at 28 days and 59.9% at 56 days.

3.5. Practice patterns for maintenance KIT

Patients who complete induction treatment and respond to treatment receive 3.6 maintenance infusions, while remitters receive 3.7 maintenance infusions. The 3518 patients who complete induction treatment receive 2.6 maintenance infusions on average.

The mean length between the final induction infusion and the first maintenance infusion for patients who achieved remission and entered maintenance was 84.3 days.

4. Discussion

This is the largest published analysis to date of the real-world effectiveness of a standard KIT induction protocol for depression. The response rate was both robust and durable, and contrasted with a recent study that reported a response rate of only 18.5%.

While our response rates diverge from those of Sakurai et al. (2020), they are roughly in line with those of Phillips et al. (2019), Singh et al. (2016), Aust et al. (2019) and Wilkinson et al. (2018) who observed response rates between 45 and 59% after an induction protocol.

Response rates to ketamine induction therapy did not vary as a function of initial depression severity, though more severely ill patients tended to show a greater drop in PHQ-9 scores while also having a reduced likelihood of remission. A small subset of patients worsened after ketamine induction therapy.

We observed a robust response and remission rates with a strong durability of response. The median time to a first maintenance infusion was 48 days for remitters and 43 days for responders, versus 28 days for all 1846 patients who completed induction and entered maintenance.

We and Sakurai et al. (2020) note that patients enter maintenance with a relatively small number of infusions, and that most patients exit treatment within 6 months. It is not clear whether patients exit treatment because they feel better or because they can no longer afford the treatment.

5. Limitations

We report outcomes on a fraction of the total sample due to missing mood survey data, and lack data on demographic information, past medical history, or substance use data. We also do not know who was receiving psychotherapy, which may make ketamine and other psychedelic agents more effective.

Future replication studies should incorporate more detailed data collected in Osmind’s electronic health record (EHR) platform, which captures demographic data and clinical history, and automates outcomes tracking with a patient facing mobile phone application. This data can form the basis of predictive models that directly inform clinical care.

6. Conclusions

We observed a robust and durable antidepressant response to KIT induction in 53.6% of those that completed the induction, and 28.9% of patients completing induction experienced remission. 52.5% of patients completing induction elected to continue into maintenance treatment.

CRediT authorship contribution statement

L. Alison McInnes, Jimmy J. Qian, Rishab S. Gargeya, Charles DeBattista, and Boris D. Heifets contributed to this work.

Declaration of Competing Interest

LAM, JJQ, RSG, and CD are employees or consultants of Osmind Inc., and CD has received research support from Sage Therapeutics, Compass Pathways, Relmada Therapeutics, and Janssen.