The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study

This randomized double-blind placebo-controlled study (n=56) found that a single dose of ketamine significantly reduced the level of suicidal ideation (SI). Still, in both groups, there was a high level of suicidal ideation, and the study showed diminishing results rapidly over the 30 days of the study (the effects being the largest at 3 days post-infusion).

Abstract

“This study aimed to assess the effect of a single infusion of intravenous (IV) ketamine on suicidal ideation in patients with treatment-resistant depression (TRD). Patients with TRD were randomized in a double-blind fashion to a single infusion of IV ketamine or IV midazolam placebo. Suicidal ideation was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) suicide item at 3, 5, 7, 14 and 30 days post infusion. Clinically significant suicidal ideation was defined as a MADRS suicide item score ≥2. Forty patients who received IV ketamine and 16 who received IV midazolam had suicide item scores of ≥2 at baseline (IV ketamine group mean 2.90±0.74; IV midazolam group 2.69±0.70). The mean suicide scores of these groups differed significantly from each other on day 30; the IV ketamine group had a lower mean score than controls (2.03±1.59 vs. 3.00±1.41, t-test p = 0.049; Hedges’ g 0.71). Among patients with a suicide score of ≥2 at baseline and <2 at day 3, the two groups did not differ significantly on mean scores changes at days 3, 5, 7, 14 or 30. Recurrence of suicidal ideation was extensive in both treatment groups. A single infusion of IV ketamine may reduce suicidal ideation in TRD out to 30 days post infusion, but early anti-suicidal effects appear to diminish rapidly. This post-hoc analysis was not powered to compare different doses of ketamine. A single infusion of IV ketamine might have a role as an adjunct to standard treatments in patients with TRD and suicidal ideation.“

Authors: Anna Feeney, Rebecca S. Hock, Marlene P. Freeman, Martina Flynn, Bettina Hoeppner, Dan V. Iosifescu, Madhukar H. Trivedi, Gerard Sanacora, Sanjay J. Mathew, Charles Debattista, Dawn F. Ionescu, Maurizio Fava & George I.Papakostas

Notes

Author highlights:

• “Patients with resistant depression and suicidal ideation got a single dose of ketamine or placebo.
• Those who received ketamine had lower suicide scores 30 days after the infusion.
• However, recurrence of suicidal ideation was extensive in both groups.
• Ketamine may have a role as an adjunct to standard treatments in this patient group.”

Summary

In this study, patients with treatment-resistant depression were randomized to receive a single infusion of intravenous ketamine or IV midazolam placebo. The IV ketamine group had a lower mean suicide score than the IV midazolam group on day 30, but early effects diminished rapidly.

1. Introduction

Although IV ketamine has not been FDA-approved for use in psychiatric disorders, it is now widely used off-label in the treatment of MDD and other psychiatric conditions. It is less clear whether IV ketamine can be used to treat depressive symptoms in adults with MDD and acute suicidal ideation or behavior.

Several reviews have concluded that a single IV ketamine infusion can rapidly reduce suicidal ideation, though individual double-blind trials have not consistently demonstrated the durability of this anti-suicidal effect beyond one week.

Our group has reported on the antidepressant effect of IV ketamine augmentation in MDD, followed by a 30-day blinded observation period. This study offers scope to examine the longer term effects of IV ketamine on suicidal ideation.

3. Results

Sixty patients received a single IV ketamine infusion and 19 patients received an IV midazolam placebo. Of these, 40 patients received IV ketamine and 16 patients received IV midazolam, and 56 patients were included in the analysis of change in suicide item scores over time.

Patients with baseline MADRS suicide item scores of 2 who received IV ketamine or IV midazolam had a drop in their MADRS suicide item score to 2 on assessment at day 3 post-infusion, but the effect was not sustained at 30 days.

The time-to-recurrence of suicidal ideation among 31 patients who received IV ketamine or IV midazolam placebo was analyzed through a survival analysis. There was no statistical difference between drug and placebo groups in relation to survival probability after 30 days.

4. Discussion

This study examined changes in MADRS suicide item scores following a single IV infusion of ketamine compared to an active control over 30 days post-infusion. The results showed that the effect of ketamine on suicidal ideation was short-lived and weakened over the 30-day follow-up.

The primary endpoint in the original study was day 3 post-infusion. However, the results show that ketamine had a statistically significant benefit over placebo out to day 30 post-infusion.

A recent meta-analysis of studies using IV ketamine to treat suicidal ideation in a wide range of psychiatric disorders concluded that the anti-suicidal effect was rapid in onset, but not sustained beyond 72 h. Further large scale clinical trials are needed to examine the effect of repeated IV ketamine infusions.

This study contributes to our knowledge of the clinical effects of IV ketamine and has several strengths, including a double-blind, randomized, controlled design with use of an active placebo, a high rate of participant retention out to 30 days post-infusion, and use of the MADRS suicide item score.

This study was limited by the fact that it did not specifically recruit patients with suicidal ideation and that overall numbers in the subgroup analyses described here were small. However, there is evidence to suggest that the anti-suicidal effect of IV ketamine may be even greater in those with more severe suicidal ideation.

The effect of benzodiazepines may have contributed to the observed outcomes, but the present analysis is not best suited to assess this impact. Also, only a small number of participants were randomized to placebo, and the study was done post-hoc.

IV ketamine has important potential clinical applications, including the treatment of acute suicidal ideation in MDD and TRD refractory to more than five treatment trials. However, further study is needed to determine the effectiveness of IV ketamine in treating acute suicidal ideation in routine clinical settings.

This study demonstrated that IV ketamine may have a small benefit over midazolam placebo in reducing suicidal ideation in patients with TRD.

Role of funding source

The National Institute of Mental Health funded this study, but had no role in study design, data collection, analysis, interpretation, writing, or decision to submit the paper for publication.

Declaration of competing interest

Marlene P. Freeman reports having financial relationships with JayMac, Sage, Janssen, and Novartis.

Dr. Freeman is an employee of Massachusetts General Hospital and works with the MGH National Pregnancy Registry. He has received consulting honoraria and research support from multiple pharmaceutical companies.

Dr. Madhukar H. Trivedi has received grant/research funding from NIMH, NIDA, Patient-Centered Outcomes Research Institute (PCORI), and Cancer Prevention Research Institute of Texas (CPRIT).

Gerard Sanacora has served as a consultant for many companies and received research contracts from many companies over the past 36 months.

Dr. Sanacora holds equity in BioHaven Pharmaceuticals and is a co-inventor on a US patent. Yale University has a financial relationship with Janssen Pharmaceuticals.

Sanjay J. Mathew, Charles Debattista, Dawn F. Ionescu, and Maurizio Fava are supported by the Michael E. Debakey VA Medical Center and The Menninger Clinic, respectively, and have received research support from Biohaven Pharmaceuticals and VistaGen Therapeutics.

Psy Therapeutics holds patents for Sequential Parallel Comparison Design (SPCD) and for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD).

George I. Papakostas has served as a consultant for Abbott Laboratories, Acadia Pharmaceuticals, Inc, Alphasigma USA , Inc, AstraZeneca PLC, Avanir Pharmaceuticals, Axsome Therapeutics, Boston Pharmaceuticals, Inc., Brainsway Ltd, Bristol-Myers Squibb Company, Cala Health, Cephalon Inc, Dey Pharma, L.P., Eleusis Dr. Papakostas has received honoraria for lectures or consultancy from Abbott Laboratories, Acadia Pharmaceuticals Inc, Alkermes Inc, Alphasigma USA Inc, Asopharma America Cntral Y Caribe, Bristol-Myers Squibb Company, Brainsway Ltd, Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., Evotec AG, Forest Pharmaceuticals