Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial

This randomized, double-blind, placebo-controlled study (n=26) investigated the efficacy of ketamine (35mg/70kg) treatment for patients with severe depression and found that, in contrast to other studies, ketamine did not outperform placebo in terms of short- or long-term antidepressant or antisuicidal efficacy.

Abstract

“Background: Several studies indicate that ketamine has rapid antidepressant effects in patients with treatment-resistant depression (TRD). The extent to which repeated doses of ketamine (versus placebo) reduce depression in the short and long term among outpatients with TRD and chronic, current suicidal ideation remains unknown.

Methods: Twenty-six medicated outpatients with severe major depressive disorder with current, chronic suicidal ideation were randomized in a double-blind fashion to six ketamine infusions (0.5 mg/kg over 45 minutes) or saline placebo over three weeks. Depression and suicidal ideation were assessed at baseline, 240 min post-infusion, and during a three-month follow-up phase.

Results: During the infusion phase, there was no differences in depression severity or suicidal ideation between placebo and ketamine (p = 0.47 and p = 0.32, respectively). At the end of the infusion phase, two patients in the ketamine group and one in the placebo group met criteria for remission of depression. At three-month follow-up, two patients in each group met criteria for remission from depression. Limitations: Limitations include the small sample size, uncontrolled outpatient medication regimens, and restriction to outpatients, which may have resulted in lower levels of suicidal ideation than would be seen in emergency or inpatient settings.

Conclusions: Repeated, non-escalating doses of ketamine did not outperform placebo in this double-blind, placebo controlled study of patients with severe TRD and current, chronic suicidal ideation. This result may support our previously published open-label data that, in this severely and chronically ill outpatient population, the commonly used dose of 0.5 mg/kg is not sufficient.“

Authors: Dawn F.Ionescu, Kate H. Bentley, Matthias Eikermann, Norman Taylor, Oluwaseun Akeju, Michaela B. Swee, Kara J. Pavone, Samuel R. Petrie, Christina Dording, David Mischoulon, Jonathan E. Alpert, Emery N. Brown, Lee Baer, Matthew K. Nock, Maurizio Fava & Cristina Cusin

Summary

In this double-blind, placebo controlled study, patients with severe treatment-resistant depression and chronic, current suicidal ideation received six ketamine infusions (0.5mg/kg over 45 minutes) or saline placebo over three weeks. Ketamine did not reduce depression severity or suicidal ideation in the short or long term.

Major depressive disorder (MDD) is a common psychiatric disorder, but 30% of patients remain symptomatic after multiple adequate medication trials. Patients with treatment-resistant depression and current, significant suicidal ideation are especially difficult to treat, and are often excluded from clinical trials. Ketamine, an anesthetic approved by the FDA in 1970, is being studied for its antidepressant properties. It has been shown to have rapid, robust, and relatively sustained antidepressant properties.

Ketamine infusions have been shown to produce acute reductions in depressive symptoms compared to placebo conditions. Additionally, ketamine may also have rapid antisuicidal properties with minimal side effects. Most previous studies of ketamine for TRD have excluded patients with high suicide risk, and most studies have used very short follow-up periods or open-label or case study designs. However, recent studies have used randomized, double-blind, placebo-controlled studies to examine the antisuicidal properties of ketamine among TRD populations.

We examined the short-term and long-term antidepressant efficacy of repeated-dose (0.5mg/kg) ketamine augmentation compared to placebo in medicated, TRD outpatients with chronic SI. Ketamine had rapid and superior antidepressant and antisuicidal efficacy compared to placebo. This study was approved by the Partners Human Research Committee, conducted at the Massachusetts General Hospital, and included patients with a primary diagnosis of current major depressive disorder and a history of 3 failed antidepressant treatment trials.

Accepted candidates must have a current SI score of 1 on the Columbia-Suicide Severity Rating Scale, be on an adequate antidepressant regimen for 4 weeks prior to infusions, and have a treating psychiatrist in agreement with study participation. Patients with current and clinically significant SI were excluded if they had a history of pregnancy, unstable medical illness, bipolar disorder, past multiple adverse drug reactions, psychotic illness, substance use disorder within the past year, positive urine toxicology, past history of ketamine abuse, or SI requiring immediate hospitalization.

This double-blind, placebo controlled study was conducted between January 2013 and November 2015. Patients were screened by a trained study clinician, evaluated twice more within two weeks, and were admitted as outpatients to the Clinical Research Center (CRC) at MGH for ketamine infusions. Patients received six 45-minute intravenous infusions of either ketamine (0.5mg/kg) or saline placebo, over three weeks (two infusions per week). The infusions were programmed by a board-certified anesthesiologist or psychiatrist.

A nurse recorded vital signs and clinical status every five minutes, and patients were monitored for side effects for two hours post-infusion. A study doctor administered assessments of depression and SI at the four-hour post-infusion timepoint, and patients were discharged home with a responsible adult. Ketamine’s antisuicidal efficacy was assessed by a clinician-administered, 28-item rating scale. A HDRS score of 7 was considered remission.

The secondary outcome was suicidal ideation, measured with the C-SSRS SI score and C-SSRS SI intensity rating. The CADSS was also administered to assess dissociative effects, and depression and SI rating scales were administered at all visits. Demographic variables were compared using frequencies and chi-square analyses, and t-tests were used for continuous variables. A mixed effect model with repeated measures (MMRM) approach was used to model the interaction effect of group x time for all efficacy analyses.

All tests were conducted with a significance level of p 0.05 (2-sided), using STATA SE Version 12 statistical software. The study found no differences between the ketamine vs. placebo group with regard to age, sex, race, history of self-harm, history of trauma/abuse, family history of suicide, history of failed ECT, or drug dose.

26 outpatients signed informed consent and were randomized to ACCEPTED MANUSCRIPT 12 ketamine or placebo. 9 of 13 patients randomized to ketamine and 9 of 13 patients randomized to placebo completed all six infusions, with 1 patient missing the fourth infusion due to inpatient hospitalization for SI. There was no significant change in HDRS total scores between screening and baseline visits, and there were no differences between ketamine and placebo groups on HDRS total scores.

The depression decreased significantly across infusions, but there were no statistically significant differences in HDRS total scores between the ketamine and placebo groups. Both groups remained at least moderately depressed at the end of the infusions. Time had a significant effect on pre-infusion C-SSRS SI score, regardless of eventual randomization to ketamine or placebo. There was no significant group x time interaction between ketamine vs. placebo for C-SSRS SI score or intensity rating.

Patients in the ketamine group reported higher dissociative symptoms during the infusion visits, and 2 patients in the ketamine group were lost to follow-up. Overall, 14/26 patients (54%) completed all visits and 2 patients in the ketamine group met criteria for both antidepressant response and antidepressant remission at three months.

The majority of patients who received ketamine had absence of SI at the last infusion, but only 11% continued to have absence of SI at the end of the follow-up.

Ketamine has been shown to outperform control conditions in antidepressant efficacy among TRD individuals. However, in this double-blind, placebo controlled study of patients with severe TRD and current, chronic SI, ketamine did not outperform placebo in terms of short- or long-term antidepressant or antisuicidal efficacy.

A single-infusion dose finding study of ketamine was recently completed in outpatients with treatment-resistant depression and chronic SI on concomitant medications. The study did not observe an advantage to ketamine, but the small sample size may have rendered us vulnerable to Type II error. This study had a number of limitations, including a small sample size and lack of study resources to provide compensation. Additionally, all patients were maintained on their outpatient medication regimens throughout the infusion phase.

We examined outpatients with clinically significant and chronic SI, but missed a large group of patients with acute SI. Because self-reported levels of SI were relatively low during the pre-infusion phase, it may have been difficult to detect significant change across the infusions. This study had several strengths, including the use of a double-blind, placebo controlled trial, a three-month follow-up period, and a lag time between enrollment and beginning the infusions. The results suggest that separate processes may be involved in the improvement of SI vs. depressive symptoms.

Though the results of this small study were not significant, the investigation into ketamine’s potential as a rapid antidepressant and antisuicidal agent merits continuation. Further research should focus on elucidating the specific subtypes of patients for whom ketamine is most effective.