Ketamine for bipolar depression: a systematic review

This review (2021; s=6; n=135) found that ketamine (35mg/70kg; 1-6 doses) achieved a response (>50% reduction) on a score of depression for 61% of those suffering from bipolar depression (BD), compared to 5% for placebo.

Abstract

“Background: Ketamine appears to have a therapeutic role in certain mental disorders, most notably unipolar major depressive disorder. However, the efficacy in bipolar depression is less clear.

Objectives: This study aimed to assess the efficacy and tolerability of ketamine for bipolar depression.

Methods: We conducted a systematic review of experimental studies using ketamine for the treatment of bipolar depression. We searched PubMed, MEDLINE, Embase, PsycINFO, and the Cochrane Central Register for relevant studies published since database inception. We synthesized evidence regarding efficacy (improvement in depression rating scores) and tolerability (adverse events, dissociation, dropouts) across studies.

Findings: We identified six studies, with 135 participants (53% female, 44.7 years, SD 11.7 years). All studies used 0.5 mg/kg of add-on intravenous racemic ketamine, with the number of doses ranging from one to six; all participants continued a mood-stabilizing agent. The overall proportion achieving a response (defined as those having a reduction in their baseline depression severity of at least 50%) was 61% for those receiving ketamine and 5% for those receiving a placebo. The overall response rates varied from 52% to 80% across studies. Ketamine was reasonably well-tolerated; however, two participants (one receiving ketamine and one receiving placebo) developed manic symptoms. Some participants developed significant dissociative symptoms at the 40-minute mark following ketamine infusion in two trials.

Conclusions: There is some preliminary evidence for intravenous racemic ketamine to treat adults with bipolar depression. There is a need for additional studies exploring longer-term outcomes and alterative formulations of ketamine.”

Authors: Anees Bahji, Carlos A. Zarate & Gustavo H. Vazquez

Summary

Ketamine appears to be effective in treating unipolar major depressive disorder, but not bipolar depression.

Introduction

Treatment-resistant bipolar depression (TRBD) is widespread but remains understudied. Only a few trials have indicated a role for electroconvulsive therapy and repetitive transcranial magnetic stimulation, but there is more limited evidence for use of medication-based treatments in TRBD.

Ketamine is being used to treat unipolar depression. It has been shown to have rapid, potent reductions in depressive symptoms following administration of a single sub-anesthetic dose of intravenous racemic ketamine. While ketamine appears to be effective for unipolar depression, it is unclear whether it is also effective for bipolar depression. Ketamine has also led to many preclinical and biomarker discoveries, leading to new possibilities and safer alternatives for mitigating dissociation.

Although more RCTs are needed to explore the efficacy and safety of ketamine in the treatment of TRBD, previous reviews should be updated.

Eligibility Criteria

We included randomized controlled trials and nonrandomized studies examining the use of ketamine in adults with bipolar depression. We excluded observational designs, reviews, post hoc and secondary analyses, commentaries, and clinical overviews.

Information Sources and Search

We searched MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for studies on ketamine and bipolar depression.

Data Collection Process and Data Items

Two co-authors extracted data from studies using a pre-piloted, standardized data extraction tool in Microsoft Excel 2016. They contacted authors for additional information where data were missing.

Risk of Bias in Individual Studies

We assessed the risk of bias in individual trials using the Cochrane risk of bias tool.

Study Selection

The search strategy identified 2494 records. After removing duplicates and screening the remaining 1972 unique articles, 6 studies met the final inclusion criteria.

Characteristics of Studies, Participants, and Interventions

Three studies were randomized controlled trials and three were open-label, single-arm studies. Most studies were from the United States or Poland and had 135 participants.

All 6 studies used add-on racemic ketamine at a dose of 0.5 mg/kg delivered intravenously, and all participants continued treatment with a primary mood-stabilizing agent throughout ketamine treatment.

Efficacy of Intravenous, Racemic Ketamine for Bipolar Depression

Across all 6 studies, 61% of subjects receiving ketamine at some point during the trial achieved a response. The overall response rate varied from 52% to 80%, and improvements in depression rating scores over time were seen in all studies.

Tolerability of Intravenous, Racemic Ketamine for Bipolar Depression

Across most included studies, participants tolerated ketamine treatment reasonably well. However, 2 participants developed manic symptoms and 2 participants developed significant dissociative symptoms.

Study Quality and Risk of Bias

Three studies were double-blind, randomized, controlled trials with concealed allocation, while the remaining 3 were nonrandomized, open-label, single-arm studies.

Discussion

This systematic review indicates that ketamine may be an effective and relatively safe treatment for BD and TRBD, when used as an add-on treatment to primary mood-stabilizing medications.

In a previous meta-analysis, intravenous ketamine had no significant difference in the clinical response between patients with unipolar major depression and bipolar depression. However, there are no available studies on intranasal esketamine for bipolar disorder, and more research is needed to determine its role in bipolar disorder.

Most trials indicate that ketamine is reasonably well tolerated for bipolar depression treatment, with the exception of 2 trials where participants developed significant dissociative symptoms. There is also the concern that ketamine may induce rapid cycling to a manic or hypomanic episode.

There is a real necessity to discover and add more effective and safer treatments for patients with TRBD. Esketamine was approved by the US Food and Drug Administration for use in TRBD on March 5, 2019, and by Europe on December 19, 2019.

Limitations

Although this review has several strengths, there are a few fundamental limitations. These include the inability to conduct a meta-analysis given the low study yield, the possibility of publication bias, and the lack of information regarding long-term follow-up after ketamine treatment administration.

Conclusions

Ketamine is an innovative, rapidly acting, experimental treatment for bipolar depression. While it has demonstrated significant short-term benefits, the long-term benefits remain insufficiently explored, which may contribute to the current lack of Food and Drug Administration approval for use in individuals with bipolar disorder.

Statement of Interest

C.A.Z. is listed as a coinventor on several patents for the use of hydroxynorketamines in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorder.