This meta-analysis (41 studies; 5 at 6-weeks post-treatment) found ketamine to be effective up to 6 weeks later when ketamine was used for the treatment of depressive episodes (MDD, bipolar). The effects found, at all three follow-up points, were large (g = -1.28 to -1.36).

Abstract

“Rationale: Major depressive episodes are severe mood episodes which occur both in major depressive disorder and bipolar I and II disorder. Major depressive episodes are characterized by debilitating symptoms that often persist and interfere with typical daily functioning. Various treatments exist for major depressive episodes; however, most primary pharmacologic treatments may take weeks to months to provide relief from depressive symptoms. Ketamine is a demonstrated treatment for major depressive episodes, as relief from depressive symptoms can occur rapidly following treatment.

Objectives: Prior meta-analyses have been conducted to analyze the effectiveness of ketamine for the treatment of major depressive episodes, but at the time of this writing, no meta-analysis had been conducted to observe ketamine treatment efficacy beyond 2 weeks.

Methods: The present meta-analysis evaluated the efficacy of ketamine for the treatment of major depressive episodes; observations of depressive episode severity were analyzed at 2, 4, and 6-weeks post-treatment.

Results: The present meta-analysis observed large effects at 2 weeks (g = -1.28), 4 weeks, (g = -1.28), and 6 weeks (g = -1.36) post-treatment.

Conclusions: The results from the present meta-analysis indicate that ketamine can be an effective pharmacologic intervention for major depressive episodes, with treatment effects lasting up to 6 weeks post-ketamine administration, which has many positive implications for treatment.“

Authors: Ashley A. Conley, Amber E. Q. Norwood, Thomas C. Hatvany, James D. Griffith, Kathryn E. Barber

Summary

Major depressive episodes occur in both major depressive disorder and bipolar I.

Major depressive episodes are debilitating mood episodes that significantly affect daily functioning and overall quality of life in individuals with major depressive disorder (MDD) and bipolar I and II disorder. Ketamine, a traditional dissociative anesthetic, has shown promise in the treatment of major depressive episodes.

Current treatments for major depressive episodes

Different treatment approaches are utilized for patients with major depressive episodes, including evidence-based psychotherapy, electroconvulsive therapy, and a wide variety of pharmacologic treatments.

The treatment of depressive symptoms with monoamine neurotransmitters has led to the development of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and norepinephrine and dopamine reuptake inhibitors (NDRIs). However, these treatments may take weeks to months to resolve symptoms.

Ketamine for major depressive episodes

Ketamine is increasingly being explored as a pharmacologic intervention for major depressive episodes. Ketamine acts on excitatory and inhibitory systems and has been found to alleviate depressive symptoms at subanesthetic doses.

Ketamine has several routes of administration, including intravenous, subcutaneous, intramuscular, transdermal, intranasal, intrarectal, and oral. It is typically administered over the course of 40 min when administered intravenously, and the most common dosage is 0.5 mg/kg.

When ketamine is administered intravenously for the treatment of depressive symptoms, either a psychiatrist or anesthesiologist is present. Vital signs are routinely observed during treatment, and anxiety during ketamine treatment may be a predictor of treatment outcome.

Ketamine may be used to treat major depressive episodes. Several researchers hypothesized that repeated ketamine administrations extend the duration of effects, although symptoms have been observed to return 18 – 19 days following treatment.

Ketamine may be administered alone or as an adjunctive treatment for depression. Ketamine may also be used to enhance current pharmacologic treatments, such as escitalopram, by alleviating symptoms faster than an antidepressant alone.

Ketamine has been evaluated for the relief of depressive symptoms with single and repeated infusions. Often, patients are administered ketamine several times a week for several weeks.

Prior meta-analyses

Several meta-analyses have been conducted to examine the efficacy of ketamine for the treatment of depressive episodes. The largest and most robust effect sizes were observed 24 h post-treatment, while small to moderate effect sizes were observed 1 week post-treatment.

Xu et al. (2016) examined the efficacy of ketamine at various doses in individuals with MDD and bipolar disorder, and demonstrated that low-dose administrations were most effective at decreasing depression severity and suicidality.

The present meta-analysis

The present meta-analysis evaluated the efficacy of ketamine for major depressive episodes beyond 2 weeks by examining treatment effects at 2, 4, and 6 weeks post-ketamine treatment. Ketamine is emerging as a promising treatment for severe depressive episodes.

Literature search strategies

A comprehensive search was conducted within PsycINFO, MEDLINE, ClinicalTrials.gov, PubMed, and Embase databases up to December 2019. Two independent observers performed the search, and all discrepancies were mediated by a third observer.

Eligibility criteria

Studies evaluating ketamine for major depressive episodes were included if they met the following criteria: they were written in English, they assessed symptoms at 2, 4, or 6 weeks following treatment cessation, and they were randomized or open-label.

Coding procedures

Sample characteristics included sample size, mean age, and gender (% female). Ketamine was administered as a primary treatment for major depressive episode or as an adjunctive treatment, and at low and high dosages.

Ketamine is used to treat depression. The results are measured by changes in depression symptoms between treatment groups and between treatment and control groups.

After article collection, diagnoses were coded according to how patients were diagnosed in each study. However, some studies did not provide the number of patients within each diagnosis group.

Statistical analyses

Ketamine’s effect size was computed using RStudio statistical software and interpreted as small (0.2), medium (0.5), or large (0.8).

To assess statistical heterogeneity across studies, the Q statistic was calculated and the I2 index was computed. The I2 index was interpreted as low, moderate, or high, depending on the result.

A meta-regression and subgroup analyses were conducted to examine the effect of moderating variables. The Q statistic was used to evaluate heterogeneity within and between subgroups.

Publication bias was addressed by plotting the standard error of each study against each study effect size, and Egger’s regression intercept was conducted to assess for asymmetry.

Missing data were imputed using multiple datasets, with results reported from all studies with necessary outcome data first, and then from studies where multiple imputation was used to replace missing mean depression score values.

Results

Studies were selected from searches conducted in PsycINFO, MEDLINE, ClinicalTrials.gov, PubMed, and Embase databases. A total of 41 studies were included in the meta-analysis, and the characteristics of these studies are presented in Table 2.

Two-week measurement

Ketamine had a large effect size for the treatment of major depressive episodes at 2 weeks, with significant high heterogeneity.

The effect size of the different study designs was different for each moderator. The effect size was larger for high dosage, six treatments per week, and open label studies.

Four-week measurement

Ketamine’s effect size was large at 4 weeks, with significant high heterogeneity. Egger’s regression test yielded a non-significant result for publication bias.

Subgroup analyses revealed that sample comparison was a significant moderator. Studies using within-subjects comparisons had a larger effect size than studies using between-subjects comparisons.

Six-week measurement

Ketamine’s effect size was large at the 6-week measurement, with significant high heterogeneity. Egger’s regression test could not be completed because of an insufficient number of studies.

Results indicated that younger ages were associated with larger effect sizes, and that studies using the HDRS had a larger effect size than studies using the MADRS.

Discussion

Ketamine is not without risks, but its ability to provide immediate and sustained symptom relief has made it an intervention of great interest, particularly for individuals with treatment resistant depression.

The present meta-analysis examined the efficacy of ketamine for the treatment of major depressive episodes at 2, 4, and 6-weeks post-treatment. It found that ketamine was effective at 2, 4, and 6-weeks post-treatment, and that its effects were sustained beyond 2 weeks.

Moderator analyses

Subgroup analyses revealed several significant moderators at the 2-week measurement, including treatment length, dosage, treatments per week, and study design. However, the trend of lower effect sizes for shorter treatment lengths may be of interest to examine more in depth in future studies.

Studies that administered ketamine in the high dosage range had larger effect sizes than those studies that administered ketamine in the low dosage range. This finding confirms that the standard dosages of ketamine appear to produce a greater reduction in depressive symptoms.

Previous subgroup analyses have demonstrated that repeated ketamine infusions have larger effect sizes than single infusions, and that more ketamine treatments per week result in longer-lasting antidepressant effects. The present meta-analysis also demonstrated that more ketamine treatments per week result in greater efficacy.

Study design may be a significant moderator of the relationship between ketamine and depressive symptom reduction. Open label studies may have a greater decrease in depressive symptoms than randomized controlled trials.

Sample comparison was the only variable observed to have significant moderating effects at the 4-week measurement.

At the 6-week measurement, the HDRS was associated with larger effect sizes compared to the MADRS. However, there were a low number of studies in each subgroup for this measurement, so the extent to which this finding is meaningful is unclear.

The results of a meta-analysis revealed that younger patients had greater decreases in depressive symptoms following treatment with ketamine than older patients. However, Dore et al. (2019) found that ketamine-assisted psychotherapy was particularly effective for older patients.

At 2-weeks, most significant moderating variables were clinical in nature, such as dosage, treatment length, and number of treatments per week. At 4-weeks and 6-weeks, study-related variables were significant moderators, such as sample comparison and primary outcome measure.

Limitations

The results of this meta-analysis should be interpreted with caution, as some subgroups included a minimal number of studies and missing data may have inflated effect sizes. Multiple imputation was conducted on this data, although it was not presented in the results or discussion sections.

The generalizability of these findings with respect to moderators should be interpreted with caution, as consistent significant moderators across the three time intervals did not show consistent patterns.

The present meta-analysis included only articles that reported the exact percentage of participants with each diagnosis. Therefore, we were unable to analyze the difference across specific diagnoses that include major depressive episodes.

Conclusion

Although a number of evidence-based interventions are available for treating depressive symptomatology, it is important to continue to work toward innovation. Ketamine assisted psychotherapy is an intervention approach with great potential, particularly for those with severe depressive symptoms.

The present meta-analysis demonstrates that ketamine is an effective treatment for lasting antidepressant effects of up to 6-weeks post-treatment, granting patients more time to find and engage with additional long-term treatment strategies, such as evidence-based psychotherapy.