The use of ketamine as an antidepressant: a systematic review and meta-analysis

This meta-analysis (2015; n=437) examined the antidepressant effects of ketamine, with regard to its efficacy over short and long-term periods, across single or repeated infusions, moderating variables related to the experimental design, and efficacy amongst patients with depression (MDD) or bipolar disorder (BD). Results conveyed that ketamine is an effective and rapid treatment for depression in the short term, with large antidepressant effects emerging after 4 hours and lasting up to 2 weeks post-infusion in participants with a primary diagnosis of MDD or BD. Repeated infusion showed larger effect sizes but did not extend the duration of antidepressant effect.

Abstract

Objective: The current meta‐analysis examines the effects of ketamine infusion on depressive symptoms over time in major depressive disorder (MDD) and bipolar disorder (BD).

Methods: Following a systematic review of the literature, data were extracted from 21 studies (n = 437 receiving ketamine) and analysed at four post‐infusion time points (4 h, 24 h, 7 days and 12–14 days). The moderating effects of several factors were assessed including: repeat/single infusion, diagnosis, open‐label/participant‐blind infusion, pre–post/placebo‐controlled design and the sex of patients.

Results: Effect sizes were significantly larger for repeat than single infusion at 4 h, 24 h and 7 days. For single infusion studies, effect sizes were large and significant at 4 h, 24 h and 7 days. The percentage of males was a predictor of antidepressant response at 7 days. Effect sizes for open‐label and participant‐blind infusions were not significantly different at any time point.

Conclusions: Single ketamine infusions elicit a significant antidepressant effect from 4 h to 7 days; the small number of studies at 12–14 days post infusion failed to reach significance. Results suggest a discrepancy in peak response time depending upon primary diagnosis — 24 h for MDD and 7 days for BD. The majority of published studies have used pre–post comparison; further placebo‐controlled studies would help to clarify the effect of ketamine over time.”

Authors: Caoimhe M. Coyle & Keith R. Laws

Summary

Ketamine is an N-methyl-D-aspartate antagonist that acts on glutamate, a major excitatory neurotransmitter in the brain, to elicit antidepressant effects. Ketamine is administered intravenously and the effects are sustained beyond the 3h half-life.

Use of ketamine to treat depression in bipolar disorder

Ketamine has been reported to alleviate depressive symptoms in treatment-resistant bipolar depression. The effects of ketamine were observed within 40min post infusion and for up to 3days, but then returned to baseline levels at day 14.

Safety, efficacy and durability of repeated ketamine infusions

Ketamine infusions appear to be short lived, but repeated infusions may increase the duration of antidepressant response. The majority of participants who received multiple ketamine infusions relapsed within 30 days, but one participant showed decreased depressive symptoms for over 3months.

The durability of response to repeated ketamine infusions in individuals with treatment-resistant depression was recently investigated in a larger treatment group (n =24). Overall, 71% of participants responded to ketamine, but the duration of antidepressant effect may not extend much beyond that of a single infusion.

Rasmussen et al. (2013) conducted an open-label study with ketamine to determine if serial infusions elicited better response and remission rates than single infusions. However, only 20% of the participants maintained symptom remission at the end of the follow-up period.

Objectives of the current study

The authors will examine the effect of ketamine on depressive symptoms, including the immediate effect, the antidepressant effect sustained over time, and the effect of ketamine depending upon the sex of the patient.

Identification and selection of studies

The review was conducted in accordance with PRISMA guidelines and included all trials of ketamine for the treatment of depression conducted from 2000 to January 2015.

Criteria for inclusion of studies

Studies involving ketamine for depression were included if they reported on depressive symptoms using a standardised measure of depression and included eight or more participants.

Data extraction

Data were extracted from studies meeting the criteria outlined earlier, and effect sizes were calculated using Hedge’s g. Cohen’s convention was used to describe effect sizes, and an effect size of 0.20 was considered small, 0.50 moderate and 0.80 large.

Statistical heterogeneity

We assessed heterogeneity using the I2 value, which suggests that there may be moderate heterogeneity, substantial heterogeneity or considerable heterogeneity.

Risk of bias

Studies involved in the meta-analysis were assessed for possible bias. Studies with a low risk of bias employed a control group, demonstrated adequate randomisation of participants to control and experimental groups, and had no evidence of conflict of interest.

Effects of moderators

A meta-regression was conducted to examine the effects of several factors on effect size.

Identification and selection of studies

There were 21 studies on single infusion, of which 17 were single infusion studies. The majority of studies collected and reported data at 4h and 24h post infusion.

Overall pooled effect sizes

Overall, pooled Hedge’s g values were large and significant at all time points, and there were no significant differences in effect sizes between any time points.

Single infusion: moderating effect of experimental design

For pre-post design, the effect sizes were large and significant at all post-infusion time points, but for placebo-controlled design, the effect sizes were small and significant at 4h, 24h and 7days post infusion.

Single infusion: effect of sex

A meta-regression was conducted with percentage of males as a predictor of effect size. A significant positive relationship was determined at 7days, but only four data points were available.

Single infusion: publication bias

Publication bias was detected in all single infusion studies at 4h and 24h.

The results of the meta-analysis suggest that ketamine reduces depressive symptoms with large effect sizes at every time point analysed. The effect size is sustained at least up to 2weeks post infusion, and differs significantly at different time points.

Moderating effects of diagnosis

Although the effect sizes were moderate to large, some differences emerged in responsiveness. The effect size for MDD was significantly larger than for BD at 24h and 7days.

Moderating effects of experimental design

Studies using pre – post comparisons to compare treatment results to placebo results showed larger effect sizes, but more studies using blind placebo-controlled designs are required to confirm these findings.

As might be expected, open-label trials had larger effect sizes than participant-blind trials, although the difference reached significance at 12 – 14days. Further interpretations are required, including expectancy bias and the possibility that the psychoactive effects of ketamine influence its efficacy through psychological mechanisms.

To ensure blindness to ketamine, all open-label trials must use a pre-post design. This prevents confounding, and therefore we cannot eliminate experimental design differences as the cause of the discrepancy in effect sizes.

Effect of sex

At 7days post infusion, a significant effect of sex was found, but not at any other time point. This finding is not consistent with the higher sensitivity of female rats to a low dose of ketamine.

Limitations of the current meta-analysis

The main limitation of this meta-analysis is the relatively small number of studies with useable data. The reported relapse rates have varied across studies, with some participants continuing to meet response criteria for up to 32days.

Mathew et al. (2010) found that patients receiving ketamine infusion maintained an antidepressant response for 32 days. However, this group is highly selective and thus the results may be inflated.

Ketamine’s antidepressant effects may extend beyond 14days, but most studies report effects only up to 24h. Furthermore, two of the repeat infusion studies used in this meta-analysis selected participants who had previously responded to ketamine, so the effect might not be found outside of this highly selective group.

The results of this meta-analysis indicate that ketamine has a 14-day duration of effect after a single infusion, and 18-19days after a series of six infusions.

Although previous experience of ketamine was used as an exclusion criterion in some trials, others included patients who had participated in previous ketamine trials. The effect sizes of ketamine in different studies were quite different. Studies using participants who have already shown a large, albeit temporary, symptomatic reduction to ketamine use pre-post designs, and are primed to produce significant effects.

The future of ketamine as a treatment for depression

Our meta-analysis reveals that peak time differences in elicited response according to primary diagnosis may affect the antidepressant outcome of ketamine infusion. This requires further investigation, and randomised control trials are needed to establish the safety, efficacy and durability of response of single and of repeated ketamine infusions.

Ketamine has been used as an anaesthetic since the 1960s, but repeated exposure to the drug causes sensitisation and increased risk of dissociative, delusional and depressive symptoms. Ketamine infusions for depression have been shown to have rapid antidepressant effects, but the addictive potential of repeated ketamine exposure must be addressed. Additionally, many studies have documented the dissociative effects of ketamine in participants, as well as increased, if somewhat mild, psychotomimetic experiences.

Mine may be well placed in situations where an immediate alleviation of depressive symptoms is required, but it does not work on everyone. Several studies have reported response rates of around 40% at 4h post infusion, while some have reported response rates of approximately 60 – 70% between 4h and 24h following ketamine infusion. The disparity in response rates highlights the need for future studies incorporating larger samples.

The present meta-analysis has established ketamine as an effective treatment for depression in the short term, but more controlled studies are necessary to determine whether it can be used as an emergency treatment or as a longer-term treatment.

Study details

Compounds studied
Ketamine

Topics studied
Depression Bipolar Disorder

Study characteristics
Meta-Analysis Literature Review

Participants
437

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