This review (2015, n=118) found that ketamine showed reliable anti-depressive effects in patients diagnosed with either MDD or bipolar disorder (BD). The duration of effects, however, requires further research.

Abstract

“Introduction: Ketamine’s efficacy in depressive disorders has been established in several controlled trials. The aim of the present study was to determine whether or not ketamine administration significantly improves depressive symptomatology in depression and more specifically in major depressive disorder (MDD), bipolar depression, resistant depression (non-ECT studies), and as an anesthetic agent in electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary outcomes were the duration of ketamine’s effect, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerance of the treatment.

Methods: Studies were included if they met the following criteria (without any language or date restriction): design: randomized controlled trials, intervention: ketamine administration, participants: diagnosis of depression, and evaluation of severity based on a validated scale. We calculated standardized mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We used fixed and random effects models. Heterogeneity was assessed using the I2 statistic.

Results: We included nine non-ECT studies in our quantitative analysis (192 patients with major depressive disorder and 34 patients with bipolar depression). Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups (SMD = −0.99; 95 % CI −1.23, −0.75; p < 0.01). Ketamine’s efficacy was confirmed in MDD (resistant to previous pharmacological treatments or not) (SMD = −0.91; 95 % CI −1.19,−0.64; p < 0.01), in bipolar depression (SMD = −1.34; 95 % CI −1.94, −0.75), and in drug-free patients as well as patients under medication. Four ECT trials (118 patients) were included in our quantitative analysis. One hundred and three patients were diagnosed with major depressive disorder and 15 with bipolar depression. Overall, depression scores were significantly improved in the 58 patients receiving ketamine in ECT anesthesia induction compared to the 60 patients (SMD = −0.56; 95 % CI −1.10, −0.02; p = 0.04; I2 = 52.4 %). The duration of ketamine’s effects was assessed in only two non-ECT studies and seemed to persist for 2–3 days; this result needs to be confirmed. Three of four studies found significant decrease of suicidal thoughts and one found no difference between groups, but suicidal ideations were only studied by the suicide item of the depressive scales. It was not possible to determine a dose effect; 0.5 mg/kg was used in the majority of the studies. Some cardiovascular events were described (mostly transient blood pressure elevation that may require treatment), and ketamine’s use should remain cautious in patients with a cardiovascular history.

Conclusion: The present meta-analysis confirms ketamine’s efficacy in depressive disorders in non-ECT studies, as well as in ECT studies. The results of this first meta-analysis are encouraging, and further studies are warranted to detail efficacy in bipolar disorders and other specific depressed populations. Middle- and long-term efficacy and safety have yet to be explored. Extrapolation should be cautious: Patients included had no history of psychotic episodes and no history of alcohol or substance use disorders, which is not representative of all the depressed patients that may benefit from this therapy.”

Authors: Guillaume Fond, Anderson Loundou, Corentin Rabu, Alexandra Macgregor, Christophe Lançon, Marie Brittner, Jean-Arthur Micoulaud-Franchi, Raphaelle Richieri, Philippe Courtet, Mocrane Abbar, Matthieu Roger, Marion Leboyer & Laurent Boyer

Summary

Abstract

Ketamine’s efficacy in depressive disorders has been established in several controlled trials. The aim of the present study was to determine the duration of ketamine’s effect, and the safety of the treatment.

We included studies if they met the following criteria: randomized controlled trials, ketamine administration, and depression severity assessed using a validated scale.

We included nine non-ECT studies (192 patients with major depressive disorder and 34 patients with bipolar depression) and four ECT trials (118 patients) in our quantitative analysis. Ketamine improved depression scores in MDD, bipolar depression, and drug-free patients as well as patients under medication.

The present meta-analysis confirms ketamine’s efficacy in depressive disorders in non-ECT studies, as well as in ECT studies. Middle- and long-term efficacy and safety have yet to be explored.

Introduction

Major psychiatric disorders such as major depressive disorder and bipolar disorders are among the four most disabling mental, neurological, and substance-use related illnesses worldwide, and ketamine administration may be an effective new therapy. Ketamine, an anesthetic agent with N-methyl-D-aspartic acid receptor (NMDAR) antagonist properties, has been investigated for the treatment of MDD, resistant depression, and bipolar depression, and for the induction of electroconvulsive therapy (ECT) for resistant depression. However, results are inconsistent and some studies are questionable.

Methods

This meta-analysis was based on the PRISMA criteria and searched PubMed, Embase, PsycINFO, BIOSIS, Science Direct, and Cochrane Central databases, as well as unpublished dissertations.

Studies were included if they met the following criteria: randomized controlled trials, ketamine administration, and depression severity.

Two authors independently screened titles and abstracts of databases and retrieved full texts for eligible studies. Data was independently extracted into a standard electronic form, and discrepancies were resolved by consensus with a third reviewer.

We used the Cochrane risk of bias tool to assess studies for selection bias, performance bias, detection bias, and attrition bias.

We classified studies according to their level of evidence using a four-tiered system.

We used fixed effects and random effects models to analyze the differences in mean between depressed patients with ketamine administration and those without. We considered values of I2>50 % as indicative of large heterogeneity.

We used funnel plots, Rosenthal fail-safe N, Egger’s regression intercept and forest plots to estimate risk of bias in ketamine trials and conducted several subgroup and sensitivity analyses to determine the impact of various factors on effect size estimates.

Results

Nine non-ECT studies and four ECT studies were included in the quantitative analysis (Abdallah et al. 2012, Berman et al. 2000, Diazgranadosetal.2010, Ghasemi et al. 2014, Jarventausta et al. 2013; Loo et al. 2012; Murroughetal.2013).

Study characteristics

In four crossover studies, 192 patients with MDD and 34 patients with bipolar depression received ketamine hydrochloride, placebo, midazolam, ECT, or propofol-fentanyl combination as anesthetic agents before surgery.

In all studies, depression was diagnosed using a DSM-IV-based structured interview, and depression scores were assessed using the Hamilton Depression Rating Scale (HDRS) or the Montgomery-Asberg Depression Rating Scale (MADRS) before and after treatment administration.

Global effect of ketamine in non-ECT studies

Overall, patients receiving ketamine had a significantly lower depression score than controls (SMD= 0.99; 95 % CI 1.23, 0.75) (Fig. 2). The efficacy of ketamine remained significant after excluding two studies with high risk of bias (p = 0.01).

Subgroup analyses: ketamine in MDD versus bipolar depression

Six studies included only MDD patients, two included only bipolar depression patients, and one included patients with either MDD or bipolar depression.

Overall, depression scores were significantly improved in the 127 MDD cases and 27 bipolar cases compared to the 112 MDD controls.

Sensitivity analyses

Ketamine was effective in patients who were drug-free and those who were under antidepressant or mood-stabilizing treatment.

Five studies included pharmacological-resistant patients and four studies included patients with depression, independently of the resistance to a previous treatment. Resistance was not always defined as an inclusion criterion, but some studies included patients with persistent depressive symptomatology who may therefore be defined as resistant to pharmacological treatment.

The study design may have an impact on the efficacy of ketamine, but the sensitivity analysis confirms its efficacy.

Study characteristics

118 patients were included in four studies, including 58 cases and 60 controls. Thirty-two patients received a combination of ketamine hydrochloride 0.5 mg/kg and thiopental, 12 patients received ketamine hydrochloride 0.8 mg/kg alone, and 16 patients received S-ketamine 0.4 mg/kg in combination with propofol.

Qualitative analyses

Ketamine administration reduced suicidal ideations and suicide risk in five randomized controlled trials. Suicidal ideations were mostly measured by the suicide item of the depression scales in the non-ECT studies.

Three studies reported a significant decrease of suicidal thoughts in depressed patients after ketamine administration compared to controls. However, one study found no significant effect of ketamine on this item.

In non-ECT studies, depression symptoms were significantly improved as early as 40 min after injection. This effect was maintained for 2 to 3 days.

Adverse events

In non-ECT studies, ketamine administration caused dry mouth, tachycardia, increased blood pressure, and dissociation. In ECT studies, severe cardiovascular events were described only when 0.8 mg/kg ketamine hydrochloride was administered.

Discussion

Ketamine was found to be effective in MDD as well as in bipolar depression. However, only two studies were conducted in bipolar depression, and it was not possible to determine if ketamine was more effective in a specific type of bipolar disorder.

Ketamine was effective in drug-free studies as well as in studies in which patients were under active treatment. It seems recommended as adjunctive treatment in patients treated by antidepressants or mood-stabilizing agents.

Ketamine was effective when resistance to previous pharmacological treatment figured in inclusion criteria, but there are no standardized criteria for establishing resistance to bipolar depression treatments.

Suicidal ideation improvement was found in ketamine-treated patients, but it was not adjusted by global depression improvement.

Ketamine has been used in ECT anesthesia for decades, and preliminary evidence suggests that ketamine anesthesia in ECT may improve seizure duration relative to other anesthetic agents and minimize side effects, particularly cognitive impairment. However, this result should be considered with caution due to the high heterogeneity of studies’ designs. In studies by Abdallah et al., Loo et al., Wang et al., and Jarventausta et al., electric stimulation was used to improve sleep quality.

Ketamine may cause cardiovascular events in patients with cardiovascular disease, and dissociative symptoms may occur even with doses between 0.5 and 1 mg/kg. All patients should have a physical examination, routine hematologic and biochemical tests, urine toxicology measurements, and an ECG before ketamine administration.

Although a comprehensive review of the literature, stringent inclusion criteria, and an examination of potential publication bias were used, only 13 RCTs were included in this meta-analysis. No dose effect could be highlighted, and patients were middle-aged with a long history of mood disorders. In a study by Kudoh et al., depressed patients were administered ketamine for orthopedic surgery, and haloperidol 5 mg was administered for treatment of postoperative confusion.

Ketamine may be effective in the treatment of bipolar depression, but further studies are needed to assess its long-term efficacy.

Conclusion

Ketamine’s efficacy in depressive disorders was confirmed in both non-ECT studies and ECT studies, but further research is needed to determine whether ketamine improves suicidal ideations independently of global depression improvement or not.