Citation

Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A. Cochrane Database Syst. Rev. 2021; 2021(9).

Copyright

(Copyright © 2021, The Cochrane Collaboration, Publisher John Wiley and Sons)

DOI

10.1002/14651858.CD011612.pub3

PMID

unavailable

Abstract

BACKGROUND: Many studies have recently been conducted to assess the antidepressant efficacy of glutamate modification in mood disorders. This is an update of a review first published in 2015 focusing on the use of glutamate receptor modulators in unipolar depression.

OBJECTIVES: To assess the effects - and review the acceptability and tolerability - of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with unipolar major depressive disorder. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020. We did not apply any restrictions to date, language or publication status. Selection criteria: Double- or single-blinded randomised controlled trials (RCTs) comparing ketamine, memantine, esketamine or other glutamate receptor modulators with placebo (pill or saline infusion), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression. Data collection and analysis: Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes were response rate (50% reduction on a standardised rating scale) and adverse events. We decided a priori to measure the efficacy outcomes at different time points and run sensitivity/subgroup analyses. Risk of bias was assessed using the Cochrane tool, and certainty of the evidence was assessed using GRADE. Main results: Thirty-one new studies were identified for inclusion in this updated review. Overall, we included 64 studies (5299 participants) on ketamine (31 trials), esketamine (9), memantine (5), lanicemine (4), D-cycloserine (2), Org26576 (2), riluzole (2), atomoxetine (1), basimglurant (1), citicoline (1), CP-101,606 (1), decoglurant (1), MK-0657 (1), N-acetylcysteine (1), rapastinel (1), and sarcosine (1). Forty-eight studies were placebo-controlled, and 48 were two-arm studies. The majority of trials defined an inclusion criterion for the severity of depressive symptoms at baseline: 29 at least moderate depression; 17 severe depression; and five mild-to-moderate depression. Nineteen studies recruited only patients with treatment-resistant depression, defined as inadequate response to at least two antidepressants. The majority of studies investigating ketamine administered as a single dose, whilst all of the included esketamine studies used a multiple dose regimen (most frequently twice a week for four weeks). Most studies looking at ketamine used intravenous administration, whilst the majority of esketamine trials used intranasal routes. The evidence suggests that ketamine may result in an increase in response and remission compared with placebo at 24 hours odds ratio (OR) 3.94, 95% confidence interval (CI) 1.54 to 10.10; n = 185, studies = 7, very low-certainty evidence). Ketamine may reduce depression rating scale scores over placebo at 24 hours, but the evidence is very uncertain (standardised mean difference (SMD) -0.87, 95% CI -1.26 to -0.48; n = 231, studies = 8, very low-certainty evidence). There was no difference in the number of participants assigned to ketamine or placebo who dropped out for any reason (OR 1.25, 95% CI 0.19 to 8.28; n = 201, studies = 6, very low-certainty evidence). When compared with midazolam, the evidence showed that ketamine increases remission rates at 24 hours (OR 2.21, 95% CI 0.67 to 7.32; n = 122,studies = 2, low-certainty evidence). The evidence is very uncertain about the response efficacy of ketamine at 24 hours in comparison with midazolam, and its ability to reduce depression rating scale scores at the same time point (OR 2.48, 95% CI 1.00 to 6.18; n = 296, studies = 4,very low-certainty evidence). There was no difference in the number of participants who dropped out of studies for any reason between ketamine and placebo (OR 0.33, 95% CI 0.05 to 2.09; n = 72, studies = 1, low-certainty evidence). Esketamine treatment likely results in a large increase in participants achieving remission at 24 hours compared with placebo (OR 2.74, 95% CI 1.71 to 4.40; n = 894, studies = 5, moderate-certainty evidence). Esketamine probably results in decreases in depression rating scale scores at 24 hours compared with placebo (SMD -0.31, 95% CI -0.45 to -0.17; n = 824, studies = 4, moderate-certainty evidence). Our findings show that esketamine increased response rates, although this evidence is uncertain (OR 2.11, 95% CI 1.20 to 3.68; n = 1071, studies = 5, low-certainty evidence). There was no evidence that participants assigned to esketamine treatment dropped out of trials more frequently than those assigned to placebo for any reason (OR 1.58, 95% CI 0.92 to 2.73; n = 773, studies = 4,moderate-certainty evidence). We found very little evidence for the remaining glutamate receptor modulators. We rated the risk of bias as low or unclear for most domains, though lack of detail regarding masking of treatment in the studies reduced our certainty in the effect for all outcomes. Authors' conclusions: Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear. The evidence for use of the remaining glutamate receptor modulators is limited as very few trials were included in the meta-analyses for each comparison and the majority of comparisons included only one study. Long term non-inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real-world monitoring are needed to establish comprehensive data on safety and efficacy. Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Language: en

Keywords

human; systematic review; quality of life; insomnia; abdominal pain; ketamine; suicidal ideation; depression; aggression; suicide attempt; major depression; disease severity; dissociative disorder; mood disorder; emotional disorder; migraine; fatigue; vomiting; mental disease; sexual dysfunction; citalopram; sedation; tachycardia; xerostomia; hallucination; headache; somnolence; vertigo; anxiety disorder; sleep disorder; drowsiness; constipation; electroconvulsive therapy; influenza; hot flush; delusion; edema; confusion; drug safety; placebo; backache; diarrhea; drug tolerability; nausea; tremor; restlessness; disease exacerbation; irritability; dysphagia; delirium; mania; rash; hypertension; neurologic disease; hypomania; sensitivity analysis; evidence based medicine; heart rate; infection; agitation; asthenia; dystonia; heart arrhythmia; arthralgia; myalgia; pruritus; tinnitus; skin irritation; indigestion; acetylcysteine; gastrointestinal disease; musculoskeletal disease; drug response; midazolam; remission; mental instability; flatulence; concentration loss; dyspnea; coughing; sleep walking; propofol; heart palpitation; paresthesia; thorax pain; psychological rating scale; dyspepsia; malaise; cycloserine; pneumothorax; motor dysfunction; diplopia; dizziness; increased appetite; lethargy; diabetic ketoacidosis; polydipsia; mouth ulcer; euphoria; neuropathy; memory disorder; libido disorder; atomoxetine; tic; dyskinesia; Article; unconsciousness; thiopental; abdominal discomfort; dry skin; chill; coordination disorder; skin disease; hyperhidrosis; methohexital; upper respiratory tract infection; blurred vision; gait disorder; muscle cramp; connective tissue disease; genital system disease; nose obstruction; riluzole; dysmenorrhea; micturition disorder; citicoline; sore throat; eye irritation; decreased appetite; skin defect; abnormal dreaming; pericardial effusion; tooth disease; memantine; balance disorder; muscle spasm; sensory dysfunction; sleep disordered breathing; rhinopharyngitis; remifentanil; tongue disease; bone pain; limb pain; stomach discomfort; limb weakness; nose disease; traxoprodil; executive function; sarcosine; hypertransaminasemia; otalgia; body weight gain; clinical outcome; loss of appetite; lanicemine; body weight loss; esketamine; tooth abscess; basimglurant; chemosis; decoglurant; excessive dreaming; jaw pain