You are here

  • Home
  • Archive
  • Volume 33, Issue 3
  • Effects of ketamine in electroconvulsive therapy for major depressive disorder: meta-analysis of randomised controlled trials

Article Text

Article menu

Download PDFPDF

Meta-analysis
Effects of ketamine in electroconvulsive therapy for major depressive disorder: meta-analysis of randomised controlled trials
  1. Xiao-Mei Li1,
  2. Zhan-Ming Shi2,
  3. Pei-Jia Wang1 and
  4. Hua Hu1
  1. 1Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
  2. 2Department of Psychiatry, Chongqing Jiangbei Mental Health Center, Chongqing, China
  1. Correspondence to Dr Hua Hu; huhuateam{at}hotmail.com

Abstract

Background The use of ketamine in electroconvulsive therapy (ECT) has been examined in the treatment of major depressive disorder (MDD); however, there has been no systematic review and meta-analysis of related randomised controlled trials (RCTs).

Aim To examine the efficacy and safety of ketamine augmentation of ECT in MDD treatment.

Methods Two reviewers searched Chinese (China National Knowledge Infrastructure and Wanfang) and English (PubMed, PsycINFO, Embase and Cochrane Library) databases from their inception to 23 July 2019. The included studies' bias risk was evaluated using the Cochrane risk of bias assessment tool. The primary outcome of this meta-analysis was improved depressive symptoms at day 1 after a single ECT treatment session. Data were pooled to calculate the standardised mean difference and risk ratio with their 95% CIs using RevMan V.5.3. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to assess the whole quality of evidence.

Results Four RCTs (n = 239) compared ketamine alone or ketamine plus propofol (n = 149) versus propofol alone (n = 90) in patients with MDD who underwent a single ECT session. Three RCTs were considered as unclear risk with respect to random sequence generation using the Cochrane risk of bias. Compared with propofol alone, ketamine alone and the combination of ketamine and propofol had greater efficacy in the treatment of depressive symptoms at days 1, 3 and 7 after a single ECT session. Moreover, compared with propofol alone, ketamine alone and the combination of ketamine and propofol were significantly associated with increased seizure duration and seizure energy index. Compared with propofol, ketamine alone was significantly associated with increased opening-eye time. Based on the GRADE approach, the evidence level of primary and secondary outcomes ranged from very low (26.7%, 4/15) to ‘low’ (73.3%, 11/15).

Conclusion Compared with propofol, there were very low or low evidence levels showing that ketamine alone and the combination of ketamine and propofol appeared to rapidly improve depressive symptoms of patients with MDD undergoing a single ECT session. There is a need for high-quality RCTs.

  • ketamine
  • propofol
  • electroconvulsive therapy
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gpsych-2019-100117

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Electroconvulsive therapy (ECT), which is also known as electroshock therapy, is an effective treatment procedure for major mental disorders, including schizophrenia, bipolar disorder and major depressive disorder (MDD).1 General anaesthesia renders unconscious patients free from muscle paralysis and/or even recall and is wildly applied to all ECT procedures in clinical practice.2 Duration of seizure activity, recovery and haemodynamic parameters could be affected by the choice of anaesthetic agent for ECT. Thus, there is a need to determine the optimal choice of anaesthetic agent for ECT from several agents, including ketamine, propofol, etomidate, sevoflurane, ethohexital and thiopental.3

    Ketamine is an N-methyl-D-aspartate (NMDA) antagonist with a rapid antidepressant effect.4 5 Despite its risk of potential adverse drug reactions (ADRs),6 increasing randomised controlled trials (RCTs) have reported that ketamine was significantly superior to placebo in reducing depressive symptoms in patients with unipolar or bipolar depression.7–11 Ketamine is often used in ECT and can cause a favourable seizure outcome by inducing action and increasing seizure duration.12 13 However, ketamine could cause delayed recovery, as well as induce transitory psychotic episodes and cardiotoxicity.14

    Given the correlation of propofol with reasonable haemodynamic response to ECT, it has become increasingly popular in ECT anaesthesia.15 However, propofol has limitations with respect to reduced seizure duration and increased seizure threshold.16 The combination of ketamine and propofol has been successfully employed for various anaesthetic procedures.2 This could be attributed to the following: (1) ketamine can mitigate propofol-related hypotension and (2) propofol can mitigate ketamine-induced recovery agitation and vomiting. Thus, the use of the combination of propofol and ketamine has theoretical benefits, including obviating the need for opioid coadministration and minimising the propofol dose.

    There have been several RCTs12 17–19 on the use of ketamine alone or ketamine plus propofol in a single ECT treatment session for patients with MDD; however, they have reported inconsistent findings. A recent meta-analysis of seventeen RCTs found that ketamine alone did not increase the antidepressant ECT effect; moreover, ketamine combined with other anaesthetics has a short-term advantage with respect to improvement of depressive symptoms at the early ECT stages20. These findings are consistent with those of another meta-analysis.21 However, this meta-analysis20 did not include RCTs with a single ECT session.12 17–19 Notably, there has been no systematic review or meta-analysis exclusively investigating the effectiveness and safety of adjunctive ketamine with single ECT treatment in patients with MDD. Thus, we aimed to perform a meta-analysis to examine the effectiveness and safety of ketamine alone and that of ketamine combined with propofol in patients with MDD undergoing a single ECT treatment.

    Methods

    Search strategy

    This meta-analysis was conducted in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist.22 As recommended by recent meta-analyses,23 24 English (PubMed, Embase, PsycINFO and Cochrane Library databases) and Chinese (China National Knowledge Infrastructure and Wanfang database) databases were independently searched by two reviewers (X-ML and Z-MS) on the same day to retrieve studies published in Chinese and English journals from their inception to 23 July 2019 using the following search strategy: (‘depression’(MeSH) OR depressive OR depressed OR depression) AND (‘electroconvulsive therapy’(MeSH) OR ECT OR electroconvulsive therapy) AND (NMDA OR ketamine OR glutamat*OR N-methyl-D-aspartic acid) AND (‘propofol’(MeSH) OR propofol). Reference lists of the retrieved trials,20 25–28 relevant reviews and meta-analyses were manually searched to obtain missing RCTs.

    Eligibility criteria

    The inclusion criteria were as per the following PICOS acronym: participants: patients with MDD diagnosed using any criteria; intervention versus comparison: (1) ketamine alone versus propofol alone in ECT and (2) ketamine + propofol versus propofol alone in ECT; outcomes: the primary outcome was the improvement of depressive symptoms at day 1 after a single ECT treatment measured using standardised rating scales (including the Montgomery and Asberg Depression Rating Scale29 30 or the Hamilton Depression Rating Scale (HAMD)).31 32 As recommended by a previous meta-analysis, HAMD was preferred to other scales in studies using multiple rating scales.27 Key secondary outcomes were (1) improvement of depressive symptom at days 3 and 7 after a single ECT session; (2) the improvement of suicide ideation; (3) seizure duration and recovery times, and (4) ADRs. Study design: only RCT with a single ECT session. Studies with multiple ECT sessions (≥2 times) were excluded.33–46 Observational studies, conference articles, case report/series and meta-analyses and systematic reviews were excluded. Moreover, multiple-intervention studies, including ECT combined with acupuncture or Chinese herbal medicine, were excluded.

    Data extraction

    Two reviewers (X-ML and Z-MS) independently extracted and checked data. During the data extraction process, disagreements were resolved through discussion and consensus or with the involvement of a senior reviewer (HH). Study authors were contacted by email or telephone to obtain more meta-analysable data. The WebPlotDigitizer V.4.1 (https://automeris.io/WebPlotDigitizer/) was used to extract data from figures and/or graphs of the included RCTs as described by a recent meta-analysis.47 Missing SDs were calculated from test statistics or using the mean (SD) of the remaining studies.48 Three RCTs12 17 18 with three treatment arms compared propofol with ketamine alone and with ketamine combined with propofol, separately. We included propofol arms twice in the aforementioned respective analyses and used half of the number of patients in the propofol arms.49

    Statistical methods

    Two reviewers (X-ML and Z-MS) independently analysed data of the included RCTs using the Review Manager V.5.3 (http://www.cochrane.org) based on the PRISMA statement.50 Standardised mean differences (SMDs) with their 95% CIs and risk ratios (RRs) with its 95% CIs were calculated. SMD values over 0.8, 0.5–0.8 and 0.2–0.5 represented large, medium and small effect sizes, respectively.51 All meta-analysable outcomes were pooled using a random effects model.52 The Q statistics and I2 were used to assess between-study heterogeneity with a p value of <0.1 in Q test and I2 of ≥50% indicating significant heterogeneity.53 In case of a p value of <0.1 or I2 of ≥50% for the improvement of depressive symptoms at day 1 after a single ECT session, a sensitive analysis was conducted to examine the robustness of meta-analytic results after excluding an outlying study (SMD≤−3.50).17 Funnel plots and Egger’s test54 were applied to investigate the possibility of publication bias. All meta-analysable primary and secondary outcomes were considered significant with alpha set at 0.05 (two-sided).

    Quality assessment of each included study

    Two reviewers (X-ML and Z-MS) independently conducted quality assessment of each included study using the Cochrane risk of bias55 and the Jadad scale (range = 0–5).56 The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system57 58 was applied to examine the overall evidence levels for all meta-analytical outcomes.

    Results

    Search results

    We identified 209 hits from the aforementioned databases (figure 1); among them, 58 duplicates were removed. Subsequently, 151 articles were screened for titles and abstracts with 136 reports being excluded according to the inclusion and exclusion criteria. Next, 15 full texts were examined with 11 articles being excluded as follows: an S-ketamine study (one trial), multiple ECT sessions (seven trials), a case report (one trial) and conference articles (two trials). Finally, four RCTs with a single ECT session were included in this meta-analysis.12 17–19

    Figure 1
    Figure 1

    Flowchart of the literature screening.

    Study characteristics

    Four RCTs (n = 239), which compared ketamine alone or ketamine plus propofol (n = 149) versus propofol alone (n = 90), were included.

    Ketamine versus propofol

    Four RCTs (n = 178) compared ketamine alone (n = 88) versus propofol (n = 90). The mean age was 48 (range: 41–55) years in two studies with available data; moreover, 44.8% of the participants (range: 36.7%–51.9%) in three studies with available data were men. None of the studies reported the mean duration of illness (table 1).

    View this table:
    Table 1

    Summary of studies included in this meta-analysis

    Ketamin+propofol versus propofol

    Three RCTs (n = 122) compared ketamine+propofol (n = 61) with propofol (n = 61). Only one study with available data reported the mean age (56.5 years); moreover, 39.8% of the participants (range: 36.7%–42.9%) were men in two studies with available data. None of the studies reported the mean illness duration (table 1).

    Quality assessment

    In the Cochrane risk of bias (online supplementary figure 1), three RCTs (75%, 3/4) were judged as unclear risk with respect to random sequence generation. The Jadad scores ranged from 1 to 3 (mean = 2.0) with only one RCT (25%) being considered as high quality (table 1). Online supplementary table 1 summarises the overall evidence level for all meta-analytic primary and secondary measures, which ranges from very low (26.7%, 4/15) to ‘low’ (73.3%, 11/15).

    Supplemental material

    Primary outcomes

    Ketamine alone was superior to propofol with regard to the improvement of depressive symptoms at days 1 (SMD: −2.37, 95% CI −4.50 to −0.25, I2 = 90%, p = 0.03; large effect size), 3 (SMD: −3.94, 95% CI −5.08 to −2.79, I2 = 0%, p < 0.001; large effect size) and 7 (SMD: −2.98, 95% CI −3.94 to −2.01, I2 = 0%, p < 0.001; large effect size) after a single ECT session (figure 2). After excluding an outlying study (SMD≤−3.59),17 the significant difference disappeared (SMD: −1.88, 95% CI −4.49 to 0.74, I2 = 92%, p = 0.16).

    Figure 2
    Figure 2

    The ketamine group versus the propofol group: forest plot for depressive symptoms at days 1, 3 and 7 after a single electroconvulsive therapy session.

    Similarly, the combination of ketamine and propofol was superior to propofol with regard to the improvement of depressive symptoms at days 1 (SMD: −2.99, 95% CI −3.94 to −2.04, I2 = 0%, p<0.001; large effect size), 3 (SMD: −3.87, 95% CI −4.97 to −2.77, I2 = 0%, p<0.001; large effect size) and 7 (SMD: −3.08, 95% CI −4.04 to −2.11, I2 = 0%, p < 0.001; large effect size) after a single ECT session (figure 3). None of the studies examined the relationship between ketamine used in ECT and suicide ideation.

    Figure 3
    Figure 3

    Combination of the ketamine and propofol group versus the propofol group: forest plot for depressive symptoms at days 1, 3 and 7 after a single electroconvulsive therapy session.

    Secondary outcomes

    As shown in table 2, ketamine alone was significantly associated with increased seizure duration (SMD: −2.11, 95% CI 1.54 to 2.67, I2=0%, p<0.001; large effect size), seizure energy index (SMD: −1.74, 95% CI 0.97 to 2.51, I2=0%, p<0.001; large effect size) and eye-opening time (SMD: 2.73, 95% CI 1.53 to 3.94, I2=64%, p<0.001; large effect size) compared with propofol.

    View this table:
    Table 2

    Secondary outcomes

    Similarly, ketamine combined with propofol was significantly associated with increased seizure duration (SMD: −2.11, 95% CI 0.55 to 3.67, I2=84%, p=0.008; large effect size) and seizure energy index (SMD: −1.71, 95% CI 0.95 to 2.47, I2=0%, p<0.001; large effect size) compared with propofol. There was no group difference in the eye-opening time (SMD: 1.78, 95% CI −0.31 to 3.86, I2=88%, p=0.09; large effect size).

    There was no significant difference regarding hypertension between propofol and ketamine alone (p=0.51) and between propofol and ketamine combined with propofol (p=0.65). There was no group difference regarding nausea and vomiting between ketamine and propofol alone (p=0.78) (table 2).

    Publication bias

    Publication bias was not evaluated for all outcomes because a minimum of 10 RCTs are needed to perform funnel plot or Egger’s test.59

    Discussion

    Main findings

    This is the first meta-analysis to examine the effectiveness and safety of ketamine alone or ketamine combined with propofol in patients with MDD undergoing a single ECT session. Ketamine alone and ketamine combined with propofol were more efficacious than propofol alone as an ECT anaesthesia in treating depressive symptoms at days 1, 3 and 7 after a single ECT session with large effect size.51 However, the significant superiority of ketamine to propofol alone in improving depressive symptoms was driven by an outlying study.17 Compared with propofol, ketamine alone and the combination of ketamine and propofol significantly increased the seizure duration and seizure energy index. Furthermore, ketamine alone, but not ketamine combined with propofol, could significantly increase opening-eye time compared with propofol. However, a recent study found that ketamine as an anaesthetic did not enhance the antidepressant effects of six ECT treatments.45

    Limitations

    This study has several limitations. Firstly, the number of included RCTs and sample size of each included RCT were relatively small, which impeded more comprehensive analyses, including subgroup and meta-regression analyses. Secondly, the significant heterogeneity in the meta-analytic findings for the primary outcome could be partly attributed to each included study with differences in methodological characteristics, including the dosage of propofol and ketamine, electrode placements and patient property. Further, future studies should compare between single and multiple ECT sessions for MDD. Finally, none of the RCTs reported randomisation methods with a specific description as measured by the Cochrane risk of bias; moreover, three RCTs (75%, 3/4) were rated as low quality as measured by the Jadad scale. Furthermore, quality of evidence for all meta-analytic outcomes was considered as ‘very low’ or low according to the GRADE approach. However, as suggested by Guyatt et al.,60 low-quality evidence could still lead to strong recommendations.

    Implications

    We found that ECT-treated patients with MDD receiving ketamine plus propofol or ketamine alone had more significant improvements in depressive symptoms compared with patients receiving propofol alone. This suggests that ketamine alone or the combination of ketamine and propofol as an ECT anaesthesia has an early and rapid antidepressant effect superior to that of propofol anaesthesia, which was consistent with the findings of previous meta-analyses indicating that ketamine has rapid antidepressant effects.9

    Two previous meta-analyses20 21 reported that ketamine used in ECT did not reduce the depressive symptoms at the end of the treatment; however, it could accelerate the antidepressive effects in depressive patients undergoing ECT. Thus, ketamine use in ECT has considerable clinical significance because the delayed onset of antidepressant effects is closely associated with prolonged severe morbidity suicide risk.61 However, none of the included RCTs assessed the antisuicidal effects of ketamine used in ECT. The incidence of hypertension was similar in the ketamine group and ketamine combined with the propofol group compared with the propofol group. Thus, the use of ketamine and ketamine combined with propofol is safe and tolerable.

    As expected, there were significant difference regarding the seizure activity duration and the seizure energy index between propofol and ketamine alone, and ketamine combined with propofol. Interestingly, the combination of ketamine and propofol group was not associated with longer mean eye-opening time compared with the propofol group. Thus, the use of ketamine plus propofol as an ECT anaesthesia might be advantageous for analgesia and haemodynamic stability.12 Notably, ketamine-related nauseant and psychomimetic effects could be counterbalanced by the sedative and antiemetic effects of propofol. Given the potential balance of effects, the combination of ketamine and propofol as an ECT anaesthesia is superior to either agent alone.12

    Conclusion

    According to very low or low evidence level, compared with propofol alone, ketamine alone and the combination of ketamine and propofol have an advantage in rapidly improving depressive symptoms of patients with MDD undergoing a single ECT session. Due to significant heterogeneity and small sample size, high-quality RCTs are required to confirm and extend these findings.

    Acknowledgments

    We thank Wei Zheng, MD, PhD, Department of Psychiatry, the Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China, for his edits to this work.

    References

    1. ↵
      1. Petrides G,
      2. Fink M,
      3. Husain MM, et al
      . Ect remission rates in psychotic versus nonpsychotic depressed patients: a report from core. J Ect 2001;17:244–53.doi:10.1097/00124509-200112000-00003pmid:http://www.ncbi.nlm.nih.gov/pubmed/11731725
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Green SM,
      2. Andolfatto G,
      3. Krauss B
      . Ketofol for procedural sedation? pro and con. Ann Emerg Med 2011;57:444–8.doi:10.1016/j.annemergmed.2010.12.009pmid:http://www.ncbi.nlm.nih.gov/pubmed/21237532
      OpenUrlCrossRefPubMed
    3. ↵
      1. Hooten WM,
      2. Rasmussen KG
      . Effects of general anesthetic agents in adults receiving electroconvulsive therapy: a systematic review. J Ect 2008;24:208–23.doi:10.1097/YCT.0b013e31815bfe2apmid:http://www.ncbi.nlm.nih.gov/pubmed/18628717
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. McGirr A,
      2. Berlim MT,
      3. Bond DJ, et al
      . A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med 2015;45:693–704.doi:10.1017/S0033291714001603pmid:http://www.ncbi.nlm.nih.gov/pubmed/25010396
      OpenUrlCrossRefPubMed
    5. ↵
      1. Zheng W,
      2. Zhou Y-L,
      3. Liu W-J, et al
      . Investigation of medical effect of multiple ketamine infusions on patients with major depressive disorder. J Psychopharmacol 2019;33:494–501.doi:10.1177/0269881119827811pmid:http://www.ncbi.nlm.nih.gov/pubmed/30789302
      OpenUrlPubMed
    6. ↵
      1. Strayer RJ,
      2. Nelson LS
      . Adverse events associated with ketamine for procedural sedation in adults. Am J Emerg Med 2008;26:985–1028.doi:10.1016/j.ajem.2007.12.005pmid:http://www.ncbi.nlm.nih.gov/pubmed/19091264
      OpenUrlCrossRefPubMed
    7. ↵
      1. Parsaik AK,
      2. Singh B,
      3. Khosh-Chashm D, et al
      . Efficacy of ketamine in bipolar depression: systematic review and meta-analysis. J Psychiatr Pract 2015;21:427–35.doi:10.1097/PRA.0000000000000106pmid:http://www.ncbi.nlm.nih.gov/pubmed/26554325
      OpenUrlPubMed
    8. ↵
      1. Han Y,
      2. Chen J,
      3. Zou D, et al
      . Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatr Dis Treat 2016;12:2859–67.doi:10.2147/NDT.S117146pmid:http://www.ncbi.nlm.nih.gov/pubmed/27843321
      OpenUrlPubMed
    9. ↵
      1. Kishimoto T,
      2. Chawla JM,
      3. Hagi K, et al
      . Single-Dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med 2016;46:1459–72.doi:10.1017/S0033291716000064pmid:http://www.ncbi.nlm.nih.gov/pubmed/26867988
      OpenUrlCrossRefPubMed
    10. ↵
      1. Xu Y,
      2. Hackett M,
      3. Carter G, et al
      . Effects of low-dose and very low-dose ketamine among patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol 2016;19:pyv124.doi:10.1093/ijnp/pyv124pmid:http://www.ncbi.nlm.nih.gov/pubmed/26578082
      OpenUrlCrossRefPubMed
    11. ↵
      1. Wilkinson ST,
      2. Ballard ED,
      3. Bloch MH, et al
      . The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry 2018;175:150–8.doi:10.1176/appi.ajp.2017.17040472pmid:http://www.ncbi.nlm.nih.gov/pubmed/28969441
      OpenUrlPubMed
    12. ↵
      1. Yalcin S,
      2. Aydoğan H,
      3. Selek S, et al
      . Ketofol in electroconvulsive therapy anesthesia: two stones for one bird. J Anesth 2012;26:562–7.doi:10.1007/s00540-012-1378-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/22623080
      OpenUrlPubMed
    13. ↵
      1. Finnegan M,
      2. Galligan T,
      3. Ryan K, et al
      . Ketamine versus midazolam for depression relapse prevention following successful electroconvulsive therapy: a randomized controlled pilot trial. J Ect 2019;35:115–21.doi:10.1097/YCT.0000000000000560pmid:http://www.ncbi.nlm.nih.gov/pubmed/30531397
      OpenUrlPubMed
    14. ↵
      1. Rasmussen KG,
      2. Jarvis MR,
      3. Zorumski CF
      . Ketamine anesthesia in electroconvulsive therapy. Convuls Ther 1996;12:217–23.pmid:http://www.ncbi.nlm.nih.gov/pubmed/9034696
      OpenUrlPubMedWeb of Science
    15. ↵
      1. Patel AS,
      2. Gorst-Unsworth C,
      3. Venn RM, et al
      . Anesthesia and electroconvulsive therapy: a retrospective study comparing etomidate and propofol. J Ect 2006;22:179–83.doi:10.1097/01.yct.0000230362.96615.d9pmid:http://www.ncbi.nlm.nih.gov/pubmed/16957533
      OpenUrlPubMed
    16. ↵
      1. Mitchell P,
      2. Torda T,
      3. Hickie I, et al
      . Propofol as an anaesthetic agent for ECT: effect on outcome and length of course. Aust N Z J Psychiatry 1991;25:255–61.doi:10.3109/00048679109077742pmid:http://www.ncbi.nlm.nih.gov/pubmed/1877962
      OpenUrlCrossRefPubMed
    17. ↵
      1. Wang X,
      2. Chen Y,
      3. Zhou X, et al
      . Effects of propofol and ketamine as combined anesthesia for electroconvulsive therapy in patients with depressive disorder. J Ect 2012;28:128–32.doi:10.1097/YCT.0b013e31824d1d02pmid:http://www.ncbi.nlm.nih.gov/pubmed/22622291
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. XM X,
      2. JB H,
      3. Chen Y, et al
      . Effects of propofol and ketamine administration in electroconvulsive therapy for patients with major depressive disorder (in Chinese). China health care & nutrition 2013;23:7597–8.
      OpenUrl
    19. ↵
      1. Zhao HZ,
      2. Li H,
      3. Cui EL
      . A comparative study of intraocular pressure and depression reducing score in depression patients undergoing MECT with different anesthetics (in Chinese). Chinese Journal of Practical Medicine 2016;43:61–3.
      OpenUrl
    20. ↵
      1. Zheng W,
      2. Li X-H,
      3. Zhu X-M, et al
      . Adjunctive ketamine and electroconvulsive therapy for major depressive disorder: a meta-analysis of randomized controlled trials. J Affect Disord 2019;250:123–31.doi:10.1016/j.jad.2019.02.044pmid:http://www.ncbi.nlm.nih.gov/pubmed/30852364
      OpenUrlPubMed
    21. ↵
      1. Ren L,
      2. Deng J,
      3. Min S, et al
      . Ketamine in electroconvulsive therapy for depressive disorder: a systematic review and meta-analysis. J Psychiatr Res 2018;104:144–56.doi:10.1016/j.jpsychires.2018.07.003pmid:http://www.ncbi.nlm.nih.gov/pubmed/30077114
      OpenUrlPubMed
    22. ↵
      1. Moher D,
      2. Liberati A,
      3. Tetzlaff J, et al
      . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.. In: BMJ (Clinical research ed). 339, 2009: b2535.
      OpenUrlFREE Full Text
    23. ↵
      1. Zheng W,
      2. Cai D-B,
      3. Yang X-H, et al
      . Adjunctive aripiprazole for antipsychotic-related hyperprolactinaemia in patients with first-episode schizophrenia: a meta-analysis. Gen Psychiatr 2019;32:e100091.doi:10.1136/gpsych-2019-100091pmid:http://www.ncbi.nlm.nih.gov/pubmed/31673677
      OpenUrlPubMed
    24. ↵
      1. Zheng W,
      2. Zhu X-M,
      3. Zhang Q-E, et al
      . Adjunctive minocycline for major mental disorders: a systematic review. J Psychopharmacol 2019;33:1215–26.doi:10.1177/0269881119858286pmid:http://www.ncbi.nlm.nih.gov/pubmed/31294649
      OpenUrlPubMed
    25. ↵
      1. McGirr A,
      2. Berlim MT,
      3. Bond DJ, et al
      . A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: efficacy and tolerability. J Psychiatr Res 2015;62:23–30.doi:10.1016/j.jpsychires.2015.01.003pmid:http://www.ncbi.nlm.nih.gov/pubmed/25684151
      OpenUrlCrossRefPubMed
    26. ↵
      1. Fond G,
      2. Bennabi D,
      3. Haffen E, et al
      . A Bayesian framework systematic review and meta-analysis of anesthetic agents effectiveness/tolerability profile in electroconvulsive therapy for major depression. Sci Rep 2016;6:19847.doi:10.1038/srep19847pmid:http://www.ncbi.nlm.nih.gov/pubmed/26806849
      OpenUrlPubMed
    27. ↵
      1. Li D-J,
      2. Wang F-C,
      3. Chu C-S, et al
      . Significant treatment effect of add-on ketamine anesthesia in electroconvulsive therapy in depressive patients: a meta-analysis. Eur Neuropsychopharmacol 2017;27:29–41.doi:10.1016/j.euroneuro.2016.11.008pmid:http://www.ncbi.nlm.nih.gov/pubmed/27908572
      OpenUrlPubMed
    28. ↵
      1. McGirr A,
      2. Berlim MT,
      3. Bond DJ, et al
      . Adjunctive ketamine in electroconvulsive therapy: updated systematic review and meta-analysis. Br J Psychiatry 2017;210:403–7.doi:10.1192/bjp.bp.116.195826pmid:http://www.ncbi.nlm.nih.gov/pubmed/28385704
      OpenUrlAbstract/FREE Full Text
    29. ↵
      1. Montgomery SA,
      2. Asberg M
      . A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382–9.doi:10.1192/bjp.134.4.382pmid:http://www.ncbi.nlm.nih.gov/pubmed/444788
      OpenUrlAbstract/FREE Full Text
    30. ↵
      1. Zhong BL,
      2. Wang Y,
      3. Chen HH, et al
      . Reliability, validity and sensitivity of Montgomery-Åsberg Depression Rating Scale for patients with current major depressive disorder [in Chinese]. Chinese Journal of Behavioural Medicine and Brain Sciences 2011;20:85–7.
      OpenUrl
    31. ↵
      1. Hamilton M
      . A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62.doi:10.1136/jnnp.23.1.56pmid:http://www.ncbi.nlm.nih.gov/pubmed/14399272
      OpenUrlFREE Full Text
    32. ↵
      1. G. R X,
      2. Shen QJ
      . Use of the Chinese version of the Hamilton rating scale for depression in general population and patients with major depression (in Chinese). Chinese Journal of Nervous and Mental Diseases 1984;10:364.
      OpenUrl
    33. ↵
      1. Abdallah CG,
      2. Fasula M,
      3. Kelmendi B, et al
      . Rapid antidepressant effect of ketamine in the electroconvulsive therapy setting. J Ect 2012;28:157–61.doi:10.1097/YCT.0b013e31824f8296pmid:http://www.ncbi.nlm.nih.gov/pubmed/22847373
      OpenUrlCrossRefPubMedWeb of Science
    34. ↵
      1. Loo CK,
      2. Katalinic N,
      3. Garfield JBB, et al
      . Neuropsychological and mood effects of ketamine in electroconvulsive therapy: a randomised controlled trial. J Affect Disord 2012;142:233–40.doi:10.1016/j.jad.2012.04.032pmid:http://www.ncbi.nlm.nih.gov/pubmed/22858219
      OpenUrlCrossRefPubMed
    35. ↵
      1. Yoosefi A,
      2. Sepehri AS,
      3. Kargar M, et al
      . Comparing effects of ketamine and thiopental administration during electroconvulsive therapy in patients with major depressive disorder: a randomized, double-blind study. J Ect 2014;30:15–21.doi:10.1097/YCT.0b013e3182a4b4c6pmid:http://www.ncbi.nlm.nih.gov/pubmed/24091902
      OpenUrlPubMed
    36. ↵
      1. Erdil F,
      2. Begeç Z,
      3. Kayhan GE, et al
      . Effects of sevoflurane or ketamine on the QTc interval during electroconvulsive therapy. J Anesth 2015;29:180–5.doi:10.1007/s00540-014-1899-2pmid:http://www.ncbi.nlm.nih.gov/pubmed/25085036
      OpenUrlPubMed
    37. ↵
      1. Erdil F,
      2. Ozgul U,
      3. Çolak C, et al
      . Effect of the addition of ketamine to sevoflurane anesthesia on seizure duration in electroconvulsive therapy. J Ect 2015;31:182–5.doi:10.1097/YCT.0000000000000225pmid:http://www.ncbi.nlm.nih.gov/pubmed/25719444
      OpenUrlPubMed
    38. ↵
      1. Kuşçu Özlem Özkan,
      2. Karacaer F,
      3. Biricik E, et al
      . Effect of ketamine, thiopental and ketamine-thiopental combination during electroconvulsive therapy for depression. Turk J Anaesthesiol Reanim 2015;43:313–7.doi:10.5152/TJAR.2015.92668pmid:http://www.ncbi.nlm.nih.gov/pubmed/27366520
      OpenUrlPubMed
    39. ↵
      1. Salehi B,
      2. Mohammadbeigi A,
      3. Kamali AR, et al
      . Impact comparison of ketamine and sodium thiopental on anesthesia during electroconvulsive therapy in major depression patients with drug-resistant; a double-blind randomized clinical trial. Ann Card Anaesth 2015;18:486–90.doi:10.4103/0971-9784.166444pmid:http://www.ncbi.nlm.nih.gov/pubmed/26440233
      OpenUrlPubMed
    40. ↵
      1. Shams Alizadeh N,
      2. Maroufi A,
      3. Nasseri K, et al
      . Antidepressant effect of combined ketamine and electroconvulsive therapy on patients with major depressive disorder: a randomized trial. Iran J Psychiatry Behav Sci 2015;9:e1578.doi:10.17795/ijpbs-1578pmid:http://www.ncbi.nlm.nih.gov/pubmed/26576166
      OpenUrlPubMed
    41. ↵
      1. Rybakowski JK,
      2. Bodnar A,
      3. Krzywotulski M, et al
      . Ketamine anesthesia, efficacy of electroconvulsive therapy, and cognitive functions in treatment-resistant depression. J Ect 2016;32:164–8.doi:10.1097/YCT.0000000000000317pmid:http://www.ncbi.nlm.nih.gov/pubmed/27008330
      OpenUrlPubMed
    42. ↵
      1. Zhong X,
      2. He H,
      3. Zhang C, et al
      . Mood and neuropsychological effects of different doses of ketamine in electroconvulsive therapy for treatment-resistant depression. Available: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/791/CN-01158791/frame.html;
    43. ↵
      1. Anderson IM,
      2. Blamire A,
      3. Branton T, et al
      . Ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT): a multicentre, double-blind, randomised, parallel-group, superiority trial. Lancet Psychiatry 2017;4:365–77.doi:10.1016/S2215-0366(17)30077-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/28359862
      OpenUrlPubMed
    44. ↵
      1. Chen Q,
      2. Min S,
      3. Hao X, et al
      . Effect of low dose of ketamine on learning memory function in patients undergoing electroconvulsive therapy-a randomized, double-blind, controlled clinical study. J Ect 2017;33:89–95.doi:10.1097/YCT.0000000000000365pmid:http://www.ncbi.nlm.nih.gov/pubmed/27828927
      OpenUrlPubMed
    45. ↵
      1. Fernie G,
      2. Currie J,
      3. Perrin JS, et al
      . Ketamine as the anaesthetic for electroconvulsive therapy: the KANECT randomised controlled trial. Br J Psychiatry 2017;210:422–8.doi:10.1192/bjp.bp.116.189134pmid:http://www.ncbi.nlm.nih.gov/pubmed/28254962
      OpenUrlAbstract/FREE Full Text
    46. ↵
      1. Ray-Griffith SL,
      2. Eads LA,
      3. Han X, et al
      . A randomized pilot study comparing ketamine and methohexital anesthesia for electroconvulsive therapy in patients with depression. J Ect 2017;33:268–71.doi:10.1097/YCT.0000000000000413pmid:http://www.ncbi.nlm.nih.gov/pubmed/28422805
      OpenUrlPubMed
    47. ↵
      1. Zheng W,
      2. Cai D-B,
      3. Zheng W, et al
      . Brexanolone for postpartum depression: a meta-analysis of randomized controlled studies. Psychiatry Res 2019;279:83–9.doi:10.1016/j.psychres.2019.07.006pmid:http://www.ncbi.nlm.nih.gov/pubmed/31323375
      OpenUrlPubMed
    48. ↵
      1. Furukawa TA,
      2. Barbui C,
      3. Cipriani A, et al
      . Imputing missing standard deviations in meta-analyses can provide accurate results. J Clin Epidemiol 2006;59:7–10.doi:10.1016/j.jclinepi.2005.06.006pmid:http://www.ncbi.nlm.nih.gov/pubmed/16360555
      OpenUrlCrossRefPubMedWeb of Science
    49. ↵
      1. Higgins J,
      2. Green S
      . Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available: www.cochrane-handbook.org
    50. ↵
      1. Zheng W,
      2. Cai D-B,
      3. Li H-Y, et al
      . Adjunctive Peony-Glycyrrhiza decoction for antipsychotic-induced hyperprolactinaemia: a meta-analysis of randomised controlled trials. Gen Psychiatr 2018;31:e100003.doi:10.1136/gpsych-2018-100003pmid:http://www.ncbi.nlm.nih.gov/pubmed/30582119
      OpenUrlPubMed
    51. ↵
      1. Cohen J
      . Statistical power analysis for the behavioral sciences. 2nd edn. Hillsdale: Lawrence Erlbaum Associates, 1988.
    52. ↵
      1. DerSimonian R,
      2. Laird N
      . Meta-Analysis in clinical trials. Control Clin Trials 1986;7:177–88.doi:10.1016/0197-2456(86)90046-2pmid:http://www.ncbi.nlm.nih.gov/pubmed/3802833
      OpenUrlCrossRefPubMedWeb of Science
    53. ↵
      1. Higgins JPT,
      2. Thompson SG,
      3. Deeks JJ, et al
      . Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60.doi:10.1136/bmj.327.7414.557pmid:http://www.ncbi.nlm.nih.gov/pubmed/12958120
      OpenUrlFREE Full Text
    54. ↵
      1. Egger M,
      2. Davey Smith G,
      3. Schneider M, et al
      . Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.doi:10.1136/bmj.315.7109.629pmid:http://www.ncbi.nlm.nih.gov/pubmed/9310563
      OpenUrlAbstract/FREE Full Text
    55. ↵
      1. Higgins J,
      2. Higgins J P
      . Cochrane Handbook for systematic reviews of interventions. John Wiley & Sons, 2008.
    56. ↵
      1. Jadad AR,
      2. Moore RA,
      3. Carroll D, et al
      . Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12.doi:10.1016/0197-2456(95)00134-4pmid:http://www.ncbi.nlm.nih.gov/pubmed/8721797
      OpenUrlCrossRefPubMedWeb of Science
    57. ↵
      1. Balshem H,
      2. Helfand M,
      3. Schünemann HJ, et al
      . Grade guidelines: 3. rating the quality of evidence. J Clin Epidemiol 2011;64:401–6.doi:10.1016/j.jclinepi.2010.07.015pmid:http://www.ncbi.nlm.nih.gov/pubmed/21208779
      OpenUrlCrossRefPubMedWeb of Science
    58. ↵
      1. Atkins D,
      2. Best D,
      3. Briss PA, et al
      . Grading quality of evidence and strength of recommendations. BMJ 2004;328:1490.doi:10.1136/bmj.328.7454.1490pmid:http://www.ncbi.nlm.nih.gov/pubmed/15205295
      OpenUrlAbstract/FREE Full Text
    59. ↵
      ed)Sterne JAC, Sutton AJ, Ioannidis JPA, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.. In: Bmj (clinical research. 343, 2011: d4002.doi:10.1136/bmj.d4002
      OpenUrl
    60. ↵
      1. Guyatt GH,
      2. Oxman AD,
      3. Vist GE, et al
      . Grade: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924–6.doi:10.1136/bmj.39489.470347.ADpmid:http://www.ncbi.nlm.nih.gov/pubmed/18436948
      OpenUrlFREE Full Text
    61. ↵
      1. Jick H,
      2. Kaye JA,
      3. Jick SS
      . Antidepressants and the risk of suicidal behaviors. JAMA 2004;292:338–43.doi:10.1001/jama.292.3.338pmid:http://www.ncbi.nlm.nih.gov/pubmed/15265848
      OpenUrlCrossRefPubMedWeb of Science

    Xiaomei Li obtained a Bachelor’s degree from Chongqing Medical University in 2015 and a Master's degree in psychiatry and mental health from Chongqing Medical University in 2019. Her main research interest includes major depressive disorder.


    Embedded Image

    Footnotes

    • Contributors X-ML and Z-MS selected the studies, conducted the statistical analysis, extracted the data and wrote the first draft. HH reviewed all the data and helped mediate disagreements. HH and P-JW made critical revisions. All the authors contributed to the interpretation of data and approved the final manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement No additional unpublished data are sharing.