Efficacy and Safety of Ketamine-assisted Electroconvulsive Therapy in Major Depressive Episode: A Systematic Review and Network Meta-Analysis

doi:10.21203/rs.3.rs-3182771/v1

Objective: To meta-analyze clinical efficacy and safety of ketamine compared with other anesthetic agents in the course of electroconvulsive therapy (ECT) in major depressive episode (MDE).

Methods: PubMed/MEDLINE, Cochrane Library, Embase, GoogleScholar, and US and European trial registries were searched from inception through May 23, 2023, with no language limits. We included RCTs with (1) a diagnosis of MDE; (2) ECT intervention with ketamine and/or other anesthetic agents; and (3) measures included: depressive symptoms, cognitive performance, remission or response rates, and serious adverse events. Network meta-analysis (NMA) was performed to compare ketamine and 7 other anesthetic agents. Hedges’ g standardized mean differences (SMDs) were used for continuous measures, and relative risks (RRs) were used for other binary outcomes using random-effects models.

Results: Twenty-two studies were included in the systematic review. A total of 2,322 patients from 17 RCTs were included in the NMA. The overall pooled SMD of ketamine, as compared with a propofol reference group, was -2.21 (95% confidence interval [CI], -3.79 to -0.64) in depressive symptoms, indicating that ketamine had better antidepressant efficacy than propofol. In a sensitivity analysis, however, ketamine-treated patients had a worse outcome in cognitive performance than propofol-treated patients (SMD, -0.18; 95% CI, -0.28 to -0.09). No other statistically significant differences were found.

Conclusions: Ketamine-assisted ECT is tolerable and may be efficacious in improving depressive symptoms, but a relative adverse impact on cognition may be an important clinical consideration. Anesthetic agents should be considered based on patient profiles and/or preferences to improve effectiveness and safety of ECT use.

Health sciences/Diseases/Psychiatric disorders/Depression

Biological sciences/Biological techniques

ketamine

electroconvulsive therapy

depression

Major depressive disorder (MDD) is one of the most common and disabling mental health conditions, affecting about 15.7 million adults aged ≥18 years in the US.^1-3 Unfortunately, more than 30% of individuals with MDD do not achieve remission after two or more trials of antidepressants.^4,5 Such treatment-resistant depression (TRD) is associated with premature mortality including suicide,^6-8 reduced functioning and poorer quality of life.^9,10

Electroconvulsive therapy (ECT) is highly effective in treating MDD, with response rates around 70% and remission rates around 50% even in those with TRD.^11,12 Yet, ECT is often considered only after multiple prior treatment failures due in part to provider barriers (e.g., availability of well-trained ECT practitioners and physical space) and patient barriers (e.g., stigma or public attitudes).¹³ Furthermore, ECT has been criticized for adverse cognitive effects even though the risk for these side effects has been reduced by recent procedural changes (e.g., right unilateral ECT with ultra-brief pulse width).¹⁴

Anesthetic techniques have become increasingly refined to improve patient tolerability and safety of ECT.¹⁵ To date, there are multiple anesthetic agents utilized in the delivery of ECT such as: methohexital, thiopental, propofol, diazepam, ketamine, and etomidate. Of these agents, intravenous ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, has gained attention since early 2000s for its rapid-acting antidepressant properties.^16,17 Several studies also have reported that, additionally, ketamine has rapid effects at reducing suicidal ideation in patients with mood disorders.^18-21

Janssen Pharmaceuticals has recently developed and investigated the safety and efficacy of an intranasal (IN) formulation of the S-enantiomer of ketamine (i.e., IN esketamine). Intranasal delivery was chosen as preferable to IV administration to increase patient acceptance and accessibility in a broader range of psychiatric care settings. In March 2019, the US Food and Drug Administration (FDA) approved IN esketamine (Spravato®) as a therapy for TRD in the form of a nasal spray.²² In August 2020, additional data led to a FDA approval for use of Spravato® in MDD with suicidal ideation.^23,24

While ketamine was initially introduced as an anesthetic alternative to phencyclidine (PCP) in the 1960s,^17,25 it is unclear whether use of ketamine as the anesthetic in ECT (i.e., ketamine-assisted ECT) results in better efficacy and safety outcomes when compared to other anesthetic agents. Several studies highlighted the importance of resolving this issue,^26,27 but no study has yet quantified the overall treatment effect sizes of efficacy and safety outcomes between ketamine-assisted ECT and ECT inducted by other anesthetic agents, using a network meta-analysis, which allows multiple treatment comparisons. This study aims to compare anesthetic agents for ECT using a systematic review and network meta-analysis of existing clinical trials.

Search strategy

The protocol pertaining to this study was registered on PROSPERO (CRD42023427295). A systematic search was conducted from dabatase inception to May 23, 2023. The following databases were systematically searched: PubMed/MEDLINE, the Cochrane Library, and Embase using Medical Subject Headings (MeSH) terms and text keywords. We also manually searched all relevant studies in NIH-funded clinical trial registries (https://www.clinicaltrials.gov), European (EU) clinical trial registries (https://www.clinicaltrialsregister.eu), and GoogleScholar (https://scholar.google.com/). No language restrictions were imposed. Search strategies are provided in eTable 1 in the Supplement. This study followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) reporting guidelines.²⁸ Our study used publicly available data and did not include human participant research. As per 45 CFR §46.102(f), this study was not submitted for institutional review board approval and did not require informed consent procedures.

Eligibility criteria and study selection

Inclusion criteria were established prior to article reviews and were as follows: (1) patients with a diagnosis of MDE using standardized diagnostic criteria (e.g., Diagnostic and Statistical Manual of Mental Disorders, fifth Edition [DSM-5] or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]); (2) ECT with intervention/comparator groups consisting of ketamine and other anesthetic agents; and (3) severity of depressive symptoms, cognitive performance, remission rates, or response rates as an efficacy outcome using validated measures (e.g., Montgomery Asberg Depression Rating Scale [MADRS] and Hamilton Depression Rating Scale [HDRS] for depressive symptoms; Montreal cognitive assessment [MOCA] and mini-mental state examination [MMSE] for global measures of cognitive performance); and (4) human-based clinical trials. We also considered safety-related events as secondary outcomes (e.g., reports of serious adverse events). Exclusion criteria were (1) non-human studies and (2) no use of validated measures for MDE or outcomes of interest.

Study identification and data extraction

Titles and abstracts were independently screened by two reviewers (T.G.R. and S.R.S.), and articles identified as potentially relevant by at least one reviewer were retrieved and duplicates were removed. Full-text articles were independently screened by the same reviewers, and discrepancies were resolved through group discussions. Data from included articles were independently extracted by two reviewers (T.G.R. and S.R.S.) using a pilot-tested data extraction form and then corroborated, with discrepancies resolved through group discussions. Information to be extracted was established a priori and included: study characteristics (e.g., PICOTS framework), participant characteristics and subgroups, sample source and collection period, modes of ascertainment, methods of data analysis, selection of cases and controls, and quantitative data pertaining to any primary and secondary outcomes along with adjusted factors. To ensure the absence of overlapping data and to maintain the meta-integrity, data and references for each included study were carefully cross-checked.

Assessment of risk of bias and methodological quality

The risk of bias and methodological quality were evaluated using the Cochrane Collaboration Risk-of-Bias tool version 2.^29,30 We assessed 5 domains, including (1) randomization process, (2) deviations from the intended interventions, (3) missing outcome data, (4) measurement of the outcome, and (5) selection of the reported result. Each domain was classified as being indicative of a high, low, or unclear risk of bias. We used Cochrane Library’s Review Manager software, RevMan version 5.4.1,³¹ to organize extracted information on the risk of bias.

Publication bias is always a concern for evidence synthesis, and we tried to mitigate it by searching prospective trial registries. For analyses with at least 10 trials,³² we used funnel plots to visually explore for evidence of association between trials’ effect sizes and statistical precision.³³ We supplemented visual assessments with statistical testing of funnel plot asymmetry using Egger’s test (i.e., a weighted linear regression of effect size versus precision) and Begg and Mazumdar’s test (i.e., rank correlation test). Evidence of associations between effect sizes and precision across studies may indicate design heterogeneity, chance or selection biases that operate cross the evidence base (e.g., publication and outcome reporting bias).

Statistical analysis

The network meta-analysis (NMA) was performed to compare 7 different anesthetic agents and placebo used in ECT and to assess efficacy and safety in the acute phase of MDE. The NMA is advantageous as it allows multiple comparisons across different agents. In our main NMA, we compared: [1] ketamine versus [2] ketamine+propofol versus [3] propofol versus [4] methohexital versus [5] thiopental versus [6] thiopental+ketamine versus [7] midazolam versus [8] placebo (i.e., thiopental+saline). We also performed two sensitivity analyses that were limited to the most commonly used anesthetic agents: a) comparison among [1] ketamine versus [2] ketamine+propofol versus [3] propofol; and 2) comparison between [1] ketamine versus [2] methohexital. Arm-based analyses were performed to estimate the Hedges’ g standardized mean difference (SMD) of depressive symptoms and cognitive performance. Relative risk (RR) was used for remission and response rates and series adverse events (SAEs).

We conducted NMA analyses using ‘netmeta’ package in R software (version 4.2.2; The R Foundation, Vienna, Austria), which applies a frequentist method based on a graph-theoretical approach in line with the electrical network theory.³⁴ Using arm- and contrast-based models,^34,35 the ‘netmeta’ function takes within-study correlations into account by re-weighting all of each multi-arm study’s comparisons based on back-calculation of variances using the Laplacian matrix and its pseudoinverse.³⁵ Because included studies were deemed to be heterogenous, we applied random-effects models.³⁶

We tested the consistency of each network using split-node and design-decomposition analyses. For each comparison with direct data, the split node approach compares whether the effect from the direct data is concordant with that inferred from indirect-only data. The design-decomposition approach groups trials according to the subset of treatments they compare and assesses the concordance of findings across these groups. In addition, to assist the interpretation of treatment rankings, we estimated the probability that each treatment is among the top performing ones ( ) based on the NMA model, and calculated the surface under the cumulative ranking curve (SUCRA); a higher SUCRA value indicates a potentially better intervention.³⁵

Finally, as mentioned earlier, we assessed publication bias (or small-study effects) using funnel plots;³³ Egger’s test and Begg and Mazumdar’s test were also performed when assessing the publication bias.³³ Unless otherwise noted, a two-sided p-value<0.05 was considered statistically significant.

Characteristics of included studies

The literature search yielded 1,341 articles, of which 338 were duplicates. After screening titles and abstracts, 60 articles were eligible for full-text screening. Two independent investigators (TGR and SRS) discovered one additional study by manually searching clinical trial databases and reference lists. Details of study selection are provided in eFigure 1 in the Supplement. Overall, 22 RCTs^37–58 were included in the systematic review (Table 1). Of these, 17 RCTs consisting of 2,322 patients met selection criteria for quantitative analyses (i.e., 17 for depressive symptoms; 6 for cognitive performance; 9 for remission; 8 for response; and 11 for SAEs). Five studies were not included in the meta-analysis due to a study design⁵³ or insufficient data.^39,43,49,55 All of the included RCTs were conducted in single sites. Seven studies (31.8%) were conducted in the US or Canada, 4 studies (18.2%) were completed in Europe, 10 studies (45.5%) were performed in Asia, and 1 study (4.5%) was completed in Australia. All studies followed RCT designs and 16 of them (72.7%) followed double-blind RCT designs. All studies recruited patients who were ECT candidates. Sample sizes for ECT with ketamine ranged from 7 to 80, and 11 studies (50.0%) also considered bipolar depression in their inclusion criteria. 21 studies (95.5%) had an ECT for 2–3 sessions a week and all studies were completed within a month. Table 1 provides details of characteristics (including frequency and duration of treatment sessions) and summaries of key findings for all included studies.

Table 1

Characteristics of the randomized controlled trials (RCTs) included (N = 22)
Study (Year^a))	Country	Study design	Condition	Ketamine [dose] (n; mean age; % male sex)	Control [dose] (n; mean age; % male sex)	ECT characteristic	Duration^b)	Key finding
Abdallah (2012)	USA	RCT	Unipolar or bipolar depression; No history of psychosis	thiopental + ketamine [3.5mg/kg + 0.5mg/kg] (8; 47.8; 63)	thiopental [3.5mg/kg] (8; 46.5; 50)	3 times/week for 6 sessions; Unilaterally or bilaterally via a SpECTrum 5000 Q	2 weeks	Ketamine did not improve the antidepressant effect of ECT.
Alizadeh (2015)	Iran	Double-blind RCT	Major depressive disorder	propofol + ketamine [1 mg/kg + 0.3 mg/kg] (22; 34.3; 27)	propofol [1 mg/kg] (22; 35.1; 35)	3 times/week for 6 sessions; Bilaterally	2 weeks	No significant difference in depression severity between groups; However, cognitive performance recovery time was lower in the ketamine group.
Altinay (2019)*	USA	Double-blind RCT	Unipolar or bipolar depression; No history of psychosis	ketamine [0.5 mg/kg] (7; 39; 15)	midazolam [0.045 mg/kg] (5; 38; 20)	2–3 times/week; Bilaterally	3 weeks	No significant difference in depression severity between groups; However, the ketamine group showed early remission and maintained euthymia.
Anderson (2017)	UK	Double-blind RCT	Unipolar or bipolar depression	ketamine [0.5 mg/kg] (33; 52.5; 33)	propofol (or thiopental) [n/a] (37; 56.4; 40)	2 times/week; Unilaterally or bilaterally using Thymatron IV or Mecta Spectrum 5000	4 weeks	No evidence to support the use of adjunctive low-dose ketamine in routine ECT treatment.
Brunelin (2020)	France	Double-blind RCT	Unipolar or bipolar depression	propofol + ketamine [n/a + 0.5 mg/kg] (11; 57.3; 64)	propofol + placebo [n/a] (16; 59.6; 56)	2 times/week; Unilaterally or bilaterally via a SpECTrum 5000Q	4 weeks	No evidence to support the use of the combination of ketamine and propofol as an anesthetic agent for ECT.
Carspecken (2018)	USA	Double-blind RCT	Unipolar or bipolar depression	ketamine [1–2 mg/kg] (23; 47; 89)	methohexital [1–2 mg/kg] (27; 47; 89)	3 times/week; Unilaterally or bilaterally	2–4 weeks	Ketamine does not significantly improve depression when compared with methohexital.
Chen (2020)*	China	Double-blind RCT	Major depressive disorder; No history of psychosis	propofol + ketamine [1.5 mg/kg + 0.3 mg/kg] (63; 40.9; 33)	propofol [1.5 mg/kg] (64; 37.4; 36)	3 times/week for 12 sessions; Bilaterally	4 weeks	No significant differences were found in the overall response, remission and relapse rates between the groups.
Dong (2019)	China	Double-blind RCT	Major depressive disorder; No history of psychosis	propofol + ketamine [1-1.5 mg/kg + 0.3 mg/kg] (43; 36.8; 42)	propofol [1-1.5 mg/kg] (45; 35.7; 49)	3 times/week for 6–15 sessions; Bilaterally using Thymatron System Ⅳ	2–5 weeks	Ketamine-assisted ECT achieved a higher remission rate.
Fernie (2017)	UK	Double-blind RCT	Unipolar or bipolar depression	ketamine [up to 2 mg/kg] (16; 51.8; 56)	propofol [up to 2.5 mg/kg] (17; 49.9; 53)	2 times/week; Bilaterally using a brief pulse constant current apparatus (Thymatron DGx)	3–4 weeks	Ketamine as an anesthetic does not enhance the efficacy of ECT.
Gamble (2018)	Canada	Double-blind RCT	Major depressive disorder	ketamine [0.75 mg/kg] (12; 42; 50)	propofol [1 mg/kg] (12; 46; 50)	8 sessions; Unilaterally or bilaterally	3–4 weeks	ketamine-based anesthesia, compared with propofol-based anesthesia, provided response and remission after fewer ECT sessions.
Jarventausta (2013)	Finland	RCT	Major depressive disorder	propofol + ketamine [n/a + 0.4 mg/kg] (16; 48.8; 50)	propofol [n/a] (16; 53.7; 31)	6 sessions; Unilaterally or bilaterally	2–3 weeks	Adjuvant dose of S-ketamine with propofol may not increase the effects of ECT in patients with treatment-resistant depression.
Loo (2012)	Australia	Double-blind RCT	Unipolar or bipolar depression	ketamine [0.5 mg/kg] (22; 45.2; 50)	placebo [n/a] (24; 41.4; 29)	3 times/week for 6 sessions; Unilaterally using a Mecta Spectrum 5000	2 weeks	Ketamine did not decrease cognitive impairment, but was safe and slightly improved efficacy in the first week of treatment and at one-week follow up.
Okamoto (2010)*	Japan	Double-blind RCT	Major depressive disorder	ketamine [0.75 mg/kg] (11; 59.3; 45)	propofol [1 mg/kg] (20; 55.1; 50)	2 times/week for 8 sessions; n/a	4 weeks	It is possible to improve symptoms of depression earlier by using ketamine anesthesia.
Rasmussen (2014)	USA	RCT	Unipolar or bipolar depression	ketamine [1 mg/kg] (21; 47; 24)	methohexital [1 mg/kg] (17; 48.6; 53)	6 sessions; Unilaterally or bilaterally	2–3 weeks	There were no significant differences in depression or cognitive outcomes between the two drugs.
Ray-Griffith (2017)	USA	RCT	Unipolar or bipolar depression	ketamine [1 mg/kg] (8; 43.6; 25)	methohexital [1 mg/kg] (8; 38.1; 13)	3 times/week and up to 6 sessions; Unilaterally	2 weeks	No statistical difference was found between the ketamine and methohexital groups for an improvement in depressive symptoms.
Salehi (2015)	Iran	Double-blind RCT	Major depressive disorder	ketamine [0.8 mg/kg] (80; n/a; 45)	thiopental [1-1.5 mg/kg] (80; n/a; 43)	3 times/week for 8 sessions; n/a	3–4 weeks	Ketamine is an appropriate option for anesthesia with ECT in patients with drug-resistant major depression.
Wang (2012)*	China	RCT	Major depressive disorder	• ketamine [0.8 mg/kg] (12; 56.2; 50) • propofol + ketamine [1.5 mg/kg + 0.8 mg/kg] (16; 58.6; 58)	propofol [1.5 mg/kg] (12; 53.8; 42)	Single treatment; Bilaterally	1 day	Propofol combined with ketamine may be the first-choice anesthesia in patients with depressive disorder undergoing ECT.
Woolsey (2022)	Canada	Double-blind RCT	Major depressive disorder	ketamine [0.2–0.5 mg/kg] (16; 36.9; 31.3)	propofol [0.2–0.5 mg/kg] (15; 45.0; 26.7)	3 times/week up to 12 sessions; Unilaterally or bilaterally via a Mecta SpECTrum 5000Q	4–5 weeks	Ketamine does not improve psychiatric outcomes in ECT.
Yoosefi (2014)*	Iran	Double-blind RCT	Major depressive disorder	ketamine [1–2 mg/kg] (15; 40.9; 53)	thiopental [2–3 mg/kg] (14; 47; 57)	3 times/week and 6 sessions; Bilaterally	2–3 weeks	Ketamine administration during ECT is well tolerated and patients may experience earlier improvement in depressive symptoms, longer seizure duration, and better cognitive performance when compared with thiopental.
Zhang (2018)	China	Double-blind RCT	Unipolar or bipolar depression	propofol + ketamine [0.5 mg/kg + 0.5 mg/kg] (16; 48.8; 50)	propofol [0.5 mg/kg] (16; 53.7; 31)	3 times/week for 6 sessions; Bilaterally using Thymatron System Ⅳ	2 weeks	Ketamine plus propofol anesthesia in the ECT treatment of MDD and BP was not superior on any measure to propofol alone.
Zhong (2016)	China	RCT	Unipolar or bipolar depression	• ketamine [0.8 mg/kg] (30; 32.1; 47) • propofol + ketamine [0.5 mg/kg + 0.5 mg/kg] (30; 30.4; 40)	propofol [0.8 mg/kg] (30; 29.2; 33)	3 times/week for 8 sessions; Bilaterally using Thymatron System Ⅳ	3 weeks	ECT with ketamine anesthesia might be an optimized therapy for patients with treatment-resistant depression.
Zou (2021)	China	Double-blind RCT	Major depressive disorder	propofol + ketamine [1.5 mg/kg + 0.3 mg/kg] (67; 65.8; 36)	propofol [1.5 mg/kg] (70; 65.6; 33)	3 times/week for 6 sessions; n/a; used Thymatron DGx	2 weeks	Low-dose ketamine is safe as an adjunct anesthetic for elderly patients subjected to ECT. It has a protective effect on cognitive function and may accelerate the antidepressant effects of ECT.

Note: a) indicates publication year; b) denotes a period for completing a series of treatment sessions. ECT=Electroconvulsive therapy. *This study was not included in the meta-analysis due to insufficient data.

Ketamine compared with all other anesthetic agents: A full network meta-analysis

A total of 2,322 patients from 17 direct comparison RCTs were included (i.e., 7 anesthetic agents with 19 effect sizes; Fig. 1A). In our NMA, the overall pooled SMD of ketamine, as compared with propofol as a reference group, was − 2.21 (95% confidence interval [CI], -3.79 to -0.64) in depressive symptoms, indicating that ketamine was more efficacious than propofol at reducing depressive symptoms (Fig. 2A). Ketamine was not significantly different when compared to propofol in terms of cognitive performance (Fig. 2B), remission and response rates (Figs. 2C-2D), or SAEs (Fig. 2E).

Ketamine compared with propofol-involved agents: A sensitivity analysis

In our sensitivity analysis comparing [1] ketamine versus [2] ketamine + propofol versus [3] propofol, a total of 1,968 patients from 11 direct comparison RCTs were included (i.e., 3 anesthetic agents with 13 effect sizes; Fig. 1B). The overall pooled SMD of ketamine, as compared with propofol as a reference group, was − 2.10 (95% CI, -3.79 to -0.41), indicating that ketamine was better than propofol for improving depressive symptoms (Fig. 3A). However, propofol was significantly better than ketamine for cognitive performance (SMD, -0.18; 95% CI, -0.28 to -0.09) (Fig. 3B). The combination of ketamine and propofol was better than propofol alone for cognitive performance but it was not statistically significant. No statistical difference was found in terms of remission and response rates and SAEs (Figs. 3C-3E).

Ketamine compared with methohexital: A sensitivity analysis

We also reported a pairwise meta-analysis between ketamine and methohexital (eFigure 2). We did not find any statistically significant differences in overall changes of depressive symptoms or cognitive performance. These studies did not report other outcomes.

Inconsistency tests and Rankograms of SUCRA

The inconsistency tests for NMA were analyzed using the node-splitting approach, and the findings (p > 0.05) indicate consistency across the direct and indirect comparisons of all outcomes. Figure 4 presents the SUCRA values for each anesthetic agent performance based on our full NMA model. Ketamine had the highest probability (73.8%) for depressive symptoms (Fig. 4A), indicating that ketamine may be a preferred anesthetic agent when compared to other agents. Ketamine, on the other hand, also had the poorest outcome in cognitive performance (Fig. 4B).

Publication bias assessment

In our NMA, we did not find any evidence for potential publication bias (eFigure 3) using funnel plots and both Egger’s test (p > 0.05) and Begg and Mazumdar’s test (p > 0.05), respectively.

Assessment of bias and methodological quality

Methodological quality of the included studies was ‘low’ to ‘high,’ and we provided our justification on eFigures 4 and 5. 9 of 22 studies (40.9%) had ‘some concerns’ as they may have some bias arising from the randomization process or deviations from the intended intervention. A total of 5 studies (22.7%) were deemed to have ‘high’ risk of bias. All included studies did not have bias due to missing outcome data, resulting in ‘low’ risk for domain 3.

This is the first study to use a network meta-analysis to examine the efficacy and safety of ketamine as an anesthetic agent, as compared with other anesthetic agents, in the acute phase treatment of a MDE with ECT. A network meta-analysis of 2,322 patients from 17 RCTs suggests that ketamine-assisted ECT resulted in significantly greater improvement in depressive symptoms, and the effect size was considered large.⁵⁹ However, in our sensitivity analysis that compared ketamine with propofol or propofol plus ketamine, ketamine had an inferior outcome with respect to cognitive performance upon completion of a course of ECT. No statistically difference was found in terms of remission and response rates and serious adverse events.

One previous study performed a pairwise meta-analysis on ketamine versus propofol versus ketamine plus propofol using three RCTs,⁶⁰ and concluded that ketamine alone and the combination of ketamine and propofol had greater efficacy in the treatment of depressive symptoms. However, this study only considered a single ECT session and excluded studies with two or more ECT sessions. Our study extends the findings of this previous study, allowing multiple comparisons across other anesthetic agents and multiple ECT sessions.

We did not find any statistically significant difference in cognitive performance in our main analysis (i.e., full network meta-analysis). This finding is in line with one systematic review, which concluded that, when compared to placebo, ketamine does not mitigate cognitive side effects associated with ECT.⁶¹ In our sensitivity analysis comparing ketamine versus propofol versus ketamine plus propofol, however, ketamine treated individuals demonstrate worse cognitive performance than propofol, a reference group, albeit the effect size was small.

When reviewing articles qualitatively, only 4 studies^40,43,44,51 reported long-term (i.e., 3 or more months) follow-up outcomes. These studies had a follow-up period of 3 to 6 months and reported no significant differences in terms of depressive symptoms and cognitive performance. One study also reported a relapse rate of depression during the 6-month follow-up, and no significant difference was found between ketamine and propofol treatment arms.⁴³

The current study has several clinical implications. First, ketamine has been used as a general anesthetic agent since 1960s,¹⁷ and RCTs of ketamine-assisted ECT have been introduced since early 2010s. The current network meta-analysis demonstrates that ketamine-assisted ECT is not only tolerable, but may even be efficacious in improving depressive symptoms in some patients with MDE. However, because ketamine may be associated with additive cognitive side effects (e.g., a higher incidence of confusion) and/or delayed time to recovery when compared to other anesthetic agents,⁶² the selection of anesthetic should be carefully assessed prior to the use of ECT. Second, for some patients, ketamine infusion alone without ECT may also be an option because ketamine itself has shown to have rapid and robust antidepressant effects in patients with MDD,^63,64 although ECT may be more efficacious than ketamine in improving depressive symptoms.¹⁴ Such clinical decisions should include a careful informed consent process taking into consideration of known risks and potential benefits in addition to provider- and patient-level barriers and/or preferences.

This study has several limitations. First, unlike a standard, pairwise meta-analysis comparing only two interventions at a time, a network meta-analysis (or multiple treatments meta-analysis) has its own strengths and weaknesses.⁶⁵ For example, the validity of the results of a NMA depends on the soundness of several assumptions: similarity (across trial designs, study settings, etc.), transitivity, consistency, and coherence. Our network structure was not connected across all intervention types, and some of our nodes were considered a star or complex network. While we did not violate methodological assumptions, due to the small number of trials and our reliance on aggregate (rather than patient-level) data, we cannot rule out the possibility that confounding factors may potentially threaten our analytical interpretations.

Second, our findings are limited in that we were unable to assess efficacy and safety of ketamine versus other agents among specific subgroups (e.g., older patients, and those with psychotic features or with psychiatric multi-morbidities) due to insufficient data to form a consistent network. Third, we were not able to assess other potentially important outcomes (e.g., cardiovascular events) due to insufficient data or differences in the management after the ECT intervention. These limitations should be considered when interpreting our findings.

In conclusion, this systematic review and network meta-analysis suggests that ketamine-assisted ECT, when compared to other anesthetic agents, may be efficacious in improving depressive symptoms in the acute phase treatment of a MDE, but cognitive performance may be an important counter-balancing risk factor. ECT practitioners should consider different anesthetic agents based on clinical efficacy and safety, while taking into account specific patient clinical profiles and preferences to improve effectiveness and safety of ECT for major depression.

PROSPERO Registration: #CRD42023427295

Acknowledgement and disclosures

Data Availability Statement: Data are publicly available.

Author contributions: Study concept and design: Rhee; Data acquisition and statistical analyses: Rhee & Shim; Interpretation of data: All authors; Drafting of manuscript: Rhee, Shim, & Kellner; Critical revision of manuscript for important intellectual content: All authors; Supervision: Rhee & McIntyre. Rhee and Shim are co-first authors. Rhee had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Obtained funding: n/a.

Role of the funder/sponsor: n/a.

Conflict of interest disclosures: Each author completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and had none directly related to this manuscript.

Rhee was supported in part by the National Institute on Aging (NIA) through Yale School of Medicine (#T32AG019134) in the past 3 years. Dr. Rhee has also been funded by the NIA (#R21AG070666), National Institute of Mental Health (#R21MH117438) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut. Dr. Rhee serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. Dr. Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. Dr. Rhee serves as an advisory committee member for International Alliance of Mental Health Research Funders (IAMHRF). Dr. Rhee is currently a co-editor-in-chief of Mental Health Science and is pending to receive honorarium payments annually from the publisher, John Wiley & Sons, Inc.

Shim reported none.

Popp reported none.

Trikalinos reported none.

Rosenheck reported none.

Kellner has received fees from UpToDate, Inc. for writing/editing ECT-related topics, royalties from Cambridge University Press for Handbook of ECT, honoraria from Northwell Health for teaching an ECT course and fees for being an expert witness iin ECT-related legal cases.

Seiner reported none.

Espinoza has been supported by the National Institute of Mental Health (R01MH128690) and the Muriel Harris Chair of Geriatric Psychiatry, Geffen School of Medicine at UCLA. He has also received royalties from UpToDate, Inc. and is on the Editorial Board of the Journal of ECT.

Forester has received research grant funding from Biogen, Eisai, Rogers Family Foundation, Spier Family Foundation and the NIH. He also serves in the Pharmacy and Therapeutics Committee for CVS health and is a consultant for Patina Health and Rippl Care.

McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC); speaker/consultation fees from Lundbeck, Janssen, Alkermes, Mitsubishi, Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk,Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, Atai Life Sciences. Dr. RogerMcIntyre is a CEO of Braxia Scientific Corp.

World Health Organization. Depression. Accessed January 6, 2020. https://www.who.int/news-room/fact-sheets/detail/depression
National Institute of Mental Health. Major depression. Accessed May 13, 2020. https://www.nimh.nih.gov/health/statistics/major-depression.shtml
Rhee TG, Wilkinson ST, Steffens DC, Rosenheck RA, Olfson M. Prevalence of Treatment for Depression Among US Adults Who Screen Positive for Depression, 2007–2016. JAMA Psychiatry. Nov 1 2020;77(11):1193–1195. doi:10.1001/jamapsychiatry.2020.1818
Gaynes BN, Rush AJ, Trivedi MH, Wisniewski SR, Spencer D, Fava M. The STAR*D study: treating depression in the real world. Cleve Clin J Med. Jan 2008;75(1):57–66. doi:10.3949/ccjm.75.1.57
Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs. Aug 2009;23(8):627–47. doi:10.2165/00023210-200923080-00001
Mrazek DA, Hornberger JC, Altar CA, Degtiar I. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996–2013. Psychiatr Serv. Aug 1 2014;65(8):977 – 87. doi:10.1176/appi.ps.201300059
Nemeroff CB. The burden of severe depression: a review of diagnostic challenges and treatment alternatives. J Psychiatr Res. Apr-Jun 2007;41(3–4):189–206. doi:10.1016/j.jpsychires.2006.05.008
Wilkinson ST, Trujillo Diaz D, Rupp ZW, et al. Pharmacological and somatic treatment effects on suicide in adults: A systematic review and meta-analysis. Depress Anxiety. Feb 2022;39(2):100–112. doi:10.1002/da.23222
Rhee TG, Mohamed S, Rosenheck RA. Stages of major depressive disorder and behavioral multi-morbidities: Findings from nationally representative epidemiologic study. J Affect Disord. Sep 25 2020;278:443–452. doi:10.1016/j.jad.2020.09.081
Rhee TG, Steffens DC. Major depressive disorder and impaired health-related quality of life among US older adults. Int J Geriatr Psychiatry. Oct 2020;35(10):1189–1197. doi:10.1002/gps.5356
van den Broek WW, de Lely A, Mulder PG, Birkenhager TK, Bruijn JA. Effect of antidepressant medication resistance on short-term response to electroconvulsive therapy. J Clin Psychopharmacol. Aug 2004;24(4):400–3. doi:10.1097/01.jcp.0000130551.70878.56
van Diermen L, van den Ameele S, Kamperman AM, et al. Prediction of electroconvulsive therapy response and remission in major depression: meta-analysis. Br J Psychiatry. Feb 2018;212(2):71–80. doi:10.1192/bjp.2017.28
Wilkinson ST, Kitay BM, Harper A, et al. Barriers to the Implementation of Electroconvulsive Therapy (ECT): Results From a Nationwide Survey of ECT Practitioners. Psychiatr Serv. Jul 1 2021;72(7):752–757. doi:10.1176/appi.ps.202000387
Rhee TG, Shim SR, Forester BP, et al. Efficacy and Safety of Ketamine vs Electroconvulsive Therapy Among Patients With Major Depressive Episode: A Systematic Review and Meta-analysis. JAMA Psychiatry. Dec 1 2022;79(12):1162–1172. doi:10.1001/jamapsychiatry.2022.3352
Folk JW, Kellner CH, Beale MD, Conroy JM, Duc TA. Anesthesia for electroconvulsive therapy: a review. J ECT. Jun 2000;16(2):157–70. doi:10.1097/00124509-200006000-00007
Zanos P, Moaddel R, Morris PJ, et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol Rev. Jul 2018;70(3):621–660. doi:10.1124/pr.117.015198
Malhi GS, Byrow Y, Cassidy F, et al. Ketamine: stimulating antidepressant treatment? BJPsych Open. May 2016;2(3):e5-e9. doi:10.1192/bjpo.bp.116.002923
Grunebaum MF, Ellis SP, Keilp JG, et al. Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial. Bipolar Disord. May 2017;19(3):176–183. doi:10.1111/bdi.12487
Grunebaum MF, Galfalvy HC, Choo TH, et al. Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial. Am J Psychiatry. Apr 1 2018;175(4):327–335. doi:10.1176/appi.ajp.2017.17060647
Domany Y, Shelton RC, McCullumsmith CB. Ketamine for acute suicidal ideation. An emergency department intervention: A randomized, double-blind, placebo-controlled, proof-of-concept trial. Depression and anxiety. Nov 16 2019;doi:10.1002/da.22975
Nikayin S, Rhee TG, Cunningham ME, et al. Evaluation of the Trajectory of Depression Severity With Ketamine and Esketamine Treatment in a Clinical Setting. JAMA Psychiatry. Jul 1 2022;79(7):736–738. doi:10.1001/jamapsychiatry.2022.1074
Kim J, Farchione T, Potter A, Chen Q, Temple R. Esketamine for Treatment-Resistant Depression - First FDA-Approved Antidepressant in a New Class. N Engl J Med. Jul 4 2019;381(1):1–4. doi:10.1056/NEJMp1903305
Sanacora G, Frye MA, McDonald W, et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry. Apr 1 2017;74(4):399–405. doi:10.1001/jamapsychiatry.2017.0080
McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. Am J Psychiatry. May 1 2021;178(5):383–399. doi:10.1176/appi.ajp.2020.20081251
Horowitz MA, Moncrieff J. Are we repeating mistakes of the past? A review of the evidence for esketamine. Br J Psychiatry. Nov 2021;219(5):614–617. doi:10.1192/bjp.2020.89
Lyndon W, Wilson C. Anesthesia for Electroconvulsive Therapy–Time for a Review? Brain Stimul. Sep-Oct 2015;8(5):985–6. doi:10.1016/j.brs.2015.07.038
Soehle M, Bochem J. Anesthesia for electroconvulsive therapy. Curr Opin Anaesthesiol. Oct 2018;31(5):501–505. doi:10.1097/ACO.0000000000000624
Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. Jun 2 2015;162(11):777–84. doi:10.7326/M14-2385
Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. Aug 28 2019;366:l4898. doi:10.1136/bmj.l4898
Cochrane Methods Bias. RoB 2: A revised Cochrane risk-of-bias tool for randomized trials. Accessed June 6, 2022. https://methods.cochrane.org/bias/resources/rob-2-revised-cochrane-risk-bias-tool-randomized-trials
Cochrane Library. Cochrane Review Manager Accessed June 6, 2022. https://training.cochrane.org/online-learning/core-software/revman
Ioannidis JP, Trikalinos TA. The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. CMAJ. Apr 10 2007;176(8):1091–6. doi:10.1503/cmaj.060410
Cooper H, Hedges LV, Valentine JC. The handbook of research synthesis and meta-analysis. Russell Sage Foundation; 2019.
Shim SR, Kim SJ, Lee J, Rucker G. Network meta-analysis: application and practice using R software. Epidemiol Health. 2019;41:e2019013. doi:10.4178/epih.e2019013
Rucker G, Schwarzer G. Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med Res Methodol. Jul 31 2015;15:58. doi:10.1186/s12874-015-0060-8
Borenstein M, Hedges LV, Higgins JP, Rothstein HR. Introduction to meta-analysis. John Wiley & Sons; 2021.
Abdallah CG, Fasula M, Kelmendi B, Sanacora G, Ostroff R. Rapid antidepressant effect of ketamine in the electroconvulsive therapy setting. Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't. Journal of ECT. 2012;28(3):157‐161. doi:10.1097/YCT.0b013e31824f8296
Alizadeh NS, Maroufi A, Nasseri K, et al. Antidepressant effect of combined ketamine and electroconvulsive therapy on patients with major depressive disorder: A randomized trial. Article. Iranian Journal of Psychiatry and Behavioral Sciences. 2015;9(3)doi:10.17795/ijpbs-1578
Altinay M, Karne H, Anand A. Administration of Sub-anesthetic Dose of Ketamine and Electroconvulsive Treatment on Alternate Week Days in Patients with Treatment Resistant Depression: a Double Blind Placebo Controlled Trial. Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't. Psychopharmacology bulletin. 2019;49(1):8‐16.
Anderson IM, Blamire A, 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. May 2017;4(5):365–377. doi:10.1016/s2215-0366(17)30077-9
Brunelin J, Iceta S, Plaze M, et al. The Combination of Propofol and Ketamine Does Not Enhance Clinical Responses to Electroconvulsive Therapy in Major Depression—The Results From the KEOpS Study. Article. Frontiers in Pharmacology. 2020;11doi:10.3389/fphar.2020.562137
Carspecken CW, Borisovskaya A, Lan ST, et al. Ketamine Anesthesia Does Not Improve Depression Scores in Electroconvulsive Therapy: A Randomized Clinical Trial. Article. Journal of Neurosurgical Anesthesiology. 2018;30(4):305–313. doi:10.1097/ANA.0000000000000511
Chen Q, Dong J, Luo J, et al. Effects of Low-Dose Ketamine on the Antidepressant Efficacy and Suicidal Ideations in Patients Undergoing Electroconvulsive Therapy. Article. Journal of ECT. 2020;36(1):25–30. doi:10.1097/YCT.0000000000000636
Dong J, Min S, Qiu H, Chen Q, Ren L. Intermittent administration of low dose ketamine can shorten the course of electroconvulsive therapy for depression and reduce complications: a randomized controlled trial. Journal Article; Randomized Controlled Trial. Psychiatry research. 2019;281:112573. doi:10.1016/j.psychres.2019.112573
Fernie G, Currie J, Perrin JS, et al. Ketamine as the anaesthetic for electroconvulsive therapy: the KANECT randomised controlled trial. Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't. British journal of psychiatry. 2017;210(6):422‐428. doi:10.1192/bjp.bp.116.189134
Gamble JJ, Bi H, Bowen R, et al. Ketamine-based anesthesia improves electroconvulsive therapy outcomes: a randomized-controlled study. Comparative Study; Journal Article; Randomized Controlled Trial. Journal canadien d'anesthesie [Canadian journal of anaesthesia]. 2018;65(6):636–646. doi:10.1007/s12630-018-1088-0
Järventausta K, Chrapek W, Kampman O, et al. Effects of S-ketamine as an anesthetic adjuvant to propofol on treatment response to electroconvulsive therapy in treatment-resistant depression: a randomized pilot study. Journal Article; Randomized Controlled Trial. Journal of ECT. 2013;29(3):158–161. doi:10.1097/YCT.0b013e318283b7e9
Loo CK, Katalinic N, Garfield JBB, Sainsbury K, Hadzi-Pavlovic D, Mac-Pherson R. Neuropsychological and mood effects of ketamine in electroconvulsive therapy: A randomised controlled trial. Article. Journal of Affective Disorders. 2012;142(1–3):233–240. doi:10.1016/j.jad.2012.04.032
Okamoto N, Nakai T, Sakamoto K, Nagafusa Y, Higuchi T, Nishikawa T. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: comparing ketamine and propofol anesthesia. J ECT. Sep 2010;26(3):223–7. doi:10.1097/YCT.0b013e3181c3b0aa
Rasmussen KG, Kung S, Lapid MI, et al. A randomized comparison of ketamine versus methohexital anesthesia in electroconvulsive therapy. Comparative Study; Journal Article; Randomized Controlled Trial. Psychiatry research. 2014;215(2):362–365. doi:10.1016/j.psychres.2013.12.027
Ray-Griffith SL, Eads LA, Han X, Golden K, Stowe ZN. A Randomized Pilot Study Comparing Ketamine and Methohexital Anesthesia for Electroconvulsive Therapy in Patients With Depression. Comparative Study; Journal Article; Randomized Controlled Trial. Journal of ECT. 2017;33(4):268–271. doi:10.1097/YCT.0000000000000413
Salehi B, Mohammadbeigi A, Kamali AR, Taheri-Nejad MR, Moshiri I. 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. Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't. Annals of cardiac anaesthesia. 2015;18(4):486‐490. doi:10.4103/0971-9784.166444
Wang X, Chen Y, Zhou X, Liu F, Zhang T, Zhang C. Effects of propofol and ketamine as combined anesthesia for electroconvulsive therapy in patients with depressive disorder. Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't. Journal of ECT. 2012;28(2):128‐132. doi:10.1097/YCT.0b013e31824d1d02
Woolsey AJ, Nanji JA, Moreau C, et al. Low-dose ketamine does not improve the speed of recovery from depression in electroconvulsive therapy: a randomized controlled trial. Journal Article; Randomized Controlled Trial. Revista brasileira de psiquiatria (Sao Paulo, Brazil: 1999). 2022;44(1):6-14. doi:10.1590/1516-4446-2020-1705
Yoosefi A, Sepehri AS, 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. Comparative Study; Journal Article; Randomized Controlled Trial. Journal of ECT. 2014;30(1):15–21. doi:10.1097/YCT.0b013e3182a4b4c6
Zhang M, Rosenheck R, Lin X, et al. A randomized clinical trial of adjunctive ketamine anesthesia in electro-convulsive therapy for depression. J Affect Disord. Feb 2018;227:372–378. doi:10.1016/j.jad.2017.11.034
Zhong X, He H, Zhang C, et al. Mood and neuropsychological effects of different doses of ketamine in electroconvulsive therapy for treatment-resistant depression. Comparative Study; Journal Article; Randomized Controlled Trial. Journal of affective disorders. 2016;201:124–130. doi:10.1016/j.jad.2016.05.011
Zou L, Min S, Chen Q, Li X, Ren L. Subanesthetic dose of ketamine for the antidepressant effects and the associated cognitive impairments of electroconvulsive therapy in elderly patients—A randomized, double-blind, controlled clinical study. Article. Brain and Behavior. 2021;11(1)doi:10.1002/brb3.1775
Andrade C. Mean Difference, Standardized Mean Difference (SMD), and Their Use in Meta-Analysis: As Simple as It Gets. J Clin Psychiatry. Sep 22 2020;81(5)doi:10.4088/JCP.20f13681
Li XM, Shi ZM, Wang PJ, Hu H. Effects of ketamine in electroconvulsive therapy for major depressive disorder: meta-analysis of randomised controlled trials. Gen Psychiatr. 2020;33(3):e100117. doi:10.1136/gpsych-2019-100117
Verdijk J, van Kessel MA, Oud M, et al. Pharmacological interventions to diminish cognitive side effects of electroconvulsive therapy: A systematic review and meta-analysis. Acta Psychiatr Scand. Apr 2022;145(4):343–356. doi:10.1111/acps.13397
Li DJ, Wang FC, Chu CS, et al. Significant treatment effect of add-on ketamine anesthesia in electroconvulsive therapy in depressive patients: A meta-analysis. Eur Neuropsychopharmacol. Jan 2017;27(1):29–41. doi:10.1016/j.euroneuro.2016.11.008
Han Y, Chen J, 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;12:2859–2867. doi:10.2147/NDT.S117146
Kishimoto T, Chawla JM, 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. May 2016;46(7):1459–72. doi:10.1017/S0033291716000064
Cipriani A, Higgins JP, Geddes JR, Salanti G. Conceptual and technical challenges in network meta-analysis. Ann Intern Med. Jul 16 2013;159(2):130–7. doi:10.7326/0003-4819-159-2-201307160-00008

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MolecularPsychKETassistedECTSupplement.docx

Efficacy and Safety of Ketamine-assisted Electroconvulsive Therapy in Major Depressive Episode: A Systematic Review and Network Meta-Analysis

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Results

Characteristics of included studies

Ketamine compared with all other anesthetic agents: A full network meta-analysis

Ketamine compared with propofol-involved agents: A sensitivity analysis

Ketamine compared with methohexital: A sensitivity analysis

Inconsistency tests and Rankograms of SUCRA

Publication bias assessment

Assessment of bias and methodological quality

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1