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CADTH Health Technology Review
Authors; Angela M. Barbara, Weiyi Xie, Quenby Mahood, and Angie Hamson.
Depression is a debilitating mental health illness that affects approximately 5.4% of people living in Canada.1 Although there are many effective first-line pharmacotherapy treatments for depression, about 21.7% of people in Canada remain non-responsive to 2 or more antidepressant medications from different classes. Patients with such limited responsiveness to medications are often considered to have treatment-resistant depression (TRD).2,3 They are known to experience longer depressive episodes and are at increased risk of alcohol and drug misuse, suicide, and hospitalizations.4 A retrospective longitudinal cohort study using Ontario administrative data found that TRD was associated with an increased economic burden to the health care system.5
Posttraumatic stress disorder (PTSD) is a disabling mental health condition that affects about 9.2% of people in Canada in their lifetime.6 Among veterans in Canada, its prevalence has been estimated at up to 10%.7 Although anyone can get PTSD, the risk factors include being female, having experienced a prior trauma, having been abused as a child, having pre-existing mental health conditions, and having a family history of mental illnesses.6 People with PTSD commonly have associated conditions, including depression, panic attacks, and alcohol and substance misuse; challenges in relationships; and an increased risk of other medical conditions.6
Treatments for TRD and PTSD include pharmacotherapies and psychotherapies.8-10 There are a wide variety of antidepressant drugs, including selective serotonin reuptake inhibitors,11 monoamine oxidase inhibitors, and tricyclic antidepressants.12 However, as mentioned previously, 2 or more trials of antidepressants will have been ineffective in persons with TRD.2,3 There are few effective drugs available for the treatment of PTSD.8 There are somatic treatments through brain stimulation, such as electroconvulsive therapy (ECT).13 ECT is more effective (with a quicker onset of action) compared to conventional antidepressants.13 However, there are many adverse events associated with ECT, including cognitive impairment, delirium, musculoskeletal pain or injury, and anesthesia-related complications.13 Thus, there is an urgent need to identify effective, safe, and timely treatments for TRD and PTSD.
Ketamine is a hallucinogenic drug that changes one’s state of consciousness by affecting neurotransmitters in the brain.14-16 Ketamine is an N-methyl D-aspartate receptor antagonist and is a mixture of 2 mirror-image molecules: R-ketamine (arketamine) and S-ketamine (esketamine).17,18 In Canada, a number of formulations of ketamine are approved for general anesthesia.15,19,20 Ketamine is also used as a sedative and to manage pain.21 Over the past decades, preclinical and clinical studies have shown the pharmacotherapeutic potential of ketamine for the treatment of psychiatric illnesses, including TRD and PTSD.22,23
A 2022 CADTH report24 on the use of ketamine for PTSD or TRD found insufficient evidence to provide definitive conclusions about its clinical effectiveness due to mixed study findings. The report did find overall safety and tolerability of ketamine for treating PTSD or TRD. The Danish evidence-based guideline included in the 2022 CADTH report recommended against the use of IV ketamine in patients with TRD, while the Canadian guideline included in the report recommended that IV ketamine be considered as a third-line treatment for adults with TRD. The report did not identify any economic evaluations or guidelines for the use of ketamine for adults with PTSD.24 Since the publication of the 2022 CADTH report,24 new literature on this topic has emerged, warranting the present review.
To support decision-making about the use of ketamine for adults with TRD or PTSD, we prepared this Rapid Review report as an update to the 2022 CADTH report24 to summarize the most recent clinical and cost-effectiveness studies and evidence-based guidelines on the use of ketamine for adults with TRD or PTSD.
This report makes use of a literature search strategy developed for a previous CADTH report.24 For the current report, a limited literature search was conducted by an information specialist on key resources including MEDLINE, PsycInfo, the Cochrane Database of Systematic Reviews, the international HTA database, and the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were ketamine and depression or PTSD. CADTH-developed search filters were applied to limit retrieval to guidelines; randomized controlled trials (RCTs), controlled clinical trials, or any other type of clinical trial; health technology assessments; systematic reviews (SRs); meta-analyses or network meta-analyses; and economic studies. The search was completed on November 10, 2023, and limited to English-language documents published since March 1, 2022.
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed, and potentially relevant articles were retrieved and assessed for inclusion. As an update to a previous CADTH report, articles were included if they were made available since the previous search date and were not included in the 2022 CADTH report.24 The final selection of full-text articles was based on the inclusion criteria presented in Table1.
Selection Criteria.
The following were excluded:
The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)25 for SRs, the Downs and Black checklist26 for RCTs, the Drummond checklist27 for economic evaluations, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument28 for guidelines. Summary scores were not calculated for the included publications; rather, each publication’s strengths and limitations were described narratively.
A recruitment invitation was disseminated by email to patient advocacy groups, on social media, and through CADTH networks. An interested individual with TRD and experience of ketamine-assisted psychotherapy was identified to participate in an interview with CADTH project team members.
One contributor shared their personal experiences through a video call during the drafting of this report. The patient’s perspectives gained through the engagement processes were used to ensure the relevance of the outcomes of interest for the clinical assessment in this report and to provide insights, background, and context to help inform the Discussion section.
Patient involvement was guided by the Guidance for Reporting Involvement of Patients and the Public (Version 2) Short Form reporting checklist,29 which is outlined in Appendix 6.
This report includes 4 SRs,30-33 7 RCTs,34-40 1 economic evaluation,41 and 2 evidence-based guidelines.42,43 Study selection details are presented in Appendix 1. Additional references of potential interest are provided in Appendix 7.
Summaries of study characteristics are organized by research question and comparison (where appropriate). Additional details regarding the characteristics of the included publications are provided in Appendix 2. Brief descriptions of the tools used to measure effectiveness and safety outcomes are presented as footnotes in the Summary of Findings tables in Appendix 4. Of note:
We identified 2 SRs30,31 and 2 double-blind parallel RCTs,34,40 all of which compared ketamine with saline placebo. The RCTs were conducted in Egypt34 and the US.40 The SRs30,31 did not identify the countries in which the included RCTs were conducted. One SR30 and the 2 RCTs34,40 included adults with TRD.30 The other SR included adults diagnosed with both early PTSD (duration of 1 to 3 months) and chronic PTSD (duration > 3 months).31 Most of the studies (7 out of 9) in 1 SR30 and both studies in the other SR31 were crossover trials. Baseline characteristics between the intervention and comparator groups in the parallel trials were not described in 1 SR;30,31 the participants in the 2 groups were balanced in baseline demographics and clinical history in the 2 RCTs.34,40 The interventions in the included studies were single-dose ketamine administered via IV30,40 or intranasal routes,30 or repeated doses of IV ketamine.30,34 One SR did not report the route of administration.31 In most included studies, the ketamine dose was 0.5mg/kg.30,31,34,40 In the SR by Nikolin et al. (2023), 3 RCTs administered lower doses, ranging from 0.1 mg/kg to 0.4 mg/kg.30 The dose for intranasal ketamine was 50 mg.30,31,34,40 The effectiveness outcomes were depression (e.g., change in depression severity, treatment response, remission),30,34,40 psychological symptoms,34 PTSD symptoms,31 and suicidal ideation.34 The safety outcomes were adverse events.40
We identified 3 SRs30,31,33 and 5 double-blind parallel RCTs35-39 comparing ketamine with alternative interventions.
Three SRs30,31,33 and 5 RCTs35-39 compared ketamine with midazolam. The studies took place in Australia,36,38 Taiwan,37,39 and the US.33,35 Two SRs30,33 and 4 RCTs36-39 included adults with treatment-resistant major depression. One SR31 and 1 RCT35 included adults with chronic PTSD. One study in 1 SR30 was a crossover trial. Baseline characteristics between the intervention and comparator groups in the parallel trials were not described in the 3 SRs;30,31,33 the participants in the 2 groups were balanced in baseline demographics in the 5 RCTs.35-39 The interventions included single-dose IV ketamine,30,33,35,37,39 single-dose subcutaneous ketamine,30,36 single-dose IM ketamine, repeated doses of IV ketamine,30,31and repeated subcutaneous ketamine injections.38 The dose of ketamine was 0.5mg/kg in most included studies;30,31,33,37-39 ranged from 0.1 mg/kg to 0.5 mg/kg in 1 RCT in the SR by Nikolin et al.;30 and was fixed at 0.5mg/kg in 1 cohort and escalated in the other cohort from 0.5 mg/kg to 0.6, 0.75, or 0.9 mg/kg based on the participant’s response to treatment.38 In all included studies, the comparator was midazolam, a short-acting benzodiazepine medication and anesthetic drug. Midazolam has pharmacokinetic properties similar to ketamine (e.g., fast onset of action and short elimination half-life).44 The midazolam dose was 0.045 mg/kg in most studies,30,31,33,35,37,39 0.025 mg/kg in 1 RCT,36 and given as a fixed subcutaneous dose of 0.25mg/kg in 1 cohort and escalated in the other cohort from 0.25 mg/kg to 0.03, 0.0375, or 0.45 mg/kg based on the participant’s response to treatment.38 The effectiveness outcomes were depression,30,35-39 PTSD symptoms,31,35 anxiety,33,36 neurocognitive outcomes,36 and suicidal ideation.37,39 The safety outcomes were adverse events.38,39
One RCT included in 1 SR32 compared ECT versus ketamine. The study was conducted in the US and included adults with TRD.32 The intervention was ECT given 3 times per week for 3 weeks. The comparator was IV ketamine 0.5 mg/kg twice per week for 3 weeks.32 The effectiveness outcome was depression (e.g., response, change in depression severity, acute effect, and relapse).32 Safety outcomes were not reported.
One cohort study reported in 1 SR by Du et al.31 compared ketamine (0.5mg/kg) versus opioids (unknown dose). This study included adults in hospitals following accidental trauma who were experiencing early PTSD.31 The route of administration was not reported.31 The effectiveness outcome was PTSD symptoms.31 Safety outcomes were not reported.
No clinical effectiveness studies of ketamine administered via different routes for adults with TRD or PTSD were identified; therefore, no summary can be provided.
No cost-effectiveness studies of ketamine versus placebo or no treatment for adults with TRD or PTSD were identified; therefore, no summary can be provided.
One economic evaluation41 conducted a cost-utility analysis of esketamine nasal spray compared to IV ketamine in patients with TRD in the US, using a Markov model with a 1-month cycle length. The analysis was conducted from US health care and patient perspectives over a 3-year time horizon. The clinical trial efficacy data were from 4 phase III clinical trials included in an FDA Advisory Committee briefing document for esketamine and a meta-analysis for ketamine.41 The real-world effectiveness data were from psychiatric clinic electronic health records and medical chart reviews. Utility values were taken from a prospective cohort study that used the EQ-5D to assess quality of life among outpatients treated for MDD with pharmacotherapy.41 Costs under the health care perspective included medication, physician visits at each presentation of dosing, and observation by a medical assistant after each dose administration. Under the patient perspective, costs included patient time and medication copayments. The time horizon varied from 1 year to 5 years in the sensitivity analysis, with future costs and quality-adjusted life-years (QALYs) discounted at 3% annually.41
No cost-effectiveness studies of ketamine administered via different routes for adults with TRD or PTSD were identified; therefore, no summary can be provided.
Two evidence-based guidelines42,43 were included in this review. Both guidelines were developed by the US Department of Veterans Affairs (VA) and the US Department of Defense (DoD) to update previously published guidelines. Both guidelines42,43 conducted systematic searches of SRs and meta-analyses and RCTs. Recommendations for both guidelines were developed by a guideline development work group in discussion with clinical experts and reviewed by external experts. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, work group members rated evidence quality, and clinical experts assessed recommendation strength. The 2023 VA/DoD guideline42 focused on adults with PTSD or acute stress disorder, and the intended users were providers and others involved in the care of active-duty service members and veterans with PTSD. The target population of the 2022 VA/DoD guideline43 was adults with MDD, including MDD that is severe or has partial or limited response to initial treatment, with all health care providers caring for patients with MDD as intended users.
Critical appraisal summaries are organized by study design. Additional details regarding the strengths and limitations of the included publications are provided in Appendix 3.
The 4 SRs30-33 had clearly defined research questions and study eligibility criteria that included components of population, intervention, comparator, and outcomes. All 4 SRs30-33 registered their protocol a priori on PROSPERO, thus reducing the risk of reporting bias. The authors of the 4 SRs30-33 performed literature searches in 2 or more electronic databases,30-33 described the search strategies in detail,30,32,33 or provided the search terms.31 These methodological strengths increase the transparency and reproducibility of the literature searches and article selection process. Three SRs30-33 presented a flow chart illustrating the study selection process. Study selection was performed in duplicate in all SRs,30-33 thus reducing the likelihood that relevant studies were missed.30,31 Data extraction was performed in duplicate in 2 SRs,30,33 thus limiting the possibility of errors in data extraction in those 2 SRs. The 4 SRs30-33 used the Cochrane tool to assess the risk of bias of the included RCTs.
There were several limitations that were common to the included SRs.30-33 None incorporated searches of the grey literature or reported funding sources for the included primary studies. Three SRs31-33 did not provide a list of excluded studies. Two SRs30,31 did not indicate if risk of bias was accounted for in their findings.
The 7 RCTs34-40 clearly defined the objective, outcomes, inclusion and exclusion criteria, interventions used, and demographics of included participants. Six RCTs34-39 indicated that the trial protocol had been registered before conducting the trial. Each RCT used appropriate statistical tests for analysis, and outcomes of interest were assessed using validated scales.34-40
In 4 RCTs,34,36,38,39 the methods of randomization and allocation concealment were described and appropriate, reducing the risk of selection bias. The patients, personnel administering the interventions, and personnel assessing the outcomes were blinded to the interventions in all RCTs,34-40 reducing the risk of performance and detection bias. Because ketamine was administered by study personnel, it was assumed that adherence to the intervention was reliable for each RCT. Each RCT provided information related to any funding received for the trial. Four RCTs34,36,37,39 reported no conflicts of interest, and 3 RCTs35,38,40 declared potential conflicts of interests.
There were several limitations across the included RCTs.34-40 Five RCTs35-37,39 had very small study populations (ranging from 21 to 84 participants) that might not represent the entire population from which they were recruited. Four RCTs34-37 did not report adverse events. Three RCTs36,37,39 did not report a sample size calculation. In 4 RCTs,35,37,39,40 the recruitment methods were not described.
The economic evaluation by Brendle et al.41 clearly described the study design, including the research question and its economic importance, health care and patient perspectives, the selected alternative intervention, time horizon, and the form of economic evaluation used. The study41 also reported data collection methods, including the details of clinical trial efficacy data and real-world effectiveness data, sources of cost data, and sources of utility values. In addition, authors described the Markov model, key model parameters, and discount rate used.41 However, the study41 did not justify the choices of the model and discount rate and lacked details on price adjustments for inflation. For the analysis and interpretation of results, authors used deterministic (1-way) and probabilistic sensitivity analyses to determine the impact of model parameter uncertainty without providing reasons for the choice of analysis variables or the ranges over which they were varied.41 Authors presented major outcomes in disaggregated and aggregated forms.41 However, authors did not report confidence intervals of main outcome data; therefore, the uncertainty of outcome estimates was unknown.41
Both included guidelines42,43 clearly outlined their scope and purpose, including objectives, health questions, and the target population. They both reported stakeholder involvement details, including the target users, development groups, and patient groups whose preferences and views were sought.42,43 In addition, both guidelines42,43 demonstrated strength in clearly presenting specific, unambiguous, and easily identifiable recommendations as well as different options for management of the conditions. The 2 guidelines42,43 reported systematic evidence search methods, evidence selection criteria, strengths and limitations of the body of evidence, and methods for formulating the recommendations. They also considered health benefits, side effects, and risks in formulating the recommendations and demonstrated the link between the recommendations and the supporting evidence.42,43 Both guidelines42,43 were externally reviewed by experts before their publication, but neither provided a procedure for updating the guidelines.
Regarding applicability, both guidelines42,43 provided tools for implementing recommendations, but only the 2022 VA/DoD guideline43 described facilitators and barriers to the application. Moreover, both guidelines42,43 considered potential resource implications of applying the recommendations, but neither presented monitoring or auditing criteria. For editorial independence, the 2022 VA/DoD guideline43 reported no competing interests of guideline development group members, while the 2023 VA/DoD guideline42 described the disclosure process but did not present the results. Neither guideline42,43 stated whether the funding body influenced the content of the guideline.
The main findings from the included publications are summarized in the following sections and in Appendix 4.
Nine RCTs included in an SR30 and another RCT40 assessed the effects of single-dose ketamine compared to placebo on depression within 24 hours following treatment in patients with TRD and reported:
Eight RCTs included in an SR30 and 2 RCTs34,40 assessed depression from 3 to 28 days following single-dose or repeated ketamine treatment compared to placebo in adults with TRD and reported:
In patients with TRD, the RCT by Ahmed et al.34 found:
Two RCTs in the SR by Du et al.31 studied the effect of ketamine versus placebo on PTSD symptoms in patients with PTSD and found no statistically significant difference between the 2 groups at 24 hours after treatment.31 However, baseline scores were not reported for the 2 groups in the 2 trials.31
The RCT by Ahmed et al.34 found a statistically significant reduction in suicidal ideation from baseline to 1 week following treatment for TRD in the ketamine group and no change in the placebo group, but between-group differences were not reported.34
In patients with TRD, the following mild to moderate adverse events were reported more frequently at 24 hours after ketamine treatment compared to placebo (statistical significance not reported) in 1 RCT:40 dissociation, dizziness, dry mouth, and decreased energy. Most adverse events were no longer reported at 30 days after treatment.40
In patients with TRD, the following were reported on the effects of single-dose ketamine versus midazolam:
The RCT by Loo et al.38 found that the effects of a 4-week course of repeated subcutaneous ketamine injections for adults with TRD depended on dosing:
In patients with PTSD, 1 RCT35 reported no statistically significant difference in depression scores with single-dose ketamine versus midazolam at the end of treatment and at the 90-day follow-up.35
In patients with TRD, 1 RCT in the SR by Marchi et al.33 found no statistically significant between-group differences in anxiety 1 day after single-dose treatment.33 The RCT by Harvey et al.36 found statistically significant time effects on anxiety 1 day after treatment but did not attribute the significance to the single-dose ketamine or midazolam given to patients with TRD.36
One RCT in the SR by Du et al.31 found no statistically significant difference in PTSD symptoms with ketamine compared to midazolam between 1 day and 1 week following treatment for chronic PTSD.31 The RCT by Duek et al.35 recorded PTSD symptoms in patients with PTSD before treatment, at the end of a single infusion of ketamine or midazolam, at 1 week, and at 90 days. Although PTSD symptoms improved over time, there were no statistically significant between-group differences in the rate of improvement or PTSD score at any time points.35
The RCT by Harvey et al.36 assessed neurocognitive changes following single-dose ketamine or midazolam treatment in patients with TRD and reported:
One RCT37 found statistically significantly greater reductions in suicidal ideation 3 days after single-dose ketamine versus midazolam in patients with TRD. Another RCT39 found statistically significant remission rates up to 5 days after treatment in favour of single-dose ketamine versus midazolam in patients with TRD. In the same trial,39 there were no statistically significant differences between the 2 groups at 1 week and 2 weeks following treatment.
Two RCTs38,39 reported adverse events with ketamine compared to midazolam in patients with TRD. In the RCT by Su et al.,39 derealization, dizziness, and crying were reported more often during treatment with ketamine compared to midazolam, and the differences were statistically significant. The RCT by Loo et al.38 found that the following adverse events were reported statistically significantly more often 1 hour following treatment with ketamine compared to midazolam: lightheadedness, reduced concentration, dissociation, and anxiety. Loo et al.38 reported 2 severe adverse effects in the ketamine group that were related to the drug: major dissociative episode and auditory hallucination. Both acute events resolved within 2 hours. No participants required medical attention. No severe events related to the study drug were reported in the midazolam group.38
One RCT in the SR by Shafiee et al.32 found statistically significant improvements in depression scores and response rates in favour of repeated-dose ketamine over ECT following treatment in patients with TRD. There were no statistically significant differences in depression scores or relapse rates between ketamine and ECT at the 30-day follow-up.32
One cohort study in the SR by Du et al.31 reported a statistically significant increase in PTSD symptoms within 3 days of treatment with ketamine versus opioids in patients with PTSD.
No clinical effectiveness studies of ketamine administered via different routes for adults with TRD or PTSD were identified; therefore, no summary can be provided.
No cost-effectiveness studies of ketamine versus placebo or no treatment for adults with TRD or PTSD were identified; therefore, no summary can be provided.
The economic evaluation41 assessed the cost-utility of esketamine nasal spray versus IV ketamine in patients with TRD in the US.
From the health care perspective, IV ketamine was likely to be cost-effective compared to esketamine:
From a patient perspective, Brendle et al.41 found that IV ketamine was unlikely to be cost-effective compared to esketamine due to similar levels of clinical effectiveness and lower costs of esketamine attributable to insurance coverage and manufacturer assistance programs:
No cost-effectiveness studies of ketamine administered via different routes for adults with TRD or PTSD were identified; therefore, no summary can be provided.
The 2022 VA/DoD guideline43 suggests ketamine or esketamine as an option for augmentation for patients with MDD who have not responded to several “adequate” (from original source and undefined) pharmacologic trials (weak recommendation based on low-quality evidence). The guideline noted that while most patients were willing to accept the risk of adverse events associated with ketamine, they may have varying preferences about the route of administration. In addition, the guideline identified resource and feasibility challenges related to administrating ketamine.
The 2023 VA/DoD guideline42 does not suggest ketamine for the treatment of PTSD (weak recommendation based on very low-quality evidence). The guideline stated that the benefits of using ketamine as monotherapy were outweighed by the potential harm.
No evidence was found for the following; therefore, no conclusions can be formed on the respective research questions:
We identified 1 crossover RCT reported in 1 SR30 that compared IV, subcutaneous, and IM routes of administering ketamine in 15 adults with TRD. The SR authors compared ketamine administered via different routes with midazolam for this RCT (e.g., IV ketamine versus midazolam, subcutaneous ketamine versus midazolam, and IM ketamine versus midazolam). However, they did not report head-to-head comparisons (e.g., IV ketamine versus subcutaneous ketamine versus IM ketamine).30
All included studies investigated the short-term effects of ketamine, with follow-up periods ranging from 3 days37 to 3 months.35 Therefore, longer term effects of ketamine are unknown.
There was limited evidence for some comparisons, with 1 RCT in 1 SR32 comparing ketamine to ECT and 1 RCT in another SR31 comparing ketamine to opioids, potentially limiting the reliability of these findings.
None of the studies included oral or sublingual ketamine; therefore, no conclusions can be formed on the impact of these routes of administration.
None of the studies reported hospital admission or quality of life as outcomes; therefore, no conclusions can be formed on the impact of ketamine on these outcomes.
Of the included studies in the 4 SRs, as assessed by the review authors, 2 studies from 2 of the SRs31,32 were at low risk of bias, while the other studies from 3 of the SRs30,31,33 had either some concerns or high risk of bias related to random sequence generation, allocation concealment, blinding of outcome assessors, and selective reporting.
Both evidence-based guidelines42,43 provided weak recommendations based on low-quality or very low-quality evidence.
None of the clinical effectiveness studies31-39 were conducted in Canada, which may limit the generalizability of the findings of this Rapid Review to the Canadian health care context. Two SRs30,31 did not identify the countries in which the studies were conducted; therefore, the generalizability of their findings is unknown.
Most of the evidence in adults with TRD was specific to MDD, except for 2 crossover RCTs included in 1 SR30 with very small samples (n = 15 and n = 18) of adults with treatment-resistant bipolar depression. Therefore, the overall findings may not be applicable in adults with treatment-resistant bipolar depression.
There was limited clinical effectiveness evidence for veteran populations, with 2 RCTs37,39 conducted by the same group of researchers in a veterans’ hospital in Taiwan, and another RCT35 whose study population included 29% with combat trauma. The SRs30-33 did not report whether the populations were veterans or civilians; therefore, the generalizability of the findings to these specific populations is unknown.
Both evidence-based guidelines42,43 focused on adults eligible for care in the VA or DoD health care delivery systems in the US. Due to potential differences in health care systems and resource availability between the US and Canada, the generalizability of the recommendations to veterans in Canada is unknown.
The cost-effectiveness study41 was based in the US and assumed that all patients had commercial health insurance covering treatment costs and manufacturer assistance programs, raising uncertainty about the relevance of findings under a patient perspective to the Canadian context. Moreover, authors acknowledged potential differences between real-world postrelapse treatment patterns and their assumption that patients would follow a similar and consistent pattern of treatment after relapse.41 Consequently, the generalizability of findings is unclear.
The definition of TRD varied among studies.30 The mean number of unsuccessful trials of antidepressants also varied. The criteria for an “adequate” (from original source and undefined) trial were not specified in the included studies, and patients’ history with nonpharmacological therapy was inconsistently reported across studies.
Three SRs30,32,33 did not specify whether the unsuccessful trials of antidepressants were in the current episode or over the lifetime for each of their included studies.
Among the included RCTs, inclusion and exclusion criteria were not homogeneous. For example, suicidal ideation or suicidal behaviour were part of the inclusion criteria in 2 RCTs34,39 but were excluded in another RCT.37 Substance use was reported in 1 RCT35 but excluded in other RCTs.37,39
Most studies used ketamine as add-on therapy and allowed patients to continue using concomitant medication or psychotherapy during treatment, and the concomitant therapies across studies were heterogeneous. However, 2 RCTs included in 1 SR30 assessed ketamine as monotherapy and required discontinuation of other psychotropic medications.
With the exception of 1 RCT reported in the SR by Shafiee et al.,32 all included studies had small sample sizes. Therefore, the total number of events on dichotomous outcomes (e.g., depression-based response and remission) were very low. Effect estimates for several outcomes had wide confidence intervals.30,31,38 The economic evaluation41 obtained clinical efficacy data from trials with small sample sizes. Therefore, the results presented in this Rapid Review are generally imprecise.
This report comprises 4 SRs30-33 and 7 RCTs34-40 on the clinical effectiveness of ketamine, 1 economic evaluation41 on the cost-effectiveness of ketamine, and 2 evidence-based guidelines42,43 on the use of ketamine in adults with TRD or PTSD.
In adults with TRD, single-dose ketamine compared to placebo may have a favourable effect on depression severity within 24 hours and 3 days following treatment, but this finding is uncertain due to high heterogeneity and potential publication bias.30,40 The 24-hour effects on depression treatment response and remission were mixed across the included studies and therefore uncertain.30,40 Ketamine had a neutral effect (e.g., no statistically significant between-group difference) compared to placebo on depression response and remission 3 days following single-dose ketamine.30 In adults with TRD, repeated doses of ketamine may improve depression severity,30,34,40 response,34 and suicidal ideation compared to placebo,34 but these findings are uncertain due to imprecision and potential indirectness. There were no severe adverse events reported with ketamine in patients with TRD.34
In adults with TRD, single-dose ketamine may have a favourable effect on depression severity and response within 24 hours and 3 days following treatment compared to midazolam, but these findings are uncertain due to imprecision.30,36,37,39 The 24-hour effect on anxiety was mixed across included studies and therefore uncertain.33,36 Single-dose ketamine may have a favourable effect on suicidal ideation within 3 days following treatment compared to midazolam, but this result is uncertain due to imprecision and indirectness.37,39 Compared to midazolam, single-dose ketamine treatment may also improve negative affective bias but have no effect on other neurocognitive outcomes, but these results are uncertain due to imprecision.36 Repeated doses of ketamine may have a favourable effect on depression when administered with a flexible dosing schedule compared to midazolam, but this finding is uncertain due to imprecision.38 Serious adverse events related to ketamine were rare and resolved within 2 hours.37
In adults with PTSD, ketamine may not have an effect on PTSD symptoms compared to midazolam, but these findings are uncertain due to imprecision and potential indirectness.35
In patients with TRD, repeated doses of ketamine had a favourable effect on depression and response rates at end of treatment compared to ECT.32 There may be no effect of ketamine on depression scores or relapse rates at 30-day follow-up compared to ECT, but these findings are uncertain due to imprecision.32
In hospital patients with early PTSD due to accidental trauma, ketamine may aggravate PTSD symptoms within 3 days of treatment compared to opioids, but this finding is uncertain due to imprecision and low confidence in the results of the SR.31
From the health care perspective, IV ketamine was likely to be cost-effective compared to esketamine for the treatment of TRD in the US. However, from the patient perspective, IV ketamine was unlikely to be cost-effective compared to esketamine due to similar levels of effectiveness and lower costs of esketamine attributable to insurance coverage and manufacturer assistance programs.41
The VA/DoD guideline suggests using ketamine to augment treatment for TRD.43
The VA/DoD guideline does not suggest using ketamine for the treatment of PTSD.42
CADTH previously published 3 Rapid Response reports on this topic.24,45,46
The 2017 CADTH report46 identified 3 SRs, 5 primary studies, and 2 evidence-based guidelines. Overall, IV ketamine was reported to be effective at reducing depression severity within minutes or hours for patients with TRD, and effective at reducing PTSD severity in patients with PTSD. Both guidelines included in the 2017 CADTH report recommended restricting the off-label use of ketamine for TRD to research settings.46
The 2019 CADTH report identified 6 primary clinical studies and 1 evidence-based guideline.45 Three RCTs reported that IV ketamine was significantly more effective than placebo and midazolam for the treatment of adults with TRD. One RCT reported no significant difference between IV ketamine (6 repeated doses of 0.5 mg/kg) and placebo. The 2017 VA/DoD guideline reported a strong recommendation against treating PTSD with ketamine monotherapy, based on very low-quality evidence.45 In this Rapid Review, we included the most recent VA/DoD guideline on PTSD, which maintained the weak recommendation on ketamine, reflecting the findings of recently published RCTs.42
The 2022 CADTH report24 identified 7 RCTs, 1 retrospective chart review study, and 2 guidelines. In the report, there were varied findings across individual RCTs regarding the treatment effect of ketamine for patients with TRD, namely:
The 2022 CADTH report24 also suggested that repeated IV ketamine infusions showed rapid but potentially unsustainable antidepressant effects in patients with PTSD, although the 2 studies reported mixed evidence on the effectiveness of ketamine for improving PTSD.24 The Danish guideline included in the report provided weak recommendations against the use of IV ketamine as an add-on to usual antidepressant treatment in patients with TRD. The Canadian guideline included in the report recommended IV ketamine be considered as a third-line treatment for adults with TRD.24
This Rapid Review builds on these clinical effectiveness findings, provides guidance from recent guidelines, and includes evidence on cost-effectiveness.
Further effectiveness and safety data on longer follow-up and maintenance treatment in larger populations are needed in future studies of TRD. Due to the uncertainty of existing evidence on PTSD and anxiety, more robust trials are warranted. There is a need to investigate head-to-head randomized comparisons of different routes of ketamine administration. The evidence in this report focused on ketamine administered via IV in a standard dose of 0.5 mg/kg. Future research should assess whether less invasive routes of administration are more acceptable to patients. Investigators of future trials may want to consider using outcome measures identified as important by the patient contributor engaged for this review that were not included in the evidence of this Rapid Review (e.g., quality of life, potential for misuse).
To help address health equity concerns in future studies, researchers should consider collecting equity-relevant population characteristics (e.g., gender, education, socioeconomic status, place of residence) to assess potential health inequities related to ketamine treatment for TRD and PTSD. The burden of psychiatric disorders disproportionately affects people at lower levels of socioeconomic status,47,48 and as such, researchers should consider that certain equity-deserving groups may face barriers to accessing treatment. This was reinforced by the patient contributor engaged for this review, who highlighted the significant financial implications of ketamine-assisted therapy in private clinics. The patient contributor also identified the stigma surrounding ketamine use, including being dissuaded by clinicians. Both cost and stigma may lead to greater inequities in access.
The findings of this report suggest a potential benefit of ketamine use in TRD without negative neurocognitive outcomes or severe adverse events. The patient contributor engaged for this review confirmed the immediate benefits (and no adverse events) of repeated ketamine for TRD. In contrast, ketamine may aggravate symptoms of PTSD, and its use is not recommended for veterans with PTSD in the US.42
Health care providers should consider ketamine as part of an overall TRD treatment approach. They should also closely monitor patients receiving ketamine therapy. Although the short-term side effects of ketamine were well tolerated, the safety of extended use is unknown. As the evidence base on ketamine for TRD and PTSD is continually expanding, decision-makers should stay abreast of recent findings and best practices.
US Department of Defense
electroconvulsive therapy
intramuscular
major depressive disorder
posttraumatic stress disorder
randomized controlled trial
systematic review
treatment-resistant depression
US Department of Veterans Affairs
Contributor: Joanne Kim
Selection of Included Studies.
Note that this appendix has not been copy-edited.
Characteristics of Included Systematic Reviews.
Characteristics of Included Primary Clinical Studies.
Characteristics of Included Economic Evaluation.
Characteristics of Included Guidelines.
Note that this appendix has not been copy-edited.
Strengths and Limitations of SRs Using AMSTAR 225.
Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist.
Strengths and Limitations of Economic Evaluation Using the Drummond Checklist.
Strengths and Limitations of Guidelines Using AGREE II.
Summary of Findings by Comparison — Ketamine Versus Placebo.
Summary of Findings by Comparison — Ketamine Versus Midazolam.
Summary of Findings by Comparison — ECT Versus IV Ketamine.
Summary of Findings by Comparison — Ketamine Versus Opioids.
Summary of Findings of Included Economic Evaluation.
Summary of Recommendations in Included Guidelines.
Note that this appendix has not been copy-edited.
Overlap in Relevant Primary Studies Between Included Systematic Reviews.
Note that this appendix has not been copy-edited.
Summary of Patient Involvement Using the Guidance for Reporting Involvement of Patients and the Public (Version 2) Short Form Reporting Checklist.
Note that this appendix has not been copy-edited.
The authors would like to thank the anonymous individual with lived experience for their time and energy contributing to this report.
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