CADTH Health Technology Review

Ketamine for Adults With Treatment-Resistant Depression or Posttraumatic Stress Disorder: A 2023 Update

Rapid Review

Authors: Angela M. Barbara, Weiyi Xie, Quenby Mahood, Angie Hamson

What Is the Issue?

• Many drug treatments are available for depression, but 22% of people in Canada with the condition have treatment-resistant depression (TRD). For people with TRD, standard drug treatments do not improve their symptoms or do not work for long, and their depression persists.

• Posttraumatic stress disorder (PTSD) is a disabling mental health condition that affects about 9% of people in Canada in their lifetime. Few drugs are available for treating PTSD, none of which are considered effective.

• Ketamine is a hallucinogenic drug used primarily for anesthesia. Ketamine has also been explored for other indications, such as TRD and PTSD, generating questions about whether it could be a treatment option for these conditions.

What Did We Do?

• We conducted a review of the clinical effectiveness, cost-effectiveness, and evidence-based guidelines on the use of ketamine in adults with TRD or PTSD, to help guide decisions on the use of ketamine for managing these conditions.

• An information specialist conducted a search of peer-reviewed and grey literature sources published in March 2022 or later. One reviewer screened citations and selected and critically appraised the included studies.

• CADTH engaged a patient with lived experience of TRD who shared their experiences and perspectives on ketamine-assisted psychotherapy. These perspectives helped us to contextualize the literature and appreciate nuances of the experience.

What Did We Find?

• Ketamine could lead to an immediate improvement in depressive symptoms and suicidal ideation compared to placebo or midazolam in adults with TRD. The longest follow-up was 90 days, and the longest lasting effect after a dose was 28 days. Serious side effects of ketamine — such as dissociation — were rare and short-lived, lasting hours, in adults with TRD.

• It is uncertain if ketamine is an effective and safe treatment for symptoms of PTSD, due to little to no evidence suggesting its effectiveness or safety against placebo, midazolam, or opioids.

• Most studies evaluated ketamine given intravenously, and we found limited evidence on intramuscular (IM), subcutaneous, and intranasal routes of administration. We found no studies on oral or sublingual administration of ketamine and no studies comparing the different ways that ketamine can be given for TRD or PTSD.

• An economic evaluation found that IV ketamine was likely to be cost-effective compared to intranasal esketamine in adults with TRD from a health care perspective in the US. However, from a patient perspective, IV ketamine was unlikely to be cost-effective compared to esketamine, due to comparable levels of clinical effectiveness and lower costs of esketamine attributable to commercial insurance coverage and manufacturer assistance programs.

• A US guideline on TRD suggests ketamine as augmentation to antidepressants. A US guideline on PTSD does not suggest the use of ketamine as therapy.

• The patient contributor CADTH engaged for this review highlighted the benefits, stigma, and barriers of ketamine therapy, including financial implications.

What Does This Mean?

• There is some clinical effectiveness and cost-effectiveness evidence and a guideline recommendation to support the short-term use of ketamine in adults with TRD.

• Clinical effectiveness evidence and a guideline recommendation do not support the use of ketamine in adults with PTSD.

• Future research is necessary to understand the effectiveness and safety of ketamine as therapy for TRD in larger populations over longer periods and for PTSD for any follow-up duration.

• Decision-makers should consider offering ketamine in an equitable manner.

Context and Policy Issues

What Is Treatment-Resistant Depression?

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

What Is Posttraumatic Stress Disorder?

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

What Is the Current Treatment Practice?

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.

What Is Ketamine and How Might It Benefit?

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

Why Is It Important to Do This Review?

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.

Objective

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.

Research Questions

1. What is the clinical effectiveness of ketamine versus placebo or no treatment for adults with treatment-resistant depression or posttraumatic stress disorder?

2. What is the clinical effectiveness of ketamine versus alternative interventions for adults with treatment-resistant depression or posttraumatic stress disorder?

3. What is the clinical effectiveness of ketamine administered via different routes for adults with treatment-resistant depression or posttraumatic stress disorder?

4. What is the cost-effectiveness of ketamine versus placebo or no treatment for adults with treatment-resistant depression or posttraumatic stress disorder?

5. What is the cost-effectiveness of ketamine versus alternative interventions for adults with treatment-resistant depression or posttraumatic stress disorder?

6. What is the cost-effectiveness of ketamine administered via different routes for adults with treatment-resistant depression or posttraumatic stress disorder?

7. What are the evidence-based guidelines regarding the use and administration of ketamine for adults with treatment-resistant depression or posttraumatic stress disorder?

Methods

Literature Search Methods

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.

Selection Criteria and Methods

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.

Table 1: Selection Criteria

PTSD = posttraumatic stress disorder; Q = question.

Exclusion Criteria

The following were excluded:

• articles that did not meet the selection criteria outlined in Table 1

• duplicate publications

• articles included in the previous CADTH report²⁴

• SRs in which all relevant studies were captured in other more recent or more comprehensive SRs

• SRs in which all relevant studies were included in the previous CADTH report²⁴

• SRs with eligibility criteria that met our selection criteria but did not identify any primary studies from the literature search (i.e., “empty” SRs) or did not include any primary studies that met our selection criteria (i.e., SRs with no relevant primary studies)

• primary studies that were captured in 1 or more included SRs or in the previous CADTH report;²⁴ however, if such an SR did not provide outcome data from the relevant primary study or if we knew additional information was available (e.g., included paper “under review” was published with additional data and captured in our search), then the primary study was included

• nonrandomized studies, unless identified as relevant by the included SRs (due to the availability of randomized studies)

• guidelines with unclear methodology.

Critical Appraisal of Individual Studies

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.

Patient Engagement

Invitation to Participate and Consent

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.

Engagement Activities

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.

Summary of Evidence

Quantity of Research Available

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.

Summary of Study Characteristics

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:

• 2 SRs included 1 overlapping primary study.^30,31 To avoid duplication of reporting, outcome data from this individual study were reported once as part of 1 SR.³⁰ A citation matrix illustrating the degree of overlap across the 4 SRs is presented in Appendix 5

• 2 SRs^30,33 and 1 guideline⁴³ had broader inclusion criteria for the population than the present review, with 1 SR and the guideline⁴³ on major depressive disorder (MDD) and the other SR on psychiatric disorders.³³ We included findings specific to TRD^30,33,43

• the RCT by Harvey et al.³⁶ was a substudy of the larger RCT by Loo et al.³⁸ Different outcomes were reported in each trial; therefore, we included both studies in this Rapid Review. We did not include data from a third comparison group of healthy adults in the RCT by Harvey et al³⁶

• 2 RCTs^37,39 were authored by the same group of researchers. One RCT³⁷ was conducted in 1 veterans’ hospital in Taiwan with 48 participants, and the other RCT³⁹ was conducted in the same veterans’ hospital, as well as a general hospital in Taiwan, with 84 participants. To avoid potential duplication of reporting, data for a specific outcome were reported once from 1 RCT (e.g., depression severity and suicidal ideation were reported from 1 RCT;³⁷ and treatment response, remission of suicidal ideation, and adverse events were reported once from the other RCT³⁹).

Included Studies for Research Question 1

We identified 2 SRs^30,31 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 SRs^30,31 did not identify the countries in which the included RCTs were conducted. One SR³⁰ and the 2 RCTs^34,40 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 IV^30,40 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

Included Studies for Research Question 2

We identified 3 SRs^30,31,33 and 5 double-blind parallel RCTs^35-39 comparing ketamine with alternative interventions.

Ketamine Versus Midazolam

Three SRs^30,31,33 and 5 RCTs^35-39 compared ketamine with midazolam. The studies took place in Australia,^36,38 Taiwan,^37,39 and the US.^33,35 Two SRs^30,33 and 4 RCTs^36-39 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

ECT Versus Ketamine

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.

Ketamine Versus Opioids

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.

Included Studies for Research Question 3

No clinical effectiveness studies of ketamine administered via different routes for adults with TRD or PTSD were identified; therefore, no summary can be provided.

Included Studies for Research Question 4

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.

Included Studies for Research Question 5

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

Included Studies for Research Question 6

No cost-effectiveness studies of ketamine administered via different routes for adults with TRD or PTSD were identified; therefore, no summary can be provided.

Included Studies for Research Question 7

Two evidence-based guidelines^42,43 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 guidelines^42,43 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.

Summary of Critical Appraisal

Critical appraisal summaries are organized by study design. Additional details regarding the strengths and limitations of the included publications are provided in Appendix 3.

Systematic Reviews

The 4 SRs^30-33 had clearly defined research questions and study eligibility criteria that included components of population, intervention, comparator, and outcomes. All 4 SRs^30-33 registered their protocol a priori on PROSPERO, thus reducing the risk of reporting bias. The authors of the 4 SRs^30-33 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 SRs^30-33 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 SRs^30-33 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 SRs^31-33 did not provide a list of excluded studies. Two SRs^30,31 did not indicate if risk of bias was accounted for in their findings.

Randomized Controlled Trials

The 7 RCTs^34-40 clearly defined the objective, outcomes, inclusion and exclusion criteria, interventions used, and demographics of included participants. Six RCTs^34-39 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 RCTs^34,36,37,39 reported no conflicts of interest, and 3 RCTs^35,38,40 declared potential conflicts of interests.

There were several limitations across the included RCTs.^34-40 Five RCTs^35-37,39 had very small study populations (ranging from 21 to 84 participants) that might not represent the entire population from which they were recruited. Four RCTs^34-37 did not report adverse events. Three RCTs^36,37,39 did not report a sample size calculation. In 4 RCTs,^35,37,39,40 the recruitment methods were not described.

Economic Evaluation

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

Evidence-Based Guidelines

Both included guidelines^42,43 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 guidelines^42,43 demonstrated strength in clearly presenting specific, unambiguous, and easily identifiable recommendations as well as different options for management of the conditions. The 2 guidelines^42,43 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 guidelines^42,43 were externally reviewed by experts before their publication, but neither provided a procedure for updating the guidelines.

Regarding applicability, both guidelines^42,43 provided tools for implementing recommendations, but only the 2022 VA/DoD guideline⁴³ described facilitators and barriers to the application. Moreover, both guidelines^42,43 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 guideline^42,43 stated whether the funding body influenced the content of the guideline.

Summary of Findings

The main findings from the included publications are summarized in the following sections and in Appendix 4.

Clinical Effectiveness of Ketamine Versus Placebo or no Treatment for Adults With TRD or PTSD

Ketamine Versus Placebo

Depression

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:

• depression severity: statistically significantly greater reductions from baseline with IV ketamine (0.5 mg/kg) or intranasal ketamine compared to placebo in some studies (6 RCTs in 1 SR³⁰ and 1 RCT⁴⁰), but no statistically significant differences between the 2 groups in others (3 RCTs in 1 SR³⁰)

  • one RCT in the SR³⁰ found subgroup effects: a statistically significantly greater reduction from baseline in depression severity 4 hours following a single high dose (≥ 0.5mg/kg) of IV ketamine compared to placebo, but not at a single low dose (< 0.5mg/kg), in patients with TRD

• treatment response (50% or higher reduction in depressive symptoms from baseline): no statistically significant differences between the 2 groups in some studies (6 RCTs in 1 SR³⁰) but statistically significantly greater treatment response rates with ketamine compared to placebo in others (2 RCTs in 1 SR³⁰ and 1 RCT⁴⁰), with some reporting wide confidence intervals (2 RCTs in 1 SR³⁰)

• remission: no statistically significant differences between the 2 groups in some studies (5 RCTs in 1 SR³⁰) but statistically significantly greater remission rates with ketamine compared to placebo in another (1 RCT⁴⁰).

Eight RCTs included in an SR³⁰ and 2 RCTs^34,40 assessed depression from 3 to 28 days following single-dose or repeated ketamine treatment compared to placebo in adults with TRD and reported:

• depression severity:

  • statistically significantly greater reductions from baseline at 3 days following treatment with single-dose IV ketamine compared to placebo in some studies (4 RCTs in 1 SR³⁰) but no statistically significant differences between the 2 groups in others (4 RCTs in 1 SR³⁰)

  • statistically significantly greater reductions from baseline at 1 week following treatment with a single dose or repeated treatment of ketamine compared to placebo (1 RCT in 1 SR³⁰ and 1 RCT³⁴)

  • statistically significantly greater reductions from baseline at 28 days following treatment with single-dose ketamine or repeated-dose ketamine plus automated self-association training (automated training designed to shift implicit self-associations in a positive direction) compared to placebo (1 RCT in 1 SR³⁰ and 1 RCT⁴⁰)

• treatment response: no statistically significant differences in response rates at 3 days following treatment with single-dose ketamine versus placebo in some studies (5 RCTs in 1 SR³⁰) but statistically significantly greater treatment response rates with ketamine compared to placebo in others (3 RCTs in 1 SR³⁰)

• remission: no statistically significant differences in remission rates at 3 days following treatment with single-dose ketamine and placebo (4 RCTs in 1 SR³⁰).

Psychological Symptoms

In patients with TRD, the RCT by Ahmed et al.³⁴ found:

• higher frequency of “abnormal” (as reported by study authors) responses in obsessive-compulsive, interpersonal sensibility, and paranoid ideation measures with ketamine compared to placebo at 1 week following treatment, and the differences between the 2 groups were statistically significant³⁴

• higher frequency of “abnormal” (as reported by study authors) responses in somatization, anxiety, anger-hostility, phobic anxiety, and psychosis measures with ketamine compared to placebo at 1 week following treatment, but the differences between the 2 groups were not statistically significant.³⁴

PTSD

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

Suicidal Ideation

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

Adverse Events

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

Clinical Effectiveness of Ketamine Versus Alternative Interventions for Adults With TRD or PTSD

Ketamine Versus Midazolam

Depression

In patients with TRD, the following were reported on the effects of single-dose ketamine versus midazolam:

• depression severity:

  • statistically significantly greater reduction at 24 hours after single-dose IV or subcutaneous ketamine (0.5 mg/kg) compared to midazolam (1 RCT in 1 SR³⁰ and 1 RCT³⁶)

  • statistically significantly greater reductions in depression scores with low-dose subcutaneous or IM ketamine (0.2 mg/kg or 4 mg/kg) compared to midazolam at 24 hours after treatment, but no statistically significant differences between low-dose IV ketamine and midazolam (1 RCT in 1 SR³⁰)

  • statistically significantly greater reductions in depression 3 days after single-dose ketamine compared to midazolam (1 RCT³⁷)

• treatment response:

  • no statistically significant differences in response rates between low-dose subcutaneous, IM, or IV ketamine and midazolam at 24 hours following treatment (1 RCT in 1 SR³⁰ and 1 RCT³⁶)

  • statistically significantly greater response rates 3 days following single ketamine infusion compared to midazolam in 1 study (1 RCT³⁹), but no statistically significant differences between the 2 groups in another study (1 RCT in 1 SR³⁰)

• remission: no statistically significant differences in remission rates between low-dose subcutaneous, IM, or IV ketamine and midazolam at 24 hours following treatment (1 RCT in 1 SR³⁰ and 1 RCT³⁶).

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:

• With fixed-dose ketamine (0.5 mg/kg) compared to fixed-dose midazolam (0.25 mg/kg), there were no statistically significant differences in change in depression scores, response rates, or remission rates after treatment.³⁸ There were also no statistically significant differences between the 2 groups in response or remission rates at the 4-week follow-up. There were no statistically significant between-group differences in mental health scores after treatment, but there were statistically significant differences at 4 weeks favouring midazolam.³⁸

• With flexible-dose ketamine (0.5 to 0.9 mg/kg) compared to flexible-dose midazolam (0.025 to 0.045 mg/kg), where dosing was increased depending on response, there were statistically significant differences in posttreatment depression scores and remission rates in favour of flexible-dose ketamine.³⁸ At the 4-week follow-up, there was a statistically significant difference in depression scores favouring flexible-dose ketamine but no statistically significant difference in remission rates.³⁸ There were statistically significantly greater changes in mental health scores in the ketamine group after treatment but no statistically significant between-group differences at 4 weeks.³⁸

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

Anxiety

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

PTSD

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

Neurocognitive Outcomes

The RCT by Harvey et al.³⁶ assessed neurocognitive changes following single-dose ketamine or midazolam treatment in patients with TRD and reported:

• statistically significant time effects and statistically significant group effects for verbal fluency, showing better overall performance in the midazolam group

• a statistically significant time by group interaction was found for negative affective bias; post hoc testing revealed that participants in the ketamine group performed significantly better on the Scramble Sentence test after treatment

• no statistically significant interactions for response time to affective stimuli, concentration and selective attention (total speed), and affective bias.³⁶

Suicidal Ideation

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.

Adverse Events

Two RCTs^38,39 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

ECT Versus Ketamine

Depression

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

Ketamine Versus Opioids

PTSD

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.

Clinical Effectiveness of Ketamine Administered via Different Routes for Adults With TRD or 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.

Cost-Effectiveness of Ketamine Versus Placebo or no Treatment for Adults With TRD or PTSD

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.

Cost-Effectiveness of Ketamine Versus Alternative Interventions for Adults With TRD or PTSD

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:

• In the base-case analysis, IV ketamine was dominant, regardless of the source of effectiveness data (i.e., clinical trial or real-world data).

• In the sensitivity analysis, there were no scenarios in which esketamine was cost-effective compared to IV ketamine.⁴¹

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:

• In the base-case analysis, the incremental cost-effectiveness ratio of ketamine compared to esketamine was $867,606 per QALY with clinical trial estimates and $7,037,560 per QALY with real-world effectiveness data. Both incremental cost-effectiveness ratios exceeded the willingness-to-pay threshold of $150,000 per QALY, with medication costs driving the total costs.

• In the sensitivity analysis, at a threshold of $150,000 per QALY, the probability that esketamine was superior compared to ketamine was 0.0055 using clinical trial efficacy estimates and 0.35 using real-world evidence.

Cost-Effectiveness of Ketamine Administered via Different Routes for Adults With TRD or PTSD

No cost-effectiveness studies of ketamine administered via different routes for adults with TRD or PTSD were identified; therefore, no summary can be provided.

Evidence-Based Guidelines on the Use and Administration of Ketamine for Adults With TRD or PTSD

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.

Limitations

Evidence Gaps

No evidence was found for the following; therefore, no conclusions can be formed on the respective research questions:

• the clinical effectiveness of ketamine administered via different routes for adults with TRD or PTSD

• the cost-effectiveness of ketamine versus placebo or no treatment for adults with TRD or PTSD

• the cost-effectiveness of ketamine administered via different routes for adults with TRD or PTSD.

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.

Certainty of the Evidence

Risk of Bias of Included Studies in Systematic Reviews

Of the included studies in the 4 SRs, as assessed by the review authors, 2 studies from 2 of the SRs^31,32 were at low risk of bias, while the other studies from 3 of the SRs^30,31,33 had either some concerns or high risk of bias related to random sequence generation, allocation concealment, blinding of outcome assessors, and selective reporting.

Quality of Evidence in Included Guidelines

Both evidence-based guidelines^42,43 provided weak recommendations based on low-quality or very low-quality evidence.

Generalizability

None of the clinical effectiveness studies^31-39 were conducted in Canada, which may limit the generalizability of the findings of this Rapid Review to the Canadian health care context. Two SRs^30,31 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 RCTs^37,39 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 SRs^30-33 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 guidelines^42,43 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.

Heterogeneity

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 SRs^30,32,33 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 RCTs^34,39 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.

Imprecision

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.

Conclusions and Implications for Decision- or Policy-Making

This report comprises 4 SRs^30-33 and 7 RCTs^34-40 on the clinical effectiveness of ketamine, 1 economic evaluation⁴¹ on the cost-effectiveness of ketamine, and 2 evidence-based guidelines^42,43 on the use of ketamine in adults with TRD or PTSD.

Ketamine Compared to Placebo

Patients With TRD

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

Patients With PTSD

In adults with PTSD, ketamine may not have an effect on PTSD symptoms 24 hours after treatment compared to placebo, but this finding is uncertain due to imprecision.³¹ Also, our confidence in the results of this SR³¹ is low (based on our assessment using AMSTAR 2).

Ketamine Compared to Alternative Therapies

Ketamine Compared to Midazolam

Patients With TRD

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

Patients With PTSD

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

Ketamine Compared to ECT

Patients With TRD

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

Ketamine Compared to Opioids

Patients With PTSD

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

Ketamine Compared to Esketamine

Patients With TRD

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

Recommendations Regarding Ketamine

Patients With TRD

The VA/DoD guideline suggests using ketamine to augment treatment for TRD.⁴³

Patients With PTSD

The VA/DoD guideline does not suggest using ketamine for the treatment of PTSD.⁴²

Findings From Previous CADTH Reports

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:

• significantly greater reduction in depressive symptoms with repeated administration of oral ketamine compared with placebo

• faster improvement in depressive symptoms and fewer ECT treatments for disease remission with IV ketamine-based anesthesia versus propofol-based anesthesia

• improvement of depression in patients with TRD using IV ketamine as an anesthetic drug or methohexital anesthesia for ECT

• comparable acute antidepressant effects 24 hours after infusion for IV ketamine and IV esketamine

• no significant differences in depression and anxiety improvement between repeated administration of IM ketamine and repeated transcranial magnetic stimulation.²⁴

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.

Considerations for Future Research

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.

Implications for Clinical Practice

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.

References

1.Canadian Mental Health Association. Fast facts about mental health and mental illness. 2021; https://cmha.ca/brochure/fast-facts-about-mental-illness/. Accessed 2023 Nov 27.

2.Rizvi SJ, Grima E, Tan M, et al. Treatment-resistant depression in primary care across Canada. Can J Psychiatry. 2014;59(7):349-357. PubMed

3.Rybak YE, Lai KSP, Ramasubbu R, et al. Treatment-resistant major depressive disorder: Canadian expert consensus on definition and assessment. Depress Anxiety. 2021;38(4):456-467. PubMed

4.Mood Disorders Society of Canada. 2018 Treatment Resistant Depression Study. 2018; https://mdsc.ca/wp-content/uploads/2018/04/MDSC-Treatment-Resistant-Depression-Study-April-25.pdf. Accessed 2023 Nov 27.

5.McIntyre RS, Millson B, Power GS. Burden of Treatment Resistant Depression (TRD) in patients with major depressive disorder in Ontario using Institute for Clinical Evaluative Sciences (ICES) databases: economic burden and healthcare resource utilization. J Affect Disord. 2020;277:30-38. PubMed

6.Veteran Affairs Canada. Learn about PTSD. 2019; https://www.veterans.gc.ca/eng/health-support/mental-health-and-wellness/understanding-mental-health/learn-ptsd#b3. Accessed 2023 Nov 27.

7.Veteran Affairs Canada. Post-traumatic stress disorder (PTSD) and war-related stress. 2019; https://www.veterans.gc.ca/eng/health-support/mental-health-and-wellness/understanding-mental-health/ptsd-warstress. Accessed 2023 Nov 27.

8.Hoskins M, Pearce J, Bethell A, et al. Pharmacotherapy for post-traumatic stress disorder: systematic review and meta-analysis. Br J Psychiatry. 2015;206(2):93-100. PubMed

9.Beck JS. Cognitive behavior therapy: Basics and beyond. New York (NY): Guilford Publications; 2020.

10.Stein MB, Norman S. Posttraumatic stress disorder in adults: psychotherapy and psychosocial interventions. In: Post TW, ed. UpToDate. Waltham (MA): UpToDate; 2023: http://www.uptodate.com. Accessed 2023 Nov 27.

11.Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366. PubMed

12.Rossi GN, Hallak JEC, Baker G, Dursun SM, Dos Santos RG. The effects of ketamine and classic hallucinogens on neurotrophic and inflammatory markers in unipolar treatment-resistant depression: a systematic review of clinical trials. Eur Arch Psychiatry Clin Neurosci. 2023;273(1):129-155. PubMed

13.de A Simoes Moreira D, Gauer LE, Teixeira G, Fonseca da Silva AC, Cavalcanti S, Quevedo J. Efficacy and adverse effects of ketamine versus electroconvulsive therapy for major depressive disorder: A systematic review and meta-analysis. J Affect Disord. 2023;330:227-238. PubMed

14.Dehestani S, Mohammadpour AH, Sadjadi SA, Sathyapalan T, Sahebkar A. Clinical use of ketamine in psychiatric disorders. Ann Med Psychol (Paris). 2023;181(6):495-508.

15.Ketamine hydrochloride injection USP (ketamine hydrochloride): 10 mg/mL ketamine; 50 mg/mL [product monograph]. Boucherville (QC): Sandoz Canada Inc.; 2021: https://pdf.hres.ca/dpd_pm/00060020.PDF. Accessed 2023 Nov 27.

16.Yavi M, Lee H, Henter ID, Park LT, Zarate CA, Jr. Ketamine treatment for depression: a review. Discov Ment Health. 2022;2(1):9. PubMed

17.Andrade C. Ketamine for depression, 3: does chirality matter? J Clin Psychiatry. 2017;78(6):e674-e677. PubMed

18.Zhang K, Hashimoto K. An update on ketamine and its two enantiomers as rapid-acting antidepressants. Expert Rev Neurother. 2019;19(1):83-92. PubMed

19.Ketamine hydrochloride injection USP: 50 mg/ML sterile solution [product monograph]. Oakville (ON): SteriMax Inc.; 2021: https://pdf.hres.ca/dpd_pm/00063099.PDF. Accessed 2023 Nov 27.

20.Ketamine injection, BP: 50 mg/ML Ketamine (as Ketamine hydrochloride), 2 mL (100 mg/2mL) and 10 mL (500 mg/10mL) vials sterile solution for intravenous or intramuscular administration [product monograph]. Mississauga (ON): Baxter Corporation; 2022: https://pdf.hres.ca/dpd_pm/00064969.PDF. Accessed 2023 Nov 27.

21.Andrade C. Ketamine for depression, 1: clinical summary of issues related to efficacy, adverse effects, and mechanism of action. J Clin Psychiatry. 2017;78(4):e415-e419. PubMed

22.Beaglehole B, Glue P, Clarke M, Porter R. Multidisciplinary development of guidelines for ketamine treatment for treatment-resistant major depression disorder for use by adult specialist mental health services in New Zealand. BJPsych Open. 2023;9(6):e191. PubMed

23.Albuquerque TR, Macedo LFR, Delmondes GA, et al. Evidence for the beneficial effect of ketamine in the treatment of patients with post-traumatic stress disorder: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2022;42(12):2175-2187. PubMed

24.Tran K, Mahood Q. Ketamine for adults with treatment-resistant depression or post-traumatic stress disorder (CADTH health technology review). Can J Health Technolog. 2022;2(4). https://www.cadth.ca/sites/default/files/pdf/htis/2022/RC1420-Ketamine-for-treatment-resistant-depression-and-PTSD.pdf. Accessed 2023 Nov 10.

25.Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. PubMed

26.Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377-384. PubMed

27.Higgins JPT, Green S, editors. Figure 15.5.a: Drummond checklist (Drummond 1996). Cochrane handbook for systematic reviews of interventions. London (GB): Cochrane Collaboration; 2011: http://handbook-5-1.cochrane.org/chapter_15/figure_15_5_a_drummond_checklist_drummond_1996.htm. Accessed 2023 Nov 27.

28.Agree Next Steps Consortium. The AGREE II Instrument [Hamilton, ON]: AGREE Enterprise; 2017: https://www.agreetrust.org/wp-content/uploads/2017/12/AGREE-II-Users-Manual-and-23-item-Instrument-2009-Update-2017.pdf. Accessed 2023 Nov 27.

29.Staniszewska S, Brett J, Simera I, et al. GRIPP2 reporting checklists: tools to improve reporting of patient and public involvement in research. BMJ. 2017;358:j3453. PubMed

30.Nikolin S, Rodgers A, Schwaab A, et al. Ketamine for the treatment of major depression: a systematic review and meta-analysis. EClinicalMedicine. 2023;62:102127. PubMed

31.Du R, Han R, Niu K, et al. The multivariate effect of ketamine on PTSD: systematic review and meta-analysis. Front Psychiatry. 2022;13:813103. PubMed

32.Shafiee A, Soltani Abhari F, Jafarabady K, Bakhtiyari M. Ketamine versus electroconvulsive therapy for treatment-resistant depression: an updated meta-analysis of randomized clinical trials. Asian J Psychiatr. 2023;88:103720. PubMed

33.Marchi M, Magarini FM, Galli G, et al. The effect of ketamine on cognition, anxiety, and social functioning in adults with psychiatric disorders: a systematic review and meta-analysis. Front Neurosci. 2022;16:1011103. PubMed

34.Ahmed GK, Elserogy YM, Elfadl GMA, Ghada Abdelsalam K, Ali MA. Antidepressant and anti-suicidal effects of ketamine in treatment-resistant depression associated with psychiatric and personality comorbidities: a double-blind randomized trial. J Affect Disord. 2023;325:127-134. PubMed

35.Duek O, Korem N, Li Y, et al. Long term structural and functional neural changes following a single infusion of Ketamine in PTSD. Neuropsychopharmacology. 2023;48(11):1648-1658. PubMed

36.Harvey AJ, Nikolin S, Chand N, et al. Change in negative affective bias following a single ketamine treatment for treatment-resistant depression. Depress Anxiety. 2023;2023:3371272.

37.Li WC, Chen LF, Su TP, et al. Right dorsolateral prefrontal cortex volumetric reduction is associated with antidepressant effect of low-dose ketamine infusion: a randomized, double-blind, midazolam-controlled PET-MRI clinical trial. J Affect Disord. 2023;335:105-110. PubMed

38.Loo C, Glozier N, Barton D, et al. Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial. Br J Psychiatry. 2023:1-9. PubMed

39.Su TP, Li CT, Lin WC, et al. A randomized, double-blind, midazolam-controlled trial of low-dose ketamine infusion in patients with treatment-resistant depression and prominent suicidal ideation. Int J Neuropsychopharmacol. 2023;26(5):331-339. PubMed

40.Price RB, Spotts C, Panny B, et al. A novel, brief, fully automated intervention to extend the antidepressant effect of a single ketamine infusion: a randomized clinical trial. Am J Psychiatry. 2022;179(12):959-968. PubMed

41.Brendle M, Robison R, Malone DC. Cost-effectiveness of esketamine nasal spray compared to intravenous ketamine for patients with treatment-resistant depression in the US utilizing clinical trial efficacy and real-world effectiveness estimates. J Affect Disord. 2022;319:388-396. PubMed

42.Department of Veteran Affairs, Department of Defense. VA/DoD clinical practice guideline for management of posttraumatic stress disorder and acute stress disorder. Washington (DC): U.S. Government Printing Office; 2023: https://www.healthquality.va.gov/guidelines/MH/ptsd/VA-DoD-CPG-PTSD-Full-CPG.pdf. Accessed 2023 Nov 27.

43.Department of Veteran Affairs, Department of Defense. VA/DoD clinical practice guideline for the management of major depressive disorder. Washington (DC): U.S. Government Printing Office; 2022: https://www.healthquality.va.gov/guidelines/MH/mdd/VADoDMDDCPGFinal508.pdf. Accessed 2023 Nov 27.

44.Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142. PubMed

45.Li K, Loshak H. Intravenous ketamine for adults with treatment resistant depression or post-traumatic stress disorder: a review of clinical effectiveness, cost-effectiveness and guidelines. (CADTH rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2019: https://www.cadth.ca/sites/default/files/pdf/htis/2019/RC1203%20IV%20Ketamine%20for%20Depression%20and%20PTSD%20Final.pdf. Accessed 2023 Nov 24.

46.Kim J, Mierzwinski-Urban M. Ketamine for treatment resistant depression or post-traumatic stress disorder in various settings: a review of clinical effectiveness, safety, and guidelines. (CADTH rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2017: https://www.cadth.ca/sites/default/files/pdf/htis/2017/RC0855%20Ketamine%20for%20Resistant%20Depression%20Final.pdf. Accessed 2023 Nov 24.

47.Freeman A, Tyrovolas S, Koyanagi A, et al. The role of socio-economic status in depression: results from the COURAGE (aging survey in Europe). BMC Public Health. 2016;16:1-8. PubMed

48.Hopper S, Best JR, Wister AV, Cosco TD. Contributors to mental health resilience in middle-aged and older adults: an analysis of the Canadian Longitudinal Study on Aging. Int Psychogeriatr. 2023:1-10. PubMed

49.Blum L. Montgomery Asberg Depression Rating Scale (MADRS) In: Korner-Bitensky N, ed. Stroke Engine Assessments. Montreal (QC): Stroke Engine; 2009 Sept 21: https://strokengine.ca/en/assessments/montgomery-asberg-depression-rating-scale-madrs/. Accessed 2023 Nov 23.

50.Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23(1):56-62. PubMed

51.Derogatis LR, Kathryn L. The SCL-90-R and Brief Symptom Inventory (BSI) in primary care. Handbook of Psychological Assessment in Primary Care Settings. New York (NY): Routledge; 2000:310-347.

52.Weathers FW, Litz B, Herman D, Juska J, Keane T. PTSD checklist: civilian version (PCL-C). APA PsycTests. 1993. https://psycnet.apa.org/doiLanding?doi=10.1037%2Ft02622-000. Accessed 2023 Nov 27.

53.Weathers FW, Keane TM, Davidson JR. Clinician-administered PTSD scale: a review of the first ten years of research. Depress Anxiety. 2001;13(3):132-156. PubMed

54.Beck AT, Steer RA, Ball R, Ranieri WF. Comparison of Beck Depression Inventories-IA and-II in psychiatric outpatients. J Person Assess. 1996;67(3):588-597. PubMed

55.Ronk FR, Korman JR, Hooke GR, Page AC. Assessing clinical significance of treatment outcomes using the DASS-21. Psychol Assess. 2013;25(4):1103. PubMed

56.Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37. PubMed

57.Spielberger CD. State-trait anxiety inventory for adults. APA PsycTests. 1983.

58.U.S. Department of Veteran Affairs. Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). 2021; https://www.ptsd.va.gov/professional/assessment/adult-int/caps.asp. Accessed 2023 Nov 23.

59.Motlagh H. Impact of event scale-revised. J Physiother. 2010;56(3):203. PubMed

60.U.S. Department of Veteran Affairs. PTSD checklist for DSM-5 (PCL-5). 2023; https://www.ptsd.va.gov/professional/assessment/adult-sr/ptsd-checklist.asp. Accessed 2023 Nov 23.

61.Costin F. The scrambled sentence test: a group measure of hostility. Educ Psychol Meas. 1969;29(2):461-468.

62.Controlled Oral Word Association Test (COWAT). Health ABC Study: Operations Manual. Vol XV.2012: https://healthabc.nia.nih.gov/sites/default/files/COWATOMY16_0.pdf.

63.Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-1277. PubMed

64.Brown ES, Murray M, Carmody TJ, et al. The Quick Inventory of Depressive Symptomatology-Self-report: a psychometric evaluation in patients with asthma and major depressive disorder. Ann Allergy, Asthma Immunol. 2008;100(5):433-438. PubMed

65.Bryant RA, Moulds ML, Guthrie RM. Acute Stress Disorder Scale: a self-report measure of acute stress disorder. Psychol Assess. 2000;12(1):61. PubMed

Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Note that this appendix has not been copy-edited.

Table 2: Characteristics of Included Systematic Reviews

ASDS = Acute Stress Disorder Scale; CAPS-5 = Clinician-Administered PTSD Scale; DSM = Diagnostic and Statistical Manual of Mental Disorders; ECT = electroconvulsive therapy; HDRS = Hamilton Depression Rating Scale; ICD = International Classification of Diseases; IES-R = Impact of Event Scale-Revised; MADRS = Montgomery-Asberg Depression Rating Scale; MDD = major depressive disorder; NR = not reported; PCL-C = PTSD Checklist — Civilian Version; PTSD = posttraumatic stress disorder; QIDS-SR-16 = Quick Inventory of Depressive Symptomatology-Self-Report; RCT = randomized controlled trial; SR = systematic review; STAI-S = State-Trait Anxiety Inventory — State; TRD = treatment-resistant depression.

Table 3: Characteristics of Included Primary Clinical Studies

AGNG = Affective Go/No Go; ASAT = automated self-association training; BDI = Beck Depression Inventory; CAPS-5 = Clinician-Administered PTSD Scale for DSM-5; CGI = Clinical Global Impression; CGI-I = CGI-improvement; CGI-S = CGI-severity; COWAT: Controlled Word Association Test; CSSRS-ISS = Columbia-Suicide Severity Rating Scale — Ideation Severity Subscale; CTI = Cognitive Triad Inventory; DASS-21 = Depression Anxiety Stress Scale; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ECT = electroconvulsive therapy; EMA = European Medicines Agency; EST = Emotional Stroop Test; GSE = Global Self-Evaluation of Memory; HDRS = Hamilton Depression Rating Scale; IN = Intranasal; KADS = Ketamine for Adult Depression Study; MADRS = Montgomery-Asberg Depression Rating Scale; MDD = major depressive disorder; PGI-I = Patient Global Impression — Improvement; PCL-5 = PTSD Checklist for DSM-5; QIDS-SR-16 = Quick Inventory of Depressive Symptomatology-Self-Report; RCT = randomized controlled trial; SC = subcutaneous; SD = standard deviation; SPS = Suicide Probability Scale; SST = Scrambled Sentence Test; TRD = treatment-resistant depression.

Note: Sex and/or gender categories were reported differently in the studies included in this table; the original source wording from each study has been retained here.

Table 4: Characteristics of Included Economic Evaluation

EHR = electronic health record; IM = intramuscular; MDD = major depressive disorder; TRD = treatment-resistant depression.

Table 5: Characteristics of Included Guidelines

ASD = acute stress disorder; CPG = clinical practice guideline; DSM-5 = Statistical Manual of Mental Disorders, Fifth Edition; DoD = US Department of Defense; DTD = difficult-to-treat depression; GRADE = Grades of Recommendation Assessment, Development and Evaluation; ICD = International Classification of Diseases; MAGICapp = Making GRADE the Irresistible Choice; MDD = major depressive disorder; PTSD = posttraumatic stress disorder; QoL = quality of life; VA = US Department of Veterans Affairs.

^aUpdate to 2017 guideline.

^bUpdate to 2016 guideline.

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 6: Strengths and Limitations of SRs Using AMSTAR 2²⁵

AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; RCT = randomized controlled trial; ROB = risk of bias; SR = systematic review.

Table 7: Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist²⁶

DSMB = Data Safety Monitoring Board; ECT = electroconvulsive therapy; ITT = intention to treat; RCT = randomized controlled trial.

Table 8: Strengths and Limitations of Economic Evaluation Using the Drummond Checklist²⁷

Table 9: Strengths and Limitations of Guidelines Using AGREE II²⁸

AGREE II = Appraisal of Guidelines for Research and Evaluation II; NR = not reported; VA/DoD = US Department of Veterans Affairs and Department of Defense.

Appendix 4: Main Study Findings

Table 10: Summary of Findings by Comparison — Ketamine Versus Placebo

ASAT = automated self-association training; BDI = Beck Depression Inventory; CAPS = Clinician-Administered PTSD Scale; CI = confidence interval; HDRS = Hamilton Depression Rating Scale; IN = intranasal; MADRS = Montgomery-Asberg Depression Rating Scale; MD = mean difference; MDD = major depressive disorder; NA = not applicable; NR = not reported; OR = odds ratio; PCL-C = PTSD Checklist — Civilian Version; PTSD = posttraumatic stress disorder; RCT = randomized controlled trial; SCL = Symptom Checklist; SD = standard deviation; SMD = standardized mean difference; SPS = Suicide Probability Scale; SR = systematic review, TRD = treatment-resistant depression.

Note that this appendix has not been copy-edited.

^aMADRS has 10 items and is used by clinicians to assess the severity of depression in patients with a diagnosis of depression. Higher scores indicate more severe depression.⁴⁹

^bHDRS is used to measure the severity of symptoms of depression based on 17-item scales. The sum of all items makes up the total score: 0 to 7 = no depression; 8 to 13 = mild depression; 14 to 18 = moderate depression; 19 to 22 = severe depression; and ≥ 23 = very severe depression.⁵⁰

^cAssessed 4 hours following treatment.

^dIV high dose = ≥ 0.5 mg/kg.

^eIV low dose = < 0.5 mg/kg.

^fSCL-90 is a self-report instrument that includes 90 items and 9 subscales to assess a wide range of psychological issues and psychopathology symptoms.⁵¹ Scores on the depression subscale were not reported in the RCT by Ahmed et al.³⁴

^gPCL is a standardized self-report rating scale for PTSD comprising 17 Likert-type items that correspond to the key symptoms of PTSD. Two versions of the PCL exist: PCL-M is specific to PTSD caused by military experiences and PCL-C is applied generally to any traumatic event. Higher scores indicate more severe PTSD.⁵²

^hCAPS is a structured interview for PTSD diagnostic status and symptom severity. Hight scores indicate more severe PTSD.⁵³

ⁱSPS is a self-report 36-item Likert-type scale to assess suicide risk. Suicide probability is calculated by total scores. In males, 0 to 36 = no clinical depression; 37 to 44 = mild; 45 to 51 = moderate; and > 52 = severe. In females, a total score of 0 to 33 = no clinical depression; 34 to 38 = mild; 39 to 43 = moderate; and > 44 = severe.³⁴

Table 11: Summary of Findings by Comparison — Ketamine Versus Midazolam

AGNG Neg = Affective Go/No Go Task Negative Shift; AGNG Pos = Affective Go/No Go Positive Shift; aOR = adjusted odds ratio; BDI-II = Beck Depression Inventory, version 2; CAPS = Clinician-Administered PTSD Scale; CCSRS-ISS = Columbia-Suicide Severity Rating Scale — Ideation Severity Subscale; CGI = Clinical Global Impression; CGI-I = CGI — improvement; CGI-S = CGI — severity; CI = confidence interval; COWAT = Controlled Word Association Test; DASS-21 = Depression Anxiety Stress Scale; EST Emotional Stroop Task; Impact of Event Scale-Revised; MADRS = Montgomery-Asberg Depression Rating Scale; NA = not applicable; NEB = Negative Expressions Bias; NR = not reported; nss = not statistically significant; PCL = PTSD Checklist; OR = odds ratio; PEB = Positive Expressions Bias; PTSD = posttraumatic stress disorder; RCT = randomized controlled trial; Ruff 2 and 7 = Ruff 2 and 7 Selective Attention Test; SC = subcutaneous; SD = standard deviation; SST = Scrambled Sentence test; STAI-S = State-Trait Anxiety Inventory — State; TRD = treatment-resistant depression.

^aMADRS has 10 items and is used by clinicians to assess the severity of depression in patients with a diagnosis of depression. Higher scores indicate more severe depression.⁴⁹

^bBDI-II assesses depression severity and consists of 21 Likert-type items. Higher scores indicate more severe depression.⁵⁴

^cDASS-21 is a self-rating scale which assesses depressive, anxiety, and stress symptoms. Higher scores indicate elevated depression, anxiety, or stress.⁵⁵

^dHDRS is used to measure the severity of symptoms of depression based on 17-item scales. The sum of all items makes up the total score: 0 to 7 = no depression; 8 to 13 = mild depression; 14 to 18 = moderate depression; 19 to 22 = severe depression; and ≥ 23 = very severe depression.⁵⁰

^eFixed dose = 0.025 mg/kg.

^fFlexible dose = started at 0.025 mg/kg and escalated to 0.03 mg/kg, 0.0375 mg/kg, and 0.045 mg/kg based on MADRS score.

^gCGI is a standardized assessment scale for determining the effect of mental health treatment among patients with psychiatric conditions. It has 2 separate global subscales: Severity Illness (CGI-S) and Global Improvement (CGI-I). The CGI-S rates the severity on a 1 to 7 scale, with 1 representing normal symptoms (patient is not ill), 4 representing moderately ill, and 7 representing most severely ill. The CGI-I is taken after treatment and compared with baseline. It rates the improvement on a 1 to 7 scale, with 1 representing very much improved, 4 for no change from treatment, 7 for very much worse due to treatment.⁵⁶

^hSTAI is the definitive instrument for measuring anxiety in adults. The STAI clearly differentiates between the temporary condition of “state anxiety” and the more general and long-standing quality of “trait anxiety.” The qualities evaluated by the STAI-S Anxiety scale are feelings of apprehension, tension, nervousness, and worry. Higher scores indicate greater anxiety.⁵⁷

ⁱPTSD scale was NR.

^jCAPS was adapted as the Diagnostic and Statistical Manual of Mental Disorders (DSM) moved from DSM-IV (CAPS-IV) to DSM-5 (CAPS-5). CAPS-5, a 30-item structured interview, is the gold standard in PTSD assessment. Higher scores indicate more frequent and intense PTSD symptoms.⁵⁸

^kIES-R is a self-report measure of current subjective distress in response to a specific traumatic event). The 22-item scale comprises 3 subscales: intrusion, avoidance, and hyperarousal. Higher scores indicate a greater degree of distress.⁵⁹

^lPCL-5 is a 20-item self-report Likert-type measure that assesses the 20 DSM-5 symptoms of PTSD. Each item was rated on a 5-point Likert (0 = “not at all” to 4 = “extremely”). A total symptom severity score (0 to 80 range) can be obtained by summing the scores for each of the 20 items. A 5-to-10-point change represents reliable change (i.e., change not due to chance) and a 10-to-20-point change represents clinically significant change.⁶⁰

^mSST assesses hostility (negative cognitive bias, referring to tendency to react more strongly to negative stimuli). Participants unscramble as many sentences as possible from 20 trials of scrambled words into grammatically correct sentences within 4 minutes. The total score is the number of hostile (negative) sentences assembled.^36,61

ⁿEST assesses response inhibition in the context of affective stimuli. 25 words were presented in random order and colour in each of 5 categories (positive, negative, aggressive, neutral, and colour). The primary outcomes were mean response time (minutes) for positive and negative words subtracted from the mean response time for neutral words.³⁶

^oAGNG assesses affective bias. The tasks consisted of 10 blocks (of 18 words each) with rapidly presented positive (intrinsically attractive) and negative (intrinsically aversive) valence words. The outcomes were the response latencies (minutes) in blocks where the target valence had shifted from negative to positive or positive to negative.³⁶

^pRuff 2 and 7 assesses concentration and selective attention. Participants were required to cross out 2s and 7s as quickly as possible without making mistakes. The task has 20 blocks, each containing 3 lines. Each line had 10 targets and 40 distractors. The outcome was total speed t score, which reflects the total accurate identifications, adjusted based on age and education.³⁶

^qCOWAT is a verbal fluency test that measures spontaneous production of words with the given letter (C, F, or L). Individuals are also instructed to exclude proper nouns, numbers, and the same word with a different suffix.⁶²

^rCCSRS-ISS assesses suicide symptoms using 5 yes or no questions, including question 1: wish to be dead; question 2: nonspecific suicidal thoughts; and questions 3 to 5: more specific suicidal thoughts and intent to act. Higher scores indicate more severe symptoms.^39,63

Table 12: Summary of Findings by Comparison — ECT Versus IV Ketamine

CI = confidence interval; ECT = electroconvulsive therapy; MADRS = Montgomery-Asberg Depression Rating Scale; NR = not reported; PTSD = posttraumatic stress disorder; QIDS-SR-16 = Quick Inventory of Depressive Symptomatology-Self-Report; RCT = randomized controlled trial; RR = risk ratio; SMD = standardized mean difference; TRD = treatment-resistant depression.

^aQIDS-SR-16 is a 16-item self-report rating scale of depressive symptom severity within the past 7 days. The measure assesses all of the clinical domains used in making a diagnosis of major depressive disorder.⁶⁴

^bMADRS has 10 items and is used by clinicians to assess the severity of depression in patients with a diagnosis of depression. Higher scores indicate more severe depression.⁴⁹

Table 13: Summary of Findings by Comparison — Ketamine Versus Opioids

ASDS = Acute Stress Disorder Scale; CI = confidence interval; MD = mean difference; PTSD = posttraumatic stress disorder; SR = systematic review; TRD = treatment-resistant depression.

^aASDS is a self-report 19-item inventory that assesses acute stress disorder and predicts PTSD on the following subscales: avoidance, dissociation, hyperarousal, and reexperiencing. Higher scores indicate greater acute stress.⁶⁵

Table 14: Summary of Findings of Included Economic Evaluation

ICER = incremental cost-effectiveness ratio; NR = not reported; QALY = quality-adjusted life-year; RWE = real-world effectiveness; TRD = treatment-resistant depression; USD = US dollars; vs = versus.

Table 15: Summary of Recommendations in Included Guidelines

MDD = major depressive disorder; PTSD = posttraumatic stress disorder; RCT = randomized controlled trial; SR = systematic review; VA/DoD = US Department of Veterans Affairs and Department of Defense.

Appendix 5: Overlap Between Included Systematic Reviews

Note that this appendix has not been copy-edited.

Table 16: Overlap in Relevant Primary Studies Between Included Systematic Reviews

Appendix 6: Patient Involvement

Note that this appendix has not been copy-edited.

Table 17: Summary of Patient Involvement Using the Guidance for Reporting Involvement of Patients and the Public (Version 2) Short Form Reporting Checklist²⁹

TRD = treatment-resistant depression.

Appendix 7: References of Potential Interest

Note that this appendix has not been copy-edited.

Previous CADTH Reports

Ketamine for adults with treatment-resistant depression or post-traumatic stress disorder. (CADTH rapid response report). Ottawa (ON): CADTH; 2022. https://www.cadth.ca/ketamine-adults-treatment-resistant-depression-or-post-traumatic-stress-disorder. Accessed 2023 Nov 27.

Intravenous ketamine for adults with treatment-resistant depression or post-traumatic stress disorder: a review of clinical effectiveness, cost-effectiveness and guidelines. (CADTH rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2019. https://www.cadth.ca/intravenous-ketamine-adults-treatment-resistant-depression-or-post-traumatic-stress-disorder-review. Accessed 2023 Nov 27.

Esketamine hydrochloride (Spravato). (CADTH Common Drug Review). Ottawa (ON): CADTH: 2019. https://www.cadth.ca/esketamine-hydrochloride. Accessed 2023 Nov 27.

Systematic Reviews

All Relevant Studies Captured in Included Systematic Reviews

de Albuquerque TR, Macedo LFR, Delmondes GA, et al. Evidence for the beneficial effect of ketamine in the treatment of patients with post-traumatic stress disorder: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2022;42:2175-2187. PubMed

Hartland H, Mahdavi K, Jelen LA, Strawbridge R, Young AH, Alexander L. A transdiagnostic systematic review and meta-analysis of ketamine's anxiolytic effects. J Psychopharm. 2023;37(8):764-774. PubMed

Kew BM, Porter RJ, Douglas KM, Glue P, Mentzel CL, Beaglehole B. Ketamine and psychotherapy for the treatment of psychiatric disorders: systematic review. BJPsych Open. 2023;9:e79. PubMed

Levinta A, Meshkat S, McIntyre RS, et al. The association between stage of treatment-resistant depression and clinical utility of ketamine/esketamine: a systematic review. J Affect Disord. 2022;318:139-149. PubMed

Meiering MS, Weigner D, Gartner M, Schafer T, Grimm S. Does route of administration affect antidepressant efficacy of ketamine? A meta-analysis of double-blind randomized controlled trials comparing intravenous and intranasal administration. J Psychiatr Res. 2022;156:639-646. PubMed

Shamabadi A, Ahmadzade A, Aqamolaei A, Mortazavi SH, Hasanzadeh A, Akhondzadeh S. Ketamine and other glutamate receptor modulating agents for treatment-resistant depression: a systematic review of randomized controlled trials. Iran J Psychiatry. 2022;17:320-340. PubMed

Sicignano DJ, Kurschner R, Weisman N, Sedensky A, Hernandez AV, White CM. The impact of ketamine for treatment of post-traumatic stress disorder: a systematic review with meta-analyses. Ann Pharmacother. 2023. PubMed

Tully JL, Dahlen AD, Haggarty CJ, Schioth HB, Brooks S. Ketamine treatment for refractory anxiety: a systematic review. Br J Clin Pharmacol. 2022;88:4412-4426. PubMed

All Relevant Studies Captured in Previous CADTH Reports

Alnefeesi Y, Chen-Li D, Krane E, et al. Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. J Psychiatr Res. 2022;151:693-709. PubMed

Meshkat S, Haikazian S, Di Vincenzo JD, et al. Oral ketamine for depression: an updated systematic review. World J Biol Psychiatry. 2023;24:545-557. PubMed

O’Neil ME, Cheney TP, Yu Y, et al. Pharmacologic and nonpharmacologic treatments for posttraumatic stress disorder: 2023 update of the evidence base for the PTSD Trials Standardized Data Repository. Rockville (MD): Agency for Healthcare Research and Quality (US). 2023. https://www.ncbi.nlm.nih.gov/books/NBK595090/. Accessed 2023 Nov 27.

Sukhram SD, Yilmaz G, Gu J. Antidepressant effect of ketamine on inflammation-mediated cytokine dysregulation in adults with treatment-resistant depression: rapid systematic review. Oxid Med Cell Longev. 2022;1061274. PubMed

WorkSafeBC Evidence-Based Practice Group, Martin CW. Intravenous ketamine for PTSD and treatment-resistant depression. Richmond (BC): WorkSafe BC Evidence-Based Practice Group, 2022 Mar. https://www.worksafebc.com/en/resources/health-care-providers/guides/intravenous-ketamine-ptsd-treatment-resistant-depression?lang=en&origin=s&returnurl=https%3A%2F%2Fwww.worksafebc.com%2Fen%2Fforms-resources%23sort%3DDate%26f%3Alanguage-facet%3D%5BEnglish%5D%26tags%3DGuide%7C2d7eb4b30f6a4a319e0d40565c9abbab%2CHealth%2520Care%2520Provider%7C13468b0b3f074f6bade3f57ac3cdfb8e%2CSystematic%2520Review%7Cf78c29d570c14ec3b5a394385905df70. Accessed 2023 Nov 27.

Systematic Reviews With No Relevant Studies

Kwasny A, Wlodarczyk A, Ogonowski D, Cubala WJ. Effect of ketamine on sleep in treatment-resistant depression: a systematic review. Pharmaceuticals (Basel). 2023;16(4):568. PubMed

Smith-Apeldoorn SY, Veraart JK, Spijker J, Kamphuis J, Schoevers RA. Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. Lancet Psychiatry. 2022;9(11):907-921. PubMed

Alternative Population: Major Depressive Disorder

Menon V, Varadharajan N, Faheem A, Andrade C. Ketamine vs Electroconvulsive therapy for major depressive episode: a systematic review and meta-analysis. JAMA Psychiatry. 2023;80(6):639-642. PubMed

de A Simoes Moreira D, Gauer LE, Teixeira G, et al. Efficacy and adverse effects of ketamine versus electroconvulsive therapy for major depressive disorder: a systematic review and meta-analysis. J Affect Disord. 2023;330:227-238. PubMed

Nonrandomized Studies

Populations With Depression or Posttraumatic Stress Disorder

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. 2022;79:736-738. PubMed

Singh B, Kung S, Pazdernik V, et al. Comparative effectiveness of intravenous ketamine and intranasal esketamine in clinical practice among patients with treatment-refractory depression: an observational study. J Clin Psychiatr. 2023;84(2):22m14548. PubMed

Tsang VWL, Ragazan DC, Kryskow P, Walsh Z, Dames S. A pilot study comparing a community of practice program with and without concurrent ketamine-assisted therapy. J Psychoactive Drugs. 2023. PubMed

Xu R, Pan Y, Gorenflo MP, Davis PB, Kaelber DC, De Luca S. Suicidal ideation and suicide attempt following ketamine prescription in patients with treatment-resistant depression: a nation-wide cohort study [preprint, non peer-reviewed]. Res Sq. 2023:rs.3.rs-3207199. PubMed

Veteran Populations

Albott CS, Lim KO, Erbes C, et al. Neurocognitive effects of repeated ketamine infusions in comorbid posttraumatic stress disorder and major depressive disorder. J Affect Disord. 2022;308:289-97. PubMed

Artin H, Bentley S, Mehaffey E, et al. Effects of intranasal (S)-ketamine on veterans with co-morbid treatment-resistant depression and PTSD: a retrospective case series. Eclinicalmedicine. 2022;48:101439. PubMed

Cohen B, Talmy T, Gelikas S, et al. Opioid sparing effect of ketamine in military prehospital pain management: a retrospective study. J Trauma Acute Care Surg. 2022;93(2S):S71-7. PubMed

Melcer T, Walker GJ, Dye JL, et al. Is prehospital ketamine associated with a change in the prognosis of PTSD? Mil Med. 2023; 188(7-8):e2165-74. PubMed

Morgan C. Unique U of M study looking at impact of using ketamine for treating veterans with comorbid PTSD and MDD. University of Minnesota. Department of Psychiatry & Behavioral Sciences. 2023 Oct 3. https://med.umn.edu/psychiatry/news/unique-u-m-study-looking-impact-using-ketamine-treating-veterans-comorbid-ptsd-and-mdd. Accessed 2023 Nov 12.

Vitek G, Langenfeld R, Walters RW, Elson A, Driscoll D, Ramaswamy S. Therapeutic and safety outcomes of intravenous ketamine for treatment-refractory depression in a veteran population: a Case Series. Mil Med. 2022. PubMed