CADTH Health Technology Review

Ketamine for Adults With Treatment-Resistant Depression or Post-Traumatic Stress Disorder

Rapid Review

Authors: Khai Tran, Quenby Mahood

Key Messages

• Two randomized controlled trials reported mixed evidence on the efficacy of repeated IV ketamine infusions for improving post-traumatic stress disorder. One randomized controlled trial with small sample size found that repeated IV ketamine infusions significantly improved post-traumatic stress disorder symptoms compared with midazolam in civilian population, while the other randomized controlled trial with larger sample size could not demonstrate a significant efficacy on post-traumatic stress disorder symptoms compared with placebo in military population. The antidepressant effects of ketamine were rapid, but the effects were not sustained after few weeks of post-treatment follow-up.

• One randomized controlled trial comparing IV ketamine with IV esketamine found both treatments had comparable acute antidepressant effects for treatment-resistant depression 24 hours following infusion.

• Two randomized controlled trials provided mixed evidence on the efficacy of single infusion of IV ketamine that was used as anesthetic agent for electroconvulsive therapy for treatment-resistant depression. One randomized controlled trial involving military population showed that patients undergoing electroconvulsive therapy for treatment-resistant depression with ketamine anesthesia had similar improvement of depression when compared with patients undergoing electroconvulsive therapy with methohexital anesthesia. However, in other randomized controlled trial comparing with propofol-based anesthesia in a civilian population, ketamine-based anesthesia provided faster improvement in depressive symptoms and fewer electroconvulsive therapy treatments to achieve disease remission.

• In a small randomized controlled trial, alternate infusions of subanesthetic dose of ketamine or midazolam with alternate electroconvulsive therapy showed no significant difference in antidepressant effects between groups.

• The efficacy of oral ketamine was demonstrated in 1 randomized controlled trial that repeated administration of oral ketamine significantly reduced depressive symptoms compared with placebo.

• A small retrospective chart review study showed that repeated administration of intramuscular ketamine had no significant differences in the improvement of depressive and anxiety symptoms compared with repeated transcranial magnetic stimulation.

• Findings suggest overall safety and tolerability of ketamine for treatment of post-traumatic stress disorder or treatment-resistant depression. Most frequent side effects associated with ketamine were dissociative symptoms and cardiovascular changes such as increased blood pressure and heart rate, but these effects were transient.

• The Danish guideline recommend against the use of IV ketamine in patients with treatment-resistant depression, due to low quality and insufficient evidence regarding the lack of long-term efficacy and the risk of abuse of ketamine. Likewise, the Canadian guideline recommends IV ketamine be considered as third-line treatment for adults with TRD, because of the short-lived efficacy of ketamine, its side effects, and the lack of strategies for relapse prevention after ketamine infusions.

Context and Policy Issues

Depression is a debilitating mental illness that affects approximately 5.4% of the Canadian population.¹ Although there are many effective first-line pharmacotherapy treatments for depression, about 21.7% of Canadians remain non-responsive to at least 2 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 drug (including alcohol) abuse, suicide, and hospitalizations.⁴ A wide variety of antidepressant drug medications and 2 somatic treatments through brain stimulation, namely electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS), are available for TRD.⁴

Ketamine, an noncompetitive N-methyl-D-aspartate receptor antagonist, has been approved and primarily used as an IV anesthetic induction drug in doses ranging between 1.0 and 4.5 mg/kg.⁵ As it also interacts with other receptors, ketamine has been explored for other indications such as depressive disorders, suicidal ideation, substance use disorders, anxiety disorders, refractory status epilepticus, bronchial asthma exacerbations, and pain management.⁶ Over the past decades, numerous clinical and preclinical studies have demonstrated the rapid antidepressant effects of ketamine in subanesthetic dosages (e.g., 0.5 m/kg) in patients with major depressive disorders and TRD.^7,8 Ketamine is a racemic mixture of 2 enantiomers, S(+)-ketamine (esketamine) and R(-)-ketamine (arketamine).⁹ Recently intranasal esketamine has received FDA approval for TRD in the US.¹⁰ There are limited research on the use of other formulations of ketamine for TRD including the oral, subcutaneous, and intramuscular forms.¹¹

Post-traumatic stress disorder (PTSD) is a disabling mental condition that affects about 9.2% of Canadians in their lifetime.¹² In Canadian war zone veterans, its prevalence has been estimated up to 10%.¹³ Although anyone can get PTSD, the risk factors for PTSD include being female, having experienced a prior trauma, having been abused as a child, having pre-existing mental health problems, and having a family of mental illness.¹² People with PTSD commonly have associated problems including depression, panic attacks, alcohol and substance abuse, problems in relationship, and increased risk of other medical problems.¹² There are few drugs with insufficient efficacy available for treatment of PTSD.¹⁴ A previous proof-of-concept RCT¹⁵ provided the first evidence of rapid reduction in PTSD and depressive symptoms 24 hours after a single dose of IV ketamine infusion compared to midazolam in primarily civilian population. However, a recent RCT¹⁶ involving patients with chronic pain with or without PTSD found no significant effects of a single infusion of ketamine in improving PTSD or pain symptoms compared with ketorolac.

This report aims to summarize the clinical effectiveness and cost-effectiveness of ketamine compared with all relevant comparators including placebo or no treatment for adults with TRD or PTSD. Additionally, this report also aims to summarize the recommendations from evidence-based guidelines regarding the use and administration of ketamine for those populations.

Research Questions

• What is the clinical effectiveness of ketamine versus placebo or no treatment for adults with TRD or PTSD?

• What is the clinical effectiveness of ketamine versus alternative interventions for adults with TRD or PTSD?

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

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

• What is the cost-effectiveness of ketamine versus alternative interventions for adults with TRD or PTSD?

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

• What are the evidence-based guidelines regarding the use and administration of ketamine for adults with TRD or PTSD?

Methods

Literature Search Methods

This report makes use of a literature search strategy developed for a previous CADTH report.¹⁷ 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, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised 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, controlled clinical trials, or any other type of clinical trial, health technology assessments, systematic reviews, meta-analyses, or network meta-analyses, and economic studies. The search was limited to documents published in English between January 1, 2017, and March 7, 2022.

Selection Criteria and Methods

One reviewer screened citations and selected studies. Titles and abstracts were reviewed in the first screening level, and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, were duplicate publications, or were published before 2017. Studies retrieved by the search were excluded if they were included in the previous CADTH reports.^17,18

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: The Downs and Black checklist¹⁹ for randomized and non-randomized studies, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument²⁰ for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 1,004 citations were identified in the literature search. Following screening of titles and abstracts, 959 citations were excluded and 45 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 37 publications were excluded for various reasons, and 10 publications met the inclusion criteria and were included in this report. These comprised 7 RCTs, 1 non-randomized study, and 2 evidence-based guidelines. Appendix 1 presents the PRISMA²¹ flow chart of the study selection. Additional references of potential interest are provided in Appendix 5.

Summary of Study Characteristics

Additional details regarding the characteristics of included primary clinical studies^22-29 (Table 2) and guidelines^30,31 (Table 3) are provided in Appendix 2.

Study Design

The 8 included primary clinical studies comprises 7 RCTs and 1 retrospective chart review study. The RCTs^22-28 were published between 2018 and 2022, while the retrospective chart review study²⁹ were published in 2021. All of the RCTs were parallel and double-blinded. Six RCTs^22-24,26-28 reported that sample size calculation for primary outcomes was performed; however, 2 RCTs^23,27 reported results from interim analysis based on smaller sample sizes than originally planned. The retrospective chart review study²⁹ did not perform sample size calculation. Four RCTs^23,24,26,27 analyzed the data using the intention-to-treat (ITT) approach, while 3 RCTs^22,25,28 analyzed the data as per protocol.

Both included guidelines were evidence-based, providing recommendations on 6 interventions including ketamine in 1 guideline,³⁰ and on the use of ketamine for treatment of TRD in the other.³¹ A systematic search of the literature was conducted, and the quality of evidence and the strength of recommendations were assessed and graded using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) in 1 guideline,³⁰ while the Cochrane risk of bias tool was used to assess the study quality in the other.³¹

Country of Origin

The primary clinical studies were conducted by authors from US,^22,23,25,28 Brazil,²⁴ Israel,²⁶ Canada,²⁷ and the Netherlands.²⁹

The guidelines were conducted by authors from Denmark³⁰ and Canada.³¹

Patient Population

One study²² involved veterans and service members with PTSD who failed previous antidepressant treatment, 1 study²³ involved patients with chronic PTSD, who were stable with psychotropic medications for at least 3 months before randomization, and 4 studies involved patient with TRD, referring to patients who failed to respond to at least 1 antidepressant,²⁴ or 2 antidepressants.^25,26,28 Two studies did not provide definition for TRD.^27,29 Mean age of patients among included studies ranged between 39²⁵ and 49²⁸ years. The percent of male ranged between 17%²⁵ to 82%.²⁶ The sample sizes of the studies ranged between 12²⁵ to 158.²²

In both guidelines^30,31 the target population was patients with TRD, while the intended users were health care professionals who treat patients with TRD.

Interventions and Comparators

The interventions used in the included studies were IV ketamine, oral ketamine, or intramuscular (IM) ketamine. The comparators were placebo (i.e., saline), midazolam, IV esketamine, IV propofol, IV methohexital, and rTMS. Overall, 2 studies^22,26 compared ketamine with placebo and 6 studies^23-25,27-29 compared ketamine with other treatment modalities. One study²² compared IV ketamine with placebo, 1 study²⁶ compared oral ketamine with placebo, 1 study²⁴ compared IV ketamine with IV esketamine, 2 studies^23,25 compared IV ketamine with midazolam, 2 studies compared anesthesia-based IV ketamine with IV propofol²⁷ or IV methohexital²⁸ for ECT, and 1 study²⁹ compared IM ketamine with rTMS.

The Danish guideline³⁰ formulated its recommendations concerning 6 selected interventions comprising unilateral high frequency rTMS, IV ketamine or esketamine, bright light therapy, cognitive behavioural analysis system of psychotherapy, psychotherapy targeting rumination, and cognitive remediation for treatment of TRD. The Canadian guideline³¹ provides recommendations for the use of ketamine in adults with TRD.

Outcomes

Seven RCTs^22-28 reported both efficacy and safety outcomes, while the retrospective chart review study²⁹ reported only efficacy outcomes. The efficacy outcomes comprised PTSD symptoms, depression, and anxiety. PTSD symptoms were measured using the PTSD Checklist for DSM-5 (PCL-5) or the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Depression was measured using the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HDRS or HAMD), the Beck Depression Inventory – II (BDI-II), the Patient Health Questionnaire-9 (PHQ-9), or the Clinical Global Impression scale (CGI). Anxiety was measured using the Hamilton Anxiety Rating Scale (HAM-A).

The safety outcomes assessed in the included studies included dissociation, presence and severity of positive and negative symptoms, anxiety, cognitive changes, verbal fluency, and sudden mood changes over the past week. Changes in those outcomes were measured, respectively, using the Clinician-Administered Dissociative State Scale (CADSS), the Positive and Negative Syndrome Scale (PANSS), the Young Mania Rating Scale (YMRS), the Montreal Cognitive Assessment (MoCA), the Controlled Oral Word Association Test (COWAT), and the short form of the Affective Lability Scale (ALS-18). Other adverse events (AEs) related to ketamine treatment were also reported.

Brief descriptions of the scorings of the tools used to measure the efficacy and safety outcomes are presented as footnotes of Table 2 in Appendix 2.

Three studies^23,26,29 assessed the outcomes at the end of treatment, while 5 studies measured the outcomes after last treatment at 4 weeks,²² 7 days,²⁴ 3 weeks,²⁵ 3 days²⁸ and 30 days.²⁷

Both guidelines^30,31 considered all efficacy, tolerability, and safety outcomes that were clinically relevant for making recommendations.

Summary of Critical Appraisal

Additional details regarding the strengths and limitations of included primary clinical studies (Table 4) and guidelines (Table 5) are provided in Appendix 3.

With respect to reporting, all primary studies including 7 RCTs^22-28 and 1 retrospective chart review study²⁹ clearly described the objective of the study, the interventions of interest, the main outcomes, and the main findings of the study. The baseline characteristics of the patients included in the study were clearly described in all studies, except in 1 study.²⁵ Without a clear description of patient baseline characteristics, it was not possible to assess if there were potential confounders that could potentially affect the interpretation of the results. One RCT²⁴ had no patients lost to follow-up. Two RCTs^23,26 reported the reasons why patients were lost to follow-up, and 4 RCTs^22,25,27,28 did not. None of the studies that lost patients to follow-up described the characteristics of those patients. In 1 RCT,²² missing data were treated as treatment failure (i.e., nonresponder). Three RCTs^23,26,27 used the ITT approach in the data analyses to account for patients lost to follow-up. Not accounting for patients lost to follow-up in the analyses may increase potential risk of attrition bias. Actual P values (i.e., P values) and the random variability in the data for the main outcomes (e.g., confidence interval, standard deviation, or interquartile range) were reported in all included studies.^22-29 In a non-inferiority study,²⁴ the pre-specified margin was set at 20%, meaning a difference in remission rates between groups that was less than 20% would be considered non-inferiority. As the difference in remission rates between groups was only 5.3%, the margin was totally valid. Regarding external validity, all studies, except 1,²² had relatively small sample size (i.e., 15 to 52 patients in total), whose participants may not be representative of the entire population from which they were recruited.^23-29 For internal validity, all RCTs were double-blinded to the investigators and patients; thus, the risk of biases for selection, performance, and detection were low. Two RCTs^22,24 reported the methods of randomization and allocation concealment, while 4 RCTs^23,25-27 did not report either, and 1 RCT²⁸ only reported the method of randomization. Not performing allocation concealment may result in risk of selection bias. The retrospective chart review study²⁹ may be prone to high risk of bias for selection, performance, and detection due to the nature of the observational study design. Additionally, confounding variables that may have significant impact to the findings were not identified and adjusted for in the analyses in this study.²⁹

Appropriate statistical tests were used to assess the main outcomes, and reliable and validated outcome measures were used in all studies.^22-29 Patients in different intervention groups appeared to be recruited from the same population and over the same period of time in all studies.^22-29 Six studies^22-24,26-28 reported sample size calculation, while 2 studies^25,29 did not. Of those reported sample size calculation, 2 RCTs^23,27 reported results from the interim analysis based on a much smaller sample sizes than that pre-determined by the calculation. It was unclear if using data from a smaller sample size than originally planned may have reduced the studies’ power to detect significant differences in certain outcomes. Patient compliance was not assessed in all studies.^22-29 Overall, 5 included studies^22-24,26,28 were of moderate methodological quality, and 3 studies^25,27,29 were of low methodological quality.

Both guidelines^30,31 were explicit in terms of scope and purpose (i.e., objectives, health questions, and populations), and had clear presentation (i.e., specific, and unambiguous recommendations, different options for management of the condition or health issue, and easy to find key recommendations). In terms of stakeholder involvement, both guidelines^30,31 clearly defined target users and the development groups. However, it was unclear if the views and preferences of the patients were sought in the Canadian guideline.³¹ For rigour of development, both guidelines^30,31 reported systematic methods used to search for evidence, criteria for selecting evidence, explicit link between recommendations and the supporting evidence, and methods of formulating the recommendations. Both guidelines^30,31 considered health benefits, side effects, and risks in formulating the recommendations, and were externally peer-reviewed before publication. One guideline³⁰ used GRADE methodology to assess and grade its recommendations, while the other³¹ used the Cochrane risk of bias tool to assess the study quality, based on which the line-of-treatment recommendations were determined by expert consensus after assessing the efficacy, tolerability, safety, and feasibility of the intervention. For clarity, the recommendations in both guidelines^30,31 are specific and unambiguous, provide different options for management of the condition, and are easily identifiable. For applicability, both guidelines^30,31 were not explicit in terms of facilitators and barriers to application, advice and/or tools on how the recommendations can be put into practice, resource implications (e.g., considering costs in recommendations), and monitoring or auditing criteria. For editorial independence, both guidelines^30,31 reported competing interests of guideline development group members, and that the views of the funding body did not have influence on the content of the guidelines. Overall, both included guidelines^30,31 were of good methodological quality.

Summary of Findings

Appendix 4 presents the main study findings of the primary clinical studies^22-29 (Table 6 to Table 9) and the summary of guideline recommendations^30,31 (Table 10). The findings are presented by outcome, which are PTSD (Table 6), depression (Table 7), anxiety (Table 8), and safety (Table 9).

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

Two RCTs compared IV ketamine²² or oral ketamine²⁶ with placebo (i.e., saline) were identified.

PTSD

The RCT by Abdallah et al. (2022)²² tested whether IV ketamine at standard dose (0.5 mg/kg) and low dose (0.2 mg/kg) could reduce PTSD symptoms compared with placebo in veterans. Eight 40-minute IV infusions of ketamine or saline were administered twice weekly for 4 weeks, followed by 4 weeks follow-up. Analyses on the PCL-5 scores revealed that the scores improved over time in all treatment groups, and there was no significant difference in PCL-5 scores between standard dose and placebo after first infusion (i.e., 24 hour), at end of treatment (i.e., 4 weeks), and at 4 weeks of follow-up. Similarly, the PCL-5 scores between low dose and placebo were not significantly different after first infusion and at the end of treatment. There were no significant differences in PCL-5 scores between standard and low dose of ketamine. Similar results were obtained for the effect of ketamine on CAPS-5 scores. There were no significant differences in response rates among the 3 groups. Response was defined as a 25% or more improvement in PCL-5 scores from baseline.

Depression

The RCT by Abdallah et al. (2022)²² found that standard dose, but not the low dose, of ketamine significantly lowered MADRS scores compared with placebo at 24 hours post-infusion (P = 0.05), and at end of treatment (P = 0.01) However, the difference in MADRS scores between standard dose and placebo were not significant at 4 weeks of follow-up. There were no significant differences in MADRS scores between standard and low dose of ketamine.

The RCT by Domany et al. (2019)²⁶ compared oral ketamine (1 mg/kg thrice weekly for 21 days) with placebo in patients with TRD and found that ketamine significantly reduced MADRS scores at end of treatment (P < 0.001). The response was defined as achieving a 50% or more reduction of MADRS scores from baseline. At 21 days, the response rate was significantly higher in the ketamine group (31.8%) than the placebo group (5.6%); P < 0.05. Similar results were obtained for the effect of ketamine on remission, defined as MADRS fewer than 10 points. After 21 days of treatment, 27.3% patients in the ketamine group achieved remission compared to none in the placebo group (P < 0.05).

Safety

The RCT by Abdallah et al. (2022)²² used CADSS to examine the dissociative effects of ketamine. Ketamine dose-dependently induced increase in the CADSS scores at 30 minutes from the start of infusion, and both the standard and low doses of ketamine had significantly higher CADSS scores than those of placebo (P < 0.05). However, the dissociative symptoms induced by ketamine returned to the placebo levels after the treatment was completed at 120 minutes. At post-treatment follow-up, there were no significant differences between treatment groups (P > 0.05). Additionally, the authors used the PANSS to examine the psychotomimetic effects of ketamine and found that there were no significant differences in PANSS scores between ketamine (both standard and low dose) and placebo during treatment. At post-treatment follow-up, both ketamine doses had significantly lower in PANSS scores compared to placebo (P < 0.05). The incidences of treatment-related AEs in the standard dose, low dose, and placebo were 39.5%, 39.5% and 21%, respectively. The AEs most likely associated with both ketamine doses and not present in the placebo were agitation (5.7%), anxiety (3.8%), irritability (7.6%), constipation (2.9%), and sweating (2.9%).

The RCT by Domany et al. (2019)²⁶ found that 40% in the ketamine group compared to 18.2% in the placebo group had transient elevation of systolic blood pressure more than 20 mm Hg at first administration. Common AEs associated with ketamine included euphoria, dizziness, and drowsiness. The authors stated that those AEs and blood pressure increase were resolved within 1 hour and were milder at later administration of ketamine.

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

Two RCTs^23,25 compared IV ketamine with midazolam, 1 RCT²⁴ compared IV ketamine with IV esketamine, 2 RCTs^27,28 compared anesthesia-based IV ketamine with anesthesia-based IV propofol or IV methohexital, and 1 retrospective chart review²⁹ compared IM ketamine with rTMS.

PTSD

The RCT by Feder et al. (2021)²³ randomized patients with chronic PTSD, who were stable on psychotropic medications for at least 3 months before randomization to receive 6 infusions of ketamine (0.5 mg/kg per day) or midazolam (0.045 mg/kg per day) 3 days per weeks over 2 consecutive weeks. PTSD severity assessment using the CAPS-5 showed that improvement in the total scores over the course of treatment were significantly lower in the ketamine group compared with the midazolam group at week 1 (P = 0.030) and at week 2 (P = 0.004). Response rate, defined as a 30% or more reduction in CAPS-5 scores from baseline, was significantly higher in the ketamine group (67%) compared with the midazolam group (20%); P = 0.03. However, the effects of ketamine on CAPS-5 scores were gradually lost over time. The median time to loss of response (defined as < 30% improvement from baseline) among responders was 27.5 days (IQR: 23 days to 32 days).

Depression

The RCT by Feder et al. (2021)²³ found that depressive symptoms in PTSD patients measured by MADRS scores was significantly improved in the ketamine group compared with the midazolam groups at week 1 and week 2 (P < 0.05).

The RCT by Altinay et al. (2019)²⁵ compared ketamine (0.5 mg/kg) with midazolam (0.045 mg/kg) infused on alternate days with ECT days for 1 week in patients with TRD. Depressive symptoms measured using MADRS scores showed no significant difference between ketamine and midazolam groups. Similar results were also observed with the HAMD scores. The response rates and remission rates were also not statistically significantly different between the treatment groups.

The non-inferiority clinical trial by Correia-Melo et al. (2020)²⁴ assessed the efficacy of esketamine compared to ketamine in patients with TRD. There were no significant differences in mean MADRS scores between the 2 treatments at 24 hours, 72 hours, and 7 days after a single infusion of ketamine 0.5 mg/kg or esketamine 0.25 mg/kg. There were also no significant differences between treatment groups in the response rates or the remission rates at all follow-up time points. Similar results were observed with the CGI scores, with both ketamine and esketamine groups showing improvement in depressive symptoms without significant differences between groups at any time point.

Two RCTs, 1 by Carspecken et al. (2018)²⁸ and 1 by Gamble et al. (2018)²⁷ evaluated the ketamine’s antidepressant effects in ECT as a primary anesthetic . In the RCT by Carspecken et al. (2018),²⁸ veterans with TRD were infused with IV ketamine (1 mg/kg to 2 mg/kg) or IV methohexital (1 mg/kg to 2 mg/kg) for induction of general anesthesia for each ECT session, and ECT course was scheduled with consecutive sessions 3 times a week with length determined by clinical response per the treating psychiatrist. Patients in both groups had depressive symptom improvement (i.e., decreased of HAMD or PHQ-9 scores) after completing the ECT index course compared with baseline.²⁸ However, there was no significant difference in HAMD scores or PHQ-9 scores between ketamine and methohexital groups at final ECT session or at 72 hours follow-up.²⁸

The RCT by Gamble et al. (2018)²⁷ also compared the antidepressive effects between IV ketamine-based anesthesia (0.75 mg/kg) and IV propofol-based anesthesia (1 mg/kg) in TRD patients referred to ECT. Compared to the propofol group, the ketamine group had higher response rates (100% versus 83%) and remission rates (100% versus 58%) assessed using MADRS scores. Multivariate survival analysis adjusted for age and sex showed that patients in the ketamine group were more than twice as likely to achieve response and remission compared with the propofol group. Patients allocated in the ketamine groups significantly required fewer number of ECT treatments to achieve a 50% reduction in MADRS scores compared with those in the propofol group (P = 0.01). There were no significant differences in the relapse rates (MADRS > 20) between groups at 30-day follow-up.

The retrospective chart review study by Mikellides et al. (2021)²⁹ compared the antidepressant efficacy of both ketamine therapy and rTMS therapy in patients with TRD. Intramuscular ketamine was administered twice weekly for 8 sessions at an initial dose of 0.25 mg/kg, then the dosage was titrated upwards to a maximum of 1 mg/kg by session 4. There were significant decreases in HAMD and BDI-II scores in the post-treatment compared to pre-treatment in both groups. However, there was no significant differences in the response rates or remissions rates between groups.

Anxiety

In the retrospective chart review study by Mikellides et al. (2021),²⁹ the HAM-A scores were significantly reduced in the post-treatment compared to pre-treatment in both IM ketamine and rTMS group, but there were no significant differences in the response rates or remissions rates between groups.

Safety

The RCT by Feder et al. (2021)²³ found that the dissociative symptoms observed during ketamine infusions were transient, resolving by 2 hours after the start of infusion. No significant psychotic or manic symptoms were observed after ketamine infusions. There were no suicidal behaviours present during the assessment period. Most frequent AEs of ketamine compared with midazolam after the start of infusions included blurred visions (54% versus 0%), dizziness (33% versus 13%), headache (27% versus 13%), and nausea, or vomiting (20% versus 7%). Statistical comparisons were not reported.

The RCT by Altinay et al. (2019)²⁵ found no significant difference between ketamine and midazolam groups in cognitive testing (by MoCA or COWAT scores), or in manic symptoms (by YMRS scores).

The RCT by Correia-Melo et al. (2020)²⁴ found that no significant difference in dissociative symptoms between ketamine and esketamine groups. The authors reported that most common treatment emergent AEs associated with ketamine or esketamine were increased blood pressure, heart rate, nausea, and dissociation. However, proportions and statistical comparisons between groups were not described. Three patients (1 ketamine and 2 esketamine) had to pause the infusion due to increased blood pressure above 30% of the baseline values. The authors reported that no life-threatening or other serious adverse events were observed.

The RCT by Carspecken et al. (2018),²⁸ found no significant difference in cognitive impairment between IV ketamine-based anesthesia and IV methohexital-based anesthesia administered before and after ECT. There were also no significant differences between groups in blood pressure, heart rate, mean number of seizures in index course per patient, mean seizure length, or mean length of post-anesthesia care unit stay. Two patients in the ketamine group experienced transient memorable dissociative symptoms during treatment, but no recurrences were reported during follow-up visits.

The RCT by Gamble et al. (2018)²⁷ found no significant difference in dissociative symptoms between IV ketamine-based anesthesia and IV propofol-based anesthesia groups across ECT sessions. For both groups, there was a decrease in CADSS scores with an increased number of ECT treatments. The ALS-18 scores for measuring sudden mood change over the past week significantly decreased at 30-day follow-up, but the change did not significantly differ between groups. The rates of AEs such as blood pressure increase or decrease, nausea or vomiting, and headache were not significantly different between groups.

Clinical Effectiveness of Ketamine Administered Via Different Routes for Adults With TRD or PTSD

No studies comparing 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

No cost-effectiveness studies of ketamine versus alternative interventions for adults with TRD or PTSD were identified; therefore, no summary can be provided.

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.

Guidelines

The Danish guideline by Moeller et al. (2021)³⁰ provides weak recommendation against the use of IV ketamine as add-on to usual antidepressant treatment in patients with TRD. The rationale for the recommendation was that the benefits was short-lived, while the evidence on long-term efficacy and side effects, including the risk of abuse, was unclear.

The Canadian guideline by Swainson et al. (2021)³¹ acknowledges the short-term efficacy of IV ketamine (relapse within 10 days for most patients), the lack of strategies for relapse prevention, and limited evidence on the efficacy of repeated ketamine treatment either by IV infusions of IV or different routes of administration, including oral, intranasal, and sublingual formulations. Therefore, the guideline recommends IV ketamine be considered as third line of treatment for adults with TRD.

Limitations

A general limitation of the included primary clinical studies was that 7 of 8 studies had small sample sizes that limit the generalizability of the findings. In double-blind RCTs, the high rate of transient dissociative symptoms in the ketamine group potentially affects the blinding that may lead to negative outcome expectations from the comparators, thus exaggerating differences between groups. Definition of TRD varied among studies, and 1 study²³ examining the effect of ketamine in PTSD did not require history of nonresponse to antidepressant. As all studies used ketamine as add-on therapy that allow patients to continue using stable dosages of other psychotropic medications (e.g., antidepressants, antipsychotic drugs, or mood stabilizers) during treatment, the concomitant antidepressant treatments across studies were not standardized. The retrospective chart review study²⁹ was limited by its retrospective design, without the advantages of randomization to minimize bias. The study²⁹ was prone to selection and attrition biases as it selected only patients who completed the total number of rTMS or ketamine sessions required, and patients with complete clinical evaluations before and after treatment, without collecting information of patients who terminated the treatment prematurely or those with incomplete assessment.

The recommendations from both included guidelines^30,31 were mostly based on low-quality evidence. No guidelines regarding the use of ketamine for treatment of PTSD were identified.

Conclusions and Implications for Decision- or Policy-Making

This report identified 7 RCTs,^22-28 1 retrospective chart review study,²⁹ and 2 guidelines.^30,31 The identified primary clinical studies provided evidence for the efficacy and safety of ketamine compared with placebo or alternative interventions for treatment of TRD or PTSD in adults. Evidence comparing the clinical effectiveness of ketamine administered via different routes were not identified. Also, no evidence was identified regarding the cost-effectiveness of ketamine compared with placebo or alternative interventions; or of 1 ketamine formulation versus others for adults with TRD or PTSD.

The effects of ketamine on PTSD symptoms were reported in 2 RCTs^22,23 with mixed findings. A small sample size RCT²³ (15 patients per group) found that repeated IV ketamine infusions significantly improved PTSD symptoms compared with midazolam in civilian population of mostly females. A larger RCT²² (around 50 patients per groups) could not demonstrate a significant efficacy on PTSD symptoms compared with placebo in military population of mostly males. It is unclear if the population and sex differences may have played a role in differing outcomes. However, the standard dose of IV ketamine (0.5 mg/kg) in both studies was superior to placebo²² or midazolam²³ to reduce depressive symptoms. The antidepressant effects of ketamine were rapid, but the effects were not sustained during 4 weeks of post-treatment follow-up.²² An RCT²⁴ comparing IV ketamine with IV esketamine found both treatments had comparable acute antidepressant effects for TRD 24 hours following infusion. When a single infusion of IV ketamine was used as anesthetic agent for ECT, patients undergoing ECT for TRD with ketamine anesthesia had similar improvement of depression when compared with patients undergoing ECT with methohexital anesthesia.²⁸ However, in another study²⁷ comparing with propofol-based anesthesia, ketamine-based anesthesia provided faster improvement in depressive symptoms and required fewer ECT treatments to achieve disease remission. It is unclear if the differences in outcomes between studies^27,28 may be due difference in comparators. In a small RCT,²⁵ alternate infusions of ketamine or midazolam with alternate ECT showed no significant difference in antidepressant effects between groups. The efficacy of oral ketamine was demonstrated in 1 RCT²⁶ in which repeated administration of oral ketamine significantly reduced depressive symptoms compared to placebo. A small retrospective chart review study²⁹ showed that the reduction in depressive and anxiety symptoms with repeated administration of IM ketamine was not significantly different compared with rTMS. Findings from included RCTs suggest overall safety and tolerability of ketamine for treatment of PTSD or TRD.^22-28 Most frequent AEs associated with ketamine were dissociative symptoms and cardiovascular changes such as increased blood pressure and heart rate, but these effects were transient. The Danish guideline³⁰ recommend against the use of IV ketamine in patients with TRD, due to low-quality and insufficient evidence regarding the lack of long-term efficacy and the risk of abuse of ketamine. Likewise, the Canadian guideline³¹ recommends that IV ketamine be considered as third-line treatment for adults with TRD, because of the short-lived efficacy of ketamine, its side effects, and the lack of strategies for relapse prevention after ketamine infusions.

CADTH previously published 2 Rapid Response reports^17,18 on this topic. The 2017 CADTH report¹⁸ identified 3 systematic reviews, 5 primary studies, and 2 evidence-based guidelines. The 2019 CADTH report¹⁷ identified 6 primary clinical studies and 1 evidence-based guideline. Overall, the included studies showed that the IV ketamine had rapid antidepressant effects for treatment of TRD and single-dose infusion of ketamine was effective at reducing PTSD severity. However, an RCT involving repeated infusions found no difference in depression severity or suicidal ideation between ketamine and placebo. All 3 guidelines included in the 2 previous CADTH reports^17,18 recommended against the use of ketamine for patients with TRD or PTSD. The current report extends the scope of the 2 previous CADTH reports to include all ketamine formulations and all comparators of interest.

Given the aforementioned limitations of the included studies in this report, there is insufficient evidence to provide definitive conclusions about the clinical effectiveness of ketamine for treatment of TRD or PTSD. Future research is needed to address questions such as optimal dose regimens, patient selection, and treatment duration with longer follow-up period to determine whether ketamine should be used for treatment of TRD or PTSD.

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25.Altinay M, Karne H, Anand A. Administration of sub-anesthetic dose of ketamine and electroconvulsive treatment on alternate week days in patients with treatment resistant depression: a double blind placebo controlled trial. Psychopharmacol Bull. 2019;49(1):8-16. PubMed

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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 Primary Clinical Studies

AEs = adverse events; ALS-18 = the short form of the Affective Lability Scale (also known as ALS-SF); BDI-II = Beck Depression Inventory – II; CADSS = Clinician-Administered Dissociative State Scale; ALS-18 = the short form of the Affective Lability Scale; CAPS-5 = Clinician-Administered PTSD Scale for DSM-5; CGI = Clinical Global Impression; CGI-I = CGI-improvement; CGI-S = CGI-severity; COWAT = Controlled Oral Word Association Test; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition); ECT = electroconvulsive therapy; HAM-A = Hamilton Anxiety Rating Scale; HAMD = Hamilton Depression Scale; HDRS = Hamilton Depression Rating Scale; HVLT-R = Hopkins Verbal Learning Test – Revised; IM = intramuscular; iTBS = intermittent theta-burst stimulation; ITT = intention-to-treat; MADRS = Montgomery-Asberg Depression Rating Scale; MoCA = Montreal Cognitive Assessment; NR = not reported; NRS = non-randomized study; PANSS = Positive and Negative Syndrome Scale; PCL-5 = PTSD Checklist for DSM-5; PHQ-9 = Patient Health Questionnaire-9; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial; rTMS = repetitive transcranial magnetic stimulation; SD = standard deviation; TRD = treatment-resistant depression; YMRS = Young Mania Rating Scale.

^aThe PCL-5 is a 20-item self-report 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 (range - 0 to 80) 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.³²

^bThe CAPS-5, a 30-item structured interview, is the gold standard in PTSD assessment. The frequency and intensity information were converted into a single 5-point (0 to 4) symptom severity scale. The anchor points for this severity scale are 0 = absent, 1 = mild/subthreshold, 2 = moderate/threshold, 3 = severe/markedly elevated, and 4 = extreme/incapacitating.³³

^cThe MADRS has 10 items and used by clinicians to assess the severity of depression in patients with a diagnosis of depression. Each item has a severity scale from 0 to 6, with higher scores reflecting more severe symptoms. Ratings can be added to form an overall score (from 0 to 60). The proposed cut-offs: scores of 0 to 6 indicate an absence of symptoms; 7 to 19 represent mild depression; 20 to 34 moderate; 35 to 60 indicate severe depression.³⁴

^dThe CADSS is a scale used to measure dissociative states, consisting of 23 clinician-administered items, each scored from 0 (not at all) to 4 (extreme).³⁵

^eThe PANSS is a standardized, clinical interview that rates the presence and severity of positive and negative symptoms, as well as general psychopathology for people with schizophrenia. It consists of 30 items, 7 are positive symptoms, 7 are negative symptoms, and 16 are general psychopathology symptoms. Symptom severity for each item is rated in the 7-point scale (1 = absent; 7 = extreme).³⁶

^fThe HAMD, also termed HDRS, is used to measure the severity of symptoms of depression based on 17-item scales rated on either a 3- or 5-point scale, with the sum of all items making up the total score. The scores of 0 to 7 are considered as being normal, 8 to 16 suggest mild depression, 17 to 23 moderate depression and scores over 24 are indicative of severe depression; the maximum score being 52.³⁷

^gThe YMRS is an 11-item rating scale used to assess manic symptoms. Four items are rated on a 0 to 8 scale, while the remaining 7 items are rated on a 0 to 4 scale. The optimal YMRS severity threshold of 25 (positive predictive value [PPV] = 83.0%; negative predictive value [NPV] = 66.0%) was determined to be classified as severely ill. The YMRS minimal clinically significant difference was 6.6 points.³⁸

^hThe MoCA is a 30-point screening test for detecting cognitive impairment. MoCA scores range between 0 and 30. A score of ≥ 26 is considered to be normal. People with mild cognitive impairment had an average score of 22.1. People with Alzheimer disease scored an average of 16.2.³⁹

^IThe HVLT-R provides a brief assessment of verbal learning and memory (delayed recall and recognition) for individuals aged 16 years and older. The test is a 12-item 3 learning trial verbal learning test with delayed recall and recognition memory test. Raw scores are derived from Total Recall, Delayed Recall, Retention (% retained), and a Recognition Discrimination Index.⁴⁰

^jThe COWAT 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.⁴¹

^kThe CGI is a standardized assessment scale for determining the effect of mental health treatment among psychiatric patients. 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 taken after treatment and compared with baseline. It rates the improvement on a 1 to 7 scale, with 1 representing ‘very much improved,’ 7 for ‘very much worse’ due to treatment, and 4 for no change from treatment.⁴²

^lThe ALS-18 is an 18-item scale that retrospectively measures sudden mood change over the past week. Each item is rated on a 4-point (0 to 3) scale, ranging from 0 = “Very uncharacteristic of me” to 3 = “Very characteristic of me.” The ALS-18 also includes a total score and scores of three subscales: Anxiety/ Depression, depression/Elation, and Anger.⁴³

^mThe HAM-A that assesses anxiety severity, consists of 14 items measuring different symptoms. Each item is rated on a 5-point (0 to 4) scale, ranging from 0 = Not present to 4 = Very severe. Total score ranges from 0 to 56, where scores < 17 indicate mild severity, scores between 18 and 24 indicate mild to moderate severity, and scores between 25 to 30 indicate moderate to severe anxiety.⁴⁴

ⁿThe BDI-II that assesses depression severity, consists of 21 items. Each item is rated on a 4-point (0 to 3) scale, with a total score ranging from 0 to 63. Scores of 0 to 10 indicate absent or minimal depression, 14 to 19 for mild depression, 20 to 28 for moderate depression, and 29 to 63 for severe depression.⁴⁵

^oThe PHQ-9 is a 9-item depression scale. Each item is rated on 4-point (0 [not at all] to 3 [nearly every day]) scale, with a total score ranging from 0 to 27. Scores of 0 to 4 indicates none or minimal depression, 5 to 9 mild depression, 10 to 14 moderate depression, 15 to 19 moderately severe depression, and 19 to 27 severe depression.⁴⁶

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 4: Strengths and Limitations of Clinical Studies Using the Downs and Black checklist¹⁹

CI = confidence interval; ITT = intention-to-treat; NRS = non-randomized study; RCT = randomized controlled trial.

Table 5: Strengths and Limitations of Guidelines Using AGREE II²⁰

AGREE II = Appraisal of Guidelines for Research and Evaluation II; CANMAT = The Canadian Network for Mood and Anxiety Treatments; DHA = Danish Health Authority; NR = not reported; NA = not applicable.

Appendix 4: Main Study Findings

Note that this appendix has not been copy-edited.

Table 6: Summary of Findings by Outcome – PTSD symptoms

Adj. = adjusted; CAPS-5 = Clinician-Administered PTSD Scale for DSM-5; CI = confidence interval; IQR = interquartile range; MD = mean difference; OR = odds ratio; PCL-5 = PTSD checklist for DSM-5; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial; SEM = standard error of the mean; vs. = versus.

Table 7: Summary of Findings by Outcome – Depression

adj. = adjusted; BDI-II = Beck Depression Inventory – II; CGI = Clinical Global Impression; CI = confidence interval; CGI = Clinical Global Impression; ECT = electroconvulsive therapy; HAMD = Hamilton depression scale; HDRS = Hamilton Depression Rating Scale; HR = hazard ratio; IQR = interquartile range; IV = IV; LB = lower bound; MADRS = Montgomery-Asberg Depression Rating Scale; LM = lower bound; MD = mean difference; PHQ-9 = Patient Health Questionnaire-9; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial; rTMS = repetitive transcranial magnetic stimulation; SEM = standard error of the mean; SE = standard error; TRD = treatment-resistant depression; vs. = versus.

Table 8: Summary of Findings by Outcome — Anxiety

HAM-A = Hamilton Anxiety Rating Scale; TRD = treatment-resistant depression; rTMS = repetitive transcranial magnetic stimulation.

Table 9: Summary of Findings by Outcome — Safety

AE = adverse event; ALS-18 = the short form of the Affective Lability Scale; CADSS = Clinician-Administered Dissociative State Scale; COWAT = Controlled Oral Word Association Test; ECT = electroconvulsive therapy; MoCA = Montreal Cognitive Assessment; PACU = post-anesthesia care unit; PANSS = Positive and Negative Syndrome Scale; PTSD = post-traumatic stress disorder; RCT = randomized controlled trial; SD = standard deviation; SE = standard error; TEAE = treatment emergent adverse events; TRD = treatment-resistant depression; YMRS = Young Mania Rating Scale.

Table 10: Summary of Recommendations in Included Guidelines

CANMAT = The Canadian Network for Mood and Anxiety Treatments; DHA = Danish Health Authority; DTD = difficult-to-treat depression.

Appendix 5: References of Potential Interest

Studies Included in the Previous CADTH Report¹⁷

Chen MH, Li CT, Lin WC, et al. Cognitive function of patients with treatment-resistant depression after a single low dose of ketamine infusion. J Affect Disord. 2018;241:1-7. PubMed

Chen MH, Lin WC, Wu HJ, et al. Antisuicidal effect, BDNF Val66Met polymorphism, and low-dose ketamine infusion: reanalysis of adjunctive ketamine study of Taiwanese patients with treatment-resistant depression (AKSTP-TRD). J Affect Disord. 2019;251:162-169. PubMed

Fava M, Freeman MP, Flynn M, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2018;03:03.

Ionescu DF, Bentley KH, Eikermann M, et al. Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: a randomized, double blind, placebo controlled trial. J Affect Disord. 2019;243:516-524. PubMed

Phillips JL, Norris S, Talbot J, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176(5):401-409. PubMed

Su TP, Chen MH, Li CT, et al. Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression. Neuropsychopharmacology. 2017;42(13):2482-2492. PubMed

VA/DoD clinical practice guideline for the management of posttraumatic stress disorder and acute stress disorder. Washington (DC): Department of Veterans Affairs, Department of Defense; 2017: https://www.healthquality.va.gov/guidelines/MH/ptsd/VADoDPTSDCPGFinal012418.pdf. Accessed 2019 Oct 24.

Additional References

Bentley S, Artin H, Mehaffey E, et al. Response to intravenous racemic ketamine after switch from intranasal (S)-ketamine on symptoms of treatment-resistant depression and post-traumatic stress disorder in Veterans: A retrospective case series. Pharmacotherapy:The Journal of Human Pharmacology & Drug Therapy. 2022 Feb 05;05:05. PubMed

Melcer T, Walker GJ, Dye JL, et al. Is Prehospital Ketamine Associated With a Change in the Prognosis of PTSD? Mil Med. 2022 Feb 01;01:01. PubMed

Shiroma PR, Thuras P, Wels J, Erbes C, Kehle-Forbes S, Polusny M. A Proof-of-Concept Study of Subanesthetic Intravenous Ketamine Combined With Prolonged Exposure Therapy Among Veterans With Posttraumatic Stress Disorder. J Clin Psychiatr. 2020 11 10;81(6):10. PubMed

Ross C, Jain R, Bonnett CJ, Wolfson P. High-dose ketamine infusion for the treatment of posttraumatic stress disorder in combat veterans. Ann Clin Psychiatry. 2019 11;31(4):271-279. PubMed

Albott CS, Lim KO, Forbes MK, et al. Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression. J Clin Psychiatr. 2018 May/Jun;79(3). PubMed

Mion G, Le Masson J, Granier C, Hoffmann C. A retrospective study of ketamine administration and the development of acute or post-traumatic stress disorder in 274 war-wounded soldiers. Anaesthesia. 2017 Dec;72(12):1476-1483. PubMed