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Authors; Khai Tran, and Quenby Mahood.
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.
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.
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.
Selection 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
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.
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.
Additional details regarding the characteristics of included primary clinical studies22-29 (Table 2) and guidelines30,31 (Table 3) are provided in Appendix 2.
The 8 included primary clinical studies comprises 7 RCTs and 1 retrospective chart review study. The RCTs22-28 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 RCTs22-24,26-28 reported that sample size calculation for primary outcomes was performed; however, 2 RCTs23,27 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 RCTs23,24,26,27 analyzed the data using the intention-to-treat (ITT) approach, while 3 RCTs22,25,28 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
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
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 guidelines30,31 the target population was patients with TRD, while the intended users were health care professionals who treat patients with TRD.
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 studies22,26 compared ketamine with placebo and 6 studies23-25,27-29 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 studies23,25 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.
Seven RCTs22-28 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 studies23,26,29 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 guidelines30,31 considered all efficacy, tolerability, and safety outcomes that were clinically relevant for making recommendations.
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 RCTs22-28 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 RCTs23,26 reported the reasons why patients were lost to follow-up, and 4 RCTs22,25,27,28 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 RCTs23,26,27 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 RCTs22,24 reported the methods of randomization and allocation concealment, while 4 RCTs23,25-27 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 studies22-24,26-28 reported sample size calculation, while 2 studies25,29 did not. Of those reported sample size calculation, 2 RCTs23,27 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 studies22-24,26,28 were of moderate methodological quality, and 3 studies25,27,29 were of low methodological quality.
Both guidelines30,31 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 guidelines30,31 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 guidelines30,31 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 guidelines30,31 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 guidelines30,31 are specific and unambiguous, provide different options for management of the condition, and are easily identifiable. For applicability, both guidelines30,31 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 guidelines30,31 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 guidelines30,31 were of good methodological quality.
Appendix 4 presents the main study findings of the primary clinical studies22-29 (Table 6 to Table 9) and the summary of guideline recommendations30,31 (Table 10). The findings are presented by outcome, which are PTSD (Table 6), depression (Table 7), anxiety (Table 8), and safety (Table 9).
Two RCTs compared IV ketamine22 or oral ketamine26 with placebo (i.e., saline) were identified.
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.
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).
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.
Two RCTs23,25 compared IV ketamine with midazolam, 1 RCT24 compared IV ketamine with IV esketamine, 2 RCTs27,28 compared anesthesia-based IV ketamine with anesthesia-based IV propofol or IV methohexital, and 1 retrospective chart review29 compared IM ketamine with rTMS.
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).
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.
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.
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.
No studies comparing ketamine administered via different routes for adults with TRD or PTSD were identified; therefore, no summary can be provided.
No cost-effectiveness studies of ketamine versus placebo or no treatment for adults with TRD or PTSD were identified; therefore, no summary can be provided.
No cost-effectiveness studies of ketamine versus alternative interventions for adults with TRD or PTSD were identified; therefore, no summary can be provided.
No cost-effectiveness studies of ketamine administered via different routes for adults with TRD or PTSD were identified; therefore, no summary can be provided.
The 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.
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 guidelines30,31 were mostly based on low-quality evidence. No guidelines regarding the use of ketamine for treatment of PTSD were identified.
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 RCTs22,23 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 studies27,28 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 reports17,18 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 reports17,18 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.
adverse event
Affective Lability Scale short form
Appraisal of Guidelines for Research and Evaluation II
Beck Depression Inventory – II
Clinician-Administered Dissociative State Scale
Clinician-Administered PTSD Scale for DSM-5
Clinical Global Impression scale
Controlled Oral Word Association Test
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
Electroconvulsive Therapy
Grades of Recommendation Assessment, Development and Evaluation
Hamilton Anxiety Rating Scale
Hamilton Depression Rating Scale
intramuscular
intention to treat
Montgomery-Asberg Depression Rating Scale
Montreal Cognitive Assessment
Positive and Negative Syndrome Scale
PTSD Checklist for DSM-5
Patient Health Questionnaire-9
post-traumatic disorder
treatment-resistant depression
randomized controlled trial
Repetitive Transcranial Magnetic Stimulation
Young Mania Rating Scale
Selection of Included Studies.
Note that this appendix has not been copy-edited.
Characteristics of Included Primary Clinical Studies.
Characteristics of Included Guidelines.
Note that this appendix has not been copy-edited.
Strengths and Limitations of Clinical Studies Using the Downs and Black checklist.
Strengths and Limitations of Guidelines Using AGREE II.
Note that this appendix has not been copy-edited.
Summary of Findings by Outcome – PTSD symptoms.
Summary of Findings by Outcome – Depression.
Summary of Findings by Outcome — Anxiety.
Summary of Findings by Outcome — Safety.
Summary of Recommendations in Included Guidelines.
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