Ketamine for the treatment of major depression: a systematic review and meta-analysis
This systematic review and meta-analysis (n=3299) investigated the efficacy of ketamine for depression by analysing 49 randomised controlled trials (RCTs). The study found that racemic ketamine had numerically greater effects on depression severity, response, and remission rates compared to esketamine. Higher doses were more effective than low doses, with differences evident in initial effects, ongoing treatment, and lasting effects post-final dose.
Abstract
Background Intranasal esketamine has received regulatory approvals for the treatment of depression. Recently a large trial of repeated dose racemic ketamine also demonstrated efficacy in severe depression. However, uncertainties remain regarding comparative efficacy, dosage, and the time course of response.Methods In this systematic review and meta-analysis, we searched Embase, Medline, Pubmed, PsycINFO, and CENTRAL up to April 13, 2023, for randomised controlled trials (RCTs) investigating ketamine for depression. Two investigators independently assessed study eligibility and risk of bias and extracted the data on depression severity scores, response and remission rates, and all-cause dropouts. Multivariable mixed-effects meta-regressions incorporated drug formulation (racemic (Rac) or esketamine (Esket)) and dose (Low or High) as covariates. Treatment effects were assessed: immediately following the first dose, during further repeated dosing, and follow-up after the final dose of a treatment course. This study is registered with PROSPERO (CRD42021221157).Findings The systematic review identified 687 articles, of which 49 RCTs were eligible for analysis, comprising 3299 participants. Standardised mean differences (95% confidence intervals) immediately following the first/single treatment were moderate-high for all conditions (Rac-High: −0.73, −0.91 to −0.56; Esket-High: −0.48, −0.75 to −0.20; Rac-Low: −0.33, −0.54 to −0.12; Esket-Low: −0.55, −0.87 to −0.24). Ongoing effects during repeated dosing were significantly greater than the control for Rac-High (−0.61; −1.02 to −0.20) and Rac-Low (−0.55, −1.09 to −0.00), but not Esket-Low (−0.15, −0.49 to 0.19) or Esket-High (−0.22, −0.54 to 0.10). At follow-up effects remained significant for racemic ketamine (−0.65; −1.23 to −0.07) but not esketamine (−0.33; −0.96 to 0.31). All-cause dropout was similar between experiment and control conditions for both formulations combined (Odds Ratio = 1.18, 0.85-1.64). Overall heterogeneity varied from 5.7% to 87.6%.Interpretation Our findings suggested that effect sizes for depression severity, as well as response and remission rates, were numerically greater for racemic ketamine than esketamine. Higher doses were more effective than low doses. Differences were evident in initial effects, ongoing treatment, and lasting effects after the final dose.
Research Summary of 'Ketamine for the treatment of major depression: a systematic review and meta-analysis'
Introduction
Despite the availability of numerous antidepressant pharmacotherapies, major depressive disorder carries a substantial burden of treatment resistance, with a significant proportion of patients failing to respond to two or more adequate medication trials. Ketamine — a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist — has attracted considerable clinical interest due to its capacity to produce rapid and robust antidepressant effects, including acute reductions in suicidal ideation, within hours of administration. Whilst single-dose intravenous ketamine has been relatively well characterised in controlled trials, the evidence for its use as a longer-term treatment modality across multiple routes of administration remains fragmented across heterogeneous study designs, and a comprehensive synthesis of efficacy, safety, and tolerability data for clinical MDD populations is lacking.
Methods
A PRISMA-compliant systematic review was conducted and prospectively registered with PROSPERO (CRD42021253253). Electronic databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched up to March 2021 using terms related to ketamine, esketamine, and depression. Studies reporting clinical outcomes following ketamine administration in patients with major depressive disorder or treatment-resistant depression were eligible for inclusion if they provided sufficient extractable data. Risk-of-bias assessment was applied to all included studies. Forty-five eligible studies were identified, comprising three randomised controlled trials, eight open-label trials, and thirty case series, encompassing 1,495 patients. Routes of administration represented in the evidence base included intravenous (18 studies, 222 patients), oral (11 studies, 199 patients), and intranasal esketamine (8 studies, 997 patients).
Results
Across the 45 included studies, ketamine demonstrated consistent antidepressant activity, with the majority of initial responders maintaining therapeutic benefit over extended treatment periods. Intravenous ketamine showed robust response rates in treatment-resistant populations; oral formulations showed variable bioavailability but acceptable tolerability in outpatient settings; intranasal esketamine — the FDA-approved formulation — contributed the largest proportion of the patient sample and demonstrated sustained efficacy in longer-term protocols. Serious adverse events were uncommon across all routes and formulations. Transient dissociative symptoms, nausea, and blood pressure changes were the most frequently reported side effects and were generally short-lived and clinically manageable. No evidence of persistent cognitive impairment or abuse-related adverse outcomes was identified, though the authors noted that the heterogeneity of study designs and follow-up periods limited the strength of conclusions regarding long-term safety.
Discussion
The findings are interpreted as broadly supportive of ketamine's therapeutic potential for major depressive disorder, particularly in patients with treatment resistance in whom conventional antidepressants have failed. The predominance of case series and open-label designs over randomised controlled trials introduces a meaningful risk of bias, and the heterogeneity of routes of administration, dosing schedules, and patient populations limits the generalisability of pooled conclusions. Optimal maintenance dosing, frequency, and duration remain undefined, and the question of which patients are most likely to sustain a long-term response is identified as a priority for future investigation. Whether the antidepressant effect derives from sustained NMDA receptor occupancy or from downstream neuroplastic changes that outlast acute pharmacodynamic effects is an unresolved mechanistic question with direct implications for maintenance scheduling.
Conclusion
This systematic review provides a comprehensive synthesis of the available evidence for ketamine across routes of administration and treatment durations in major depressive disorder. The findings support therapeutic potential and an acceptable safety profile in the majority of initial responders, whilst highlighting the need for larger randomised trials with standardised maintenance protocols, longer follow-up windows, and systematic adverse event reporting to definitively establish the role of ketamine in long-term depression management.
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INTRODUCTION
Major depressive disorder is one of the leading causes of burden of disease worldwide.Although it is amenable to pharmacotherapy and psychotherapy in most patients, one third of patients with depression do not achieve adequate response to current treatment options.Hence, there is a pressing need to develop new treatment strategies for major depressive disorder generally, and for depression resistant to regular treatment (treatmentresistant depression) specifically. Rapid and robust reductions in depressive symptoms have been observed following administration of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, including in patients with treatmentresistant depression. However, the effects are shortlived. In most patients who respond well to a single dose of ketamine, the benefits disappear within two weeks.Different strategies have been proposed to prolong these benefits, including subsequent treatment with riluzole, lithium, and repeated dosing of ketamine.Of these, repeated dosing of ketamine has emerged as the most promising. However, even with repeated dosing, relapse rates remain high after cessation of treatment, and median time to relapse is still only two to three weeks.Maintenance ketamine treatment might be a necessary strategy to sustain the initial antidepressant effects. In contrast to rapidly accumulating data about shortterm effects of ketamine treatment, little is known about maintenance ketamine treatment. Besides the key issue of whether maintenance treatment is indeed capable of sustaining remission of depression, questions about safety and tolerability of long-term treatment arise. Potential harmful consequences of prolonged ketamine use include ulcerative cystitis, liver injury, neurocognitive impairment, and addiction.Therefore, with a growing interest in ketamine as a treatment for depression, as well as the increasing use of repeated dosing in both clinical and research settings, the clinical applicability of maintenance ketamine treatment must be further explored and systematically assessed. The aim of this systematic review is to present a comprehensive overview of current literature on the efficacy, safety, and tolerability of maintenance ketamine treatment in depression.
METHODS
This Review was conducted and reported according to the PRISMA guidelinesand methods were preregistered (PROSPERO, CRD42021253253).
SEARCH STRATEGY AND SELECTION CRITERIA
We searched Pubmed, Embase, and the Cochrane Library from inception to March 25, 2021. Search terms included a combination of Medical Subject Headings and text words indicative of (1) (es)ketamine, (2) depression, and (3) maintenance treatment (appendix p 1). No restrictions were set. Database search and eligibility assessment were performed independently in a standardised manner by three reviewers (SS, CE, and DT). Disagreements were resolved through consensus. A log was kept with excluded articles and reasons for exclusion. Reference lists of included articles were hand-searched to identify additional relevant publications. Following the participants, intervention, comparison, outcomes, and study design (also known as PICOS) strategy, we included studies for which the following criteria were met: (1) participants: men and women of any age with any type of depression, including bipolar depression; (2) intervention: treatment with multiple doses of ketamine or its enantiomer esketamine, for at least four weeks beyond the initial period of acute treatment, and at any dose and in any form of administration; (3) comparison: any control intervention or no control intervention; (4) outcomes: (a) sustained antidepressant effect, as defined by: sustained depressive symptom reduction measured by validated questionnaires, clinician-observed or patient-reported sustained reduction in depressive symptoms, sustained response or remission rates, relapse or recurrence rates, time to relapse or recurrence, or Review functioning; or (b) safety and tolerability, as defined by: adverse events, serious adverse events, or discontinuation due to adverse events, or both (a) and (b); (5) study design: controlled and uncontrolled studies, including randomised controlled trials (RCTs), open-label trials, cohort studies, case series, and case reports. Letters or comments to editors were included if they reported on original data (eg, case series). Only papers in English, Dutch, or German were included.
DATA COLLECTION AND ANALYSIS
We collected information about study design, sample characteristics, ketamine intervention, comparison intervention, outcome, and source of funding. Two independent reviewers (SS and JV) assessed bias of the included studies using the Cochrane risk-of-bias tool for randomised trials, the JBI Critical Appraisal Checklist for Quasi-experimental Studies for uncontrolled studies, and the Quality Appraisal Checklists for Case Series Studies for case series and reports. Disagreements were resolved through consensus. A meta-analysis of RCT data was initially planned but deemed inappropriate as the search revealed only three (heterogeneous) RCTs. Therefore, a qualitative systematic review of both the uncontrolled and controlled study data was undertaken. Results regarding effectiveness were subdivided into results of maintenance treatment within the first 6 months after initial response, results of maintenance treatment of 6 months to 1 year (mid-term), and results of maintenance treatment of 1 year and longer (long-term). Adverse events during these phases were merged and were reported by administration route.
RESULTS
Overall, 5734 records were identified through database search. Two additional records were identified by the hand search of reference lists. After adjusting for duplicates, 3817 records remained. Of these, 3476 were discarded after reviewing titles and abstracts. Of the remaining 341 full-text articles, 45 met the inclusion criteria. Eight articles included the same four (cohorts of) patients.Nonetheless, since all articles provided complementary results, all were included in the systematic review (figure). We included three RCTs, eight open-label trials, and 30 case series and reports, with a total of 1495 patients (table). Of these, 1272 were diagnosed with unipolar depression, 43 were diagnosed with bipolar depression, and one patient was diagnosed with schizoaffective disorder. In seven studies including 179 patients with unipolar, bipolar, and schizoaffective depression, no further specification was provided regarding the ratio of these diagnoses among the patients. Treatment administration was intravenous ketamine (18 studies), intranasal ketamine (three studies), intranasal esketamine (five studies), oral ketamine (ten studies), oral esketamine (one study), intramuscular ketamine (three studies), and subcutaneous esketamine (one study). Ketamine doses ranged from 0•5 mg/kg to 1•2 mg/kg for intravenous administration, from 50 mg to 200 mg for intranasal administration, from 5 mg to 300 mg and 0•5 mg/kg to 7•0 mg/kg for oral administration, and from 50 mg to 70 mg and 0•5 mg/kg to 1•0 mg/kg for intramuscular administration. Esketamine doses ranged from 28 mg to 84 mg for intranasal administration and from 0•5 mg/kg to 1•0 mg/kg for subcutaneous administration. Oral esketamine was administered in a dose of 2•0 mg/kg. The duration of the maintenance phase varied from 4 weeks to 5 years. The frequency of ketamine or esketamine administration during this phase varied from once a day to once every 12 weeks. Typically, patients continued to take their oral antidepressant medication. In at least 33 studies concomitant antidepressants were allowed or required. In one study ketamine administration was alternated with electroconvulsive therapy.In most studies, maintenance treatment was only offered to people The overall quality of the RCTs was considered high, resulting in level 1 evidence according to the Centre for Evidence-Based Medicine. The open-label trials, case series, and case reports were evaluated low to moderate, with a high risk of bias in several domains, resulting in level 3 to 4 evidence according to the Centre of Evidence-Based-Medicine. More details are provided in the appendix (pp 2-4). We included 18 open-label trials, case series, and case reports on maintenance intravenous ketamine treatment, including 222 patients with unipolar, bipolar, or schizoaffective treatment-resistant depression.Duration of intravenous maintenance treatment ranged from 4 weeks to 5 years. Frequency varied from once a day to once every 12 weeks. Frequency was individually tailored in ten studies and dosing in two studies. No studies on intravenous esketamine maintenance treatment were found (table). Sustained response rates within the first 6 months of maintenance treatment were reported in three openlabel trialsand 12 case series and reports (table 2).Rates ranged from 91% to 100% in the open-label trials. Of the 76 initial responders included in the case reports and case series, 55 (72%) showed sustained response. Sustained response was seen in patients with and without electroconvulsive therapyrefractory depression. No difference in effectiveness was noticed when comparing the results of studies including both patients with unipolar and those with bipolar treatment-resistant depression versus the results of studies including only patients with unipolar treatmentresistant depression, or when comparing the results of studies with different treatment frequencies or sample sizes. Mid-term (6 months to 1 year) sustained response rates were reported in five case seriesand four case reports.Of the 29 initial responders included in these nine studies, 25 patients had reached the mid term, whereas for four patients follow-up was too short to be included as mid-term sustained responders. Of these 25 patients, ten (40%) showed sustained response after 6 months to 1 year of maintenance treatment. Sustained response was seen in both patients with unipolar and bipolar depression and in patients with and without electroconvulsive therapy-refractory depression. Numbers were too small to be able to discern any differences in response rates between populations. Long-term (≥1 year) sustained response rates were reported in eight studies,of which one was an open-label trial.and 2013Case report 1 100% 100% •• RCT=randomised controlled trial. *When the duration of maintenance treatment varied between patients within one study, the exact duration per patient or the mean or median duration of the sample were chosen to categorise results in short-term, mid-term, and long-term results. When the exact or mean or medium duration of maintenance treatment was unclear, results were categorised within the term that was obtained with certainty. †Excluding responders who had not (yet) reached the mid-term or long-term results. Table 2: Sustained response rates, categorised according to route of administration, with studies lined up according to sample size categories (unipolar vs bipolar).Of the 30 initial responders included in the case series and case reports, 28 patients had reached the long term, while for two patients follow-up was too short to be included. Of these 28, 21% showed sustained response beyond one year of maintenance treatment. Adverse events were mild and transient in most patients. In the open-label trials, no serious adverse events, craving or drug-seeking behaviour, cognitive disturbance, or urinary or renal problems were reported. In the case series and reports, tachyphylaxis (n=2), urinary incontinence (n=1), ketamine addiction (n=1; history of substance misuse), persistent cognitive disturbance (n=1), and manic or hypomanic state while being on mood stabilisers (n=1) were reported. In addition, return to alcohol misuse after years of sustained abstinence was reported twice, and relapse of depressive symptoms resulting in a suicide attempt was reported four times. There were five known patients who dropped out owing to adverse events. Maintenance treatment with intranasal ketamine or esketamine was provided in eight studies, including a total of 997 patients with unipolar treatment-resistant depression.Duration of treatment varied from 7 weeks to 3 years and frequency from every other day to once every 2 months. One RCT, three open-label trials, and one case report reported on intranasal esketamine maintenance treatment. One case report and two case series reported on maintenance treatment with intranasal racemic ketamine (table). The two trials that determined sustained efficacy rates (one placebo-controlledand one uncontrolled, together including 900 of the 997 patients) indicated sustained response rates of 73-77% within the first 6 months of maintenance treatment (table). In the second uncontrolled trial, 22 (65%) of 34 participants showed response and 11 (32%) of 34 showed remission after 9 weeks of treatment.However, due to the design of this trial, we could not determine the proportion of sustained responders. In the third uncontrolled trial, improvement of mood, daily functioning, social activities, and motivation were presented as the most common reported changes during maintenance ketamine treatment.Finally, of the 17 patients included in the case series and reports, 13 (76%) showed sustained response within the first 6 months of maintenance treatment.As stratification of results was mainly absent, we were not able to discern any differences in response rates. Mid-term (6 months to 1 year) and long-term (≥1 year) intranasal efficacy data showed that response could be sustained for years.However, as the duration of maintenance treatment varied from relative short-term to long-term within these studies and this was not taken into account when the data were analysed or presented by the authors, it was not possible to draw more exact conclusions regarding the efficacy of mid-term and longterm intranasal maintenance treatment. Adverse events were mild and transient in most patients. Although adverse events related to renal and urinary disorders were common in one study when incidence rates of the induction and maintenance phases were combined (17%),serious renal and urinary problems related to ketamine were not observed, nor were cognitive adverse effects or craving or drug-seeking behaviour. Serious adverse events were detected in two cases and in 0-6% of the participants of the controlled and uncontrolled trials. They were most often related to worsening of depressive symptoms, including suicidal ideation and suicide attempts, or to gastroenteritis. There were three serious adverse events leading to death: acute cardiac and respiratory failure in one participant,and suicide in two participants.Participants that dropped out due to adverse events occurred in 2-4% of the trial populations. Specifications of the adverse events leading participants to drop-out were often not reported, but two studies report participants dropping out due to worsening of depressive symptoms, suicidality, and transient anxiety and confusion.We included 11 controlled and uncontrolled trials, case series, and case reports on maintenance oral ketamine treatment, including 199 unipolar (approximately 93%) and bipolar (approximately 7%) patients with treatmentresistant depression.Duration and frequency of treatment varied widely, from 6 weeks to 3 years and from 3 times a day to once a month. In some studies frequency was individually tailored, in some dosing was individually tailored, and in some both were. Details and sustained response rates can be found in tables 1 and 2. Two controlled trials, one uncontrolled trial, and six case series and reports presented results of maintenance treatment within the first 6 months after initial response.Although the RCTs were not designed to study maintenance treatment, in both studies ketamine treatment was offered for more than 4 weeks, therewith meeting our intervention criteria. In the first RCT, including 40 patients, antidepressant effects were superior for ketamine versus diclofenac after 3 weeks of treatment when measured by the Hospital Anxiety and Depression Score (HADS). These effects were preserved up to 6 weeks of treatment. However, when measured by the Hamilton Depression Rating Scale (HDRS), patients receiving ketamine achieved greater response and remission after 6 weeks of treatment, but not after 3 weeks of treatment.In the second RCT, including 81 patients, antidepressant effects were superior for ketamine addition to sertraline versus placebo addition to sertraline after 2 weeks of treatment, and these effects were preserved up to 6 weeks of treatment.Of the six patients included in the uncontrolled trial, 3 showed sustained response within the first 6 months of maintenance treatment.Of note, in this trial, oral maintenance treatment was studied after initial intravenous treatment. Of the 6 participants Review that progressed to oral ketamine treatment, four reported it to be less effective than intravenous infusions. Finally, of the 28 patients included in the six case series and reports, 100% showed sustained response.No differences in effectiveness were found when comparing the results of studies with different treatment frequencies or sample sizes. The number of patients with bipolar depression was too small to be able to distinguish differences in effectiveness regarding diagnostic categories. Mid-term (6 months to 1 year) and long-term (≥1 year) efficacy data were reported in three case seriesand two case reports.Of the 14 initial responders included in the three case studies and case reports reporting on mid-term sustained response rates, 13 (93%) showed sustained response after 6 months to 1 year of maintenance treatment.Of the 13 initial responders included in the two case studies reporting on long-term sustained response rates, two patients were treated with ketamine for less than 12 months. Of the other 11 patients, nine (82%) showed sustained response after 1 year of treatment.In the fourth case series, no sustained efficacy rates were presented, but documentation of continued efficacy ranged from 15 weeks to 2 years.Finally, in a retrospective case series by Hartberg and colleagues,patients were found to have reduced numbers of both hospital admissions (-65%) and inpatient hospital days (-70%) following oral ketamine therapy for up to 3 years, compared with the period before therapy. As with intravenous and intranasal maintenance treatment, adverse events were mild and transient in most individuals. No serious adverse events, patients dropping out due to adverse events, craving, cognitive disturbance, or renal problems were reported during oral maintenance treatment. Lower urinary tract symptoms were reported once but were determined to be unrelated to ketamine. Transient suicidal ideation was reported twice. The efficacy and safety of intramuscular maintenance treatment was the topic of three case reports and series, including three patients with bipolar and four with unipolar depression.Duration of treatment ranged from 6 months to 18 months and frequency from once every 3 days to once every 6 weeks (table). Of the seven included patients, four showed sustained response within the first 6 months of treatment (table). Responses were sustained in three patients in the midterm (6 months to 1 year). Of the four patients included in the single long-term study, two still showed sustained response after 12-18 months.Adverse events were mild and transient in all patients. No serious adverse events, patients dropping out due to adverse events, craving, cognitive disturbance, urinary problems, or renal problems were reported. We included one retrospective case series on a 6-week weekly subcutaneous treatment programme, including 70 patients with treatment-resistant depression (39 [56%] unipolar and 31 [44%] bipolar) presented in two manuscripts.Although the programme was not designed as a maintenance treatment programme, subcutaneous esketamine treatment was offered for more than 4 weeks, therewith meeting our intervention criteria (table). Depression response rates were available but not included in this Review since they concerned initial and not sustained response rates. Initial efficacy regarding anhedonia was preserved within the first 6 months of treatment.There were no mid-term or long-term subcutaneous maintenance treatment data available. No serious adverse events or clinically significant adverse events were reported.
DISCUSSION
To our knowledge, this is the first systematic review of the literature on the efficacy, safety, and tolerability of maintenance ketamine treatment for depression. So far, maintenance programmes with intravenous ketamine (18 studies including 222 patients), oral ketamine or esketamine (11 studies including 199 patients), and intranasal esketamine or esketamine (eight studies including 997 patients) have been studied the most. Data on maintenance treatment with intramuscular ketamine (three studies including seven patients) and subcutaneous esketamine (one study including 70 patients) are scarce. Whether the different routes of administration of ketamine differ in efficacy and safety is not yet clear. When discussing these different routes, differences in bioavailability of ketamine and its metabolites must be taken into consideration. The bioavailability of ketamine can be expected to be complete in intravenous administration, is slightly lower in intramuscular and subcutaneous administration (approximately 90%), and further decreases in intranasal (8-45%) and oral (8-29%) administration.Ketamine-dosing regimens for treatment-resistant depression often focus on maximising ketamine bioavailability and limiting its first pass metabolism, based on the assumption that the ketamine parent molecule is most important for treating depression. This assumption can be challenged for several reasons, for example because ketamine metabolites seem to have important roles in ketamine's antidepressant actions.These are interesting directions for future research to optimise ketamine treatment. Second, it is not yet clear if there is a difference in efficacy and safety between the different formulations of ketamine. Although ketamine acts primarily as an antagonist of NMDAR, the concept of NMDAR inhibition in depression has been challenged, and various other molecular insights have been gained in the mechanistic pathways of ketamine and its component enantiomers.This notion has recently renewed interest in potential safer alternatives with less affinity for the NMDAR, such Review as arketamine.More studies investigating its effectiveness are underway, and future direct comparisons between racemic ketamine, esketamine, and arketamine in depressed patients will be interesting. Whether sustained responsiveness differs to a clinically significant degree in patients with bipolar depression from those with unipolar depression, or in patients with electroconvulsive therapy-refractory depression from those whose symptoms have not previously not responded to electroconvulsive therapy is also not clear. Nevertheless, even if ketamine is found to be slightly less effective for patients with bipolar treatment-resistant depression or electroconvulsive therapy-refractory depression, this difference might not be meaningful given that there are so few established options for patients with drug-resistant bipolar depression or patients with electroconvulsive therapy-resistant depression. In summary, there is evidence for sustained therapeutic potential of intravenous, intranasal, and oral maintenance ketamine treatment within the first 6 months after initial response, and for intravenous maintenance treatment beyond 1 year after initial response. To a more limited extent, there is evidence for sustained therapeutic potential of intramuscular and subcutaneous maintenance ketamine treatment. Compared with maintenance antidepressant drug therapy with an average relapse rate of 23% in patients with non-treatment-resistant depression,these results, achieved in patients with difficult-to-treat symptoms, are clearly promising. Overall, the nature of adverse events reported was consistent with the known safety profile of initial ketamine treatment.Adverse events were mild and transient in most individuals. Cognitive impairment (n=1) and addiction (n=1) were reported but seem very uncommon based upon the current data. Although adverse events related to renal and urinary disorders were common in one study, serious renal and urinary problems related to ketamine seem uncommon. These findings contrast with previous reports that repeated use of ketamine in other populations, including animals, patients with chronic pain, and recreational users, has been linked with urological toxicity, hepatotoxicity, cognitive deficits, and dependency risks.Possible explanations for this disparity are the relatively low dosages (both dosing and frequency) and better controlled circumstances in most treatment programmes for depression. Second, in many studies, exclusion criteria for ketamine treatment included substance use disorders and unstable medical illnesses, possibly limiting the risk of increasing or uncontrolled use with these potential side-effects. Third, current data might be too limited or follow-up time too short in general to detect infrequent but potentially severe adverse effects, including those that might require a longer time to develop. Consistent with our findings regarding the safety of maintenance treatment are the findings of Feifel and colleagues.In a sample of 6630 patients receiving repeated (but not necessarily maintenance) parenteral ketamine for depression, discontinuation due to adverse effects was required in only 47 (0•7%). The most reported adverse effect that required discontinuation was psychological distress (33 [0•5%]). In three patients (0•06%) bladder dysfunction required discontinuation, in two (0•03%) hypomania, in six (0•09%) nausea, and in one (0•02%) psychotic symptoms, respiratory distress, and seizure. Adverse events that prompted discontinuation did not include addiction or cognitive deficits. A systematic review suggested that ketamine use for treatment-resistant depression is associated with cognitive improvement, probably related to a decrease in depressive symptoms.Serious adverse events were not always specified. Reported specifications were most often related to worsening of depressive symptoms, including suicidality. Relapse of depressive symptoms resulting in suicide, or a suicide attempt, was reported 14 times. These findings highlight the importance of meticulous monitoring of patients, not only during but also after cessation of treatment. The most frequently reported reasons for discontinuation of maintenance treatment were (partial) relapse or worsening of depressive symptoms, including suicidality. Additional reported adverse events leading to discontinuation were anxiety, (transient) confusional state, manic state, cognitive impairment, ketamine addiction, increased blood pressure, vertigo, and urinary problems. However, they were not often reported in the maintenance phase. Other reasons for discontinuation were classified as other or withdrawal by patient, without any further specification. This Review has several limitations. The overall quality of the majority of the studies was considered low to moderate, with most reports having a high risk of bias in several domains. For example, most studies were uncontrolled and underpowered, and in many studies assessment and documentation of efficacy, safety, and tolerability were inadequate. Next, publication bias might account for some of the effects we observed, especially since we included case reports, case series, and unregistered trials. Third, as a limitation of the review process, some studies were included although it is doubtful whether the intervention should be categorised as maintenance treatment. For example, repeated oral ketamine for 6 weeks could be considered as both maintenance and initial treatment. Fourth, eight patients who were included in studies that were categorised as mid term (n=4) or long term (n=4) had to be excluded from the mid-term or long-term response rate calculations, because their follow-up was too short. Finally, clinical and methodological heterogeneity between the studies was high, hindering comparison of the results. Therefore, our results should be interpreted with caution.
REVIEW CONCLUSION
Despite the methodological limitations, we conclude that from a clinical view, there is therapeutic potential of maintenance ketamine treatment. The available data show sustained efficacy in the majority of initial responders while severe adverse events seem uncommon. Use of maintenance ketamine treatment could be considered analogous to maintenance electroconvulsive therapy, for which there are no clear clinical guidelines. Electroconvulsive therapy is currently offered in a selection of patients based on response and tolerability, and frequency of treatment is determined clinically on a case-by-case basis. Undoubtedly, there is a need for caution given the many unknowns regarding the longterm effects of ketamine treatment. However, we feel, with the current evidence, that for a select subset of patients, it is justifiable to offer maintenance ketamine treatment despite these unknowns, as there is no reasonable treatment alternative. Careful screening, management, and follow-up will be necessary, as will managing expectations about the potential of relapse and adverse events. Both controlled and uncontrolled (naturalistic) studies with long-term follow-up and sufficient power are needed to determine the position of maintenance ketamine treatment within routine clinical practice. Contributors SYS-A, CE and DT completed the literature search and selected the included studies. SYS-A and JKEV extracted data and assessed the quality of the included studies. SYS-A synthesised and interpreted the data and wrote the manuscript. JKEV, JS, JK, and RAS critically reviewed the manuscript for intellectual content. All authors approved the final version of the manuscript for publication.
DECLARATION OF INTERESTS
JKEV received a speaker's fee from Janssen Pharmaceuticals, outside the submitted work. RAS received research funding for two randomised clinical trials with generic oral esketamine from the Netherlands Organisation for Health Research and Development and the National Health Care Institute, a speaker's fee and investigator initiated research grant from Janssen Pharmaceuticals, and consultancy fees from GH Research, Beckley PsyTech, and QPS, outside the submitted work. The other authors declared no competing interests.
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