Abstract
Background
Intravenous Ketamine has shown robust antidepressant efficacy although other routes of administration are currently needed. We conducted a systematic review and meta-analysis of studies evaluating the efficacy and tolerability of oral ketamine for depression.
Methods
A comprehensive search of major electronic databases from inception to April 2020 was performed. Studies of oral ketamine for depression, from case series to randomized clinical trials, were eligible. Randomized controlled trials were included in a meta-analysis, focusing on response, remission, time to effect, and side effects.
Results
A total of 917 articles were identified with 890 studies screened, yielding a total of 10 studies included in our systematic review.Three randomized controlled trials (RCTs) (N = 161, mean age 37.9 ± 9.5 years, 58.6% females) were included in the meta-analysis. Pooled analysis suggested a significant antidepressant effect of oral ketamine (SMD: −0.75; 95% CI: −1.08, −0.43; p<0.0001; I2 = 0%) although remission rates (RR:2.77; 95% CI:0.96, 8.00; p = 0.06) and response rates (RR:2.58; 95% CI:0.94,7.08; p = 0.07) were marginal compared to placebo at the endpoint. Oral ketamine antidepressant effects seemed to take effect at the 2nd week (SMD: −0.71; 95% CI: −1.08, −0.35; p = 0.001; I2 = 0%). There were no significant differences in the overall side-effects between oral ketamine and the placebo group (RR 1.28, 95% CI: 0.89-1.83; p = 0.19).
Conclusion
This focused meta-analysis of oral ketamine suggests a marginal efficacy for major depressive disorder without increased risk of adverse events. Further larger sample studies are needed to confirm these preliminary findings, analyzing differential response/remission rates by affective disorder, optimal dosing strategies, and its long-term effects.
Keywords: oral ketamine, unipolar depression, bipolar depression, mood disorders, efficacy
Introduction
Major depression is a recurrent and chronic illness that has a lifetime prevalence of 14%1 and constitutes a significant worldwide burden.2 After the pharmacological revolution introduced with fluoxetine in 1987,3 antidepressants have been one of the most commonly prescribed medicines for major depressive disorder (MDD), with more than 25 US FDA approved anti-depressants available. Despite many advances in the field related to pharmacological and non-pharmacological treatments for depression, strategies to improve refractory depression (ie., patients who fail to respond to 2 or more consecutive treatments) continue to be inadequate.
Ketamine, a non-competitive antagonist which exerts its pharmacological effects on the N-methyl-D-aspartate (NMDA) receptor,4,5 has demonstrated rapid antidepressant efficacy in patients with treatment-resistant depression (TRD).6–8 Importantly, the effects of intravenous (IV) ketamine may last up to several weeks after repetitive infusions.9 Ketamine has also been shown to rapidly reduce suicidal thoughts in depressed patients with suicidal ideation.6 Several studies now provide evidence of ketamine’s ability to produce rapid and robust antidepressant effects in patients with MDD and bipolar depression who were previously treatment-resistant.10,11 Moreover, clinical predictors of ketamine response in refractory depression have been proposed such as increased body mass index,12 family history of alcoholism, and no history of suicide attempts.13
Patients who respond to ketamine often need multiple treatments to maintain the antidepressant response. IV ketamine is not FDA-approved for depression and is usually not covered by insurance, leading to a fairly expensive ($400–500/infusion) treatment. Intranasal esketamine is FDA-approved for TRD but is also expensive. There is limited data regarding the long-term use of ketamine.14 Patients requiring multiple treatments to maintain efficacy may be at increased potential for tolerance and addiction.15
Oral ketamine is suggested as a more convenient alternative and is widely available. However, oral ketamine has yet to be thoroughly investigated. Low bioavailability of oral ketamine may impact the efficacy of oral ketamine and its comparisons between different routes of administrations and scheduling regimens.16 Other concerns have related to the increased possibility of psychiatric adverse events such as addiction since it has been highly comorbid with depression.17 Recently in the literature there has been a controversial debate whether there is merit in recommending oral ketamine to patients with refractory depression.18,19 Additionally, a recent meta-analysis examined different routes of ketamine administration demonstrating short-term efficacy for intravenous and intranasal ketamine but limited data analysis for oral ketamine.20
Our aim in this narrower systematic review and meta-analysis focusing on oral ketamine is to provide and facilitate an evidence base regarding the use of oral ketamine in the treatment of major depression concerning its efficacy and tolerability.
Methods
Our systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.21 A protocol was registered to PROSPERO (http://www.crd.york.ac.uk/prospero: CRD42020184512).
Data Sources and Search
A comprehensive search of several databases from each database’s inception to April 7th, 2020 was conducted. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Ovid PsycINFO, and Scopus. We also searched for the databases of ongoing clinical trials (e.g. http://www.controlled-trials.com or http://clinicaltrials.gov) through April 2020. The search was designed and conducted by an expert librarian (LJP) with input from senior author (BS) using a controlled vocabulary and key words (“major depression”, “bipolar disorder”, “ketamine”, “NMDA antagonist”, “response”, “remission”, “depression scores”, “mood”, “affective disorders”). The search was performed in all languages and was limited to human subjects. The complete search strategy is available in the “Supplement –Table S1”. We also performed a manual search of references in included studies to avoid selection bias.
Study Selection and Eligibility Criteria
Two reviewers (NAN and BS) independently screened the titles and abstracts of potentially eligible articles. Subsequently, the full texts of eligible articles were reviewed separately by the same two reviewers. The study’s inclusion criteria were the following: 1) Population—adult patients (≥ 18 years) experiencing a major depressive episode as part of a bipolar disorder (BD) or MDD defined by the DSM-5/DSM-IV-TR; 2) Intervention—studies evaluating the use of oral ketamine treatment; 3) Control—placebo or control; 4) Outcome—studies reporting a change in the severity of depressive symptoms; assessed by the use of standardized scales or validated measures; studies reporting the outcome data on remission and response rates, causes of discontinuation, and occurrences; 5) Study—randomized controlled clinical trials (RCTs), open label trials, observational studies, and case series (≥ 10 patients).
Exclusion criteria were: 1) Unpublished data; 2) Studies which evaluated post-partum or prenatal depression; 3) case series with fewer than 10 patients; 4) Use of ketamine for accelerating neuro-modulation techniques (ie. ECT); 5) Multiple reports from the same data set (only the original research studies were included to prevent unintended duplication of the data set). In cases of missing data, we reached out to the corresponding authors of the articles for additional information.
For meta-analysis, we selected only the RCTs, comparing oral ketamine with control or placebo in patients with MDD examining efficacy and reported adverse events data. Our primary outcome measures were clinical response and remission rate from the behavioral scales utilized in the RCT eg., Hamilton Depression Rating Scale (HDRS)22 and Montgomery Asberg Depression Scale (MADRS).23 As seconday outcome we included the change from baseline to endpoint quantified by the standardized mean difference (SMD). For the pooled analysis of adverse events we grouped events by system: psychiatric (euphoria, dissociative, nervousness, restlessness), neurological (dizziness, headache, sedation, drowsiness, tremor, blurred vision), and gastrointestinal (diarrhea, loss of appetite, nausea, vomiting, abdominal pain).
Quality of Bias Assessment
The methodological quality of the RCTs was assessed using the Cochrane Collaboration’s Risk of Bias Tool examining selection, performance, detection, attrition, reporting, and other biases. Each criterion was reported as low, high, or unclear risk of bias.24 Quantitative tests to assess publication bias were not performed due to the limited number of studies.25
Statistical Analyses
Continuous variables were reported as mean ± standard deviations (SD) or standard errors (SE). We computed the SMD for the variables analyzed, reporting the effect sizes with a 95% confidence interval (CI) using the Der-Simonian and Laird random effects model.26 For dichotomous variables such as response and remission rates, relative risk (RR) was calculated using the Mantel-Haenszel random effects model. In cases of missing data such as SD or missing summary data, we made efforts to contact authors from the original studies. If not successful, we estimated SD from SE, t statistics and P values for differences in means.27 We also calculated the number needed to treat (NNT), which is the number of patients who will need to be treated for one favorable outcome, summarizing which intervention may be superior to another one. Clinical Response was defined across studies as greater than 50% reduction in depressive symptoms given by the HDRS or MADRS scale and remission with a total MADRS score ≤ 10 and HDRS score ≤ 7.
Heterogeneity between the studies was assessed using the I2 statistic.28 The I2 statistic measures the percentage of variability that cannot be attributed to random error. All the statistical analyses were conducted using the “meta” (version 4.9.6) and “metafor” (version 2.1.0) packages of R software for statistical computing (version 3.6.1) in R Studio (version 1.2.1335).29–32 An alpha level of 0.05 was chosen for statistical significance.
Results
Our search identified a total of 890 articles (after removing duplicates) of which 16 studies were selected for eligibility (Figure 1). A total of 10 studies met the inclusion criteria for our qualitative analysis and were included in the systematic review: 3 RCTs (ketamine, N = 83, placebo N = 78),33–35 2 open-label studies (N = 21),36,37 3 retrospective studies (N = 83),38–40 and 2 case series (N = 48)41,42 (Table 1). Participants were mostly female (58.6%) with a mean age between 34 and 68 years of age. Duration of oral ketamine administration varied among the studies; for example for the RCTs, duration of treatment ranged from 3 to 6 weeks while retrospective studies included follow-up visits up to 3 years.39 Across the studies there was variability in the behavioral scales utilized to assess and quantify improvement of depression. Two RCTs utilized the HDRS,33,35 another used the MADRS34; while an open label study36 used the Hospital Anxiety and Depression Scale (HADS),43 and a case series used the Beck Depression Inventory- II (BDI-II) scale.42 There was also variability of ketamine dosages which ranged from 0.5 mg/kg to 7 mg/kg. Variability was also observed in the dosing frequency from several times a day, to daily dosing, to several times per week, or even less frequently, up to 3 years. We did not identify any RCT which investigated oral ketamine in bipolar depression.
Figure 1.
Flow Diagram of the Procedure for Study Selection
Table 1. Characteristics of the Studies Included in the Review.
Author | Type of Study | Total Patients, Males [n (%)] |
Dosage regimen | Diagnosis and criteria | Mean Age (SD)/Median |
Primary Outcome Measure | Conclusions |
Lara et al. 201341 | Case series | 26, 8(30.8) |
Sublingual 10mg (100mg/ml) |
MDD & BD | 45.2 (17.3) |
Refractory unipolar depression- Likert scale used for assessment |
Effective in 20 patients with an onset effect within 90 minutes. |
Irwin et al. 201336 | Open-label | 8, 1(12) |
Oral ketamine- 0.5mg/kg |
MDE defined by a HADS score ≥15 or depression > 8. subscale ≥ 8 | 63.0 (18) |
HADS | 8 patients completed the study and reported ≥ 30% improvement in depressive and anxiety symptoms |
Iglewicz et al. 201538 | Retrospective study | 31, 11(35.5) |
Oral ketamine 0.5mg/kg single dose (n = 22), repeat single dose (n = 5) and three times a day (n = 4). | Patients in hospice care center receiving ketamine for MDE | 66.0 | CGI | Ketamine was well tolerated and effective in the first week of treatment. 93% patients showed improvement in the first 3 days, 80% during days 4–7, and 60% during days 8–21 after dosing. |
Nguyen et al. 201540 | Retrospective study | 17, 2(11.8) |
Oral ketamine 0.5–1mg/kg every 1–2 weeks | MDD | 48.0 | Retrospective assessment of clinical notes | 13 patients (76%) had a response noted in the first 24 hrs of administration. |
Jafarinia et al. 201635 | RCT | 40, 10(25.0) |
Oral ketamine. 50mg three times a day | MDD HDRS < 19 Comorbid Headaches |
Ketamine=40.7 (8.7) Placebo=38.9 (9.2) |
HDRS | There was significant improvement in depressive symptoms at 6 weeks post-ketamine intervention compared to control. No differences in discontinuation rates. |
Al Shirawi et al. 201742 | Case series | 22, 9(40.9) |
Oral ketamine. Initiated at 50mg, titrated up by 25mg every 3 days | MDD by MINI | 39.0 | BDI-II | 18% of patients showed ≥ 50% improvement, 14% reported partial improvement, 45% had no response, 23% showed a mild worsening. |
Hartberg et al. 201839 | Retrospective study | 37, 9(24.3) |
Oral ketamine. Initiated at 0.5 mg/kg (twice daily, 3hr apart), titrated up (at most twice per week) by 20–50% at subsequent treatment. Once titrated, patients received treatment between twice weekly and fortnightly. | MDD with PTSD or Anxiety disorders. | 46.0 | Number of days spent as inpatient in a hospital before or after treatment | Hospital admissions were reduced by 65% and inpatient hospital days by 70% after ketamine intervention. |
Arabzadeh et al. 201833 | RCT | 81, 31(38.3) |
Oral ketamine 25mg twice daily. | MDD HDRS ≥ 20 |
Ketamine=34.3 (6.7) Placebo=33.7 (8.3) |
HDRS | There was a significantly higher response rate with ketamine as compared to placebo (85% vs 58%), although no differences in remission rates. Ketamine was well tolerated. |
Domany et al. 201934 | RCT | 41, 26(63.4) |
Oral ketamine. 1mg/kg 3x weekly. | MDD by MINI and MADRS ≥ 19 | Ketamine=38.7 (13.3) Placebo=37.9 (13.4) |
MADRS | 31.8% of patients achieved response in ketamine group compared to only 5.6% in placebo, whereas 27.3% achieved remission in ketamine group whereas none of the patients in the placebo group achieved remission at the end of study. |
Glue et al. 202037 | Open-label | 7, 4(57.1) |
Oral ketamine extended release 60-240mg 12 hourly. |
MDE by MADRS > 20 GAD/SAD by HAMA > 20 and LSAS > 60 |
27.0 | MADRS HAMA FQ |
All patients had >50 % improvements occurring gradually over a 96h period. Onset of mood improvement is slightly delayed compared with parenteral dosing. |
MDD: Major depressive disorder; MDE: Major depressive episode; BD: Bipolar Disorder; GAD: General Anxiety Disorder; SAD: Social Anxiety Disorder; FQ: Fear questionnaire; PTSD: Post-traumatic stress disorder; M.I.N.I : Mini International Neuropsychiatric Interview ; RCT: randomized controlled trial; HDRS: Hamilton depression rating scale; HAMA: Hamilton anxiety scale; HADS: Hospital Anxiety and Depression Scale; LSAS: Liebowitz Social Anxiety Scale ; BDI-II: Beck Depression Inventory II; MADRS: Montgomery–Åsberg Depression Rating Scale. TRD: Treatment resistant depression. SD: Standard deviation.
Retrospective Studies and Case Series
Of the retrospective studies/case series assessing the effect of oral ketamine, Lara and colleagues41 included a sublingual route of administration (dose:10mg from a 100 mg/ml solution), administered every 2–3 days or, with 77% (20/26) of the patients improving depression severity. The other case series included in our systematic review42 used oral ketamine (mean dose of 222 mg/day) where patients were treated every 3 days until reaching the study end point, finding that only 4/22 patients (18%) had at least 50% improvement in depression ratings using the BDI-II. None of the included retrospective studies38–40 examined ketamine as a monotherapy. Hartberg and colleagues examined reduction in hospitalization days in 37 patients with TRD and comorbid post-traumatic stress disorder or anxiety disorders during a period of 3 years before and after ketamine treatment (dose varied from 0.5mg/kg to 7mg/kg) reporting a 70% reduction in the inpatient hospital days and 65% reduction in new admissions after oral ketamine administration.39 In a 72 week study, Nguyen and colleagues examined the use of trans mucosal ketamine (0.5–1 mg/kg) in a group of patients with TRD with multiple comorbidities. They showed improvement in depressive symptoms in 13/17 (76%) patients using a retrospective assessment of clinical notes.40 Iglewicz and colleagues examined oral ketamine (0.5mg/kg) in 31 inpatients in hospice care with variability in dosing regimen from once a day dosing to three times per day (29 received oral ketamine, 1 subcutaneous and 1 oral followed by subcutaneous). Oral ketamine was well tolerated and showed an improvement in 93% of the patients in the first 3 days.38
Open-Label Studies
One of the two open-label studies included by Irwin and colleagues examined the efficacy of oral ketamine (dose range: up to 0.5mg/kg) in 14 patients with depression and anxiety receiving hospice care. Only 8 patients completed the trial, all of whom reporting an improvement (≥ 30%) in depressive and anxiety symptoms quantified by the HADS scale.36 Glue and colleagues assessed the efficacy and tolerability of a multiple dose oral extended release ketamine in seven patients with a diagnosis of TRD and anxiety disorder.37 This open label study showed that all patients had improvements in mood symptoms with good tolerability quantified by the MADRS and the Hamilton Anxiety Rating scale.
Randomized Controlled Trials
One RCT34 of 41 patients with TRD who received either oral ketamine (1mg/kg) three times per week or placebo for 3 weeks, showed that there was a significant improvement in depressive symptoms with oral ketamine compared to placebo. At 3 weeks, response (32% vs. 6%) and remission (27% vs. 0%) rates were significantly higher in the ketamine group (n = 22) compared to placebo (n = 18). Jafarinia and colleagues,35 in a 6 week RCT, included 46 mildly or moderately depressed patients with comorbid headaches who were randomized to receive either 50mg of oral ketamine three times per day compared to oral diclofenac. Eighty-seven percent (n = 40) of the patients completed the trial; there was a significant improvement in those patients who received oral ketamine as compared to control (diclofenac) in terms of response rates (60% vs. 15%) and remission rates (45% vs. 10%).35 In a 6 week RCT, Arabzadeh and colleagues compared augmentation of sertraline with oral ketamine (50mg/day) versus placebo in 90 patients with moderate or severe MDD. Ninety percent (n = 81) of the patients completed the trial and showed a significant effect in response rates (85% vs. 58%) at 6 weeks for the ketamine augmentation group compared to placebo.33 None of the RCTs included in this review provided evidence for drug misuse in the population.
Outcomes
A meta-analysis was conducted on 3 RCT studies33–35 (ketamine, N = 83; placebo, N = 78) showing a significant effect for ketamine at the end of the trial (SMD: −0.75; 95% CI: −1.08, −0.43; p < 0.0001; I2 = 0%). Importantly, the antidepressant effect of oral ketamine seemed to occur at the 2nd week of treatment (SMD: −0.71; 95% CI: −1.08, −0.35; p = 0.001; I2 = 0%).33,34 Similarly, we examined the 2 studies which provided data at 3 weeks of treatment34,35 and there was a significant difference from the placebo/control (SMD −0.79; 95% CI: −1.40, −0.17; p = 0.012; I2 = 43.8 %) (Figure 2). Remission rates (RR: 2.77; 95% CI: 0.95, 8.00; p = 0.06; I2 = 36.0%) and response rates (RR: 2.58; 95% CI: 0.94, 7.08; p = 0.07; I2 = 66%) were marginal compared to placebo at the endpoint (Figure 3).
Figure 2.
Forest Plot of Pooled Standardized Mean Differences by Week of Treatment and at End of Trial for Oral Ketamine
Figure 3.
A. Forest Plot of Pooled Remission Rates for Oral Ketamine. B. Forest Plot of Pooled Response Rates for Oral Ketamine
Number-Needed-to-Treat (NNT)
The number-needed-to-treat for a response and remission were 3 (95% CI 2–6) and 5 (95% CI 3–15) patients, respectively. In other words, 3 patients needed to be treated with oral ketamine for one additional patient to achieve a response, and 5 patients needed to treated with oral ketamine for an additional patient to reach remission, in comparison to the patients who received placebo.
Adverse Events
Overall, oral ketamine was fairly well tolerated among the studies. There were no significant differences between ketamine and the placebo/control group when we analyzed total (RR 1.28, 95% CI, 0.89–1.83; p = 0.19), psychiatric (RR 1.44, 95% CI, 0.42–4.95; p = 0.56), neurological (RR 1.51, 95% CI, 0.77–2.94; p = 0.23), and gastrointestinal (RR 0.90, 95% CI, 0.40–2.03; p = 0.80) adverse events. (Figure 4)
Figure 4.
A. Forest Plot of Pooled Rates of Significant Overall Side Effects for Oral Ketamine. B. Forest Plot of Pooled Rates of Significant Gastrointestinal Side Effects for Oral Ketamine. C. Forest Plot of Pooled Rates of Significant Neurological Side Effects for Oral Ketamine. D. Forest Plot of Pooled Rates of Significant Psychiatric Side Effects for Oral Ketamine
Quality Assessment
The assessment of methodological quality of the RCTs included in the meta-analysis was done using the Cochrane Collaboration’s Risk of Bias Tool (Supplemental appendix. Table-S2 and Figure-S1). The studies showed an overall low risk of bias. There was an unclear risk of bias for the selective reporting criteria among all the studies and two studies33,35 showed a high risk for attrition bias.
Discussion
In this comprehensive systematic review and meta-analysis, we summarized the available evidence for the efficacy and tolerability of oral ketamine in MDD. Our systematic review included 10 studies of which 3 RCTs were part of the meta-analysis. From the qualitative analysis, the included studies reported efficacy of oral ketamine in reducing either depressive symptomatology or number of hospitalizations. Among the 3 RCTs, one study did not report significant findings in terms of remission rates.33 Our quantitative analysis showed an antidepressant effect of oral ketamine that was significant and sustained from the 2nd week of treatment. Oral ketamine was well tolerated, although some studies lacked cardiovascular data such as blood pressure and heart rate. Our review did not show a significant increase in total side effects when we compared the individual psychiatric/gastrointestinal/neurological side-effects to placebo. Our results were in concordance with previous studies where authors highlighted a positive effect of oral ketamine.19,44
Nevertheless, by using relative risk, which is a more conservative method to avoid overestimation,45 remission and response rates were marginally non-significant compared to placebo. This could be due to reasons such as an overall small sample size of the studies. However, the NNT for both remission and response rates were below 6, highlighting that oral ketamine may constitute a promising treatment intervention. Our meta-analysis of efficacy for the primary outcomes (response and remission rates) do not provide substantial evidence for a strong recommendation for oral ketamine, underscoring caution when considering oral ketamine for depression. On the other hand, our study found encouraging data regarding the safety and efficacy of oral ketamine, and highlighted the need to further investigate and standardize oral ketamine treatment. In addition, there is merit in examining the potential role of oral ketamine as an option for a maintenance phase after response with IV ketamine.
This meta-analyis provides important insight into the appropriateness and efficacy of oral ketamine for TRD and plausible explanations of these mixed findings. There is no consensus among the researchers of a standardized dose and frequency of oral ketamine for TRD. For example, Arabzadeh and colleagues33 used 50 mg daily as an augmentation option whereas Jafarinia and colleagues35 used 50 mg three times daily. It is possible that Arabzadeh and colleagues33 likely underdosed patients in their study. However, this needs further exploration since it has been proposed that the bioavailability of oral ketamine to be approximate 20%.46 Domany and colleagues34 administered oral ketamine 1 mg/kg three times a day and showed good efficacy and safety of oral ketamine. In a recent study, Fava and colleagues investigated IV ketamine as adjunctive treatment for TRD showing no benefit at lower dosages (0.1mg/kg and 0.2 mg/kg) as compared to placebo,47 which underscores the importance of identifying and standardizing the dosage of oral ketamine for TRD. If we were to estimate an equivalent dose of oral ketamine based on a 20% bioavailability and the standard IV ketamine dose of 0.5 mg/kg for a 70 kg individual, the dose would be 35 mg for the IV formulation, and 175 mg (35 mg ÷ 0.2) for the oral formulation, suggesting that 50 mg oral ketamine three times a day would be closer to a clinical dose.
There are several limitations of our systematic review and meta-analysis that should be acknowledged, such as the small number of included studies for the quantitative analysis which did not permit a meta-regression or sub-analysis adjusting for dosing, frequency, or gender. Additionally, we found a remarkable variability amongst the included studies in terms of dosing and duration of ketamine administration, measures of assessing depressive symptoms improvement, and a heterogeneous sample with multiple medical comorbidities. In addition, in the included studies there were no data on maintenance or a sustainability effect of ketamine on alleviating depressive symptoms.
Despite a dearth of well-powered studies, our findings suggest a marginal efficacy of oral ketamine for major depression without increasing the risk for adverse events. Moreover, the onset of action of oral ketamine was not immediate. This finding needs further exploration as to whether it is due to subtherapeutic dosage in some of the studies. If the efficacy of oral ketamine is delayed for 2 weeks, this provides an exciting opportunity to investigate the role of oral ketamine as a viable option for the maintenance phase among patients with TRD who are responders to IV ketamine with awareness of starting oral before the IV ketamine course is completed. Moreover, according to the consensus guidelines of pain medicine, there is low-level of evidence to support the use of oral ketamine following IV administration.48 While ketamine can constitute a life-saving treatment for some patients, it also has a potential for abuse, and the long term addiction potential of oral ketamine needs to investigated in longitudinal studies.
In conclusion, oral ketamine showed borderline efficacy for major depression and is well-tolerated. Our focused meta-analysis underscores the need of further well-designed and powered clinical trials which should consider different dosing and titration strategies in order to provide a more integrative and robust evidence base recommendation regarding oral ketamine. In addition, future clinical trials should consider ketamine’s different bioavailability by comparing multiple routes of administration (e.g., oral vs. IV, oral vs. sublingual; IV vs. sublingual and intranasal), differential outcomes regarding different depressive phenotypes, long-term efficacy and side-effect profiles, as well as individual genetic variations that may influence treatment outcomes. It is important to confirm these preliminary findings with more extensive studies analyzing acute vs. maintenance phase outcomes and the sustainability of the antidepressant effects, which may improve quality of life and decrease the burden of depressive disorders and reduce utilization of mental health services.
Acknowledgments
We want to thank Dr. Zhen Wang for his contributions on the statistical analysis.
Footnotes
Financial Disclosures
Dr. Singh received research time support from Medibio. It is unrelated to the current study. Dr. Singh reports grant support from Mayo Clinic.
Dr. Frye reports grant support from Assurex Health, Mayo Foundation, Medibio. Consultant (Mayo)—Actify Neurotherapies, Allergan, Intra-Cellular Therapies, Inc., Janssen, Myriad, Neuralstem Inc., Takeda, Teva Pharmaceuticals. He reports CME/Travel/Honoraria from the American Physician Institute, CME Outfitters, Global Academy for Medical Education.
Dr. Vande Voort has received supplies and genotyping services from Assurex Health, Inc. for investigator-initiated studies.
Other authors have none to declare.
All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplements
Table S1. Search Strategy.
# | Searches | Results | Type |
Ovid | |||
1 | exp Bipolar Disorder/ | 134389 | Advanced |
2 | exp bipolar depression/ | 48614 | Advanced |
3 | exp major depression/ | 191387 | Advanced |
4 | exp Mood Disorders/ | 781474 | Advanced |
5 | exp affective disorders/ (((affective or mood or anxiety or panic or “post-traumatic stress” or “obsessive-compulsive” or dysthymic or “premenstrual dysphoric”) adj3 (disorder* or disturbance* or illness*)) or “affective neuros*” or “affective psychos*” or Bipolar |
781474 | |
6 | or “blunted affect” or Cyclothymia* or Cyclothymic or depressed or Depression* or depressive or mania or manias or “manic disorder*” or “manic state*” or maniodepress* or melancholia* or “schizoaffective psychos*” or “social anxiet*” or unipolar).ti,ab,hw,kw. | 2033410 | Advanced |
7 | or/1-6 | 2038516 | Advanced |
8 | exp Administration, Oral/ | 554593 | |
9 | exp oral drug administration/ (oral or orally or “po administration” or “po dosage” or “po dose” or “po drug” or |
554593 | |
10 | “per os drug” or “per os administration” or “per os dosage” or “per os dose”).ti,ab,hw,kw. | 2217388 | Advanced |
11 | 8 or 9 or 10 | 2220871 | Advanced |
12 | exp Administration, Intravenous/ | 516555 | Advanced |
13 | “intravenous drug administration”/ | 356177 | Advanced |
14 | (infusion* or injection* or intravenous*).ti,ab,hw,kw. | 3085820 | Advanced |
15 | 12 or 13 or 14 | 3085842 | Advanced |
16 | 15 not 11 | 2779980 | Advanced |
17 | exp Ketamine/ (anesject or calipsol or calypsol or “ci 581” or ci581 or “cl 369” or cl369 or “cn 52372 2” or “cn 523722” or “cn52372 2” or cn523722 or imalgene or kalipsol or katamine or “keta-hameln” or ketaject or ketalar or ketalin or ketamax or ketamine |
54339 | Advanced |
18 | or ketaminol or ketanest or ketased or ketaset or ketaved or ketavet or ketmin or ketoject or ketolar or narkamon or narketan or “soon-soon” or tekam or velonarcon or vetalar).ti,ab,hw,kw. | 70341 | Advanced |
19 | 17 or 18 | 70341 | Advanced |
20 | 19 not 16 | 45988 | Advanced |
21 | 7 and 20 | 7740 | |
22 | exp Randomized Controlled Trial/ | 1103008 | Advanced |
23 | exp triple blind procedure/ | 249 | Advanced |
24 | exp Double-Blind Method/ | 463482 | Advanced |
25 | exp Single-Blind Method/ | 87064 | Advanced |
26 | exp latin square design/ | 368 | Advanced |
27 | exp Placebos/ | 407025 | Advanced |
28 | exp Placebo Effect/ ((randomized adj3 study) or (randomized adj3 trial) or (randomised adj3 study) or (randomised adj3 trial) or “pragmatic clinical trial” or (random* adj1 allocat*) or (doubl* adj blind*) or (doubl* adj mask*) or (singl* adj blind*) or (singl* adj |
12077 | Advanced |
29 | mask*) or (tripl* adj blind*) or (tripl* adj mask*) or (trebl* adj blind*) or (trebl* adj mask*) or “latin square” or placebo* or nocebo* or (“open label” adj5 (study or trial))).mp,pt. | 3215493 | Advanced |
30 | or/22-29 | 3216032 | Advanced |
31 | 21 and 30 limit 31 to (“all adult (19 plus years)” or “young adult (19 to 24 years)” or “adult (19 to 44 years)” or “young adult and adult (19-24 and 19-44)” or “middle age (45 |
1357 | Advanced |
32 | to 64 years)” or “middle aged (45 plus years)” or “all aged (65 and over)” or “aged (80 and over)”) [Limit not valid in APA PsycInfo,CCTR,CDSR,Embase; records were retained] | 1245 | Advanced |
33 | limit 32 to (adult <18 to 64 years> or aged <65+ years>) [Limit not valid in APA PsycInfo,CCTR,CDSR,Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] | 573 | Advanced |
34 | limit 31 to (“all infant (birth to 23 months)” or “all child (0 to 18 years)” or “newborn infant (birth to 1 month)” or “infant (1 to 23 months)” or “preschool child (2 to 5 years)” or “child (6 to 12 years)” or “adolescent (13 to 18 years)”) [Limit not valid in APA PsycInfo,CCTR,CDSR,Embase; records were retained] | 1197 | Advanced |
35 | limit 34 to (embryo or infant or child or preschool child <1 to 6 years> or school child <7 to 12 years> or adolescent <13 to 17 years>) [Limit not valid in APA PsycInfo,CCTR,CDSR,Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] | 372 | Advanced |
36 | 35 not 33 | 50 | Advanced |
37 | 31 not 36 | 1307 | Advanced |
38 | (exp animals/ or exp nonhuman/) not exp humans/ | 11026631 | Advanced |
39 | ((alpaca or alpacas or amphibian or amphibians or animal or animals or antelope or armadillo or armadillos or avian or baboon or baboons or beagle or beagles or bee or bees or bird or birds or bison or bovine or buffalo or buffaloes or buffalos or “c elegans” or “Caenorhabditis elegans” or camel or camels or canine or canines or carp or cats or cattle or chick or chicken or chickens or chicks or chimp or chimpanze or chimpanzees or chimps or cow or cows or “D melanogaster” or “dairy calf” or “dairy calves” or deer or dog or dogs or donkey or donkeys or drosophila or “Drosophila melanogaster” or duck or duckling or ducklings or ducks or equid or equids or equine or equines or feline or felines or ferret or ferrets or finch or finches or fish or flatworm or flatworms or fox or foxes or frog or frogs or “fruit flies” or “fruit fly” or “G mellonella” or “Galleria mellonella” or geese or gerbil or gerbils or goat or goats or goose or gorilla or gorillas or hamster or hamsters or hare or hares or heifer or heifers or horse or horses or insect or insects or jellyfish or kangaroo or kangaroos or kitten or kittens or lagomorph or lagomorphs or lamb or lambs or llama or llamas or macaque or macaques or macaw or macaws or marmoset or marmosets or mice or minipig or minipigs or mink or minks or monkey or monkeys or mouse or mule or mules or nematode or nematodes or octopus or octopuses or orangutan or “orang-utan” or orangutans or “orang-utans” or oxen or parrot or parrots or pig or pigeon or pigeons or piglet or piglets or pigs or porcine or primate or primates or quail or rabbit or rabbits or rat or rats or reptile or reptiles or rodent or rodents or ruminant or ruminants or salmon or sheep or shrimp or slug or slugs or swine or tamarin or tamarins or toad or toads or trout or urchin or urchins or vole or voles or waxworm or waxworms or worm or worms or xenopus or “zebra fish” or zebrafish) not (human or humans or patient or patients)).ti,ab,hw,kw. | 9861833 | Advanced |
40 | 37 not (38 or 39) | 1251 | Advanced |
41 | limit 40 to (dissertation abstract or editorial or erratum or note or addresses or autobiography or bibliography or biography or blogs or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient education handout or periodical index or portraits or published erratum or video-audio media or webcasts) [Limit not valid in APA PsycInfo,CCTR,CDSR,Embase,Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] | 71 | Advanced |
42 | from 41 keep 13–15 | 3 | Advanced |
43 | (40 not 41) or 42 | 1183 | Advanced |
44 | remove duplicates from 43 | 917 | Advanced |
Scopus | |||
1 | TITLE-ABS-KEY(((affective or mood or anxiety or panic or “post-traumatic stress” or “obsessive-compulsive” or dysthymic or “premenstrual dysphoric”) W/3 (disorder* or disturbance* or illness*)) or “affective neuros*” or “affective psychos*” or Bipolar or “blunted affect” or Cyclothymia* or Cyclothymic or depressed or Depression* or depressive or mania or manias or “manic disorder*” or “manic state*” or maniodepress* or melancholia* or “schizoaffective psychos*” or “social anxiet*” or unipolar) | ||
2 | TITLE-ABS-KEY(oral or orally or “po administration” or “po dosage” or “po dose” or “po drug” or “per os drug” or “per os administration” or “per os dosage” or “per os dose”) | ||
3 | TITLE-ABS-KEY(infusion* OR injection* OR intravenous*) | ||
4 | TITLE-ABS-KEY(anesject OR calipsol OR calypsol OR “ci 581” OR ci581 OR “cl 369” OR cl369 OR “cn 52372 2” OR “cn 523722” OR “cn52372 2” OR cn523722 OR imalgene OR kalipsol OR katamine OR “keta-hameln” OR ketaject OR ketalar OR ketalin OR ketamax OR ketamine OR ketaminol OR ketanest OR ketased OR ketaset OR ketaved OR ketavet OR ketmin OR ketoject OR ketolar OR narkamon OR narketan OR “soon-soon” OR tekam OR velonarcon OR vetalar) | ||
5 | TITLE-ABS-KEY((randomized W/3 study) OR (randomized W/3 trial) OR (randomised W/3 study) OR (randomised W/3 trial) OR “pragmatic clinical trial” OR (random* W/1 allocat*) OR (doubl* W/1 blind*) OR (doubl* W/1 mask*) OR (singl* W/1 blind*) OR (singl* W/1 mask*) OR (tripl* W/1 blind*) OR (tripl* W/1 mask*) OR (trebl* W/1 blind*) OR (trebl* W/1 mask*) OR “latin square” OR placebo* OR nocebo* OR (“open label” W/5 (study or trial))) | ||
6 | 1 and (4 and not (3 and not 2)) and 5 | ||
7 | TITLE-ABS-KEY(newborn* or neonat* or infant* or toddler* or child* or adolescent* or paediatric* or pediatric* or girl or girls or boy or boys or teen or teens or teenager* or preschooler* or “pre-schooler*” or preteen or preteens or “pre-teen” or “pre-teens” or youth or youths) AND NOT TITLE-ABS-KEY(adult or adults or “middle age” or “middle aged” OR elderly OR geriatric* OR “old people” OR “old person*” OR “older people” OR “older person*” OR “very old”) | ||
8 | 6 and not 7 | ||
9 | TITLE-ABS-KEY((alpaca OR alpacas OR amphibian OR amphibians OR animal OR animals OR antelope OR armadillo OR armadillos OR avian OR baboon OR baboons OR beagle OR beagles OR bee OR bees OR bird OR birds OR bison OR bovine OR buffalo OR buffaloes OR buffalos OR “c elegans” OR “Caenorhabditis elegans” OR camel OR camels OR canine OR canines OR carp OR cats OR cattle OR chick OR chicken OR chickens OR chicks OR chimp OR chimpanze OR chimpanzees OR chimps OR cow OR cows OR “D melanogaster” OR “dairy calf” OR “dairy calves” OR deer OR dog OR dogs OR donkey OR donkeys OR drosophila OR “Drosophila melanogaster” OR duck OR duckling OR ducklings OR ducks OR equid OR equids OR equine OR equines OR feline OR felines OR ferret OR ferrets OR finch OR finches OR fish OR flatworm OR flatworms OR fox OR foxes OR frog OR frogs OR “fruit flies” OR “fruit fly” OR “G mellonella” OR “Galleria mellonella” OR geese OR gerbil OR gerbils OR goat OR goats OR goose OR gorilla OR gorillas OR hamster OR hamsters OR hare OR hares OR heifer OR heifers OR horse OR horses OR insect OR insects OR jellyfish OR kangaroo OR kangaroos OR kitten OR kittens OR lagomorph OR lagomorphs OR lamb OR lambs OR llama OR llamas OR macaque OR macaques OR macaw OR macaws OR marmoset OR marmosets OR mice OR minipig OR minipigs OR mink OR minks OR monkey OR monkeys OR mouse OR mule OR mules OR nematode OR nematodes OR octopus OR octopuses OR orangutan OR “orang-utan” OR orangutans OR “orang-utans” OR oxen OR parrot OR parrots OR pig OR pigeon OR pigeons OR piglet OR piglets OR pigs OR porcine OR primate OR primates OR quail OR rabbit OR rabbits OR rat OR rats OR reptile OR reptiles OR rodent OR rodents OR ruminant OR ruminants OR salmon OR sheep OR shrimp OR slug OR slugs OR swine OR tamarin OR tamarins OR toad OR toads OR trout OR urchin OR urchins OR vole OR voles OR waxworm OR waxworms OR worm OR worms OR xenopus OR “zebra fish” OR zebrafish) AND NOT (human OR humans or patient or patients)) | ||
10 | 8 and not 9 | ||
11 | DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR DOCTYPE(sh) | ||
12 | 10 and not 11 | ||
13 | INDEX(embase) OR INDEX(medline) OR PMID(0* OR 1* OR 2* OR 3* OR 4* OR 5* OR 6* OR 7* OR 8* OR 9*) | ||
14 | 12 and not 13 |
Table S2. Risk of bias for RCTs Included in Meta-Analysis.
Criteria | Arabzadeh et al. 2018 | Domany et al. 2019 | Jafarinia et al. 2016 |
Random sequence generation (selection bias) | Low | Low | Low |
Allocation concealment (selection bias) | Low | Low | Low |
Blinding of participants and personnel | Low | Low | Low |
Blinding of outcome assessment (detection bias) | Low | Low | Low |
Incomplete outcome data addressed (attrition bias) | High | Low | High |
Selective reporting (reporting bias) | Low | Low | Low |
Other bias | Unclear | Unclear | Unclear |
Figure S1.
Risk of bias for RCTs Included in Meta-Analysis
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