In this phase 2 randomised, placebo‑controlled enrichment study, extended‑release oral ketamine tablets (R‑107) given twice weekly maintained antidepressant response in treatment‑resistant depression, with the 180 mg dose producing a significant 13‑week MADRS improvement versus placebo (least‑square mean difference −6.1, P = 0.019). R‑107 was generally well tolerated with minimal blood‑pressure, sedation or dissociation effects, showed a dose–response reduction in relapse rates, and most dosing was performed at home.
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Ketamine has rapid-onset antidepressant activity in patients with treatment-resistant major depression (TRD). The safety and tolerability of racemic ketamine may be improved if given orally, as an extended-release tablet (R-107), compared with other routes of administration. In this phase 2 multicenter clinical trial, male and female adult patients with TRD and Montgomery–Asberg Depression Rating Scale (MADRS) scores ≥20 received open-label R-107 tablets 120 mg per day for 5 days and were assessed on day 8 (enrichment phase). On day 8, responders (MADRS scores ≤12 and reduction ≥50%) were randomized on a 1:1:1:1:1 basis to receive double-blind R-107 doses of 30, 60, 120 or 180 mg, or placebo, twice weekly for a further 12 weeks. Nonresponders on day 8 exited the study. The primary endpoint was least square mean change in MADRS for each active treatment compared with placebo at 13 weeks, starting with the 180 mg dose, using a fixed sequence step-down closed test procedure. Between May 2019 and August 2021, 329 individuals were screened for eligibility, 231 entered the open-label enrichment phase (days 1–8) and 168 responders were randomized to double-blind treatment. The primary objective was met; the least square mean difference of MADRS score for the 180 mg tablet group and placebo was −6.1 (95% confidence interval 1.0 to 11.16, P = 0.019) at 13 weeks. Relapse rates during double-blind treatment showed a dose response from 70.6% for placebo to 42.9% for 180 mg. Tolerability was excellent, with no changes in blood pressure, minimal reports of sedation and minimal dissociation. The most common adverse events were headache, dizziness and anxiety. During the randomized phase of the study, most patient dosing occurred at home. R-107 tablets were effective, safe and well tolerated in a patient population with TRD, enriched for initial response to R-107 tablets. ClinicalTrials.gov registration: ACTRN12618001042235 .
Over the past two decades, research has established that ketamine can produce rapid-onset antidepressant effects in patients with treatment-resistant depression (TRD), but most trials have used intravenous racemic ketamine or intranasal esketamine. Oral dosing has been much less studied despite pharmacokinetic features of oral ketamine that increase exposure to metabolites such as norketamine and hydronorketamines, which may contribute to antidepressant activity and to a more favourable tolerability profile (for example, less dissociation and smaller blood pressure effects). An extended-release oral formulation (R-107) was developed to exploit prolonged first-pass metabolism and delayed peak concentrations, with absolute bioavailability reported as under 20% and sustained metabolite exposure over 24 hours. Glue and colleagues designed a multicentre Phase II proof-of-concept trial to evaluate the efficacy, dose–response and safety of R-107 in adults with TRD. The study used an open-label enrichment phase with once-daily 120 mg R-107 for 5 days to identify acute responders, followed by randomised, double-blind relapse-prevention treatment with multiple fixed R-107 doses or placebo administered twice weekly for 12 weeks. The authors also included a dose-finding element because the effective oral dose range was uncertain and because enrichment designs can reduce placebo response and study failure rates in antidepressant trials.
This was a multicentre Phase II trial conducted between May 2019 and August 2021. Adult men and women with TRD and baseline Montgomery–Åsberg Depression Rating Scale (MADRS) scores ≥20 entered an open-label enrichment phase during which they received 120 mg R-107 once daily for 5 days and were assessed on day 8. Responders at day 8 (defined in the extracted text as MADRS reduction ≥50% and in some places remission defined as MADRS ≤10) proceeded to randomisation; nonresponders exited the study. Responders (n = 168) were randomised on a 1:1:1:1:1 basis to double-blind R-107 doses of 30 mg, 60 mg, 120 mg or 180 mg, or to placebo, given twice weekly for 12 weeks (double-blind phase). The primary endpoint was the least squares mean change in MADRS score for each active treatment compared with placebo at week 13 (day 92), analysed using a fixed-sequence step-down closed testing procedure starting with the highest dose (180 mg). Key secondary measures included remission and response rates, Clinical Global Impression–Severity (CGI-S), Patient Global Impression–Improvement (PGI-I), time to relapse (Kaplan–Meier and restricted mean survival time), and safety assessments (adverse events, Clinician-Administered Dissociative States Scale (CADSS), bladder pain/interstitial cystitis symptom score (BPIC-SS), vitals, laboratory tests, ECGs, Brief Psychiatric Rating Scale positive symptoms (BPRS+) and Montreal Cognitive Assessment (MoCA)). The extracted text reports screening and enrolment counts (329 screened, 231 entered enrichment, 168 randomised) and indicates that most double-blind dosing occurred at home with high reported adherence (96.4% of participants with ≥80% compliance). The extraction does not clearly state whether analyses followed an intention-to-treat population or provide full statistical modelling details beyond the fixed-sequence testing approach.
From 329 individuals screened, 231 entered the open-label enrichment phase and by day 8 there was a mean MADRS reduction of 18.5 points (95% CI 17.37 to 19.69). In the enrichment phase, 132/231 (57.1%) met remission criteria (MADRS ≤10) and 168/231 (72.7%) met response criteria (≥50% reduction) and were randomised into the double-blind phase. By day 92, 100 participants had discontinued; 94 discontinued for lack of efficacy (MADRS ≥22), with counts by arm reported as placebo 26, 30 mg 22, 60 mg 19, 120 mg 16 and 180 mg 11. Completion rates rose with dose, from 29.7% in the placebo arm to 56.2% in the 180 mg arm. The primary outcome found a statistically significant benefit for the highest dose: the least squares mean difference in MADRS change from baseline at day 92 for the 180 mg group versus placebo was −6.1 (95% CI 1.0 to 11.16; P = 0.019). Numerically greater but non‑significant reductions versus placebo were observed for 120 mg (4.5; 95% CI −0.60 to 9.69; P = 0.083), 60 mg (0.7; 95% CI −4.32 to 5.70; P = 0.785) and 30 mg (1.9; 95% CI −3.08 to 6.92; P = 0.450). Secondary efficacy outcomes showed dose-related trends: remission and response rates at week 13 were numerically higher for active arms versus placebo, with a statistically significant higher response rate for the 120 mg group (48% versus 24.3%; P = 0.046) but no consistent significant differences on the CGI‑S. Patient-reported improvement (PGI‑I) showed mixed odds ratios across doses. Relapse during double-blind treatment exhibited a clear dose response. Relapse rates ranged from about 70.6% for placebo to 42.9% for the 180 mg group (reported elsewhere in the text as 70.3% and 43.7%). Median time to relapse increased with dose (placebo 45 days; 30 mg 28 days; 60 mg 56 days; 120 mg 64 days; 180 mg >85 days). The restricted mean survival time difference for 180 mg versus placebo was 19.0 days (95% CI 4.9 to 33.1), a statistically significant effect. Tolerability was generally favourable. During the open-label phase the most common adverse events were dizziness, headache, dissociation, feeling abnormal, fatigue and nausea; 26 participants (11.6%) reported dissociation but mean CADSS scores were <3. After 5 days of open‑label dosing mean systolic and diastolic blood pressure changes were −1.2 mmHg and −0.1 mmHg, respectively. In the double‑blind phase most adverse events were mild (56.7%) or moderate (18.2%), and mean CADSS scores were <1 at all visits. Sedation of mild severity occurred in five participants (four in 30 mg, one in 120 mg). Ten severe adverse events occurred in eight participants (including severe headache, severe depression, a completed suicide in a 65‑year‑old male in the 180 mg group, noncardiac chest pain, nausea, intervertebral disc protrusion and nephrolithiasis/ureterolithiasis). Five participants experienced serious adverse events: three in the 180 mg group (wound dehiscence, suicidal ideation, completed suicide), one in the 60 mg group (noncardiac chest pain) and one in the placebo group (urinary calculus). The investigators judged none of the SAEs to be treatment related; the completed suicide was attributed by the site investigator to the underlying illness. No notable changes were reported in laboratory tests, urinalyses, vital signs, body weight, ECGs, BPRS+ or MoCA scores. Bladder symptom scores (BPIC‑SS) remained low (<3/38) with no differences between placebo and 180 mg.
Glue and colleagues interpret the findings as evidence that, in an enriched sample of patients with TRD who responded acutely to R-107, twice‑weekly 180 mg extended‑release ketamine tablets produced a statistically significant and clinically meaningful reduction in depressive symptoms at week 13 versus placebo, with a between‑group MADRS difference of 6.1 points that exceeds commonly cited minimum clinically important difference thresholds. The investigators note clear dose‑related effects on relapse rates and median time to relapse and report overall good tolerability: low rates and intensity of dissociation, minimal sedation and no clinically important blood pressure elevations. The authors place their findings in the context of prior ketamine research, arguing that the extended‑release oral formulation’s pharmacokinetics—sustained metabolite exposure due to first‑pass metabolism—may underlie the favourable tolerability profile relative to parenteral or intranasal formulations. They also highlight pragmatic advantages observed in the study, such as predominantly at‑home dosing and brief clinic visits, which could support scalability and lower delivery costs. Several limitations are acknowledged. The enrichment design, which removed nonresponders before randomisation, reduces the risk of study failure but likely overestimates population‑level effectiveness and introduces expectation effects owing to the open‑label enrichment phase. The relatively short duration of the open‑label lead‑in (5 days) may have contributed to higher relapse rates after randomisation compared with studies that include longer open‑label exposure. Small group sizes for each dose may have limited statistical power to detect differences on secondary outcomes. The authors also note constraints on directly comparing these results with non‑oral ketamine studies and indicate uncertainty about differential effects in participants who were versus were not taking concurrent antidepressants, recommending larger future studies to address these questions. In summary, the investigators conclude that R‑107 extended‑release ketamine tablets were effective, safe and well tolerated in this enriched TRD population, and they suggest potential advantages of the oral extended‑release formulation including reduced dissociation, lower apparent abuse risk related to tablet hardness, fewer cardiovascular and sedative effects, and greater convenience for community administration. They stress the need for further unenriched trials and larger studies to confirm generalisability and longer‑term safety and efficacy.
more treatment-responsive sample and, thus, increasing effect size. A similar design was used in Daly's esketamine randomized withdrawal study. We included a dose-finding component in our double-blind relapse prevention phase as it was unclear what the effective oral dose range might be.
Between May 2019 and August 2021, 329 individuals were screened for eligibility, 231 entered the open-label enrichment phase (days 1-5). At day 8 assessment, 132/231 (57.1%) of participants were in remission, and 168/231 (72.7%) were responders. After exclusion of nonresponders, the 168 responders were randomized to double-blind treatment (see CONSORT diagram in Fig.). Participant demographic details are provided in Table. Mean pretreatment Montgomery-Asberg Depression Rating Scale (MADRS) scores were approximately 30, and mean number of failed antidepressant trials was approximately 4.8 (Table). By the end of the study (day 92), 100 participants had discontinued, of whom 94 were for lack of efficacy as defined by an MADRS total score of ≥22 (placebo, 26; 30 mg, 22; 60 mg, 19; 120 mg, 16; 180 mg, 11) (Fig.). The proportion of participants who completed the study ranged from 29.7% in the placebo arm through to 56.2% for the 180 mg dose arm, with higher proportions of completers associated with higher R-107 doses. Treatment compliance was high, with almost all participants (96.4%) reported to have compliance of 80% or more (at home and in clinic).
Estimated marginal mean reductions at days 36, 64 and 92 are presented in Extended Data Table. Numerically, greater mean reductions in the MADRS total score from baseline to day 92 were observed in all treatment groups compared with placebo (R-107 30 mg: 1.9 (95% confidence interval (CI) -3.08 to 6.92), P = 0.450; 60 mg: 0.7 (95% CI -4.32 to 5.70), P = 0.785; 120 mg: 4.5 (95% CI -0.60 to 9.69), P = 0.083). The largest reduction was in the 180 mg treatment group: 6.1 (95% CI 1.00 to 11.16; P = 0.019), and this result was statistically significant. Mean (standard deviation, s.d.) reductions in MADRS scores by treatment group are presented in Table. The 120 mg and 180 mg dose groups had lower mean reductions (<10 points) compared with lower-dose groups. Compared with placebo, numerically greater reductions in day Over the past two decades, there has been a growing evidence base demonstrating the rapid-onset antidepressant properties of ketamine in patients with treatment-resistant depression (TRD). The majority of published research has been with off-label use of racemic ketamine 1 , most commonly administered intravenously, with a more recent regulatory approval of intranasal esketamine for TRD. Only 2/72 treatment arms in published randomized controlled trials for TRD involved oral dosing. Ketamine and esketamine can be effectively administered via multiple routes, with higher doses associated with greater improvement in depression compared with lower doses. Published dose ranges and bioavailability vary by formulation and route of administration. The pharmacology of ketamine relating to its antidepressant activity has been linked to several of its metabolites, including norketamine and the hydronorketamines. After oral dosing, pharmacokinetic exposure to norketamine and the hydronorketamines is considerably more prolonged than exposure to ketamine. Furthermore, ketamine is still active as an antidepressant even when dosed by routes where bioavailability of parent ketamine is low. A synthesis of these observations suggests that ketamine may be acting as a prodrug, where its antidepressant activity is substantially due to its metabolites. A meta-analysis of ketamine formulations identified that formulations that maximize first-pass metabolism of ketamine and delay time to maximum concentrations were better tolerated (less dissociation) and safer (less blood pressure change) than formulations that lack those characteristics. We hypothesized that an extended-release tablet formulation of ketamine could be an effective and well-tolerated treatment option for patients with TRD. Details of the formulation and its pharmacokinetic profile have been published. Due to its pronged absorption phase, it undergoes extensive first-pass metabolism, and its absolute bioavailability is <20% (ref. 8). In this Article, we report on a multicenter phase 2 study of the extended-release ketamine tablets (R-107) in patients with TRD. The study design for this proof-of-concept trial is shown in Fig.. We chose this design owing to observations that acute antidepressant clinical trials in non-TRD depression have high failure rates (inability to separate clinical response between active and placebo arms), as high as 50% (refs. 11,12). Failure rates can be reduced by using an enrichment design, in which nonresponders to acute treatment are excluded, followed by a subsequent relapse-prevention phase in treatment responders; study failure rates using this design are as low as 25%. Temple has described this strategy as a type of predictive enrichment, producing a92 MADRS scores (95% CI) were observed for females (-10.1 (-18.7 to -1.5)) compared with males (-4.2 (-10.8 to 2.4)), patients younger than 65 years (-6.9 (-12.3 to -1.6)) compared with patients 65 years and older (0.1 (-23.4 to 23.7)), those taking antidepressants (-6.5 (-12.5 to -0.6)) compared with those not taking antidepressants (-2.5 (-12.6 to 7.7)), and those with greater than median body weight (-7.1 (-14.0 to -0.1)) compared with those below median body weight (-5.3 (-13.1 to 2.5)).
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Nikolin, S., Rodgers, A., Schwaab, A. et al. · EClinicalMedicine (2023)
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During the open-label enrichment phase (days 1-8), there was mean reduction in MADRS total score of 18.5 points (95% CI 17.37 to 19.69) at day 8. A total of 132 participants (57.1%) of the 231 enrolled in the enrichment phase achieved remission with as MADRS total score ≤10 at day 8. A total of 168 participants (72.7%) of the 231 patients enrolled in the enrichment phase achieved a response to treatment, defined as ≥50% reduction from baseline in MADRS score at day 8. Rates of remission and response at week 13 were numerically greater for the active treatment arms compared with placebo; however, these were not statistically significant (remission) or were significant for only the 120 mg dose group for treatment response (48% versus 24.3%, P = 0.046; Extended Data Tablesand). Compared with baseline, Clinical Global Improvement-Severity (CGI-S) scores improved in participants randomized to ketamine; however, this was not statistically significant compared with placebo. With the exception of the 60 mg dose group, the 120 mg and 180 mg ketamine dose groups had higher probability of improvement in depression severity from the subject's perspective, using the Patient Global Impression-Improvement (PGI-I) scale, compared with the placebo group (OR (95% CI) 30 mg: 0.52 (0.09 to 2.78); 60 mg: 1.62 (0.36 to 7.42); 120 mg: 0.28 (0.06 to 1.25); 180 mg: 0.82 (0.19 to 3.51) (where 'OR' is 'odds ratio' and ORs <1 signify higher probabilities for the active treatment group for lower categories compared with the placebo group; Extended Data Table). Temporal trends in relapse and numbers of patients in each dose group are shown in the Kaplan-Meier plot in Fig.. The majority of relapses occurred within the first 4 weeks of double-blind treatment. The median relapse time after randomization increased with higher R-107 doses (placebo: 45 days; 30 mg: 28 days; 60 mg: 56 days; 120 mg: 64 days; and 180 mg: >85 days). The difference in the restricted mean survival time for the 180 mg treatment group was statistically significantly greater compared with the placebo group (19.0 (95% CI 4.9 to 33.1)).
Adverse events were rated predose and postdose before leaving clinic, and on scheduled telephone calls. During the open-label enrichment phase, the most common adverse events included dizziness, headache, dissociation, feeling abnormal, fatigue and nausea. Twenty-six participants (11.6%) reported dissociation. Mean dissociation (Clinician-Administered Dissociative States Scale, CADSS)scores were <3 for all participants throughout this phase. Mean blood pressure changes after 5 days of open-label 120 mg daily dosing in the enrichment phase were systolic and diastolic blood pressure changes of -1.2 mmHg and -0.1 mmHg, respectively. The most common side effects reported in the double-blind treatment phase are presented in Table. The majority of these were of mild intensity (131 subjects; 56.7%) or moderate intensity (42 subjects; 18.2%). Mean CADSS scores were <1 point at all visits during the double-blind phase of the study. Sedation of mild severity was reported by a total of five participants (30 mg, n = 4; 120 mg, n = 1). Mean CADSS scores were <1 point at all time points during this phase of the study. Mean ratings of cystitis symptoms using the BPIC-SS questionnaire remained less than 3 points throughout the study, out of a maximum of 38, with no differences between placebo and 180 mg dose groups. During double-blind treatment, there were ten severe adverse events in eight participants: severe headache (30 mg and 60 mg dose groups); severe depression (120 mg and 180 mg dose groups); completed suicide at day 42 in a 65-year-old male (180 mg dose group); noncardiac chest pain (60 mg dose group); nausea (30 mg dose group); intervertebral disc protrusion (120 mg dose group); and nephrolithiasis and ureterolithiasis (in one participant in the placebo group). Five subjects experienced serious adverse events (SAEs): three participants in the 180 mg group (wound dehiscence (n = 1), suicidal ideation (n = 1) and completed suicide (n = 1); one participant in the 60 mg group had noncardiac chest pain; and one participant in the placebo group had a urinary calculus. None of the SAEs was considered treatment related (the suicide was considered by the site principal investigator to be due to the disease under study), and all SAEs resolved except for the completed suicide. There were no changes of note in safety laboratory tests, urinalyses, vital signs, body weights or electrocardiograms (ECGs). There were no changes of note in Brief Psychiatric Rating Scale (BPRS+) or Montreal Cognitive Assessment scores during the study. The P values were calculated using Fisher's exact test for the differences between dose groups. URTI, upper respiratory tract infection.
In this study, 231 patients with TRD were treated with R-107 120 mg per day for 5 days, and 168 (72.7%) were included as an enriched responder population who were randomized to a range of double-blind R-107 doses or placebo for the next 12 weeks. In this double-blind phase, the 180 mg dose given twice weekly showed statistically significant and clinically meaningful improvement in depressive symptoms based on MADRS score compared with placebo, with a group-treatment difference of 6.1. Side effects commonly observed in clinical trials of injected or intranasal ketamine (for example, dissociation, sedation and increased blood pressure) were minimal, and overall tolerability was good. Most patient dosing during the double-blind phase occurred at home. Acute placebo-controlled antidepressant clinical trials in non-TRD patients have high failure rates, up to 50% (refs. 11,12). Study failure rates in patients with TRD may be similarly high (47%), based on the proportion of industry-funded studies of ketamine or esketamine registered on clinicaltrials.gov between 2010 and 2022, where no results have been published. As discussed in the introduction, failure rates (inability to separate responses between active and placebo arms) can be reduced by using an enrichment design to remove treatment nonresponders, before a double-blind relapse-prevention phase, and is consistent with a regulatory guidance on enrichment designs. Failure rate across all studies using this design was 25% (ref. 13). We included a dose-finding component in the double-blind phase of the present study as it was not clear what the effective oral dose range might be. The R-107 dose used in the enrichment phase (120 mg daily for 5 days) was based on observations from case reports from patients with pain and TRD receiving continuous ketamine infusions for 5 days, who reported mood improvements occurring by 24-72 h (ref. 17). The tablet formulation's sustained exposure to norketamine over 24 h after once-daily dosing provided a similar prolonged pharmacokinetic exposure. Ketamine dosing was open-label during the enrichment phase; therefore, the high remission (57.1%) and response (72.7%) rates for participants during this phase have to be considered cautiously due to likely expectation effects. During the double-blind treatment phase, clear dose responses were observed, for the proportion of patients relapsing and median time to relapse, and there were dose-related trends for reductions in the MADRS total score. Most relapses in the 0-120 mg dose groups occurred within 1 month of randomization (Fig.). Only the mean between-group treatment difference between the 180 mg and placebo groups (-6.1) was statistically significant, and this value exceeds the minimum clinically important difference threshold for antidepressants reported in the literature. The relapse rates between weeks 2 and 13 in patients randomized to the placebo and 180 mg dose groups (70.3% and 43.7% respectively) are both higher than those reported in a meta-analysis of relapse-prevention studies of antidepressants in non-TRD patientsand in patients with TRD enrolled in an esketamine randomized withdrawal study(Extended Data Table). This could be due to the much shorter duration of open-label dosing in the present study (5 days) compared with 16 weeks in patients with TRD, and a mean of 16.4 weeks in non-TRD patients with depression. These longer dosing periods before randomized withdrawal could select for stable responders, which would reduce subsequent relapse rates. Many of the secondary efficacy outcome variables also showed dose-related trends compared with placebo; however, these were not statistically significant, presumably because of small dose group sizes, which may have reduced statistical power. Commonly reported adverse events during the open-label enrichment phase included dizziness, headache, dissociation, feeling abnormal, fatigue and nausea. The intensity of dissociation in the 26 participants (11.6%) who reported this adverse event was minor, as demonstrated by mean CADSS scores of 3 or less for all participants. The most common side effects reported in the double-blind relapse-prevention phase were headache, dizziness, anxiety, depressed mood and dissociation (Table), most of which were mild to moderate in intensity. Other notable differences from adverse events commonly reported after administration of ketamine or esketaminewere the absence of cardiovascular side effects, especially relating to increased blood pressure, low rates of dissociation and also very low rates of sedation. Mean ratings of cystitis symptoms using the bladder pain/interstitial cystitis symptom score (BPIC-SS) questionnaire remained less than 3 points throughout the study, out of a maximum of 38, with no differences between placebo and 180 mg dose groups. Another common concern about most currently available ketamine and esketamine formulations is the risk of diversion and abuse. The extended-release ketamine tablets used in this study are exceptionally hard and difficult to shatter, due to annealing of polyethylene oxide during their manufacturing process. This property may make this formulation less likely to be diverted for abuse, due to difficulty in manipulation of the tablets. We were not aware of any participants reporting craving for the tablets, and only one participant was removed from the study for lack of compliance. Most of the dosing of double-blind tablets after day 8 occurred at home rather than in clinic, and clinic visits were brief, which participants anecdotally reported to be convenient. These attributes potentially improve scalability of ketamine use in the community, due to reduced need for in-clinic monitoring, and would also reduce costs associated with clinic visits. There are several important limitations to the trial. The study design (enrichment followed by relapse prevention) was intended to reduce risk of study failure. Because this type of design eliminates nonresponders before randomization, this strategy is likely to overestimate population levels of treatment response to R-107, and future unenriched clinical trials are needed to address this issue. There are relatively few data for efficacy and tolerability after oral ketamine dosing compared with intravenous or intranasal dosing, and it is not possible to directly compare the present study's findings with studies using nonoral routes of administration. This study included both participants established on antidepressants (n = 165) as well as those who were not on antidepressants (n = 60). Secondary analyses did not show differences in the acute (open-label phase) response to ketamine (the mean (95% CI) reduction in MADRS score for those taking an antidepressant was -19.2 versus -16.6 for those not taking an antidepressant (-2.6 (-5.19 to 0.02)). During the double-blind phase, there was a small but statistically significant greater reduction in MADRS scores at day 92 in patients taking antidepressants than those not respectively, -6.5 (-12.5 to -0.6) versus -2.5 (-12.6 to 7.7). Further larger studies are required to determine if these two populations respond differently to oral ketamine. Also, the protocol did not require patients to start a new antidepressant at the time of starting study medication, as this design would have complicated interpretation of this intervention. In conclusion, extended-release R-107 tablets were effective, safe and well tolerated in an enriched patient population with TRD. Use of an extended-release oral dosage ketamine formulation may be advantageous compared with intranasal or intravenous dosing, in terms of reduced intensity of dissociation, lower risk of abuse, reduced frequency and intensity of sedative and cardiovascular side effects, and improved convenience for administration in the community.
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