A Double-Blind, Randomized, Placebo-Controlled,... — Research Summary & Context

A Double-Blind, Randomized, Placebo-Controlled,... — Research Summary & Context | Blossom

Abstract

Objective

Ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression.

Method

In a multicenter, double-blind study, adults (ages 18-64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS).

Results

In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was −18.4 (SD=12.0) for ketamine and −5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was −17.7 (SD=7.3) for ketamine and −3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, −12.2 [SD=12.8] on day 4; thrice-weekly, −14.0 [SD=12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing.

Conclusions

Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.

Unlocked with Blossom Pro

Research Summary of 'A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression'

Methods

This multicentre, double-blind, randomised, placebo-controlled study evaluated two dosing frequencies of intravenous ketamine in adults with treatment-resistant depression. Eligible adults were aged 18-64 years and had treatment-resistant depression; the active treatment was ketamine 0.5 mg/kg administered intravenously over 40 minutes. Patients were randomised to receive ketamine or placebo given either twice weekly or thrice weekly for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase receiving ketamine at the same frequency as in the double-blind phase. The primary outcome was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary and other assessments included clinician- and patient-rated global impressions (CGI and PGI scales) and the Clinician-Administered Dissociative States Scale (CADSS) to assess dissociative/perceptual changes. Pharmacokinetic sampling for ketamine and norketamine was performed and noncompartmental parameters (including Cmax and AUC6h) were summarised descriptively, with comparisons between day 1 and day 15 planned. The intent-to-treat (ITT) efficacy set comprised all randomised patients who received at least one dose and had baseline plus at least one postbaseline assessment; the safety set included all randomised patients who received at least one dose. For MADRS any missing individual item scores were imputed; for other scales a visit score was left blank if any item was missing. The primary and day-29 MADRS changes were analysed using a mixed-effects model with repeated measures, with baseline MADRS as a covariate, centre and time-by-treatment as fixed effects, and patient as a random effect. The study used a relatively liberal threshold for detecting a therapeutic signal (one-sided alpha of 0.15), and the sample size calculation assumed an 8-point treatment difference on MADRS, yielding a planned 14 patients per group (56 total); in practice 68 patients were randomised and 67 received treatment.

Results

Sixty-eight patients were randomised and 67 received at least one dose of study drug. Efficacy analyses were performed on the ITT set; patients entering open-label treatment were analysed in an open-label ITT set and all treated patients contributed to the safety analyses. On the primary endpoint (change from baseline to day 15 in MADRS score), both ketamine dosing frequencies showed greater improvement than placebo. In the twice-weekly groups the mean change in MADRS at day 15 was −18.4 (SD=12.0) for ketamine versus −5.7 (SD=10.2) for placebo. In the thrice-weekly groups the mean change at day 15 was −17.7 (SD=7.3) for ketamine versus −3.1 (SD=5.7) for placebo. The authors report that MADRS improvement with ketamine progressed through the first 8–11 days and was consistent across time points through day 15. Using responder definitions, reported response rates at day 15 were 68.8% for the twice-weekly ketamine group and 53.8% for the thrice-weekly ketamine group. During the optional open-label phase ketamine showed similar early improvements: twice-weekly open-label dosing reached a mean MADRS change of −12.2 (SD=12.8) by day 4 and thrice-weekly open-label dosing reached −14.0 (SD=12.5) by day 5. The authors note that most participants receiving placebo were nonresponders and discontinued after day 15 to enter open-label ketamine per protocol, though a subset of placebo-treated patients who remained on placebo appeared to respond. Adverse events occurring in 20% or more of ketamine-treated patients included headache, anxiety, dissociation, nausea, and dizziness. Dissociative and perceptual-change adverse events, as measured by CADSS, were transient and attenuated with repeated dosing. Two serious treatment-emergent adverse events were reported in the twice-weekly ketamine group (anxiety and a suicide attempt), and no deaths occurred. The paper indicates pharmacokinetic parameters were summarised and day-15 versus day-1 comparisons of Cmax and AUC6h were planned, but the extracted text does not clearly report the numerical pharmacokinetic results.

View full paper sections

RESULTS

All efficacy analyses were performed on the intent-to-treat set, which included all randomized patients who received at least one dose of the study drug during the double-blind phase and for whom data were available for both the baseline assessment and at least one postbaseline assessment. Patients who entered the open-label treatment phase were included in the open-label intent-to-treat analysis set. The safety analysis set included all randomized patients who received at least one dose of the study drug. Assuming a treatment difference of $8 points in the mean change from baseline to endpoint in MADRS score between the ketamine and placebo groups, 14 patients were required in each group in order to detect this treatment difference with a power of 90% at an overall one-sided p value of 0.15 (common in phase 2 studies) based on a two-sample t test. Thus, a total of 56 patients were to be recruited across the four treatment groups. For MADRS score, imputation of any missing individual item scores was applied. For all other scales, if any item of the scale was missing on one visit, the total score for that scale at that visit was left blank. The primary efficacy endpoint and the change from baseline in MADRS score to day 29 were analyzed using a mixed-effect model with repeated measures, with baseline MADRS score as a covariate, center and timeby-treatment interaction as fixed effects, and patient as a random effect. The threshold for detecting a therapeutic signal was based on least-squares means using a one-sided alpha of 0.15. For each time point, descriptive statistics were provided for MADRS score and changes from baseline. All statistical analyses were performed using SAS, version 9.2 (SAS Institute, Cary, N.C.). The proportion of patients who had an onset of clinical response within the first week in each ketamine group was compared with the corresponding placebo group using the exact Mantel-Haenszel test. The analysis of the change in CGI-S and PGI-S scores was performed using a rank-based analysis of covariance model, whereas the analysis of CGI-I and PGI-C scores was performed using a rank-based analysis of variance model. The plasma concentrations of ketamine and norketamine and their corresponding noncompartmental pharmacokinetic parameters were summarized using descriptive statistics. Statistical analyses were performed to compare the C max and AUC 6h values on day 15 with those on day 1.

CONCLUSION

Full Text PDF

Full Paper PDF

Create a free account to open full-text PDFs.

Create Free Account Already have an account? Sign in

Study Details

Study Type
individual
Population
humans
Characteristics
multi sitedouble blindrandomizedplacebo controlledparallel groupdose finding
Journal
American Journal of Psychiatry
Compound
Ketamine
Topics

This study was designed to evaluate the efficacy of two dosing regimens of ketamine at 0.5 mg/kg administered intravenously over 40 minutes in sustaining the antidepressant effects of ketamine in patients with treatment-resistant depression beyond the initial dose. Onceweekly administration was not tested, as previous data have shown an average duration of effect of 5 days after a single dose of ketamine. At day 15, MADRS score was significantly improved in patients receiving ketamine compared with those receiving placebo; the two dosing frequencies (twice and thrice weekly) were equally successful in sustaining the antidepressant response throughout the study period. The mean improvement in MADRS score in both ketamine groups was progressive through the first 8-11 days and was consistent through all time points (Figure). Because the effect size of the antidepressant signal did not differ significantly between the two dosing frequencies, a twice-weekly initiation treatment regimen appears to be sufficient as an initial repeated-dose strategy in patients with treatment-resistant depression. A previous multiple-dose pilot study evaluated six doses (thrice weekly) of intravenous ketamine in patients with treatmentresistant depression for 2 weeks and reported response rates of 62.5% (first dose) to 70.8% (sixth dose). Another study with a similar treatment session regimen reported a gradual increase in response rate from 25% (first dose) to 92% (sixth dose). In the present study, we evaluated repeated intravenous doses with two different dosing regimens and observed response rates of 68.8% for twiceweekly dosing and 53.8% for thrice-weekly dosing at day 15. Thus, although the study designs differ, a progressive increase in response rate beyond the first dose was also observed here. Overall, analyses of primary and secondary endpoints showed better efficacy for ketamine compared with placebo during the double-blind phase; the results also appeared similar across the study groups. Few patients remained in either placebo group at day 29. Most of the participants receiving placebo were nonresponders and discontinued from the study after day 15 because of lack of efficacy and then received 2 weeks of open-label ketamine treatment, per protocol. However, among the patients who continued placebo across the double-blind period, a subset appeared responsive to placebo. The efficacy results in the open-label and follow-up phases appeared consistent with the double-blind treatment phase. Those who responded or remitted maintained the efficacy for the 4-week followup under either twice-weekly or thrice-weekly ketamine regimens. The safety and tolerability of ketamine was consistent with earlier reports in patients with treatment-resistant depression. Our study was not powered to detect a significant difference in the treatment-emergent adverse event profiles between the two ketamine groups. No deaths occurred. During the double-blind phase, patients receiving twice-weekly ketamine reported two serious treatment-emergent adverse events of anxiety and suicide attempt, with the latter occurring more than. The intensity of dissociative/perceptual change treatment-emergent adverse events, as assessed using the CADSS, decreased with consecutive doses. Several limitations of our study merit comment. The study had a relatively short duration and assessed the induction and maintenance of response for only 4-6 weeks. Treatment-resistant depression is a chronic condition, and studies with a longer duration are warranted to fully characterize whether the clinical benefits of ketamine can be maintained, and if so, whether they can be sustained despite reductions in the dosing frequency during chronic treatment. Additionally, no active control was used in the study. This is a limitation of all studies with multiple doses of ketamine, as the adverse events associated with ketamine conceivably may unblind the active drug administration to patients and/or clinicians. Finally, the aim of the study was to assess the efficacy of two dosing regimens that differed only in frequency of administration, although it was not powered to detect a statistically significant difference between the two regimens.

Company

Product

Legal

A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression

Authors

Published

Links

Related Clinical Trial

A Study of Ketamine in Patients With Treatment-resistant Depression

References (2)