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

This multicenter, double-blind, randomized, placebo-controlled study (n=67) investigated the antidepressant effects of ketamine (35mg/70kg) in relation to the dose frequency administered to patients with depression (TRD). Results indicated that both a twice-weekly and thrice-weekly administration regimen maintained antidepressant efficacy over 15 days.

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.”

Authors: Jaskaran B. Singh, Maggie Fedgchin, Pharm D., Ella J. Daly, Peter De Boer, Kimberly Cooper, Pilar Lim, Christine Pinter, James W. Murrough, Gerard Sanacora, Richard C. Shelton, Benji Kurian, Andrew Winokur, Maurizio Fava, Husseini Manji, Wayne C. Drevets & Luc Van Nueten

Summary

Major depressive disorder is a highly prevalent illness that often has significant morbidity and mortality. Despite recent advances, 35% of patients fail to respond to drug therapy for major depression.

Ketamine is a noncompetitive, N-methyl-D-aspartate glutamate receptor antagonist that has been approved for use as an anesthetic. Its antidepressant effect is rapid and short-lived, but how to sustain ketamine’s efficacy for a longer duration through an optimal long-term dosing regimen has not yet been determined.

This study evaluated two dosing regimens of intravenous ketamine (at 0.5 mg/kg of body weight) in patients with treatment-resistant depression.

Patients

The study enrolled men and women 18 to 64 years of age with recurrent major depressive disorder without psychotic features who had inadequate response to at least two antidepressants and a score $34 on the 30-item Inventory of Depressive Symptomatology – Clinician Rated.

Key exclusion criteria were a primary DSM-IV diagnosis of obsessive-compulsive disorder, posttraumatic stress disorder, anorexia nervosa, or bulimia nervosa, a prior history of psychotic disorders, and substance abuse or dependence.

The study was approved by independent ethics committees at each site and all patients provided written informed consent to participate.

Study Design

This was a randomized, double-blind, placebo-controlled, parallel-group study conducted at 14 sites in the United States between July 2012 and September 2013. Patients were randomized to receive intravenous ketamine (0.5 mg/kg) two or three times weekly or intravenous placebo two or three times weekly.

Patients fasted overnight ($8 hours) before study drug administration, and were discharged after completion of the pharmacokinetic blood sampling. Patients who discontinued the study before the day 29 visit were allowed to participate in an optional open-label treatment phase.

Study Evaluations

In the double-blind phase, patients were assessed for change from baseline to day 15 on the Montgomery-sberg Depression Rating Scale (MADRS). In the open-label phase, patients were assessed for change from baseline to day 29 on the MADRS, CGI-S, CGI-I, PGI-S, and PGI-C.

Venous blood samples were collected before and up to 6 hours after dosing to measure plasma concentrations of ketamine and norketamine. The following noncompartmental pharmacokinetic parameters were estimated for both ketamine and norketamine.

Statistical Analysis

All efficacy analyses were performed on the intent-to-treat set, and all safety analyses were performed on the open-label intent-to-treat set.

For a study with 90% power, 56 patients were required across 4 treatment groups to detect a treatment difference of $8 points in MADRS score.

The primary efficacy endpoint was the change from baseline in MADRS score to day 29. The change from baseline in CGI-S and PGI-S scores were analyzed using a rank-based analysis of covariance model, whereas the change in CGI-I and PGI-C scores were analyzed using a rank-based analysis of variance model.

Patients

A total of 68 patients were randomized into the four arms of the double-blind phase. Of the 31 patients who were enrolled in the optional 2-week open-label phase, 27 (87%) completed it.

Overall, baseline demographic and clinical characteristics did not differ significantly across treatment groups. The most commonly used antidepressants were fluoxetine, citalopram, and bupropion.

Primary Outcomes

The mean change in MADRS score from baseline to day 15 was significantly improved in both ketamine frequency groups compared with the respective placebo groups. The difference was progressive through the first 8 – 11 days.

Secondary Outcomes

Both ketamine groups showed improvement in MADRS scores from baseline to day 29 compared with placebo. A higher proportion of patients in both ketamine groups exhibited a clinical response within week 1 compared with the respective placebo groups.

Both groups showed improvement in mean MADRS score compared with baseline during the open-label ketamine phase, and the change in both frequency groups was similar.

Pharmacokinetic Outcomes

Ketamine and norketamine had similar pharmacokinetic profiles across treatment regimens and study days, with similar Cmax and AUC6h values. There was no significant correlation between individual body weight and ketamine or norketamine.

Safety

During the double-blind phase, treatment-emergent adverse events were higher in the ketamine groups compared with the placebo groups. No deaths were reported, but two patients in the twice-weekly ketamine group had serious treatment-emergent adverse events, and one patient in the thrice-weekly ketamine group had a suicide attempt.

Ketamine open-label and ketamine-free follow-up phases showed similar proportions of treatment-emergent adverse events, and no serious adverse events were reported. Two patients experienced nausea and irritability, which led to treatment discontinuation.

During the double-blind and open-label phases, dissociative symptoms were observed shortly after start of the infusion and resolved by 3 hours postinfusion. The intensity of dissociative symptoms diminished with repeated dosing, and suicidal ideation improved in all four treatment groups.

DISCUSSION

This study evaluated the efficacy of two dosing regimens of ketamine administered intravenously over 40 minutes in sustaining the antidepressant effects of ketamine in patients with treatment-resistant depression beyond the initial dose. Both dosing frequencies were equally successful in sustaining the antidepressant response throughout the study period.

A previous study reported a progressive increase in response rate from 62.5% (first dose) to 70.8% (sixth dose) for intravenous ketamine in patients with treatment-resistant depression.

Overall, ketamine showed better efficacy compared with placebo during the double-blind phase. Few patients remained in either placebo group at day 29, and those who responded or remitted maintained the efficacy for the 4-week follow-up under either twice-weekly or thrice-weekly ketamine regimens.

Overall, treatment-emergent adverse events were similar in frequency between double-blind and open-label phases, with acute transient psychotomimetic and dissociative symptoms resolving within 2 hours.

The study had several limitations, including a short duration and use of only one dose of ketamine. Additionally, no active control was used, and the study was not powered to detect a statistically significant difference between two dosing regimens.

CONCLUSIONS

Ketamine, administered intravenously at 0.5 mg/kg of body weight either two or three times weekly, appeared comparably effective in treating treatment-resistant depression. The effect was similar in the two frequency groups.