Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression

Abstract

Background: Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original.

Methods: Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion.

Results: The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days.

Conclusions: Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.

Trial registration: ClinicalTrials.gov NCT00548964.

Keywords: Antidepressant; experimental therapeutics; glutamate; ketamine; major depressive disorder; treatment-resistant depression.

Figure 1. Change in Depression Severity Following Repeated Ketamine Infusions in Treatment-Resistant Major Depression

Figure depicts change in depression severity as measured by the Montgomery–Asberg Depression Rating Scale (MADRS) (mean±SD) over a 12-day period during which ketamine (0.5 mg/kg) was administered IV on a Monday-Wednesday-Friday schedule, corresponding to study days 0, 3, 5, 8, 10 and 12. Trajectories of depression severity are plotted for phase I responder and non-responder subgroups, defined using the final observed MADRS score. Depression severity was initially measured at baseline prior to the first ketamine infusion and then at 2 h, 4 h and 24 h while participants were inpatient. Subsequent infusions occurred on an outpatient basis and depression severity was measured in the morning prior to each infusion and then at 4 hours. *MADRS score significantly decreased at given time point compared to baseline, p<0.05. ^#MADRS score significantly different at given time point between responder and non-responder subgroups. ^aThree participants in the non-responder group did not receive all six ketamine infusions.

Figure 2. Change in Individual Depressive Symptoms Two Hours Following the First Infusion of Ketamine

Figure depicts absolute decrease in individual items of the Montgomery–Asberg Depression Rating Scale (MADRS) from baseline to two hours following the first infusion of ketamine for the total sample, phase I responders and non-responders. The score of each item of the MADRS ranges from 0 (no symptom) to 6 (maximally severe symptom). Bars represent means±SEM. *Item score significantly decreased at two-hour time point compared to baseline, p<0.05.

Figure 3. Risk of Relapse Among Responders to Repeated Ketamine Infusions in Treatment-Resistant Major Depression

Figure depicts survival analysis conducted in 17 phase I responders following six infusions of ketamine (maximum follow up time = 83 days). Relapse in phase II was defined as <50% improvement in MADRS score at that visit compared to baseline for two consecutive visits. The number at risk at each time point is indicated along the bottom of the graph.