Herein we report the results of the largest study conducted to date on the antidepressant effects of repeated ketamine infusions in TRD. The major findings of this study are that (1) the antidepressant effect of ketamine is evident very early in the course of treatment, (2) ketamine exerts a broad-spectrum effect on individual symptoms of depression, and (3) rapid response to the first infusion is highly predictive of a sustained response to subsequent infusions.
An initial infusion of ketamine was associated with a large antidepressant effect (MADRS score decreased 18.9±6.6 from baseline to two hours) and this effect was generally maintained throughout the course of up to five additional infusions. The effect of ketamine was observed across nearly the full spectrum of depressive symptoms in the total study sample. Of particular note, suicidal ideation (SI) rapidly decreased across the total study sample, even among study non-responders. While preliminary, this result suggests that ketamine may exert a unique anti-SI effect even in the absence of a full response and is consistent with previous reports highlighting the potential anti-SI effects of ketamine in depressed populations (10
We found that antidepressant response very early in the course of treatment with ketamine strongly predicted subsequent antidepressant response. Specifically, response status at 4 hours was 94% sensitive and 71% specific for predicting response status at the end of phase I. Although preliminary, these findings suggest that patients who will benefit from a course of repeated ketamine infusions will manifest a rapid improvement in depression that is then maintained over the course of treatment. Conversely, lack of a rapid response is a poor prognostic indicator for improvement following additional ketamine infusions. These data are in contrast to the time-course of response to standard antidepressants. For example, in the first step of the STAR*D study, 56% of participants who responded at some point during a 12-week trial of the serotonin selective reuptake inhibitor citalopram did so only at or after 8 weeks of treatment (26
). Other groups, however, have reported that improvements within a few weeks of initiating standard antidepressant treatment are predictive of a later stable response (27
). A more definitive conclusion regarding the validity of early response to ketamine predicting a more durable response must await the results of future controlled studies.
Following the final ketamine infusion, the observed median time to relapse among responders was 18 days and there was considerable inter-subject variability (range 4 to > 83 days). Characterizing the durability of antidepressant response following ketamine is a critical issue in determining the potential clinical utility of ketamine as a treatment for TRD. Initial reports suggested a duration of response of several days or up to one week following a single ketamine infusion (5
). A recent study of a single ketamine infusion in bipolar depression found a time to relapse of just two days using the Kaplan-Meier method (11
). The findings of the current study may therefore suggest that repeated infusions yield a more durable antidepressant response compared to a single infusion, even after the infusions are discontinued. Interestingly, in a pervious placebo-controlled study of riluzole for relapse prevention following a single administration of ketamine we observed a mean time-to-relapse of 22 and 24.4 days for placebo or riluzole, respectively (6
). This difference was not significant in part due to the unexpectedly long time-to-relapse of the placebo group (6
). A second study of riluzole for relapse prevention following ketamine reported a time-to-relapse of 9.8 and 17.2 days for placebo or riluzole, respectively (12
). Taken together, the data from the current study provide preliminary evidence for an enhanced durability of response following repeated ketamine infusions but also highlights the need to identify effective relapse prevention strategies for patients who respond to ketamine.
Future studies testing relapse prevention strategies following response to ketamine may be guided by hypothesized mechanistic synergy. While the riluzole for relapse prevention strategy was based on potential synergy between ketamine and riluzole involving modulation of glutamate signaling, the recent identification of additional signaling pathways implicated in the antidepressant action of ketamine suggests new targets for synergy (7
). In particular, the finding that inhibition of glycogen synthase kinase-3 (GSK-3) is obligatory for the antidepressant effect of ketamine in mice (31
) suggests lithium – a well-known inhibitor of GSK-3 – as a potential pharmacotherapeutic strategy following ketamine.
Regarding side effects observed in this study, dissociative and psychotomimetic changes associated with ketamine were only present acutely (during and immediately post infusions) and were generally mild and well tolerated. We observed an expected increase in dissociative symptoms during administration of ketamine that returned to baseline within four hours of the start of the infusion. At no time did any participant evidence clinically significant psychotomimetic effects resulting from ketamine (e.g. paranoid, delusions, hallucinations). Other adverse effects were generally mild and no individual discontinued study participation due to side effects. Importantly, there was no evidence of increasing severity of these effects over the 12-day infusion period. There was no correlation between acute dissociative or psychotomimetic effects of ketamine and antidepressant treatment response.
Overall, our results suggest that repeated ketamine infusions may be a viable treatment strategy in the future for patients suffering from TRD. A strategy involving repeated ketamine infusions is currently being investigated as treatment for chronic pain disorders in ambulatory patients that may provide a model for ketamine treatment in TRD in the future (32
). Concerns persist, however, regarding the safety and feasibility of prolonged treatment with ketamine and the optimal number of repeated treatments for safety and efficacy purposes. More preclinical and clinical research will be required before this treatment strategy can be recommended (33
). Chief among our concerns are a series of early preclinical studies showing that repeated administrations of very high doses of ketamine or other NMDA receptor antagonists may be neurotoxic in rodents (35
). Neuroimaging studies in human populations suggest that prolonged abuse of ketamine as an illicit drug may result in deleterious brain changes (37
), although these studies have been cross-sectional in nature and are confounded by significant comorbid substance abuse beyond ketamine. Research investigating the role of ketamine in TRD must balance concerns regarding potential toxicity against the unmet need for rapidly acting, more effective treatments for patients suffering from enormous morbidity and disability.
Our study has several limitations. Most notably, the open-label design limits the interpretation of efficacy. Specifically, it is not known to what extent the observed decrease in depression severity would have occurred even under placebo conditions. However, there are currently at least four placebo-controlled studies of ketamine in TRD or bipolar depression showing that ketamine results in a rapid antidepressant effect superior to placebo (4
). Therefore, the current study was not designed to test the antidepressant effect of ketamine per se, but rather to investigate the pattern for response to repeated administrations of ketamine over time. The second significant limitation is the modest sample size of 24 that limits the interpretations that can be drawn and the generalizability of the sample to the broader population of patients with TRD. Despite the limited sample size, however, the current report represents the largest prospective study of repeated ketamine administrations in TRD conducted to date. Notwithstanding the important limitations, we believe that the current report contributes significantly to the small but growing literature on the clinical impact of ketamine in patients with TRD.