This open-label pilot study (n=5) investigated the use of naltrexone pretreatment (380 mg) with ketamine infusions (35mg/70kg, 4 infusions over 4 weeks) for depression and found that it does not interfere with ketamine's antidepressant effects. On the contrary, the study found that it might help in treating co-morbid alcohol use disorder and called for pre-clinical research to further understand these results, also in light of earlier conflicting research.
Papers in Blossom that reference this study
Gent, E. M., Bryan, J. W., Cleary, M. A. et al. · Journal of Psychopharmacology (2024)
Ketamine has rapid and robust antidepressant effects. However, there are concerns about the abuse liability of ketamine. This concern was heightened recently owing to a preliminary report suggesting that antidepressant effects of ketamine might be dependent on opiate receptor stimulation. Below, we present pilot data that indicate that the antidepressant effects of ketamine are not attenuated by naltrexone pretreatment. As a result, the combination of opiate receptor antagonism with ketamine might be a strategy to reduce addiction risk among patients with depression at risk for substance abuse.
Methods
We recruited and obtained written informed consent from 5 patients with current major depressive disorder and alcohol use disorder. In this 8-week open-label pilot study, which received institutional review board approval by the VA Connecticut Healthcare System Human Subjects Subcommittee, patients received injectable naltrexone (380 mg once 2-6 days prior to the first ketamine infusion) and repeated intravenous ketamine treatment (0.5 mg/kg once a week for 4 weeks; a total of 4 ketamine infusions). The study had 2 phases: (1) a 4-week ketamine treatment phase and (2) a 4-week follow-up phase. All patients were abstinent from alcohol for 5 days or longer prior to the first ketamine infusion. The primary outcome measure was clinical response defined as a 50% or higher improvement from baseline in the Montgomery-Åsberg Depression Rating Scale scores at 4 hours postinfusion.
Results
The combination of naltrexone and ketamine was associated with reduced depressive symptoms. The Figure shows that 60% (3 of 5) of patients met response criteria after their initial ketamine dose and 100% (5 of 5) met response criteria by their fourth dose, although 1 patient left the trial after receiving 2 ketamine infusions. The Table shows that depressive symptoms improved about 57% to 92%. Also, 80% (4 of 5) of patients reported improvement in alcohol craving and consumption as measured by the Obsessive Compulsive Drinking Scale. The combination treatment was safe and well tolerated in all participants. No serious adverse effects were reported in the trial.
Discussion
Our pilot data suggest that naltrexone pretreatment did not interfere with the antidepressant effects of ketamine and might enhance the treatment of comorbid alcohol use disorder. This result conflicts with that reported by Williams et al in which pretreatment with 50 mg of naltrexone reduced the rate of clinical response to ketamine from 71% (5 of 7 individuals) to 0% (0 of 7 individuals). Their data and an editorial by George, although preliminary, make a case for a central role for opiate agonism in the antidepressant effects of ketamine. Although our pilot data were collected under somewhat different conditions than those of Williams et al (eg, different primary outcome time of 4 hours vs 1 day postinfusion, presence vs absence of alcohol use disorder, injectable vs oral naltrexone), they do not support the hypothesis that opiate receptor stimulation mediates the antidepressant effects of ketamine. Since Williams et al did not provide depression ratings over a 4-hour period postinfusion, we cannot examine whether 50 mg of oral naltrexone blunted ketamine response in this early 4-hour period. Our findings are consistent with an earlier study in healthy individuals showing that the behavioral effects of an antidepressant dose of ketamine were not altered by pretreatment with 25 mg of naltrexone, and some preclinical evidence that ketamine isomers may be weak partial agonists at μ opiate receptors. The initial report by Williams et al and our preliminary data should be interpreted with great caution. Larger randomized clinical trials are needed to better understand whether opiate receptor stimulation contributes to the antidepressant effects of ketamine. If so, then preclinical research will be needed to help us to understand this role for opiates and its implications for future rapid-acting antidepressant treatments.
This report presents an open-label pilot case series designed to examine whether naltrexone pretreatment attenuates the antidepressant effects of ketamine in patients with comorbid major depressive disorder and alcohol use disorder. Institutional review board approval was obtained from the VA Connecticut Healthcare System Human Subjects Subcommittee and written informed consent was collected from participants. Five patients with current major depressive disorder and alcohol use disorder were enrolled in an 8-week study comprising a 4-week ketamine treatment phase followed by a 4-week follow-up phase. All participants were abstinent from alcohol for at least 5 days prior to the first ketamine infusion. Injectable naltrexone (380 mg) was administered once, 2–6 days before the first ketamine infusion. Intravenous ketamine was given at a dose of 0.5 mg/kg once weekly for up to four weeks (a total of four infusions planned). The primary outcome was clinical response, defined as a 50% or greater reduction from baseline in depressive symptoms measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at 4 hours after each infusion. The extracted text does not report detailed analytic methods (for example, statistical tests, handling of missing data, or intention-to-treat procedures) nor does it provide extensive procedural detail beyond dosing and timing.
Combination treatment with injectable naltrexone followed by repeated ketamine infusions was associated with marked reductions in depressive symptoms in this small sample. Sixty percent (3 of 5) of participants met the pre-specified response criterion (≥50% MADRS improvement) after the first ketamine infusion measured at 4 hours postinfusion. By the fourth infusion the authors report that 100% (5 of 5) of participants met response criteria, although one participant discontinued the trial after receiving only two infusions. Quantitatively, depressive symptom reductions were reported in the range of about 57% to 92% (the extracted text attributes this range to a Table but does not clarify whether it refers to individual participant changes or group-level summaries). Alcohol-related outcomes also improved: 80% (4 of 5) of participants reported decreases in alcohol craving and consumption as assessed by the Obsessive Compulsive Drinking Scale (OCDS). In terms of safety and tolerability, the combination was described as safe and well tolerated; no serious adverse events were reported. The extracted text refers to a Figure and Table showing timing and magnitude of effects (including minute-by-minute annotations around infusion), but those visual details are not present in the provided extraction.
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Bentley, S., Artin, H., Mehaffey, E. et al. · Pharmacotherapy (2022)
Aday, J. S., Heifets, B. D., Pratscher, S. D. et al. · Psychopharmacology (2021)
Worrell, S. D., Gould, T. J. · Neuroscience and Biobehavioral Reviews (2021)
Alexander, L., Jelen, L. A., Mehta, M. A. et al. · Neuroscience and Biobehavioral Reviews (2021)
Mcintyre, R. S., Rosenblat, J. D., Nemeroff, C. B. et al. · American Journal of Psychiatry (2021)
Jelen, L. A., Young, A. H., Stone, J. M. · Journal of Psychopharmacology (2020)
Shiroma, P. R., Thuras, P., Wels, J. et al. · Translational Psychiatry (2020)
Dakwar, E., Levin, F. R., Hart, C. L. et al. · American Journal of Psychiatry (2020)
Hashimoto, K. · Psychiatry and Clinical Neurosciences (2019)
Williams, N. R., Heifets, B. D., Bentzley, B. S. et al. · Molecular Psychiatry (2019)
Krystal and colleagues interpret these pilot data as indicating that naltrexone pretreatment did not block the rapid antidepressant effects of ketamine in this small group of patients with co-occurring alcohol use disorder, and they suggest the combination might also reduce alcohol craving and consumption. The authors explicitly contrast their findings with a prior report by Williams et al, which had found that 50 mg oral naltrexone eliminated ketamine response in a small sample. Several methodological differences between the studies are noted: timing of the primary outcome (4 hours postinfusion in the present series versus 1 day postinfusion in Williams et al), the presence of alcohol use disorder in the present sample, and the use of a single injectable 380 mg naltrexone dose here versus 50 mg oral dosing in the earlier report. The investigators also point to other data consistent with their observations: a study in healthy volunteers in which 25 mg naltrexone did not alter behavioural effects of an antidepressant ketamine dose, and preclinical evidence suggesting some ketamine isomers may act as weak partial agonists at μ-opioid receptors. Nonetheless, they emphasise caution in interpreting both their own preliminary findings and the prior report. The extracted text states that larger randomised clinical trials are required to determine whether opiate receptor stimulation is mechanistically important for ketamine’s antidepressant effects, and that additional preclinical research would be needed to understand any role for opioid systems if such a contribution is confirmed.