Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder

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.

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.