In Reply We thank Heifets et al for their feedback on our case series describing the inability of naltrexone pretreatment to block the antidepressant effects of ketamine in patients with depression and comorbid alcohol use disorder.¹ We are concerned about overinterpreting preliminary results based on small samples. Instead, we would emphasize the big picture. We believe that the role of opiate receptor stimulation in the antidepressant effects of ketamine is unresolved and that well-powered rigorous randomized clinical trials are needed to answer this question.

However, we find that Heifets et al do not make a compelling case for their assertion that the rapid antidepressant effects of ketamine in our case series could be attributed to naltrexone. We note a paradox in the position taken by Heifets et al, who suggest that levels of naltrexone, a high-potency opiate receptor antagonist, may have been too low to block the actions of ketamine, a low-affinity partial agonist at 渭 opiate receptors. Yet, they suggest that levels of naltrexone were still high enough to produce robust antidepressant effects in patients, particularly at times during which naltrexone levels were declining. Neither of the articles cited by the authors in defense of their assertion of antidepressant effects of naltrexone describe, in their primary analyses, an antidepressant effect attributable to naltrexone alone or in combination with a selective serotonin reuptake inhibitor (SSRI).^2,3 One of the articles describes the absence of a difference between naltrexone plus SSRI vs naltrexone.³ In the absence of a comparator for naltrexone, no inferences should be drawn regarding naltrexone-specific effects. The other article, in a secondary analysis, reported antidepressant effects of the naltrexone-SSRI combination, but not naltrexone alone, only in a subgroup of patients without depression but with alcohol use disorder. This subgroup only responded to the naltrexone-SSRI combination and reductions in depression only reached significance in post hoc tests at week 14.² Thus, this 鈥減ositive鈥� result was not in a relevant patient group, was not associated with naltrexone monotherapy, and was not a rapid antidepressant effect.