Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism: Is It a Ketamine-Specific Effect?

To the Editor: I was delighted to read the article by Williams and colleagues (1) that made an important and intriguing contribution to the field. In the article, published in the December 2018 issue of the Journal, the authors show that 50 mg of naltrexone that saturates both mu and kappa opioid receptors taken 45 minutes before intravenous injection of ketamine attenuated the acute effect of ketamine. The authors’ conclusion was that naltrexone can act either as an antidepressant or as a “mood neutral” compound. In this study, patients were taking selective serotonin reuptake inhibitors (SSRIs) or other antidepressants along with naltrexone or placebo and intravenous ketamine. Because all patients received ketamine, the effect of adding naltrexone without ketamine was not tested. Specifically, the risk of naltrexone exacerbating symptoms in this population was ignored. Studies concerning the combination of antidepressants and naltrexone in a population of abstinent alcoholic-depressive patients who were already taking naltrexone show that the addition of SSRIs had no additional effect (2, 3). It has been claimed that one of the main side effects of naltrexone in this population is depression (4, 5).

The effect of naltrexone on mood in a population without a history of substance abuse is not fully established. Low-dose naltrexone as an add-on treatment may improve depression in patients with fibromyalgia (6, 7), while a higher dose of naltrexone in combination with SSRIs might exacerbate depressive symptoms (8).

Nevertheless, this work raises many interesting questions concerning the involvement of the opiate system in the treatment of depression. It would be interesting to further investigate whether opiate antagonists can attenuate the effect of other antidepressant treatments (e.g., ECT).