Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study

Abstract

We investigated the potential role of the opioid system in modulating glutamatergic effects of ketamine administration in major depressive disorder. Twenty-six adults with major depressive disorder participated in a double-blind crossover study, receiving oral placebo or 50 mg naltrexone before an intravenous infusion of 0.5 mg per kg ketamine. Brain glutamatergic activity in the anterior cingulate cortex was measured using functional magnetic resonance spectroscopy and depressive symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale. Naltrexone attenuated the increase in glutamate + glutamine to total N-acetylaspartate ratio during ketamine infusion compared to placebo (F_1,253 = 4.83, P = 0.029) and also attenuated the reduction in Montgomery-Åsberg Depression Rating Scale scores on day 1 (condition-by-time interaction, F_1,74 = 5.39, P = 0.023). These findings demonstrate that the opioid system modulates the acute response to ketamine and subsequent antidepressant effects. Interactions between the glutamate and opioid systems may have implications for the development of new depression treatment strategies. ClinicalTrials.gov registration: NCT04977674 .

Fig. 1. ¹H-fMRS experimental overview.

Spectra were acquired continuously for a 5-min baseline period and during the initial 30 min of the ketamine infusion using point-resolved spectroscopy with chemical selective suppression for water suppression (repetition time (TR) = 2,000 ms, echo time (TE) = 40 ms, 8-step phase cycle, 1,040 transients). Each block consisted of 144 transients (18 × 8-step phase cycles). A total of 16 water unsuppressed transients (2 × 8-step phase cycles) were acquired at the end of the sequence.

Fig. 2. Clinical measure outcomes.

a, MADRS total scores at preinfusion and at day 1 postinfusion. The thick lines represent the mean values for each condition, with individual data points connected by thinner lines. b, Change in MADRS scores from preinfusion to day 1 postinfusion. c, Change in QIDS–SR scores from preinfusion to day 1 postinfusion. d, Change in M3VAS scores from preinfusion to day 1 postinfusion e, Change in SHAPS scores from preinfusion to day 1 postinfusion. f, Change in TEPS-A scores from preinfusion to day 1 postinfusion. g, Change in TEPS-C scores from preinfusion to day 1 postinfusion. Note an increase in TEPS-A and TEPS-C scores indicates a reduction in anhedonia symptoms. Box plot elements: box spans the IQR (25th–75th percentile), central line is the median (50th percentile), + marks the mean, whiskers extend to the lowest and highest values within 1.5 × IQR of the box and values beyond that range are shown individually. Each plot shows data from n = 26 participants who completed the crossover.

Fig. 3. ¹H-fMRS voxel position and spectra.

a, Voxel center placement. b, Voxel density map across participants and sessions in Montreal Neurological Institute (MNI) space. Blue, placebo condition; orange, naltrexone. The shading of the contour lines represents the percentage (%) overlap at that point. c, Sample spectrum from averaged block for single participant with output of the fit (red) overlaid on the acquired spectrum (black). The estimated baseline is displayed under the spectrum in black. Plotted in units of parts per million (ppm). d, Combined spectra for single block across participants and conditions. Blue, placebo; orange, naltrexone. e, Combined spectra fit for single block across participants and conditions. Blue, placebo; orange, naltrexone.

Fig. 4. Mean Glx/tNAA change across ketamine-infusion blocks.

Mean Glx/tNAA change in each of six infusion blocks relative to the preinfusion baseline block, shown separately for placebo and naltrexone pretreatment conditions. n = 24 participants with complete MRS data passing quality control. Error bars ± standard errors.

Fig. 5. Mean Glx/tNAA change from baseline across ketamine-infusion blocks by sex.

Mean Glx/tNAA change across six infusion blocks relative to the preinfusion baseline, shown separately for placebo and naltrexone pretreatment conditions, split by sex. Females, n = 11 and males, n = 13, with complete MRS data passing quality control. Error bars ± standard errors.

Extended Data Fig. 1. Clinical scores and change scores, by visit.

MADRS, QIDS-SR, M3VAS, SHAPS, TEPS-A, and TEPS-C scores at pre-infusion and Day 1 post-infusion by visit (Panels A1—F1), and Day 1 change in scores by visit (Panels A2—F2). Effect sizes (Cohen’s d) and significance (*p < 0.05) are shown for Day 1 changes between placebo and naltrexone conditions, comparing Visit 1, Visit 2, Placebo-Naltrexone, and Naltrexone-Placebo orders. Independent t-tests were used for between-subject comparisons; paired t-tests for within-subject comparisons. Box plot elements: Box spans the interquartile range (IQR) (25th–75th percentile), central line is the median (50th percentile), ‘+’ marks the mean, whiskers extend to the lowest and highest values within 1.5 × IQR of the box, and values beyond that range are shown individually. Each plot shows data from n = 26 participants who completed the crossover.