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Brief Report

Depressive Symptomatology Is Associated With Smaller Reductions in Drug Cue Reactivity During Extended-Release Naltrexone Treatment of Opioid Use Disorder

Zhenhao Shi, PhDa,*; Xinyi Li, PhDa; Kyle M. Kampman, MDa; Anna Rose Childress, PhDa; Corinde E. Wiers, PhDa; and Daniel D. Langleben, MDa

Published: April 17, 2023

J Clin Psychiatry 2023;84(3):22br14567

To cite: Shi Z, Li X, Kampman KM, et al. Depressive symptomatology is associated with smaller reductions in drug cue reactivity during extended-release naltrexone treatment of opioid use disorder. J Clin Psychiatry. 2023;84(3):22br14567.
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© 2023 Physicians Postgraduate Press, Inc.

aDepartment of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
*Corresponding author: Daniel D. Langleben, MD, 3535 Market St Ste 500, Philadelphia, PA 19104 (


The high incentive value attributed to a drug in substance use disorders leads to the heightened dopaminergic responses to drug-related conditioned stimuli (ie, cue reactivity),1 stimulating drug-seeking behavior and promoting relapse.2 The nucleus accumbens (NAcc) is the key brain region implicated in cue reactivity in general. Specifically, in opioid use disorder (OUD), greater NAcc response to opioid drug cues has been associated with heavier drug use.3 The once-monthly injectable extended-release opioid antagonist naltrexone (XR-NTX) is an effective relapse prevention medication for OUD4,5 that significantly reduces NAcc cue reactivity.6,7 Depression and OUD are highly comorbid,8,9 and both involve endogenous opioid dysregulation.10,11 Patients with more severe depressive symptoms show poorer response to OUD treatment.12–14 Here, we used functional magnetic resonance imaging (fMRI) to test the hypothesis that depressive symptomatology in OUD is associated with reduced sensitivity of subjective or neural indices of drug cue reactivity to the XR-NTX treatment of OUD.


We performed a secondary analysis on a previously described dataset.6 Briefly, 23 detoxified OUD patients (9 female; 21–47 years old) were offered up to 3 monthly XR-NTX injections. Participants completed pre-treatment fMRI before the first injection and on-treatment fMRI approximately 2 weeks after the first injection. Each fMRI session included a cue reactivity task that presented drug-related, sexual, aversive, and neutral images. Before and after the task, participants reported craving for opioids on a 10-point scale (0 = none, 9 = extremely). Cue-induced craving was indexed by the change from before to after the task. The Beck Depression Inventory (BDI), which demonstrates good reliability and validity in the OUD population,15,16 was administered approximately 1 week after the first injection.

Preprocessed fMRI data were analyzed by modeling each stimulus category. The NAcc was defined as the a priori region of interest. Neural activity was evaluated by contrasting the drug, sexual, and aversive conditions with the neutral condition. Pearson correlation was performed between BDI scores and changes in cue-induced craving and NAcc drug cue reactivity (on-treatment minus pre-treatment). We also tested the correlation for sexual and aversive stimuli. Whole-brain analysis explored correlation in other brain regions.17

See the Supplementary Material and Shi et al6 for additional details on the methods.


Participants’ BDI scores ranged from 0 (no depression) to 24 (moderate depression) (mean ± SD = 9.91 ± 6.22). A higher BDI score was associated with smaller reductions in cue-induced craving and NAcc cue reactivity at the ROI level (r = 0.44 and 0.50, P = .035 and .014; Figure 1) from pre-treatment to on-treatment. BDI score was not correlated with changes in NAcc response to sexual or aversive stimuli, (r = 0.21 and 0.07, P = .34 and .75). Whole-brain analysis did not show correlation with BDI score in other regions. See the Supplementary Material for additional results.


Greater depressive symptoms were associated with smaller reductions in cue-induced craving and NAcc drug cue reactivity during XR-NTX treatment, suggesting that depression may hamper XR-NTX’s ability to restore normal incentive salience processing. The lack of correlation between depressive symptoms and changes in NAcc response to the non-drug stimuli is consistent with our prior observation that XR-NTX effect was specific to drug cues.6 Although there is no evidence of XR-NTX causing depression,18–20 patients with greater depressive symptoms show more drug-related thoughts during XR-NTX treatment.21 Our data corroborate this finding and point to NAcc as a key region mediating the impact of depressive symptoms on XR-NTX effectiveness. Given that depression and OUD are highly comorbid,9 interventions targeting depressive symptoms may improve XR-NTX treatment success.22 Study limitations include small sample size, potential confounds in the visual stimulus parameters, and limited number of follow-up timepoints (see Supplementary Material). Future studies are needed to confirm our findings and explore other factors that contribute to individual differences in relapse vulnerability.

Published online: April 17, 2023.
Relevant financial relationships: None.
Funding/support: This work was supported by the Commonwealth of Pennsylvania CURE grant SAP#4100055577 (Dr Childress) and the following National Institutes of Health grants: DA051709 (Dr Shi), DA028874 (Dr Childress), AA026892 (Dr Wiers), and DA036028 (Dr Langleben).
Role of the sponsor: The funders had no role in the design, analysis, interpretation, or publication of this study.
Previous presentation: Presented as an oral communication at the Annual Meeting of the American Society of Clinical Psychopharmacology; May 31, 2022; Scottsdale, Arizona.
ORCID ID: Zhenhao Shi:
Supplementary material: Available at

Volume: 84

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