Work

190. Effects of Low-dose Naltrexone on Salience Network Connectivity in Major Depressive Disorder

Year: 2025

Type: article

Abstract: Background Major depressive disorder (MDD) is a leading cause of disability worldwide and current treatment options are ineffective in one-third of patients. With inflammation being increasingly recognized as a underlying factor that impacts brain function in MDD, anti-inflammatory treatments, like low-dose naltrexone (LDN), have been investigated with promising effects. However, without neuroinflammation biomarkers it remains difficult to know who will respond to anti-inflammatory treatments in MDD. The dorsal anterior cingulate cortex (dACC) and anterior insula (AI), which are nodes of the salience network (SN), are thought to play a role in mediating the relationship between neuroinflammation, brain function and depressive symptoms, but there is a lack of research investigating the effect of anti-inflammatories on these regions in MDD. Aims & Objectives This preliminary study aims to investigate the effects of the putative central nervous system anti-inflammatory, LDN, on dACC and AI connectivity to the rest of the brain in MDD. Method We recruited 30 participants with MDD who were moderately depressed and receiving pharmacological antidepressant therapy to participate in a double-blind randomized control trial of 12 weeks of LDN vs. inactive placebo. Resting state functional magnetic resonance imaging (rsfMRI) was performed at baseline and 12 weeks. Seed-to-whole brain functional connectivity analysis was performed using four seeds positioned in the salience network inclusive of the left and right dACC and AI. Our analysis examined the overall effects of LDN vs. placebo on the voxelwise change in connectivity between timepoints and used permutation testing (n = 5,000) and threshold-free cluster enhancement (TFCE) to identify clusters of significant differences (p < 0.05) between groups. Results 23 participants completed baseline and 12 week scans and were included in this analysis. The LDN group (n = 10) showed increased connectivity compared to the placebo group (n = 13) between the right AI seed and a cluster in the right posterior superior temporal gyrus (pSTG) containing the auditory cortex (p = 0.035). We found no significant difference between LDN and placebo groups in seed-to-whole brain connectivity changes for the left AI and both dACC seeds. Discussion & Conclusions These preliminary results indicate that LDN increases connectivity between the right AI and right pSTG relative to placebo in MDD. The pSTG contains the auditory cortex, potentially indicating increased connectivity between the SN and auditory network following LDN treatment. Enhanced connectivity between these regions may resemble greater sensory input to the SN, which could confer more effective attribution of salience with treatment. However, this study is preliminary and limited by a small sample size. Future studies should seek to correlate right AI and pSTG connectivity with clinical measures and inflammatory markers to gain a richer picture of the relationship this has to inflammation, salience attribution and MDD.

Source: The International Journal of Neuropsychopharmacology

DOI: 10.1093/ijnp/pyaf052.176