{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T09:26:13Z","timestamp":1772789173938,"version":"3.50.1"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Major depressive disorder (MDD) is a leading cause of global disability. Current treatments are limited by poor efficacy in approximately one-third of patients. Neuroinflammation may be an underlying mechanism of MDD and represents a novel target for pharmacological therapy. This study aimed to investigate the effects of a putative centrally acting anti-inflammatory agent, low-dose naltrexone (LDN), in MDD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients with MDD experiencing moderate depressive symptoms and receiving antidepressant treatment were randomized to receive 12\u00a0weeks of LDN (up to 4.5\u00a0mg per day) or 12\u00a0weeks of inactive placebo. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS) at 12\u00a0weeks, analyzed using a linear mixed-effects model adjusted for baseline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Thirty-seven patients were randomized. At 12\u00a0weeks, MADRS scores (M \u00b1 SD) were reduced by 10.5 \u00b1 5.6 in the LDN group and 9.8 \u00b1 5.9 placebo group; with no difference between groups (p = 0.97). LDN did not affect high-sensitivity C-reactive protein (hsCRP) levels or exploratory measures of depression, behavioral activation, quality of life, sickness symptoms and mood. There was no evidence that baseline hsCRP modified the effect of LDN on MADRS score.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Adjunctive LDN does not appear to alter depressive symptoms in moderate MDD. Larger studies are warranted to evaluate LDN in a population with a higher likelihood of neuroinflammatory pathology, such as those with severe, treatment-resistant MDD or comorbid inflammatory conditions. Future studies should utilize stratification tools that are more sensitive and specific to neuroinflammation than hsCRP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.anzctr.org.au\/Trial\/Registration\/TrialReview.aspx?id=383741&amp;amp;isReview=true<\/jats:ext-link>\n                      , identifier [ACTRN12622000881730].\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1767654","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T06:42:00Z","timestamp":1772779320000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Low-dose naltrexone as an adjunctive treatment for major depressive disorder: findings from a randomized, double-blind, placebo-controlled hybrid parallel-arm study"],"prefix":"10.3389","volume":"17","author":[{"given":"Ben D.","family":"Moloney","sequence":"first","affiliation":[{"name":"School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland","place":["Auckland, New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Forsyth","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland","place":["Auckland, New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachael L.","family":"Sumner","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland","place":["Auckland, New Zealand"]},{"name":"Department of Biomedicine and Medical Diagnostics, Auckland University of Technology","place":["Auckland, New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie C.","family":"Glover","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland","place":["Auckland, New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas R.","family":"Hoeh","sequence":"additional","affiliation":[{"name":"Department of Psychological Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland","place":["Auckland, New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederick","family":"Sundram","sequence":"additional","affiliation":[{"name":"Department of Psychological Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland","place":["Auckland, New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alana","family":"Cavadino","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Population Health, Faculty of Medical and Health Sciences, University of Auckland","place":["Auckland, New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suresh","family":"Muthukumaraswamy","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland","place":["Auckland, New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne C.","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland","place":["Auckland, New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1177\/1359105316659917","article-title":"A global measure of sickness behaviour: development of the sickness questionnaire","volume":"23","author":"Andreasson","year":"2018","journal-title":"J. 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