{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T12:47:20Z","timestamp":1784378840522,"version":"3.55.0"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,2,17]],"date-time":"2020-02-17T00:00:00Z","timestamp":1581897600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,2,17]],"date-time":"2020-02-17T00:00:00Z","timestamp":1581897600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Pharmacol Toxicol"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; <jats:italic>N<\/jats:italic>\u2009=\u200923) or bipolar disorder (BD; <jats:italic>N<\/jats:italic>\u2009=\u200913) to amantadine sulphate (PK-Merz\u00ae; twice 100\u2009mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2\u20133\u2009weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Primary outcomes (\u226525% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder (<jats:italic>p<\/jats:italic>\u2009=\u20090.003), a large clinical effect size (ES; Cohen\u2019s d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2\u2009weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, <jats:italic>p<\/jats:italic>\u2009=\u20090.001; PAG, <jats:italic>p<\/jats:italic>\u2009=\u20090.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction (<jats:italic>p<\/jats:italic>\u2009=\u20090,001 and <jats:italic>p<\/jats:italic>\u2009=\u20090.034, respectively). Follow-up benefits (12\u2009months) correlated with dropped cumulative infection measures over time (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). In vitro, amantadine concentrations as low as 2.4\u201310\u2009ng\/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200\u2009\u03bcg\/mL).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.drks.de\/drks_web\/setLocale_EN.do\">https:\/\/www.drks.de\/drks_web\/setLocale_EN.do<\/jats:ext-link><\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40360-020-0391-x","type":"journal-article","created":{"date-parts":[[2020,2,17]],"date-time":"2020-02-17T15:07:01Z","timestamp":1581952021000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Antiviral treatment perspective against Borna disease virus 1 infection in major depression: a double-blind placebo-controlled randomized clinical trial"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1159-6538","authenticated-orcid":false,"given":"Detlef E.","family":"Dietrich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liv","family":"Bode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten W.","family":"Spannhuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Hecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanns","family":"Ludwig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hinderk M.","family":"Emrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,17]]},"reference":[{"issue":"6","key":"391_CR1","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1056\/NEJMp1315214","volume":"370","author":"V Patel","year":"2014","unstructured":"Patel V, Saxena S. 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All participants signed written informed consent.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors of this manuscript have the following competing interests: DED and HL held non-licensed common patents on a 2nd indication of amantadine (Germany, USA, China, and Japan) which are expired. HL held non-licensed patents on BDV diagnostic procedures (Germany and USA) which are also expired. HL received personal consulting fees from medical laboratories in Germany, Diamedis () and DEDIMED (). LB and HL report a common patent application on differential BDV-1 diagnosis (first publication on 11th April, 2019) by the German Patent and Trade Mark Office), and personal fees from R-Biopharm (). CWS is a full-time employee of Idorsia Pharmaceuticals (Allschwil, Switzerland). HH and HME declared they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12"}}