{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:41:56Z","timestamp":1793148116947,"version":"4.5.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T00:00:00Z","timestamp":1516752000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T00:00:00Z","timestamp":1516752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Given evidence of chronic inflammation in bipolar disorder (BD), we tested the efficacy of aspirin and minocycline as augmentation therapy for bipolar depression. Ninety-nine depressed outpatients with BD were enrolled in a 6 week, double-blind, placebo-controlled trial, and randomized to one of four groups: active minocycline (100\u2009mg b.i.d.)\u2009+\u2009active aspirin (81\u2009mg b.i.d.) (M\u2009+\u2009A); active minocycline\u2009+\u2009placebo aspirin (M\u2009+\u2009P); placebo-minocycline\u2009+\u2009active aspirin (A\u2009+\u2009P); and placebo-minocycline\u2009+\u2009placebo aspirin (P\u2009+\u2009P). A blinded interim analysis mid-way through the study led to the dropping of the M\u2009+\u2009P and A\u2009+\u2009P arms from further enrollment giving numbers per group who were included in the final analysis of: 30 (M\u2009+\u2009A), 18 (M\u2009+\u2009P), 19 (A\u2009+\u2009P), and 28 (P\u2009+\u2009P). When the study started, there were three primary outcome measures. Based on the results of the interim analysis, the primary outcome variable, response to treatment as defined by &gt;50% decrease in Montgomery\u2013\u00c4sberg Depression Rating Scale (MADRS) score was maintained. The other two (i.e., the change in mean MADRS score from baseline to end of study and the remission rate, with remission being defined as a score of &lt;11 on the MADRS) were reduced to exploratory outcome measures because the interim analysis indicated that the study was adequately powered to test differences in response rate but not the mean change in MADRS scores or remission rates. CRP and IL-6 were assayed to measure inflammation. Urinary thromboxane B2 (11-D-TXB<jats:sub>2<\/jats:sub>) concentrations, which were significantly increased at baseline in the combined BD sample (<jats:italic>n<\/jats:italic>\u2009=\u200990) vs. a healthy control group (<jats:italic>n<\/jats:italic>\u2009=\u200927), served as an indirect marker of cyclooxygenase (COX) activity. In a two-group analysis, the M\u2009+\u2009A group showed a greater response rate than the P\u2009+\u2009P group (<jats:italic>p<\/jats:italic>(one-tailed)\u2009=\u20090.034, OR\u2009=\u20092.93, NNT\u2009=\u20094.7). When all four arms were included in the analysis, there was a main effect of aspirin on treatment response that was driven by both the M\u2009+\u2009A and the A\u2009+\u2009P groups (<jats:italic>p<\/jats:italic>(two-tailed)\u2009=\u20090.019, OR\u2009=\u20093.67, NNT\u2009=\u20094.0). Additionally, there was a significant 3-way interaction between aspirin, minocycline, and IL-6, indicating that response to minocycline was significantly greater in participants in the M\u2009+\u2009P group with higher IL-6 concentrations. Further, participants in the M\u2009+\u2009P group who responded to treatment had significantly greater decreases in IL-6 levels between baseline and visit 7 vs. non-responders. Regarding the exploratory outcomes, there was a main effect for aspirin on the remission rate (<jats:italic>\u03c7<\/jats:italic><jats:sub>1<\/jats:sub><jats:sup>2<\/jats:sup>\u2009=\u20094.14, <jats:italic>p<\/jats:italic>(2t)\u2009=\u20090.04, OR\u2009=\u20092.52, NNT\u2009=\u20098.0). There was no significant main effect of aspirin or minocycline on the mean change in MADRS score across visits. Aspirin and minocycline may be efficacious adjunctive treatments for bipolar depression. Given their potential import, additional studies to confirm and extend these findings are warranted.<\/jats:p>","DOI":"10.1038\/s41398-017-0073-7","type":"journal-article","created":{"date-parts":[[2018,1,23]],"date-time":"2018-01-23T15:16:37Z","timestamp":1516720597000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":135,"title":["Treatment of bipolar depression with minocycline and\/or aspirin: an adaptive, 2\u00d72 double-blind, randomized, placebo-controlled, phase IIA clinical trial"],"prefix":"10.1038","volume":"8","author":[{"given":"Jonathan B.","family":"Savitz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. Kent","family":"Teague","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Misaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Macaluso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent E.","family":"Wurfel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Drevets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Yates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ondria","family":"Gleason","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne C.","family":"Drevets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheldon H.","family":"Preskorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,1,24]]},"reference":[{"key":"73_CR1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jad.2010.06.036","volume":"127","author":"R Correa","year":"2010","unstructured":"Correa, R., Akiskal, H., Gilmer, W., Nierenberg, A. A., Trivedi, M. & Zisook, S. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J. Affect. Disord. 127, 10\u201318 (2010).","journal-title":"J. Affect. Disord."},{"key":"73_CR2","doi-asserted-by":"publisher","first-page":"S24","DOI":"10.1016\/S0165-0327(14)70006-0","volume":"169","author":"TA Ketter","year":"2014","unstructured":"Ketter, T. A., Miller, S., Dell\u2019Osso, B., Calabrese, J. R., Frye, M. A. & Citrome, L. Balancing benefits and harms of treatments for acute bipolar depression. J. Affect. Disord. 169, S24\u2013S33 (2014).","journal-title":"J. Affect. Disord."},{"key":"73_CR3","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.jad.2015.05.016","volume":"183","author":"GH Vazquez","year":"2015","unstructured":"Vazquez, G. H., Holtzman, J. N., Tondo, L. & Baldessarini, R. J. Efficacy and tolerability of treatments for bipolar depression. J. Affect. Disord. 183, 258\u2013262 (2015).","journal-title":"J. Affect. Disord."},{"key":"73_CR4","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1001\/jamapsychiatry.2014.1611","volume":"71","author":"O Kohler","year":"2014","unstructured":"Kohler, O., Benros, M. E., Nordentoft, M., Farkouh, M. E., Iyengar, R. L. & Mors, O. et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry 71, 1381\u20131391 (2014).","journal-title":"JAMA Psychiatry"},{"key":"73_CR5","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1111\/bdi.12373","volume":"18","author":"JD Rosenblat","year":"2016","unstructured":"Rosenblat, J. D., Kakar, R., Berk, M., Kessing, L. V., Vinberg, M. & Baune, B. T. et al. Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis. Bipolar Disord. 18, 89\u2013101 (2016).","journal-title":"Bipolar Disord."},{"key":"73_CR6","doi-asserted-by":"crossref","unstructured":"Kappelmann N., Lewis G., Dantzer R., Jones P. B., Khandaker G. M. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol. Psychiatry. 2016.","DOI":"10.1016\/j.bbi.2017.07.023"},{"key":"73_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2016.212","volume":"6","author":"N Mechawar","year":"2016","unstructured":"Mechawar, N. & Savitz, J. Neuropathology of mood disorders: do we see the stigmata of inflammation? Transl. Psychiatry 6, e946 (2016).","journal-title":"Transl. Psychiatry"},{"key":"73_CR8","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2011-000643","volume":"2","author":"J Savitz","year":"2012","unstructured":"Savitz, J., Preskorn, S., Teague, T. K., Drevets, D., Yates, W. & Drevets, W. Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2x2 clinical trial. BMJ Open. 2, e000643 (2012).","journal-title":"BMJ Open."},{"key":"73_CR9","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.tips.2009.01.002","volume":"30","author":"SH Choi","year":"2009","unstructured":"Choi, S. H., Aid, S. & Bosetti, F. The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol. Sci. 30, 174\u2013181 (2009).","journal-title":"Trends Pharmacol. Sci."},{"key":"73_CR10","first-page":"448","volume":"10","author":"SH Choi","year":"2010","unstructured":"Choi, S. H., Aid, S., Choi, U. & Bosetti, F. Cyclooxygenases-1 and -2 differentially modulate leukocyte recruitment into the inflamed brain. Pharm. J. 10, 448\u2013457 (2010).","journal-title":"Pharm. J."},{"key":"73_CR11","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.plefa.2009.10.007","volume":"82","author":"P Stolk","year":"2010","unstructured":"Stolk, P., Souverein, P. C., Wilting, I., Leufkens, H. G., Klein, D. F. & Rapoport, S. I. et al. Is aspirin useful in patients on lithium? A pharmacoepidemiological study related to bipolar disorder. Prostaglandins Leukot. Essent. Fat. Acids 82, 9\u201314 (2010).","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"73_CR12","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1097\/00004850-200607000-00005","volume":"21","author":"J Mendlewicz","year":"2006","unstructured":"Mendlewicz, J., Kriwin, P., Oswald, P., Souery, D., Alboni, S. & Brunello, N. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int. Clin. Psychopharmacol. 21, 227\u2013231 (2006).","journal-title":"Int. Clin. Psychopharmacol."},{"key":"73_CR13","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2012.79","volume":"2","author":"OP Almeida","year":"2012","unstructured":"Almeida, O. P., Flicker, L., Yeap, B. B., Alfonso, H., McCaul, K. & Hankey, G. J. Aspirin decreases the risk of depression in older men with high plasma homocysteine. Transl. Psychiatry 2, e151 (2012).","journal-title":"Transl. Psychiatry"},{"key":"73_CR14","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.1002\/glia.23007","volume":"64","author":"T Moller","year":"2016","unstructured":"Moller, T., Bard, F., Bhattacharya, A., Biber, K., Campbell, B. & Dale, E. et al. Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor. Glia 64, 1788\u20131794 (2016).","journal-title":"Glia"},{"key":"73_CR15","first-page":"5","volume":"9","author":"LS Zheng","year":"2015","unstructured":"Zheng, L. S., Kaneko, N. & Sawamoto, K. Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice. Front. Cell. Neurosci. 9, 5 (2015).","journal-title":"Front. Cell. Neurosci."},{"key":"73_CR16","doi-asserted-by":"publisher","first-page":"10483","DOI":"10.1073\/pnas.1832501100","volume":"100","author":"X Wang","year":"2003","unstructured":"Wang, X., Zhu, S., Drozda, M., Zhang, W., Stavrovskaya, I. G. & Cattaneo, E. et al. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington\u2019s disease. Proc. Natl. Acad. Sci. USA 100, 10483\u201310487 (2003).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"73_CR17","doi-asserted-by":"publisher","first-page":"1660","DOI":"10.1016\/j.pnpbp.2008.06.010","volume":"32","author":"M Molina-Hernandez","year":"2008","unstructured":"Molina-Hernandez, M., Tellez-Alcantara, N. P., Perez-Garcia, J., Olivera-Lopez, J. I. & Jaramillo-Jaimes, M. T. Desipramine or glutamate antagonists synergized the antidepressant-like actions of intra-nucleus accumbens infusions of minocycline in male Wistar rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1660\u20131666 (2008).","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"73_CR18","first-page":"582","volume":"153","author":"J Levine","year":"1996","unstructured":"Levine, J., Cholestoy, A. & Zimmerman, J. Possible antidepressant effect of minocycline. Am. J. Psychiatry 153, 582 (1996).","journal-title":"Am. J. Psychiatry"},{"key":"73_CR19","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.pnpbp.2012.02.002","volume":"37","author":"T Miyaoka","year":"2012","unstructured":"Miyaoka, T., Wake, R., Furuya, M., Liaury, K., Ieda, M. & Kawakami, K. et al. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog. Neuropsychopharmacol. Biol. Psychiatry 37, 222\u2013226 (2012).","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"73_CR20","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1111\/bdi.12496","volume":"19","author":"JK Soczynska","year":"2017","unstructured":"Soczynska, J. K., Kennedy, S. H., Alsuwaidan, M., Mansur, R. B., Li, M. & McAndrews, M. P. et al. A pilot, open-label, 8-week study evaluating the efficacy, safety and tolerability of adjunctive minocycline for the treatment of bipolar I\/II depression. Bipolar Disord. 19, 198\u2013213 (2017).","journal-title":"Bipolar Disord."},{"key":"73_CR21","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1097\/YIC.0000000000000098","volume":"31","author":"H Emadi-Kouchak","year":"2016","unstructured":"Emadi-Kouchak, H., Mohammadinejad, P., Asadollahi-Amin, A., Rasoulinejad, M., Zeinoddini, A. & Yalda, A. et al. Therapeutic effects of minocycline on mild-to-moderate depression in HIV patients: a double-blind, placebo-controlled, randomized trial. Int. Clin. Psychopharmacol. 31, 20\u201326 (2016).","journal-title":"Int. Clin. Psychopharmacol."},{"key":"73_CR22","first-page":"26","volume":"8","author":"J Shen","year":"2011","unstructured":"Shen, J., Preskorn, S., Dragalin, V., Slomkowski, M., Padmanabhan, S. K. & Fardipour, P. et al. How adaptive trial designs can increase efficiency in psychiatric drug development: a case study. Innov. Clin. Neurosci. 8, 26\u201334 (2011).","journal-title":"Innov. Clin. Neurosci."},{"key":"73_CR23","first-page":"5","volume":"62","author":"AA Nierenberg","year":"2001","unstructured":"Nierenberg, A. A. & DeCecco, L. M. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J. Clin. Psychiatry 62, 5\u20139 (2001).","journal-title":"J. Clin. Psychiatry"},{"key":"73_CR24","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1161\/hs0102.102010","volume":"33","author":"A Bruno","year":"2002","unstructured":"Bruno, A., McConnell, J. P., Mansbach, H. H. 3rd, Cohen, S. N., Tietjen, G. E. & Bang, N. U. Aspirin and urinary 11-dehydrothromboxane B(2) in African American stroke patients. Stroke 33, 57\u201360 (2002).","journal-title":"Stroke"},{"key":"73_CR25","doi-asserted-by":"publisher","first-page":"205","DOI":"10.4088\/JCP.13r08722","volume":"75","author":"S Borges","year":"2014","unstructured":"Borges, S., Chen, Y. F., Laughren, T. P., Temple, R., Patel, H. D. & David, P. A. et al. Review of maintenance trials for major depressive disorder: a 25-year perspective from the US Food and Drug Administration. J. Clin. Psychiatry 75, 205\u2013214 (2014).","journal-title":"J. Clin. Psychiatry"},{"key":"73_CR26","unstructured":"R: A Language and Environment for Statistical Computing. http:\/\/www.r-project.org\/, 2017."},{"key":"73_CR27","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1001\/2013.jamapsychiatry.4","volume":"70","author":"CL Raison","year":"2013","unstructured":"Raison, C. L., Rutherford, R. E., Woolwine, B. J., Shuo, C., Schettler, P. & Drake, D. F. et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70, 31\u201341 (2013).","journal-title":"JAMA Psychiatry"},{"key":"73_CR28","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1111\/acps.12665","volume":"135","author":"K Jarventausta","year":"2017","unstructured":"Jarventausta, K., Sorri, A., Kampman, O., Bjorkqvist, M., Tuohimaa, K. & Hamalainen, M. et al. Changes in interleukin-6 levels during electroconvulsive therapy may reflect the therapeutic response in major depression. Acta Psychiatr. Scand. 135, 87\u201392 (2017).","journal-title":"Acta Psychiatr. Scand."},{"key":"73_CR29","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.psyneuen.2016.11.031","volume":"76","author":"D Lindqvist","year":"2016","unstructured":"Lindqvist, D., Dhabhar, F. S., James, S. J., Hough, C. M., Jain, F. A. & Bersani, F. S. et al. Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology 76, 197\u2013205 (2016).","journal-title":"Psychoneuroendocrinology"},{"key":"73_CR30","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1021\/cn500058v","volume":"5","author":"SI Rapoport","year":"2014","unstructured":"Rapoport, S. I. Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. ACS Chem. Neurosci. 5, 459\u2013467 (2014).","journal-title":"ACS Chem. Neurosci."},{"key":"73_CR31","doi-asserted-by":"publisher","first-page":"18533","DOI":"10.1074\/jbc.M112.447268","volume":"288","author":"KK Modi","year":"2013","unstructured":"Modi, K. K., Sendtner, M. & Pahan, K. Up-regulation of ciliary neurotrophic factor in astrocytes by aspirin: implications for remyelination in multiple sclerosis. J. Biol. Chem. 288, 18533\u201318545 (2013).","journal-title":"J. Biol. Chem."}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41398-017-0073-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-017-0073-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-017-0073-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T11:27:52Z","timestamp":1671535672000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41398-017-0073-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,24]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["73"],"URL":"https:\/\/doi.org\/10.1038\/s41398-017-0073-7","relation":{},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,24]]},"assertion":[{"value":"14 October 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 November 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 January 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"W.C.D., W.Y., J.B.S., and S.H.P. are co-inventors on a use patent that has been filed for treating bipolar depression with minocycline and aspirin (\u201cComposition and Method for Treating Bipolar Disorder\u201d, WO2016\/090316). W.C.D. is an employee of Janssen Pharmaceutical of Johnson and Johnson, Inc. Janssen Pharmaceutical of Johnson and Johnson played no role in the study design, data collection, data analysis, data interpretation, or writing of the report.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"27"}}