{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:19:53Z","timestamp":1790104793614,"version":"4.0.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2020,5,16]],"date-time":"2020-05-16T00:00:00Z","timestamp":1589587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U01AI125003"],"award-info":[{"award-number":["U01AI125003"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["K23AI138851"],"award-info":[{"award-number":["K23AI138851"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32AI055433"],"award-info":[{"award-number":["T32AI055433"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cryptococcal antigen (CrAg) screening in HIV-infected persons with CD4\u00a0&amp;lt;\u00a0100 cells\/\u00b5l can reduce meningitis and death, yet preemptive fluconazole therapy fails in \u223c25%. Sertraline has in vitro and in vivo activity against Cryptococcus and is synergistic with fluconazole in mice. We evaluated the efficacy and safety of sertraline in asymptomatic cryptococcal antigenemia. We conducted a randomized trial of asymptomatic CrAg-positive Ugandans from November 2017 to February 2018. All subjects received WHO standard therapy of fluconazole 800\u00a0mg for 2 weeks, then 400\u00a0mg for 10 weeks, then 200\u00a0mg through 24 weeks. Participants were randomized to receive adjunctive sertraline or placebo, given in once-weekly escalating 100\u00a0mg\/day doses up to 400\u00a0mg\/day, which was then given for 8 weeks, then tapered. The primary endpoint was meningitis-free 6-month survival. The data and safety monitoring board halted the trial after 21 subjects were enrolled due to safety concerns. Meningitis-free 6-month survival occurred in 9 of 11 of placebo participants and 10 of 10 of sertraline participants. However, seven serious adverse events (SAEs) occurred (n\u00a0=\u00a04 sertraline group; n\u00a0=\u00a03 placebo group). Three SAEs in the sertraline group presented with psychosis and aggressive behavioral changes with one meeting Hunter's criteria for serotonin syndrome while receiving 200\u00a0mg\/day sertraline. Two transient psychoses were associated with antecedent fluconazole and sertraline interruption. The serotonin syndrome resolved within 1 day, but psychosis persisted for 4 months after sertraline discontinuation. Sertraline was associated with excess SAEs of psychosis. Due to early stopping, we were unable to determine any efficacy for cryptococcal antigenemia.<\/jats:p>","DOI":"10.1093\/mmy\/myaa033","type":"journal-article","created":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T19:09:28Z","timestamp":1589310568000},"page":"1037-1043","source":"Crossref","is-referenced-by-count":21,"title":["Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial"],"prefix":"10.1093","volume":"58","author":[{"given":"David R","family":"Boulware","sequence":"first","affiliation":[{"name":"University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Nalintya","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5531-0231","authenticated-orcid":false,"given":"Radha","family":"Rajasingham","sequence":"additional","affiliation":[{"name":"University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Kirumira","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose","family":"Naluyima","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred","family":"Turya","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Namanda","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morris K","family":"Rutakingirwa","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb P","family":"Skipper","sequence":"additional","affiliation":[{"name":"University of Minnesota, Minneapolis, MN, USA"},{"name":"Infectious Diseases Institute, Makerere University, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yofesi","family":"Nikweri","sequence":"additional","affiliation":[{"name":"Medical Research Council\/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC\/UVRI & LSHTM), Uganda Research Unit, Masaka Station"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy Huppler","family":"Hullsiek","sequence":"additional","affiliation":[{"name":"University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ananta S","family":"Bangdiwala","sequence":"additional","affiliation":[{"name":"University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B","family":"Meya","sequence":"additional","affiliation":[{"name":"University of Minnesota, Minneapolis, MN, USA"},{"name":"Infectious Diseases Institute, Makerere University, Uganda"},{"name":"Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,16]]},"reference":[{"key":"2020111110131433400_bib1","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/S1473-3099(17)30243-8","article-title":"Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis","volume":"17","author":"Rajasingham","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"2020111110131433400_bib2","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1097\/QAD.0b013e32832be0fc","article-title":"High ongoing burden of cryptococcal disease in Africa despite antiretroviral roll out","volume":"23","author":"Jarvis","year":"2009","journal-title":"AIDS"},{"key":"2020111110131433400_bib3","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1086\/655143","article-title":"Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count &lt; or = 100 cells\/microL who start HIV therapy in resource-limited settings","volume":"51","author":"Meya","year":"2010","journal-title":"Clin Infect Dis"},{"key":"2020111110131433400_bib4","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1097\/00002030-200205030-00009","article-title":"Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults","volume":"16","author":"French","year":"2002","journal-title":"AIDS"},{"key":"2020111110131433400_bib5","doi-asserted-by":"crossref","first-page":"ofv046","DOI":"10.1093\/ofid\/ofv046","article-title":"Cryptococcal antigenemia in immunocompromised human immunodeficiency virus patients in rural Tanzania: a preventable cause of early mortality","volume":"2","author":"Letang","year":"2015","journal-title":"Open Forum Infect Dis"},{"key":"2020111110131433400_bib6","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1016\/S0140-6736(15)60164-7","article-title":"Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial","volume":"385","author":"Mfinanga","year":"2015","journal-title":"Lancet"},{"key":"2020111110131433400_bib7","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1097\/QAI.0000000000001899","article-title":"Laboratory-reflex cryptococcal antigen screening is associated with a survival benefit in Tanzania","volume":"80","author":"Faini","year":"2019","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2020111110131433400_bib8","doi-asserted-by":"crossref","first-page":"pii: e01238-18","DOI":"10.1128\/JCM.01238-18","article-title":"Cryptococcal meningitis diagnostics and screening in the era of point-of-care laboratory testing","volume":"57","author":"Rajasingham","year":"2019","journal-title":"J Clin Microbiol"},{"key":"2020111110131433400_bib9","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1093\/jac\/dkt221","article-title":"Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal","volume":"68","author":"Loyse","year":"2013","journal-title":"J Antimicrob Chemother"},{"key":"2020111110131433400_bib10","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1080\/21501203.2010.487054","article-title":"Effects of sertraline hydrochloride and fluconazole combinations on Cryptococcus neoformans and Cryptococcus gattii","volume":"1","author":"Nayak","year":"2010","journal-title":"Mycology"},{"key":"2020111110131433400_bib11","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1128\/AAC.00212-12","article-title":"The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections","volume":"56","author":"Zhai","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"2020111110131433400_bib12","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/S1473-3099(16)00074-8","article-title":"Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study","volume":"16","author":"Rhein","year":"2016","journal-title":"Lancet Infect Dis"},{"key":"2020111110131433400_bib13","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1093\/mmy\/myv109","article-title":"Activity of sertraline against Cryptococcus neoformans: in vitro and in vivo assays","volume":"54","author":"Trevino-Rangel Rde","year":"2016","journal-title":"Med Mycol"},{"key":"2020111110131433400_bib14","doi-asserted-by":"crossref","first-page":"7197","DOI":"10.1128\/AAC.01299-15","article-title":"Increased antifungal drug resistance in clinical isolates of Cryptococcus neoformans in Uganda","volume":"59","author":"Smith","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2020111110131433400_bib15","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/S1473-3099(19)30127-6","article-title":"Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial","volume":"19","author":"Rhein","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"2020111110131433400_bib16","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1172\/JCI124516","article-title":"Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis","volume":"129","author":"Stone","year":"2019","journal-title":"J Clin Invest"},{"key":"2020111110131433400_bib17","volume-title":"Rapid Advice: Diagnosis, Prevention and Management of Cryptococcal Disease in HIV-infected Adults, Adolescents and children","author":"World Health Organization","year":"2011"},{"key":"2020111110131433400_bib18","volume-title":"Guidelines for the Diagnosis, Prevention and Management of Cryptococcal Disease in HIV-infected Adults, Adolescents and Children","author":"World Health Organization","year":"2018"},{"key":"2020111110131433400_bib19","volume-title":"Guideline for Managing Advanced HIV Disease and the Timing for Initiating Antiretroviral Therapy","author":"World Health Organization","year":"2017"},{"key":"2020111110131433400_bib20","volume-title":"Consolidated Guidelines on The Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for the Public Health Approach","author":"World Health Organization","year":"2016","edition":"2nd edn"},{"key":"2020111110131433400_bib21","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1097\/QAI.0000000000001894","article-title":"Reflexive laboratory-based cryptococcal antigen screening and preemptive fluconazole therapy for cryptococcal antigenemia in HIV-infected individuals with CD4 &lt;100 cells\/microL: A stepped-wedge, cluster-randomized trial","volume":"80","author":"Meya","year":"2019","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2020111110131433400_bib22","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1097\/QAI.0000000000001669","article-title":"A prospective evaluation of a multisite cryptococcal screening and treatment program in HIV clinics in Uganda","volume":"78","author":"Nalintya","year":"2018","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2020111110131433400_bib23","doi-asserted-by":"crossref","first-page":"229","DOI":"10.2307\/2531910","article-title":"Sample sizes based on the log-rank statistic in complex clinical trials","volume":"44","author":"Lakatos","year":"1988","journal-title":"Biometrics"},{"key":"2020111110131433400_bib24","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s10928-019-09657-0","article-title":"Pharmacokinetics-pharmacodynamics of sertraline as an antifungal in HIV-infected Ugandans with cryptococcal meningitis","volume":"46","author":"Alhadab","year":"2019","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"2020111110131433400_bib25","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3109\/10401239709147769","article-title":"Sertraline and psychotic symptoms: a case series","volume":"9","author":"Popli","year":"1997","journal-title":"Ann Clin Psychiatry"},{"key":"2020111110131433400_bib26","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1097\/JCP.0000000000000117","article-title":"Psychotic episode associated with sertraline and drug-related delirium: a case report","volume":"34","author":"Kaprinis","year":"2014","journal-title":"J Clin Psychopharmacol"},{"key":"2020111110131433400_bib27","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/psyg.12127","article-title":"Secondary mania due to AIDS and cryptococcal meningitis in a 78-year-old patient","volume":"16","author":"Chou","year":"2016","journal-title":"Psychogeriatrics"},{"key":"2020111110131433400_bib28","doi-asserted-by":"crossref","first-page":"381","DOI":"10.4103\/0253-7176.108226","article-title":"Psychiatric Manifestations in a patient with HIV-associated neurocognitive symptoms and cryptococcal meningitis","volume":"34","author":"Holikatti","year":"2012","journal-title":"Indian J Psychol Med"},{"key":"2020111110131433400_bib29","first-page":"200","article-title":"Mania with cryptococcal meningitis in two AIDS patients","volume":"49","author":"Johannessen","year":"1988","journal-title":"J Clin Psychiatry"},{"key":"2020111110131433400_bib30","doi-asserted-by":"crossref","first-page":"301 e1\u20132","DOI":"10.1016\/j.genhosppsych.2010.11.002","article-title":"Secondary mania associated with enterococcal meningitis in an elderly patient","volume":"33","author":"Liang","year":"2011","journal-title":"Gen Hosp Psychiatry"},{"key":"2020111110131433400_bib31","first-page":"301 e3\u20136","article-title":"A case of mania due to cryptococcal meningitis, successfully treated with adjunctive olanzapine, in a patient with acquired immunodeficiency syndrome","volume":"33","author":"Spiegel","year":"2011","journal-title":"Gen Hosp Psychiatry"},{"key":"2020111110131433400_bib32","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.genhosppsych.2005.03.003","article-title":"Cryptococcal meningitis mimicking primary mania in a young female","volume":"27","author":"Tang","year":"2005","journal-title":"Gen Hosp Psychiatry"},{"key":"2020111110131433400_bib33","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1056\/NEJMoa1312884","article-title":"Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis","volume":"370","author":"Boulware","year":"2014","journal-title":"N Engl J Med"},{"key":"2020111110131433400_bib34","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1093\/cid\/ciy817","article-title":"Symptomatic cryptococcal antigenemia presenting as early cryptococcal meningitis with negative cerebral spinal fluid analysis","volume":"68","author":"Ssebambulidde","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2020111110131433400_bib35","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.chom.2016.05.001","article-title":"Intracellular action of a secreted peptide required for fungal virulence","volume":"19","author":"Homer","year":"2016","journal-title":"Cell Host Microbe"},{"key":"2020111110131433400_bib36","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jbior.2017.09.007","article-title":"Microbial inositol polyphosphate metabolic pathway as drug development target","volume":"67","author":"Saiardi","year":"2018","journal-title":"Adv Biol Regul"},{"key":"2020111110131433400_bib37","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1038\/npp.2015.57","article-title":"Evaluation of myo-inositol as a potential biomarker for depression in schizophrenia","volume":"40","author":"Chiappelli","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"2020111110131433400_bib38","doi-asserted-by":"crossref","first-page":"11651","DOI":"10.1073\/pnas.91.24.11651","article-title":"Elevated dopa decarboxylase activity in living brain of patients with psychosis","volume":"91","author":"Reith","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020111110131433400_bib39","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/cid\/ciy1024","article-title":"Detection of Cryptococcus DNA by metagenomic next-generation sequencing in symptomatic cryptococcal antigenemia","volume":"68","author":"Ramachandran","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2020111110131433400_bib40","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1758-2652-15-15","article-title":"Prevalence and factors associated with cryptococcal antigenemia among severely immunosuppressed HIV-infected adults in Uganda: a cross-sectional study","volume":"15","author":"Oyella","year":"2012","journal-title":"J Int AIDS Soc"},{"key":"2020111110131433400_bib41","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1093\/cid\/ciz037","article-title":"New FDA approvals decrease generic flucytosine costs","volume":"69","author":"Rajasingham","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2020111110131433400_bib42","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1093\/cid\/ciz040","article-title":"Reply to Rajasingham and Boulware","volume":"69","author":"Jarvis","year":"2019","journal-title":"Clin Infect Dis"}],"container-title":["Medical Mycology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/mmy\/article-pdf\/58\/8\/1037\/34245475\/myaa033.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/mmy\/article-pdf\/58\/8\/1037\/34245475\/myaa033.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T15:18:22Z","timestamp":1605107902000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mmy\/article\/58\/8\/1037\/5838059"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,16]]},"references-count":42,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,5,16]]},"published-print":{"date-parts":[[2020,11,10]]}},"URL":"https:\/\/doi.org\/10.1093\/mmy\/myaa033","relation":{},"ISSN":["1369-3786","1460-2709"],"issn-type":[{"value":"1369-3786","type":"print"},{"value":"1460-2709","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,11]]},"published":{"date-parts":[[2020,5,16]]}}}