{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T22:42:42Z","timestamp":1773268962863,"version":"3.50.1"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007051","name":"Uppsala University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007051","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Psychopharmacology"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Monoamine triple reuptake inhibitors (TRIs) inhibit central dopamine, norepinephrine, and serotonin transporters, restoring functional monoamine neurotransmission.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This clinical trial evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after single-ascending-doses (SAD) of the novel monoamine TRI CSTI-500. In addition, we estimated the peak and duration of striatal serotonin transporter (SERT) and dopamine transporter (DAT) occupancies, by using positron emission tomography (PET).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Part A was a double-blinded, randomized, placebo-controlled, sequential SAD study with seven sequential dose panels (0.5-150 mg) where subjects in each panel received either a single oral dose of CSTI-500 (\n                      <jats:italic>n=<\/jats:italic>\n                      6) or placebo (\n                      <jats:italic>n=<\/jats:italic>\n                      2). Part B was an open-label, single-dose PET study to assess the peak and duration of SERT (\n                      <jats:italic>n=<\/jats:italic>\n                      4) and DAT (\n                      <jats:italic>n=<\/jats:italic>\n                      5) striatal occupancies, using the radioligands [\n                      <jats:sup>11<\/jats:sup>\n                      C]MADAM and [\n                      <jats:sup>11<\/jats:sup>\n                      C]PE2I, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The maximum tolerable acute single-dose of CSTI-500 was determined as 100 mg. No serious adverse events occurred. The median maximum CSTI-500 concentrations were attained at 1-2 hours post-dose (h pd); the estimated plasma elimination half-life was 44-50 h pd. Subsequent to a single-dose of 100 mg CSTI-500, mean striatal SERT occupancy was 72% and 62% at 4-6 and 24 h pd, respectively. Mean striatal DAT occupancy was 36% and 31% at 4-9 and 24 h pd, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CSTI-500 is a potent monoamine TRI with substantial striatal SERT and moderate DAT occupancies in healthy subjects. Together with promising safety-tolerability and pharmacokinetics profiles, the continued clinical development of CSTI-500 is strongly supported.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00213-025-06861-4","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T01:14:03Z","timestamp":1754874843000},"page":"565-580","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ascending single-dose study of the safety, pharmacokinetics, and pharmacodynamics of CSTI-500, a novel monoamine triple reuptake inhibitor, first-in-human"],"prefix":"10.1007","volume":"243","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9933-4137","authenticated-orcid":false,"given":"Lieuwe","family":"Appel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Risinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anders","family":"Wall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harald","family":"Murck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gunnar","family":"Antoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger","family":"Lane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"6861_CR1","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1097\/JCP.0000000000001575","volume":"42","author":"LA Adler","year":"2022","unstructured":"Adler LA, Adams J, Madera-McDonough J, Kohegyi E, Hobart M, Chang D, Angelicola M, McQuade R, Liebowitz M (2022) Efficacy, safety, and tolerability of centanafadine sustained-release tablets in adults with attention-deficit\/hyperactivity disorder: results of 2 phase 3, randomized, double-blind, multicenter, placebo-controlled trials. J Clin Psychopharmacol 42:429\u2013439. https:\/\/doi.org\/10.1097\/JCP.0000000000001575","journal-title":"J Clin Psychopharmacol"},{"key":"6861_CR2","doi-asserted-by":"publisher","first-page":"7874","DOI":"10.1021\/jm5006463","volume":"57","author":"A Anighoro","year":"2014","unstructured":"Anighoro A, Bajorath J, Rastelli G (2014) Polypharmacology: challenges and opportunities in drug discovery. J Med Chem 57:7874\u20137887. https:\/\/doi.org\/10.1021\/jm5006463","journal-title":"J Med Chem"},{"key":"6861_CR3","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.euroneuro.2013.10.007","volume":"24","author":"L Appel","year":"2014","unstructured":"Appel L, Bergstr\u00f6m M, Buus Lassen J, L\u00e5ngstr\u00f6m B (2014) Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: dopamine transporter occupancy as measured by PET. Eur Neuropsychopharmacol 24:251\u2013261. https:\/\/doi.org\/10.1016\/j.euroneuro.2013.10.007","journal-title":"Eur Neuropsychopharmacol"},{"key":"6861_CR4","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1093\/ijnp\/pyz003","volume":"22","author":"R Arakawa","year":"2019","unstructured":"Arakawa R, Stenkrona P, Takano A, Svensson J, Andersson M, Nag S, Asami Y, Hirano Y, Halldin C, Lundberg J (2019) Venlafaxine ER blocks the norepinephrine transporter in the brain of patients with major depressive disorder: a PET study using [18F]FMeNER-D2. Int J Neuropsychopharmacol 22:278\u2013285. https:\/\/doi.org\/10.1093\/ijnp\/pyz003","journal-title":"Int J Neuropsychopharmacol"},{"key":"6861_CR5","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1016\/S0140-6736(08)61525-1","volume":"372","author":"A Astrup","year":"2008","unstructured":"Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM (2008) Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet 372:1906\u20131913. https:\/\/doi.org\/10.1016\/S0140-6736(08)61525-1","journal-title":"Lancet"},{"key":"6861_CR6","doi-asserted-by":"publisher","first-page":"38022","DOI":"10.18632\/oncotarget.16723","volume":"8","author":"R BayatMokhtari","year":"2017","unstructured":"BayatMokhtari R, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, Yeger H (2017) Combination therapy in combating cancer. Oncotarget 8:38022\u201343. https:\/\/doi.org\/10.18632\/oncotarget.16723","journal-title":"Oncotarget"},{"key":"6861_CR7","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1097\/JCP.0000000000000335","volume":"35","author":"Z Bhagwagar","year":"2015","unstructured":"Bhagwagar Z, Torbeyns A, Hennicken D, Zheng M, Dunlop BW, Mathew SJ, Khan A, Weisler R, Nelson C, Shelton R, Thase ME, Lane R (2015) Assessment of the efficacy and safety of BMS-820836 in patients with treatment-resistant major depression: results from 2 randomized, double-blind studies. J Clin Psychopharmacol 35:454\u2013459. https:\/\/doi.org\/10.1097\/JCP.0000000000000335","journal-title":"J Clin Psychopharmacol"},{"key":"6861_CR8","doi-asserted-by":"publisher","first-page":"153","DOI":"10.3758\/BF03328003","volume":"6","author":"R Buckhout","year":"1966","unstructured":"Buckhout R, Grace T (1966) The effect of food deprivation and expectancy on heart rate. Psychonomic Science 6:153\u2013154. https:\/\/doi.org\/10.3758\/BF03328003","journal-title":"Psychonomic Science"},{"key":"6861_CR9","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1016\/S0022-3565(24)35151-1","volume":"291","author":"S Chalon","year":"1999","unstructured":"Chalon S, Garreau L, Emond P, Zimmer L, Vilar MP, Besnard JC, Guilloteau D (1999) Pharmacological characterization of (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4\u2019-methylphenyl)n ortropane as a selective and potent inhibitor of the neuronal dopamine transporter. J Pharmacol Exp Ther 291:648\u2013654","journal-title":"J Pharmacol Exp Ther"},{"key":"6861_CR10","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1124\/jpet.102.042226","volume":"304","author":"S Chalon","year":"2003","unstructured":"Chalon S, Tarkiainen J, Garreau L, Hall H, Emond P, Vercouillie J, Farde L, Dasse P, Varnas K, Besnard JC, Halldin C, Guilloteau D (2003) Pharmacological characterization of N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine as a ligand of the serotonin transporter with high affinity and selectivity. J Pharmacol Exp Ther 304:81\u201387. https:\/\/doi.org\/10.1124\/jpet.102.042226","journal-title":"J Pharmacol Exp Ther"},{"key":"6861_CR11","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1007\/s00702-020-02180-4","volume":"127","author":"X Chen","year":"2020","unstructured":"Chen X, Kudo T, Lapa C, Buck A, Higuchi T (2020) Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements. J Neural Transm (Vienna) 127:851\u2013873. https:\/\/doi.org\/10.1007\/s00702-020-02180-4","journal-title":"J Neural Transm (Vienna)"},{"key":"6861_CR12","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1176\/appi.focus.16407","volume":"391","author":"A Cipriani","year":"2018","unstructured":"Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika S, Ioannidis JPA, Geddes JR (2018) Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391:1357\u20131366. https:\/\/doi.org\/10.1176\/appi.focus.16407","journal-title":"Lancet"},{"key":"6861_CR13","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1124\/jpet.112.202895","volume":"346","author":"RA Comley","year":"2013","unstructured":"Comley RA, Salinas CA, Slifstein M, Petrone M, Marzano C, Bennacef I, Shotbolt P, Van der Aart J, Neve M, Iavarone L, Gomeni R, Laruelle M, Gray FA, Gunn RN, Rabiner EA (2013) Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and humans using positron emission tomography. J Pharmacol Exp Ther 346:311\u2013317. https:\/\/doi.org\/10.1124\/jpet.112.202895","journal-title":"J Pharmacol Exp Ther"},{"key":"6861_CR14","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1016\/j.amjmed.2015.07.001","volume":"128","author":"L Culpepper","year":"2015","unstructured":"Culpepper L, Muskin PR, Stahl SM (2015) Major depressive disorder: understanding the significance of residual symptoms and balancing efficacy with tolerability. Am J Med 128:S1\u2013S15. https:\/\/doi.org\/10.1016\/j.amjmed.2015.07.001","journal-title":"Am J Med"},{"key":"6861_CR15","doi-asserted-by":"publisher","unstructured":"Cuss F (2015) Francis c Cuss. Nat Rev Drug Discovery 14:672\u2013673. https:\/\/doi.org\/10.1038\/nrd4748","DOI":"10.1038\/nrd4748"},{"key":"6861_CR16","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1002\/ajmg.a.62041","volume":"185","author":"M Deest","year":"2021","unstructured":"Deest M, Jakob MM, Seifert J, Bleich S, Frieling H, Eberlein C (2021) Sertraline as a treatment option for temper outbursts in Prader-Willi syndrome. Am J Med Genet A 185:790\u2013797. https:\/\/doi.org\/10.1002\/ajmg.a.62041","journal-title":"Am J Med Genet A"},{"key":"6861_CR17","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.2967\/jnumed.110.084525","volume":"52","author":"C DeLorenzo","year":"2011","unstructured":"DeLorenzo C, Lichenstein S, Schaefer K, Dunn J, Marshall R, Organisak L, Kharidia J, Robertson B, Mann JJ, Parsey RV (2011) SEP-225289 serotonin and dopamine transporter occupancy: a PET study. J Nucl Med 52:1150\u20131155. https:\/\/doi.org\/10.2967\/jnumed.110.084525","journal-title":"J Nucl Med"},{"key":"6861_CR18","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.1021\/jm960795d","volume":"40","author":"P Emond","year":"1997","unstructured":"Emond P, Garreau L, Chalon S, Boazi M, Caillet M, Bricard J, Frangin Y, Mauclaire L, Besnard JC, Guilloteau D (1997) Synthesis and ligand binding of nortropane derivatives: N-substituted 2beta-carbomethoxy-3beta-(4\u2019-iodophenyl)nortropane and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3\u2019,4\u2019-disubstituted phenyl)nortropane. New high-affinity and selective compounds for the dopamine transporter. J Med Chem 40:1366\u20131372. https:\/\/doi.org\/10.1021\/jm960795d","journal-title":"J Med Chem"},{"key":"6861_CR19","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1159\/000091771","volume":"75","author":"M Fava","year":"2006","unstructured":"Fava M, Rush AJ (2006) Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. Psychother Psychosom 75:139\u2013153. https:\/\/doi.org\/10.1159\/000091771","journal-title":"Psychother Psychosom"},{"key":"6861_CR20","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/s0969-8051(97)00224-2","volume":"25","author":"D Guilloteau","year":"1998","unstructured":"Guilloteau D, Emond P, Baulieu JL, Garreau L, Frangin Y, Pourcelot L, Mauclaire L, Besnard JC, Chalon S (1998) Exploration of the dopamine transporter: in vitro and in vivo characterization of a high-affinity and high-specificity iodinated tropane derivative (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4\u2019-m ethylph enyl)nortropane (PE2I). Nucl Med Biol 25:331\u2013337. https:\/\/doi.org\/10.1016\/s0969-8051(97)00224-2","journal-title":"Nucl Med Biol"},{"key":"6861_CR21","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1006\/nimg.1998.0366","volume":"9","author":"H Hall","year":"1999","unstructured":"Hall H, Halldin C, Guilloteau D, Chalon S, Emond P, Besnard J, Farde L, Sedvall G (1999) Visualization of the dopamine transporter in the human brain postmortem with the new selective ligand [125I]PE2I. Neuroimage 9:108\u2013116. https:\/\/doi.org\/10.1006\/nimg.1998.0366","journal-title":"Neuroimage"},{"key":"6861_CR22","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1007\/s00259-003-1212-3","volume":"30","author":"C Halldin","year":"2003","unstructured":"Halldin C, Erixon-Lindroth N, Pauli S, Chou YH, Okubo Y, Karlsson P, Lundkvist C, Olsson H, Guilloteau D, Emond P, Farde L (2003) [(11)C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain. Eur J Nucl Med Mol Imaging 30:1220\u20131230. https:\/\/doi.org\/10.1007\/s00259-003-1212-3","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"6861_CR23","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1002\/syn.20189","volume":"58","author":"C Halldin","year":"2005","unstructured":"Halldin C, Lundberg J, Sovago J, Gulyas B, Guilloteau D, Vercouillie J, Emond P, Chalon S, Tarkiainen J, Hiltunen J, Farde L (2005) [(11)C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET. Synapse 58:173\u2013183. https:\/\/doi.org\/10.1002\/syn.20189","journal-title":"Synapse"},{"key":"6861_CR24","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1038\/sj.jcbfm.9600607","volume":"28","author":"J Hirvonen","year":"2008","unstructured":"Hirvonen J, Johansson J, Teras M, Oikonen V, Lumme V, Virsu P, Roivainen A, Nagren K, Halldin C, Farde L, Hietala J (2008) Measurement of striatal and extrastriatal dopamine transporter binding with high-resolution PET and [11C]PE2I: quantitative modeling and test-retest reproducibility. J Cereb Blood Flow Metab 28:1059\u20131069. https:\/\/doi.org\/10.1038\/sj.jcbfm.9600607","journal-title":"J Cereb Blood Flow Metab"},{"key":"6861_CR25","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1530\/EJE-21-0972","volume":"186","author":"K Huynh","year":"2022","unstructured":"Huynh K, Klose M, Krogsgaard K, Drejer J, Byberg S, Madsbad S, Magkos F, Aharaz A, Edsberg B, Tfelt-Hansen J, Astrup AV, Feldt-Rasmussen U (2022) Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity. Eur J Endocrinol 186:687\u2013700. https:\/\/doi.org\/10.1530\/EJE-21-0972","journal-title":"Eur J Endocrinol"},{"key":"6861_CR26","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1056\/NEJMoa1003114","volume":"363","author":"WP James","year":"2010","unstructured":"James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL, Investigators S (2010) Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 363:905\u2013917. https:\/\/doi.org\/10.1056\/NEJMoa1003114","journal-title":"N Engl J Med"},{"issue":"3","key":"6861_CR27","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1016\/j.neuroimage.2007.10.016","volume":"39","author":"H Jovanovic","year":"2008","unstructured":"Jovanovic H, Lundberg J, Karlsson P, Cerin A, Saijo T, Varrone A, Halldin C, Nordstr\u00f6m AL (2008) Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET. Neuroimage 39(3):1408\u20131419. https:\/\/doi.org\/10.1016\/j.neuroimage.2007.10.016","journal-title":"Neuroimage"},{"issue":"Suppl 1","key":"6861_CR28","doi-asserted-by":"publisher","first-page":"S11","DOI":"10.1007\/s40263-012-0029-7","volume":"27","author":"M Kato","year":"2013","unstructured":"Kato M, Chang CM (2013) Augmentation treatments with second-generation antipsychotics to antidepressants in treatment-resistant depression. CNS Drugs 27(Suppl 1):S11\u2013S19. https:\/\/doi.org\/10.1007\/s40263-012-0029-7","journal-title":"CNS Drugs"},{"key":"6861_CR29","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1006\/nimg.1996.0066","volume":"4","author":"AA Lammertsma","year":"1996","unstructured":"Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. Neuroimage 4:153\u2013158. https:\/\/doi.org\/10.1006\/nimg.1996.0066","journal-title":"Neuroimage"},{"key":"6861_CR30","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1177\/0269881114532857","volume":"28","author":"RM Lane","year":"2014","unstructured":"Lane RM (2014) Restoration of positive mood states in major depression as a potential drug development target. J Psychopharmacol 28:527\u2013535. https:\/\/doi.org\/10.1177\/0269881114532857","journal-title":"J Psychopharmacol"},{"key":"6861_CR31","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1177\/0269881114553252","volume":"29","author":"RM Lane","year":"2015","unstructured":"Lane RM (2015) Antidepressant drug development: Focus on triple monoamine reuptake inhibition. J Psychopharmacol 29:526\u2013544. https:\/\/doi.org\/10.1177\/0269881114553252","journal-title":"J Psychopharmacol"},{"key":"6861_CR32","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1038\/sj.bjp.0705693","volume":"141","author":"AK Larsen","year":"2004","unstructured":"Larsen AK, Brennum LT, Egebjerg J, S\u00e1nchez C, Halldin C, Andersen PH (2004) Selectivity of (3)H-MADAM binding to 5-hydroxytryptamine transporters in vitro and in vivo in mice; correlation with behavioural effects. Br J Pharmacol 141:1015\u20131023. https:\/\/doi.org\/10.1038\/sj.bjp.0705693","journal-title":"Br J Pharmacol"},{"key":"6861_CR33","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1177\/0269881111424931","volume":"26","author":"S Learned","year":"2012","unstructured":"Learned S, Graff O, Roychowdhury S, Moate R, Krishnan KR, Archer G, Modell JG, Alexander R, Zamuner S, Lavergne A, Evoniuk G, Ratti E (2012) Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials. J Psychopharmacol 26:653\u2013662. https:\/\/doi.org\/10.1177\/0269881111424931","journal-title":"J Psychopharmacol"},{"issue":"6","key":"6861_CR34","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/j.nucmedbio.2007.03.013","volume":"34","author":"J Logan","year":"2007","unstructured":"Logan J, Wang GJ, Telang F, Fowler JS, Alexoff D, Zabroski J, Jayne M, Hubbard B, King P, Carter P, Shea C, Xu Y, Muench L, Schlyer D, Learned-Coughlin S, Cosson V, Volkow ND, Ding YS (2007) Imaging the norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET: problems and progress. Nucl Med Biol 34(6):667\u2013679. https:\/\/doi.org\/10.1016\/j.nucmedbio.2007.03.013","journal-title":"Nucl Med Biol"},{"key":"6861_CR35","first-page":"1505","volume":"46","author":"J Lundberg","year":"2005","unstructured":"Lundberg J, Odano I, Olsson H, Halldin C, Farde L (2005) Quantification of 11C-MADAM binding to the serotonin transporter in the human brain. J Nucl Med 46:1505\u20131515","journal-title":"J Nucl Med"},{"issue":"6","key":"6861_CR36","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1017\/S1461145706007486","volume":"10","author":"J Lundberg","year":"2007","unstructured":"Lundberg J, Christophersen JS, Petersen KB, Loft H, Halldin C, Farde L (2007) PET measurement of serotonin transporter occupancy: a comparison of escitalopram and citalopram. Int J Neuropsychopharmacol 10(6):777\u2013785. https:\/\/doi.org\/10.1017\/S1461145706007486","journal-title":"Int J Neuropsychopharmacol"},{"key":"6861_CR37","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1177\/02698811221140008","volume":"37","author":"D Matuskey","year":"2023","unstructured":"Matuskey D, Gallezot JD, Nabulsi N, Henry S, Torres K, Dias M, Angarita GA, Huang Y, Shoaf SE, Carson RE, Mehrotra S (2023) Neurotransmitter transporter occupancy following administration of centanafadine sustained-release tablets: A phase 1 study in healthy male adults. J Psychopharmacol 37:164\u2013171. https:\/\/doi.org\/10.1177\/02698811221140008","journal-title":"J Psychopharmacol"},{"key":"6861_CR38","doi-asserted-by":"publisher","first-page":"394","DOI":"10.2165\/00023210-199708050-00005","volume":"8","author":"PG McManis","year":"1997","unstructured":"McManis PG, Talley NJ (1997) Nausea and Vomiting Associated With Selective Serotonin Reuptake Inhibitors. CNS Drugs 8:394\u2013401. https:\/\/doi.org\/10.2165\/00023210-199708050-00005","journal-title":"CNS Drugs"},{"key":"6861_CR39","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1176\/appi.ajp.161.5.826","volume":"161","author":"JH Meyer","year":"2004","unstructured":"Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 161:826\u2013835. https:\/\/doi.org\/10.1176\/appi.ajp.161.5.826","journal-title":"Am J Psychiatry"},{"key":"6861_CR40","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.nurt.2008.10.039","volume":"6","author":"MJ Millan","year":"2009","unstructured":"Millan MJ (2009) Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs. Neurotherapeutics 6:53\u201377. https:\/\/doi.org\/10.1016\/j.nurt.2008.10.039","journal-title":"Neurotherapeutics"},{"key":"6861_CR41","first-page":"301","volume":"1","author":"C Moret","year":"2005","unstructured":"Moret C (2005) Combination\/augmentation strategies for improving the treatment of depression. Neuropsychiatr Dis Treat 1:301\u2013309","journal-title":"Neuropsychiatr Dis Treat"},{"key":"6861_CR42","doi-asserted-by":"publisher","first-page":"442","DOI":"10.7916\/D8FJ2V9Q","volume":"7","author":"JC Morgan","year":"2017","unstructured":"Morgan JC, Kurek JA, Davis JL, Sethi KD (2017) Insights into pathophysiology from medication-induced tremor. Tremor Other Hyperkinet Mov 7:442. https:\/\/doi.org\/10.7916\/D8FJ2V9Q","journal-title":"Tremor Other Hyperkinet Mov"},{"issue":"10","key":"6861_CR43","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1016\/j.biopsych.2006.01.008","volume":"59","author":"CA Munro","year":"2006","unstructured":"Munro CA, McCaul MA, Wong DF, Oswald LM, Zhou Y, Brasic J, Kuwabara H, Kumar A, Alexander M, Ye W, Wand GS (2006) Sex differences in striatal dopamine release in healthy adults. Biol Psychiatry 59(10):966\u201374. https:\/\/doi.org\/10.1016\/j.biopsych.2006.01.008","journal-title":"Biol Psychiatry"},{"issue":"2","key":"6861_CR44","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.pscychresns.2011.12.015","volume":"202","author":"AB Newberg","year":"2012","unstructured":"Newberg AB, Amsterdam JD, Wintering N, Shults J (2012) Low brain serotonin transporter binding in major depressive disorder. Psychiatry Res 202(2):161\u2013167. https:\/\/doi.org\/10.1016\/j.pscychresns.2011.12.015","journal-title":"Psychiatry Res"},{"key":"6861_CR45","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1001\/jamapsychiatry.2019.0801","volume":"76","author":"DA Pizzagalli","year":"2019","unstructured":"Pizzagalli DA, Berretta S, Wooten D, Goer F, Pilobello KT, Kumar P, Murray L, Beltzer M, Boyer-Boiteau A, Alpert N, El Fakhri G, Mechawar N, Vitaliano G, Turecki G, Normandin M (2019) Lower striatal dopamine transporter binding in depression: In vivo PET and Postmortem Evidence. JAMA Psychiat 76:854\u2013861. https:\/\/doi.org\/10.1001\/jamapsychiatry.2019.0801","journal-title":"JAMA Psychiat"},{"key":"6861_CR46","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.1007\/s00213-013-3391-3","volume":"231","author":"R Risinger","year":"2014","unstructured":"Risinger R, Bhagwagar Z, Luo F, Cahir M, MilerL MAE, Meyer JH, Zheng M, Hayes W (2014) Evaluation of safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-820836 in healthy subjects: a placebo-controlled, ascending single-dose study. Psychopharmacology 231:2299\u20132310. https:\/\/doi.org\/10.1007\/s00213-013-3391-3","journal-title":"Psychopharmacology"},{"issue":"5","key":"6861_CR47","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1007\/s00259-006-0312-2","volume":"34","author":"AJ Severance","year":"2007","unstructured":"Severance AJ, Milak MS, Kumar JSD, Prabhakaran J, Majo VJ, Simpson NR, Van Heertum RL, Arango V, Mann JJ, Parsey RV (2007) In vivo assessment of [11C]MRB as a prospective PET ligand for imaging the norepinephrine transporter. Eur J Nucl Med Mol Imaging 34(5):688\u2013693. https:\/\/doi.org\/10.1007\/s00259-006-0312-2","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"6861_CR48","doi-asserted-by":"publisher","first-page":"2385","DOI":"10.4155\/fmc.15.134","volume":"7","author":"H Sharma","year":"2015","unstructured":"Sharma H, Santra S, Dutta A (2015) Triple reuptake inhibitors as potential next-generation antidepressants: a new hope? Future Med Chem 7:2385\u20132406. https:\/\/doi.org\/10.4155\/fmc.15.134","journal-title":"Future Med Chem"},{"issue":"11","key":"6861_CR49","doi-asserted-by":"publisher","first-page":"4502","DOI":"10.1038\/s41380-022-01733-1","volume":"27","author":"LR Silberbauer","year":"2022","unstructured":"Silberbauer LR, Rischka L, Vraka C, Hartmann AM, Godbersen GM, Philippe C, Pacher D, Nics L, Kl\u00f6bl M, Unterholzner J, Stimpfl T, Wadsak W, Hahn A, Hacker M, Rujescu D, Kasper S, Lanzenberger R, Gryglewski G (2022) ABCB1 variants and sex affect serotonin transporter occupancy in the brain. Mol Psychiatry 27(11):4502\u20134509. https:\/\/doi.org\/10.1038\/s41380-022-01733-1","journal-title":"Mol Psychiatry"},{"issue":"1","key":"6861_CR50","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/BF03165058","volume":"10","author":"T Suhara","year":"1996","unstructured":"Suhara T, Farde L, Halldin C, N\u00e5gren K, Karlsson P (1996) Effects of cocaine on [11C]norepinephrine and [11C] beta-CIT uptake in the primate peripheral organs measured by PET. Ann Nucl Med 10(1):85\u201388. https:\/\/doi.org\/10.1007\/BF03165058","journal-title":"Ann Nucl Med"},{"key":"6861_CR51","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1038\/npp.2009.182","volume":"35","author":"PS Talbot","year":"2010","unstructured":"Talbot PS, Bradley S, Clarke CP, Babalola KO, Philipp AW, Brown G, McMahon AW, Matthews JC (2010) Brain serotonin transporter occupancy by oral sibutramine dosed to steady state: a PET study using (11)C-DASB in healthy humans. Neuropsychopharmacology 35:741\u2013751. https:\/\/doi.org\/10.1038\/npp.2009.182","journal-title":"Neuropsychopharmacology"},{"key":"6861_CR52","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1002\/jlcr.2580440167","volume":"44","author":"J Tarkiainen","year":"2001","unstructured":"Tarkiainen J, Vercouillie J, Emond P, Sandell J, Hiltunen J, Frangin Y, Guilloteau D, Halldin C (2001) Carbon-11 labelling of MADAM in two different positions: a highly selective PET radioligand for the serotonin transporter. J Labelled Compd Radiopharm 44:1013\u20131023. https:\/\/doi.org\/10.1002\/jlcr.2580440167","journal-title":"J Labelled Compd Radiopharm"},{"key":"6861_CR53","unstructured":"Torok D, Kolouskova S, Walter P, Edsberg B, Dvorak R (2019) Tesomet\u2013 A new treatment opportunity in Prader-Willi Syndrome. In: International Prader-Willi Syndrome Organization Conference, 47. Havana, Cuba. https:\/\/ipwso.org\/wp-content\/uploads\/2020\/11\/IPWSO-10th-International-Conference-booklet.pdf. Accessed 14 June 2024"},{"key":"6861_CR54","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1021\/acschemneuro.1c00127","volume":"12","author":"G Tu","year":"2021","unstructured":"Tu G, Fu T, Yang F, Yang J, Zhang Z, Yao X, Xue W, Zhu F (2021) Understanding the polypharmacological profiles of triple reuptake inhibitors by molecular simulation. ACS Chem Neurosci 12:2013\u20132026. https:\/\/doi.org\/10.1021\/acschemneuro.1c00127","journal-title":"ACS Chem Neurosci"},{"key":"6861_CR55","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.jsmc.2018.02.001","volume":"13","author":"A Van Gastel","year":"2018","unstructured":"Van Gastel A (2018) Drug-induced insomnia and excessive sleepiness. Sleep Med Clin 13:147\u2013159. https:\/\/doi.org\/10.1016\/j.jsmc.2018.02.001","journal-title":"Sleep Med Clin"},{"issue":"2","key":"6861_CR56","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/s00259-012-2276-8","volume":"40","author":"A Varrone","year":"2013","unstructured":"Varrone A, Dickson JC, Tossici-Bolt L, Sera T, Asenbaum S, Booij J, Kapucu OL, Kluge A, Knudsen GM, Koulibaly PM, Nobili F, Pagani M, Sabri O, Vander Borght T, Van Laere K, Tatsch K (2013) European multicentre database of healthy controls for [123I]FP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis. Eur J Nucl Med Mol Imaging 40(2):213\u2013227. https:\/\/doi.org\/10.1007\/s00259-012-2276-8","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"6861_CR57","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1007\/s00213-002-1340-7","volume":"166","author":"ND Volkow","year":"2003","unstructured":"Volkow ND, Wang GJ, Fowler JS, Molina PE, Logan J, Gatley SJ, Gifford A, Ding YS, Wong C, Pappas NR, Zhu W, Swanson JM (2003) Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma. Psychopharmacology 166:264\u2013270. https:\/\/doi.org\/10.1007\/s00213-002-1340-7","journal-title":"Psychopharmacology"},{"key":"6861_CR58","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.2147\/NDT.S242084","volume":"16","author":"SB Wigal","year":"2020","unstructured":"Wigal SB, Wigal T, Hobart M, Madera JJ, Baker RA, Kohegyi E, McKinney A, Wilens TE (2020) Safety and efficacy of centanafadine sustained-release in adults with attention-deficit hyperactivity disorder: results of phase 2 studies. Neuropsychiatr Dis Treat 16:1411\u20131426. https:\/\/doi.org\/10.2147\/NDT.S242084","journal-title":"Neuropsychiatr Dis Treat"},{"key":"6861_CR59","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1007\/s00213-014-3688-x","volume":"232","author":"M Zheng","year":"2015","unstructured":"Zheng M, Appel L, Luo F, Lane R, Burt D, Risinger R, Antoni G, Cahir M, Keswani S, Hayes W, Bhagwagar Z (2015) Safety, pharmacokinetic, and positron emission tomography evaluation of serotonin and dopamine transporter occupancy following multiple-dose administration of the triple monoamine reuptake inhibitor BMS-820836. Psychopharmacology 232:529\u2013540. https:\/\/doi.org\/10.1007\/s00213-014-3688-x","journal-title":"Psychopharmacology"},{"key":"6861_CR60","doi-asserted-by":"publisher","unstructured":"Zhong W, Shahbaz O, Teskey G, Beever A, Kachour N, Venketaraman V, Darmani NA (2021) Mechanisms of nausea and vomiting: current knowledge and recent advances in intracellular emetic signaling systems. Int J Mol Sci 22. https:\/\/doi.org\/10.3390\/ijms22115797","DOI":"10.3390\/ijms22115797"}],"container-title":["Psychopharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00213-025-06861-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00213-025-06861-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00213-025-06861-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T06:56:16Z","timestamp":1773212176000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00213-025-06861-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,11]]},"references-count":60,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["6861"],"URL":"https:\/\/doi.org\/10.1007\/s00213-025-06861-4","relation":{},"ISSN":["0033-3158","1432-2072"],"issn-type":[{"value":"0033-3158","type":"print"},{"value":"1432-2072","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,11]]},"assertion":[{"value":"1 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The Swedish Medical Product Agency, local ethics and radiation safety protection committees approved this study. The conduct of the study followed the ethical principles of the current Declaration of Helsinki, International Conference on Harmonisation for Good Clinical Practice, and applicable regulatory requirements.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All participants provided written informed consent after the nature and possible consequences of the study procedures were explained, and prior to enrollment in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"The participant\u2019s written informed consent covered consent to publish anonymized individual data.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of Bristol-Myers Squibb or ConSynance. Shuang Liu is the founder and an employee of ConSynance Therapeutics, Inc., and owns stocks. Rob Risinger, Harald Murck, and Roger Lane are former employees of Bristol-Myers Squibb. Currently, Roger Lane is an employee of Ionis Pharmaceuticals, Inc., and has stocks. Harald Murck is the owner of Murck-Neuroscience LLC and has developed a patent related to the treatment of refractory major depression. Robert Risinger is a current employee of BioXcel Therapeutics Inc. Lieuwe Appel, Anders Wall, and Gunnar Antoni, former GE Healthcare Uppsala Imanet employees, declare no financial relationships with commercial interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}