Allopregnanolone (Zuranolone) in Post-stroke Depression

Summary

The goal of this Phase II clinical trial is to learn if the oral synthetic allopreganolone analog (zuranolone) is safe to take and is well tolerated by stroke survivors experiencing moderate to severe post-stroke depression and if it will help with the symptoms of depression. The main questions it will aim to answer are: * Is zuranolone safe to take by participants who have moderate to severe post-stroke depression? * Is zuranolone well-tolerated by participants who have moderate to severe post-stroke depression? * Does zuranolone treat moderate to severe post-stroke depression? The study will enroll six participants. All participants will be given 50 mg of zuranolone for 14 days. Participants will be asked to provide blood samples, complete some questionnaires including those related to mood and a cognitive assessment.

Timeline

Start

2026-01-14

Primary completion

2026-06-30

Completion

2026-06-30

Publications

• Background Wang S, Zhang W, Liu Z, Zhang T, Wang Y, Li W. Efficacy and safety of zuranolone in the treatment of major depressive disorder: a meta-analysis. Front Neurosci. 2024 Jan 16;17:1332329. doi: 10.3389/fnins.2023.1332329. eCollection 2023.
• Background Clayton AH, Lasser R, Parikh SV, Iosifescu DV, Jung J, Kotecha M, Forrestal F, Jonas J, Kanes SJ, Doherty J. Zuranolone for the Treatment of Adults With Major Depressive Disorder: A Randomized, Placebo-Controlled Phase 3 Trial. Am J Psychiatry. 2023 Sep 1;180(9):676-684. doi: 10.1176/appi.ajp.20220459. Epub 2023 May 3.
• Background Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, Doherty J, Jonas J, Li S, Sankoh AJ, Silber C, Campbell AD, Werneburg B, Kanes SJ, Lasser R. Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2021 Sep 1;78(9):951-959. doi: 10.1001/jamapsychiatry.2021.1559.
• Background Sripada RK, Marx CE, King AP, Rampton JC, Ho SS, Liberzon I. Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits. Biol Psychiatry. 2013 Jun 1;73(11):1045-53. doi: 10.1016/j.biopsych.2012.12.008. Epub 2013 Jan 21.
• Background Chen S, Gao L, Li X, Ye Y. Allopregnanolone in mood disorders: Mechanism and therapeutic development. Pharmacol Res. 2021 Jul;169:105682. doi: 10.1016/j.phrs.2021.105682. Epub 2021 May 18.
• Background Pinna G, Almeida FB, Davis JM. Allopregnanolone in Postpartum Depression. Front Glob Womens Health. 2022 Apr 26;3:823616. doi: 10.3389/fgwh.2022.823616. eCollection 2022.
• Background Diviccaro S, Cioffi L, Falvo E, Giatti S, Melcangi RC. Allopregnanolone: An overview on its synthesis and effects. J Neuroendocrinol. 2022 Feb;34(2):e12996. doi: 10.1111/jne.12996. Epub 2021 Jun 29.
• Background Chen S, Wang T, Yao J, Brinton RD. Allopregnanolone Promotes Neuronal and Oligodendrocyte Differentiation In Vitro and In Vivo: Therapeutic Implication for Alzheimer's Disease. Neurotherapeutics. 2020 Oct;17(4):1813-1824. doi: 10.1007/s13311-020-00874-x.
• Background Dymm B, Goldstein LB, Unnithan S, Al-Khalidi HR, Koltai D, Bushnell C, Husseini NE. Depression following small vessel stroke is common and more prevalent in women. J Stroke Cerebrovasc Dis. 2024 May;33(5):107646. doi: 10.1016/j.jstrokecerebrovasdis.2024.107646. Epub 2024 Feb 22.
• Background El Husseini N, Goldstein LB, Peterson ED, Zhao X, Olson DM, Williams JW Jr, Bushnell C, Laskowitz DT. Depression Status Is Associated with Functional Decline Over 1-Year Following Acute Stroke. J Stroke Cerebrovasc Dis. 2017 Jul;26(7):1393-1399. doi: 10.1016/j.jstrokecerebrovasdis.2017.03.026. Epub 2017 Apr 25.
• Background Redmond C, Bushnell C, Duncan P, D'Agostino R Jr, Ambrosius WT, Bishop L, Gesell S, Prvu-Bettger J, El Husseini N. Association of in-hospital depression and anxiety symptoms following stroke with 3 months- depression, anxiety and functional outcome. J Clin Neurosci. 2022 Apr;98:133-136. doi: 10.1016/j.jocn.2022.02.010. Epub 2022 Feb 15.
• Background El Husseini N, Goldstein LB, Peterson ED, Zhao X, Pan W, Olson DM, Zimmer LO, Williams JW Jr, Bushnell C, Laskowitz DT. Depression and antidepressant use after stroke and transient ischemic attack. Stroke. 2012 Jun;43(6):1609-16. doi: 10.1161/STROKEAHA.111.643130. Epub 2012 Mar 29.
• Background Schottke H, Giabbiconi CM. Post-stroke depression and post-stroke anxiety: prevalence and predictors. Int Psychogeriatr. 2015 Nov;27(11):1805-12. doi: 10.1017/S1041610215000988. Epub 2015 Jul 16.
• Background Xu J, Zhou Y, Yan C, Wang X, Lou J, Luo Y, Gao S, Wang J, Wu L, Gao X, Shao A. Neurosteroids: A novel promise for the treatment of stroke and post-stroke complications. J Neurochem. 2022 Jan;160(1):113-127. doi: 10.1111/jnc.15503. Epub 2021 Sep 21.
• Background Ishrat T, Sayeed I, Atif F, Hua F, Stein DG. Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases. Exp Neurol. 2010 Nov;226(1):183-90. doi: 10.1016/j.expneurol.2010.08.023. Epub 2010 Sep 15.
• Background Rauch SAM, Sripada R, Burton M, Michopoulos V, Kerley K, Marx CE, Kilts JD, Naylor JC, Rothbaum BO, McLean CP, Smith A, Norrholm SD, Jovanovic T, Liberzon I, Williamson DE, Yarvis CJS, Dondanville KA, Young-McCaughan S, Keane TM, Peterson AL; Consortium to Alleviate PTSD and the STRONG STAR Consortium. Neuroendocrine biomarkers of prolonged exposure treatment response in military-related PTSD. Psychoneuroendocrinology. 2020 Sep;119:104749. doi: 10.1016/j.psyneuen.2020.104749. Epub 2020 Jun 8.
• Background Kinzel P, Marx CE, Sollmann N, Hartl E, Guenette JP, Kaufmann D, Bouix S, Pasternak O, Rathi Y, Coleman MJ, van der Kouwe A, Helmer K, Kilts JD, Naylor JC, Morey RA, Shutter L, Andaluz N, Coimbra R, Lang AJ, George MS, McAllister TW, Zafonte R, Stein MB, Shenton ME, Koerte IK. Serum Neurosteroid Levels Are Associated With Cortical Thickness in Individuals Diagnosed With Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury. Clin EEG Neurosci. 2020 Jul;51(4):285-299. doi: 10.1177/1550059420909676. Epub 2020 Mar 18.
• Background Umminger LF, Rojczyk P, Seitz-Holland J, Sollmann N, Kaufmann E, Kinzel P, Zhang F, Kochsiek J, Langhein M, Kim CL, Wiegand TLT, Kilts JD, Naylor JC, Grant GA, Rathi Y, Coleman MJ, Bouix S, Tripodis Y, Pasternak O, George MS, McAllister TW, Zafonte R, Stein MB, O'Donnell LJ, Marx CE, Shenton ME, Koerte IK. White Matter Microstructure Is Associated with Serum Neuroactive Steroids and Psychological Functioning. J Neurotrauma. 2023 Apr;40(7-8):649-664. doi: 10.1089/neu.2022.0111. Epub 2023 Jan 6.
• Background Pibiri F, Nelson M, Guidotti A, Costa E, Pinna G. Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder. Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5567-72. doi: 10.1073/pnas.0801853105. Epub 2008 Apr 7.
• Background Pisu MG, Garau A, Olla P, Biggio F, Utzeri C, Dore R, Serra M. Altered stress responsiveness and hypothalamic-pituitary-adrenal axis function in male rat offspring of socially isolated parents. J Neurochem. 2013 Aug;126(4):493-502. doi: 10.1111/jnc.12273. Epub 2013 May 9.
• Background Almeida FB, Nin MS, Barros HMT. The role of allopregnanolone in depressive-like behaviors: Focus on neurotrophic proteins. Neurobiol Stress. 2020 Apr 9;12:100218. doi: 10.1016/j.ynstr.2020.100218. eCollection 2020 May.
• Background Hellgren C, Akerud H, Skalkidou A, Backstrom T, Sundstrom-Poromaa I. Low serum allopregnanolone is associated with symptoms of depression in late pregnancy. Neuropsychobiology. 2014;69(3):147-53. doi: 10.1159/000358838. Epub 2014 Apr 26.
• Background Osborne LM, Gispen F, Sanyal A, Yenokyan G, Meilman S, Payne JL. Lower allopregnanolone during pregnancy predicts postpartum depression: An exploratory study. Psychoneuroendocrinology. 2017 May;79:116-121. doi: 10.1016/j.psyneuen.2017.02.012. Epub 2017 Feb 16.
• Background He J, Evans CO, Hoffman SW, Oyesiku NM, Stein DG. Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury. Exp Neurol. 2004 Oct;189(2):404-12. doi: 10.1016/j.expneurol.2004.06.008.
• Background Xilouri M, Papazafiri P. Anti-apoptotic effects of allopregnanolone on P19 neurons. Eur J Neurosci. 2006 Jan;23(1):43-54. doi: 10.1111/j.1460-9568.2005.04548.x.
• Background Paul SM, Pinna G, Guidotti A. Allopregnanolone: From molecular pathophysiology to therapeutics. A historical perspective. Neurobiol Stress. 2020 Mar 14;12:100215. doi: 10.1016/j.ynstr.2020.100215. eCollection 2020 May.
• Background Schule C, Nothdurfter C, Rupprecht R. The role of allopregnanolone in depression and anxiety. Prog Neurobiol. 2014 Feb;113:79-87. doi: 10.1016/j.pneurobio.2013.09.003. Epub 2013 Nov 8.
• Background Wang M. Neurosteroids and GABA-A Receptor Function. Front Endocrinol (Lausanne). 2011 Oct 4;2:44. doi: 10.3389/fendo.2011.00044. eCollection 2011.
• Background El Husseini N, Laskowitz DT. The role of neuroendocrine pathways in prognosis after stroke. Expert Rev Neurother. 2014 Feb;14(2):217-32. doi: 10.1586/14737175.2014.877841. Epub 2014 Jan 13.
• Background Towfighi A, Ovbiagele B, El Husseini N, Hackett ML, Jorge RE, Kissela BM, Mitchell PH, Skolarus LE, Whooley MA, Williams LS; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Poststroke Depression: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2017 Feb;48(2):e30-e43. doi: 10.1161/STR.0000000000000113. Epub 2016 Dec 8.

Drugs

Indications

No indication recorded.