Acute and chronic dosing of the GABA A alpha 2,3 selective agonist BAER-101 do not alter behavior but may impact auditory-evoked EEG responses in adults with fragile X syndrome

Acute and chronic dosing of the GABA A alpha 2,3 selective agonist BAER-101 do not alter behavior but may impact auditory-evoked EEG responses in adults with fragile X syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Acute and chronic dosing of the GABA A alpha 2,3 selective agonist BAER-101 do not alter behavior but may impact auditory-evoked EEG responses in adults with fragile X syndrome Lisa DeStefano, Hyeonseok Kim, Craig Erickson, Ernest Pedapati, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8123031/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Apr, 2026 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Background: Fragile X syndrome (FXS) is characterized by sensory hypersensitivity and neural hyperexcitability linked to GABAergic dysfunction. BAER-101, formerly known as AZD7325, is a positive allosteric modulator of GABA A receptors with functional selectivity for α2/α3 subunits, designed to enhance inhibitory tone while minimizing sedation associated with α1 activation. Methods: This study evaluated the acute and chronic effects of BAER-101 on behavioral and electrophysiological outcomes in individuals with FXS. The study employed a within-subject 3 × 2 factorial design, with three dosing conditions (Low Dose: 5 mg; High Dose: 15 mg; Placebo, all twice a day) and two time factors (Acute: same-day pre-/post-dose comparison; Chronic: after two weeks of consecutive dosing). Behavioral endpoints included clinician- and parent-rated symptom severity and laboratory measures of attention and memory, while electrophysiological endpoints comprised resting-state and auditory-evoked scalp-recorded 128-channel EEG metrics including bandpower, inter-trial coherence, and event-related potentials. Results: Behavioral results showed limited evidence for improvements: across tasks, most effects were nonsignificant, with only marginal dose-related trends. The isolated findings lacked consistency or dose-dependence and are likely attributable to random variation. Test–retest reliability of behavioral measures was generally lower than published estimates (ICC ≈ 0.4–0.75), suggesting that measurement noise and small sample size may have obscured true drug effects. EEG spectral power analysis showed significant drug × time interactions, but follow-up comparisons did not support consistent pre-/post-drug changes, suggesting these effects reflected noise rather than drug response. ERP analyses indicated small, nonsystematic reductions in amplitude of onset-evoked potentials during chirp and habituation paradigms following BAER-101 treatment, without clear dose dependency. Test–retest reliability for EEG measures was lower than previously reported, with intraclass correlation coefficients ≈ 0.6 relative to prior work. Conclusions: Overall, no robust behavioral or electrophysiological improvements were observed with BAER-101 at the tested doses and durations. Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience Fragile X Syndrome GABA EEG biomarkers neurophysiology clinical trial Full Text Additional Declarations Competing interest reported. Dr. Erickson is an inventor on a parent held by the Cincinnati Children's Research Foundation describing the method of use of BAER-101 (previously AZD7325) in fragile X syndrome. Cite Share Download PDF Status: Published Journal Publication published 01 Apr, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 25 Dec, 2025 Reviews received at journal 24 Dec, 2025 Reviews received at journal 23 Dec, 2025 Reviews received at journal 20 Dec, 2025 Reviewers agreed at journal 15 Dec, 2025 Reviewers agreed at journal 14 Dec, 2025 Reviewers agreed at journal 12 Dec, 2025 Reviewers invited by journal 11 Dec, 2025 Editor assigned by journal 11 Dec, 2025 Editor invited by journal 08 Dec, 2025 Submission checks completed at journal 01 Dec, 2025 First submitted to journal 01 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8123031","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":560761622,"identity":"57f9df92-125e-4153-8f47-26b2d93b9ad6","order_by":0,"name":"Lisa DeStefano","email":"","orcid":"","institution":"Cincinnati Children's Hospital Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"DeStefano","suffix":""},{"id":560761624,"identity":"60cf85db-9757-48df-9370-02db239ecd4d","order_by":1,"name":"Hyeonseok Kim","email":"","orcid":"","institution":"Cincinnati Children's Hospital Medical 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Dr. Erickson is an inventor on a parent held by the Cincinnati Children's Research Foundation describing the method of use of BAER-101 (previously AZD7325) in fragile X syndrome.","formattedTitle":"Acute and chronic dosing of the GABA A alpha 2,3 selective agonist BAER-101 do not alter behavior but may impact auditory-evoked EEG responses in adults with fragile X syndrome","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Fragile X Syndrome, GABA, EEG biomarkers, neurophysiology, clinical trial","lastPublishedDoi":"10.21203/rs.3.rs-8123031/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8123031/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eFragile X syndrome (FXS) is characterized by sensory hypersensitivity and neural hyperexcitability linked to GABAergic dysfunction. BAER-101, formerly known as AZD7325, is a positive allosteric modulator of GABA\u003csub\u003eA\u003c/sub\u003e receptors with functional selectivity for α2/α3 subunits, designed to enhance inhibitory tone while minimizing sedation associated with α1 activation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis study evaluated the acute and chronic effects of BAER-101 on behavioral and electrophysiological outcomes in individuals with FXS. The study employed a within-subject 3 × 2 factorial design, with three dosing conditions (Low Dose: 5 mg; High Dose: 15 mg; Placebo, all twice a day) and two time factors (Acute: same-day pre-/post-dose comparison; Chronic: after two weeks of consecutive dosing). Behavioral endpoints included clinician- and parent-rated symptom severity and laboratory measures of attention and memory, while electrophysiological endpoints comprised resting-state and auditory-evoked scalp-recorded 128-channel EEG metrics including bandpower, inter-trial coherence, and event-related potentials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eBehavioral results showed limited evidence for improvements: across tasks, most effects were nonsignificant, with only marginal dose-related trends. The isolated findings lacked consistency or dose-dependence and are likely attributable to random variation. Test–retest reliability of behavioral measures was generally lower than published estimates (ICC ≈ 0.4–0.75), suggesting that measurement noise and small sample size may have obscured true drug effects. EEG spectral power analysis showed significant drug × time interactions, but follow-up comparisons did not support consistent pre-/post-drug changes, suggesting these effects reflected noise rather than drug response. ERP analyses indicated small, nonsystematic reductions in amplitude of onset-evoked potentials during chirp and habituation paradigms following BAER-101 treatment, without clear dose dependency. Test–retest reliability for EEG measures was lower than previously reported, with intraclass correlation coefficients ≈ 0.6 relative to prior work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eOverall, no robust behavioral or electrophysiological improvements were observed with BAER-101 at the tested doses and durations.\u003c/p\u003e","manuscriptTitle":"Acute and chronic dosing of the GABA A alpha 2,3 selective agonist BAER-101 do not alter behavior but may impact auditory-evoked EEG responses in adults with fragile X syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-16 16:32:19","doi":"10.21203/rs.3.rs-8123031/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-25T06:07:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-24T15:09:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-23T08:41:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-21T03:28:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25886653835236623922839276101852927469","date":"2025-12-15T09:13:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9846152600624937596682546754729810457","date":"2025-12-15T02:01:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"232609770067823914122494490438892842518","date":"2025-12-12T14:15:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-11T12:14:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-11T12:07:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-08T15:08:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-01T16:08:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-12-01T15:41:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f3c353bf-cb3c-4f6f-8987-f022b3517f3b","owner":[],"postedDate":"December 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":59702212,"name":"Health sciences/Medical research"},{"id":59702213,"name":"Health sciences/Neurology"},{"id":59702214,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-04-07T16:00:56+00:00","versionOfRecord":{"articleIdentity":"rs-8123031","link":"https://doi.org/10.1038/s41598-026-44380-0","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-04-01 15:58:02","publishedOnDateReadable":"April 1st, 2026"},"versionCreatedAt":"2025-12-16 16:32:19","video":"","vorDoi":"10.1038/s41598-026-44380-0","vorDoiUrl":"https://doi.org/10.1038/s41598-026-44380-0","workflowStages":[]},"version":"v1","identity":"rs-8123031","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8123031","identity":"rs-8123031","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}