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A double-blind, placebo-controlled trial tested whether d-cycloserine (DCS), a partial NMDAR agonist, enhances single-day accelerated intermittent theta-burst stimulation (iTBS) in 30 participants with major depressive disorder. Participants received 250 mg DCS or placebo before 10 iTBS sessions. Motor-evoked potentials were measured after each session and depressive severity assessed with PHQ-9 and QIDS-SR16 before and one week after treatment. Results showed no group-dependent plasticity after iTBS and only time-related clinical improvement on QIDS-SR16.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/accelerated-transcranial-magnetic-stimulation-tms-with-d-cycloserine-augmentation-for-depression-a-placebo-controlled-trial/454648/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/accelerated-transcranial-magnetic-stimulation-tms-with-d-cycloserine-augmentation-for-depression-a-placebo-controlled-trial/454648.png","ImageObject",300,407,{"name":92,"@type":93},"Melati","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What was the main purpose of the trial?","Question",{"text":113,"@type":114},"To determine whether d-cycloserine augmentation could enhance single-day accelerated iTBS for major depressive disorder compared with placebo.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How was the iTBS treatment delivered in the study?",{"text":118,"@type":114},"Participants received 10 iTBS treatments on a single day, with 1,800 pulses per treatment, delivered hourly to the left dorsolateral prefrontal cortex.",{"name":120,"@type":111,"acceptedAnswer":121},"What did the study find regarding brain plasticity after treatment?",{"text":122,"@type":114},"Post-iTBS measures did not show a significant Group × Treatment interaction, indicating no differential plasticity response between DCS and placebo.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},454648,1790790969,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":31,"preview_page_count":4},962085570644,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","McLean Hospital [https://orcid.org/0009-0001-7078-693X](https://orcid.org/0009-0001-7078-693X)  \nMcLean Hospital  \nMcLean Hospital  \n[https://orcid.org/0000-0003-1](https://orcid.org/0000-0003-1)133-3428  \nUniversity of Calgary [https://orcid.org/0000-0002-8425-3958](https://orcid.org/0000-0002-8425-3958)  \nMcLean Hospital [https://orcid.org/0000-0003-0887-2746](https://orcid.org/0000-0003-0887-2746)  \nDecember 11th, 2025  \n [https://doi.org/10.21203/rs.3.rs-7980692/v1](https://doi.org/10.21203/rs.3.rs-7980692/v1)  \n 􀁱 􀅏 This work is licensed under a Creative Commons Attribution 4.0 International License.  \nRead Full License  \n Research reported in this publication was supported by the Brain & Behavior Research Foundation Young Investigator Grant (\\#31748) . JCB is supported by the Cindy & Paul Gamble Fund, the Marlene Zuckerman Fund, the McLean Hospital Center of Excellence in Depression and Anxiety Disorders, the NIH (R01MH1389697), and the Department of Defense Advanced Research Projects Agency (HR00112320037) . The views, opinions and/or «ndings expressed are those of the author and  \nshould not be interpreted as representing the o cial views or policies of the National Institutes of Health, the Department of Defense, or the U.S. Government. JCB receives «nancial support as an editorial stipend from Elsevier. AM is a founder of MCGRx Corp and is listed as an inventor on patent 63/193,643 pertaining to the use of D-Cycloserine as an adjunct to transcranial magnetic stimulation for the treatment of Major Depressive Disorder.  \nAccelerated transcranial magnetic stimulation (TMS) protocols have the potential to rapidly treat depression, yet the synaptic mechanisms underlying these intensive interventions remain poorly understood. d-cycloserine (DCS), a partial NMDAR agonist, enhances TMS-induced corticomotor plasticity and conventional daily TMS outcomes, but its effects on accelerated protocols are unknown. We conducted a double-blind placebo-controlled trial examining whether DCS could enhance single-day accelerated intermittent theta-burst stimulation (iTBS) in 30 participants with major depressive disorder. Participants received either 250 mg DCS or placebo the night before undergoing 10 iTBS treatments (1 800 pulses/treatment) delivered hourly to the left dorsolateral prefrontal cortex. Motor-evoked potentials (MEPs) were recorded before and after each treatment to assess corticomotor excitability, while depression severity was measured at baseline and one-week post-treatment using PHQ-9 and QIDSSR16 scales. Normalized MEP amplitudes were analyzed using separate generalized linear mixed models for pre-and post-iTBS measurements, revealing a signi«cant Group × Treatment interaction in only the pre-iTBS data (χ² = 4. 19, p = .041), with placebo showing increasing trajectories and dcycloserine remaining stable. However, post-iTBS measurements showed no Group × Treatment interaction (χ² = 0.92, p = .338), indicating no differential plasticity responses. Clinical outcomes showed improvement over time on QIDS-SR16 (p = .047) but not PHQ-9 (p = .206), with no between-group differences on either scale (PHQ-9: p = . 112; QIDS: p = .286) . These «ndings suggest that high-intensity accelerated protocols may reach a plasticity ceiling that occludes further synaptic enhancement with NMDAR agonism, highlighting the importance of parameter optimization for pharmacologicallyaugmented accelerated TMS.  \nRapid and robust clinical improvements, as the ultimate aim of transcranial magnetic stimulation (TMS) research, are most likely to be attained through its underlying mechanisms of action 1 and optimization of TMS parameter space 2. Recent advances in noninvasive brain stimulation protocols and pharmacological augmentation are steps towards bringing this objective within reach 3–5.  \nTwo major innovations in the «eld of TMS have taken notable steps toward this goal. First, recent accelerated protocols, which deliver more than one treatment","cbCaic6Ncnx0OTx6","https://ap.wps.com/l/cbCaic6Ncnx0OTx6","pdf",1758914,"English","# Background\n## Accelerated TMS and pharmacological augmentation\n# Methods\n## Study design and participants\n## iTBS protocol and dosing\n## Outcome measures\n# Results\n## Corticomotor excitability\n## Clinical symptom outcomes\n# Discussion\n## Plasticity ceiling and parameter optimization","[{\"question\":\"What was the main purpose of the trial?\",\"answer\":\"To determine whether d-cycloserine augmentation could enhance single-day accelerated iTBS for major depressive disorder compared with placebo.\"},{\"question\":\"How was the iTBS treatment delivered in the study?\",\"answer\":\"Participants received 10 iTBS treatments on a single day, with 1,800 pulses per treatment, delivered hourly to the left dorsolateral prefrontal cortex.\"},{\"question\":\"What did the study find regarding brain plasticity after treatment?\",\"answer\":\"Post-iTBS measures did not show a significant Group × Treatment interaction, indicating no differential plasticity response between DCS and placebo.\"}]","Accelerated transcranial magnetic stimulation (TMS) with D-cycloserine augmentation for depression - a placebo-controlled trial | PDF",1790741060]