{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T18:22:13Z","timestamp":1788200533961,"version":"build-2803163510"},"posted":{"date-parts":[[2025,12,29]]},"group-title":"Psychiatry and Clinical Psychology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["R33MH119237"],"award-info":[{"award-number":["R33MH119237"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>Artificial Intelligence (AI) voice-based chatbots may improve access to evidence-based psychotherapy for depression and anxiety, but their therapeutic mechanisms and outcomes are largely unknown.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To investigate the mechanisms and potential efficacy of Lumen, an AI voice-based coach delivering problem-solving treatment (PST), among adults with untreated, clinically significant depression and\/or anxiety.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>Phase 2, 3-arm randomized clinical trial.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Setting<\/jats:title>\n                  <jats:p>A public university and affiliated medical center in Chicago, Illinois.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Participants<\/jats:title>\n                  <jats:p>Adults with a Patient Health Questionnaire-9 score of 10-19 and\/or a Generalized Anxiety Disorder Scale score of 10-14 were randomized to Lumen-coached PST (n=100), human-coached PST (n=50), or waitlist control (n=50).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interventions<\/jats:title>\n                  <jats:p>PST was delivered in 4 weekly sessions followed by 4 biweekly sessions, by Lumen\u2014a custom-developed, rule-based AI application on Amazon\u2019s Alexa platform\u2014or by a human coach via videoconferencing.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main Outcome(s) and Measure(s)<\/jats:title>\n                  <jats:p>The primary mechanistic outcome was change in right dorsolateral prefrontal cortex (dlPFC) activation for cognitive control, assessed with functional neuroimaging. Secondary outcomes were patient-reported, theory-based behavioral targets (e.g., problem-solving) and clinical symptoms (e.g., psychological distress).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Among 200 participants (mean (SD) age, 36.6 (11.9) years; 77% women; 25% Black American; 28% Latino), change from baseline in right dlPFC activity at 18 weeks did not differ significantly by treatment arm. Compared with waitlist control, Lumen-coached participants had significantly greater improvements from baseline to 18 weeks in overall problem-solving ability (mean difference, 1.04; 95% CI, 0.23\u20141.84]) and psychological distress (mean difference, \u22123.56; 95% CI \u22125.69 to \u22121.43) due to depressive and anxiety symptoms. Lumen- and human-coached PST did not differ significantly on either measure. One serious adverse event (hospitalization), unrelated to this study, was reported.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions and Relevance<\/jats:title>\n                  <jats:p>In this phase 2 experimental-therapeutics RCT, neither AI- nor human-coached PST significantly engaged the prespecified neural target for cognitive control. However, both interventions improved patient-reported problem-solving and psychological distress relative to waitlist control, providing exploratory evidence of a non-neural candidate mechanism and a clinical signal warranting future testing.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Trial Registration<\/jats:title>\n                  <jats:p>\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\">clinicaltrials.gov<\/jats:ext-link>\n                    ,\n                    <jats:underline>NCT05603923<\/jats:underline>\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Question<\/jats:title>\n                    <jats:p>Does Lumen, an Artificial Intelligence (AI) voice-based coach delivering problem-solving treatment (PST) for depression and anxiety, engage a mechanistic neural target for cognitive control (right dorsolateral prefrontal cortex, dlPFC) better than waitlist, and not worse than human-coached PST, and, secondarily, does it improve problem-solving behavior and clinical symptoms?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>In this phase 2, 3-arm experimental-therapeutics randomized trial among 200 adults with untreated, clinically significant depression and\/or anxiety, neither Lumen- nor human-coached PST significantly engaged the neural target versus waitlist control. Both interventions, however, significantly improved secondary outcomes related to patient-reported problem-solving ability and psychological distress due to depressive and anxiety symptoms relative to waitlist control.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Meaning<\/jats:title>\n                    <jats:p>Despite null neural-target findings, Lumen may hold promise as a scalable intervention for improving problem-solving and psychological distress in adults with depression and\/or anxiety.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.22.25342792","type":"posted-content","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T01:15:11Z","timestamp":1767057311000},"source":"Crossref","is-referenced-by-count":0,"title":["Neural, Behavioral, and Clinical Outcomes of a Voice-based AI Coach for Depression and Anxiety: A Phase 2 Randomized Trial"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4119-4836","authenticated-orcid":false,"given":"Thomas","family":"Kannampallil","sequence":"first","affiliation":[{"name":"Department of Anesthesiology"},{"name":"Institute for Informatics, Data Science, and Biostatistics Washington University School of Medicine, St Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olusola A.","family":"Ajilore","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua M.","family":"Smyth","sequence":"additional","affiliation":[{"name":"Department of Psychology The Ohio State University, Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amruta","family":"Barve","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corina R.","family":"Ronneberg","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gbenga","family":"Aborisade","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy E.","family":"Wittels","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengxin","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharathi","family":"Chinnakotla","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Population Health Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026083110351366000_2025.12.22.25342792v4.1","doi-asserted-by":"crossref","unstructured":"Terlizzi EP , Zablotsky B. 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