{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:11:04Z","timestamp":1790334664354,"version":"4.1.0"},"reference-count":99,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Loneliness and depression are widespread and severely debilitating health conditions. Notably, loneliness and depression are closely intertwined, with individuals suffering from depression being particularly vulnerable to loneliness and vice versa. However, little is known regarding the clinical significance of loneliness in the treatment of depression and the biopsychosocial mechanisms underlying this association.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This protocol presents a naturalistic longitudinal study on the clinical significance of loneliness in inpatient and post-inpatient treatment outcomes of adults with depression. The design includes three main assessment points with comprehensive diagnostics (including clinical interviews, questionnaires, and optional biospecimen collection for biomarker and microbiome analyses), as well as interim assessments and the integration of routine clinical data. The primary outcomes include depressive symptom severity and perceived loneliness across the course of treatment and follow-up. Secondary outcomes and covariates are analyzed to identify other clinically relevant indicators, such as life satisfaction and suicidality, and to better understand the biopsychosocial interplay between loneliness and depression. Descriptive and inferential statistical analyses, including (generalized) linear mixed model analyses and mixed analyses of variance (ANOVA), will be conducted following both hypothesis-driven and exploratory approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      By employing a clinical sample and longitudinal design, this study advances the understanding of the role of loneliness in the treatment and maintenance of depression. In addition to evaluating primary outcomes, analyses of secondary outcomes can provide information on shared and distinct biopsychosocial pathways, thereby identifying potential correlates of mental health outcomes that may inform future research. Limitations include the possible inflation of Type I errors in exploratory analyses and potential biases such as selection bias and cognitive distortions in self-reported data. Nevertheless, this study can provide an important foundation for subsequent clinical trials and translational research. This study was prospectively registered at ClinicalTrials.gov on 31\n                      <jats:sup>st<\/jats:sup>\n                      December 2025 before patient enrollment (Identifier: NCT07333027, Study Details | NCT07333027 | Lonely in Depression | ClinicalTrials.gov).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Study Protocol Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/clinicaltrials.gov\/study\/NCT07333027?cond=NCT07333027&amp;amp;viewType=Card&amp;amp;rank=1<\/jats:ext-link>\n                      , identifier NCT07333027.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpsyt.2026.1827062","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:35:17Z","timestamp":1784871317000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical relevance of loneliness in the treatment of depression: study protocol for a naturalistic prospective longitudinal study"],"prefix":"10.3389","volume":"17","author":[{"given":"Franziska","family":"Sonnauer","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU), Universit\u00e4tsklinikum Erlangen","place":["Erlangen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franca L.","family":"Fries","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Addiction, Psychotherapy and Psychosomatic Medicine, Bezirkskliniken Mittelfranken","place":["Erlangen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maksym","family":"Druzenko","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Addiction, Psychotherapy and Psychosomatic Medicine, Bezirkskliniken Mittelfranken","place":["Erlangen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich W.","family":"Kastner","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Addiction, Psychotherapy and Psychosomatic Medicine, Bezirkskliniken Mittelfranken","place":["Erlangen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"M\u00fchle","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU), Universit\u00e4tsklinikum Erlangen","place":["Erlangen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Kornhuber","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU), Universit\u00e4tsklinikum Erlangen","place":["Erlangen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"B1","volume-title":"From Loneliness to Social Connection: Charting a Path to Healthier Societies. 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