{
  "abstract": "Background\n\nSchizophrenia, bipolar depression and major depressive disorders collectively affect over 10 million people across the European Union and are associated with annual healthcare and societal costs of more than 600 billion euros. When diagnosed, patients are usually prescribed psychotropic medication. A substantial proportion of patients insufficiently responds to first- and second-line treatments, which is termed as treatment resistance. While third-line treatments are relatively effective in TR conditions, it remains unclear whether providing these treatments in an earlier phase provides benefits.Methods\n\nINTENSIFY consists of three international, multicenter, controlled, randomized, open-label trials, with a treatment duration of 6 weeks. After failure of a first-line treatment in the current episode, 1254 participants will be recruited by at least 16 sites and randomized to either a third-line treatment (early intensified pharmacological treatment) or treatment as usual (standard second-line treatment). Adult participants (age ≥ 18yrs) with a diagnosis of schizophrenia, schizoaffective disorder or schizophreniform disorder, major depressive disorder, or bipolar depression are eligible after a treatment failure in the current episode due to lack of efficacy. The primary objective is to compare change in symptom severity after 6 weeks. The secondary objective is to compare the two treatment arms on changes of severity symptoms, cognitive function, quality of life, functional measures, digital mental health markers, side effects and concomitant medication. ANCOVA analyses will be performed.Discussion\n\nShould the current study show clinical evidence that the use of third-line treatment is efficacious and safe earlier to treat severe mental illness, the results could impact treatment guidelines in due course. In addition, the study will contribute to the identification of clinical, digital and blood-based markers that are associated with treatment response to early and intensified treatments.Trial registration\n\nThe trials are registered in www.Clinicaltrials\n\ngov under numbers NCT05603104 (merged study protocol; study center in Israel) and under the numbers for the split protocols NCT05958875 (SZ), NCT05973786 (BD) and NCT05973851 (MDD) for the EU and UK sites. The study is registered in the Australian and New Zealand Clinical Trials Registry under Registration number ACTRN12625000327482 (SZ), ACTRN12625000328471 (BD) and ACTRN12625000329460 (MDD). Registered on April 17, 2025.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands",
    "Department of Medicine and Surgery, Kore University of Enna, Enna, Sicily, Italy",
    "Oasi Research Institute-IRCCS, Troina, Italy",
    "Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia Spain",
    "Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy",
    "Department of Psychosis Studies, King’s College London, London, UK",
    "Discipline of Psychiatry, Adelaide Medical School, Adelaide University, Adelaide, Australia",
    "Division of Mental Health, Northern Adelaide Local Health Network, SA Health, Adelaide, Australia",
    "Headspace Adelaide Early Psychosis, Sonder, Adelaide, Australia",
    "Division of Mental Health, Central Adelaide Local Health Network, SA Health, Adelaide, Australia",
    "Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, Division of Psychiatry I, Medical University of Innsbruck, Innsbruck, Austria",
    "Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, University Augsburg, Augsburg, Germany",
    "DZPG (German Center for Mental Health), partner site Munich/Augsburg, Augsburg, Germany",
    "Department of Psychiatry and Psychotherapy, Bielefeld University, Medical School and University Medical Center OWL, Evangelisches Klinikum Bethel, Bielefeld, Germany",
    "Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt - Goethe University, Frankfurt Am Main, Germany",
    "Department of Psychiatry and Psychotherapy, University Medical Center, University of Mainz, Mainz, Germany",
    "Department of Psychiatry, University of Muenster, Muenster, Germany",
    "Drora and Pinchas Zachai Division of Psychiatry, Sheba Medical Center, Ramat-Gan, Israel",
    "The Department of Psychiatry, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel",
    "Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy",
    "Genetics Unit, IRCCS Istituto Centro San Giovanni Di Dio Fatebenefratelli, Brescia, Italy",
    "Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy",
    "Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, Brescia, Italy",
    "Unit of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy",
    "Unit of Clinical Psychiatry, Department of Medical Specialties, University Hospital Agency of Cagliari, Cagliari, Italy",
    "Department of Pharmacology, Dalhousie University, Halifax, Canada",
    "Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy",
    "Department of Neuroscience, University of Turin, Turin, Italy",
    "First Department of Psychiatry, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece",
    "Mental mHealth Lab, Institute of Sports and Sports Science, Karlsruhe Institute of Technology, Karlsruhe, Germany",
    "Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany",
    "Department of Psychiatry, Paris Brain Institute-Institut du Cerveau (ICM), UMR 7225/UMRS 1127, Sorbonne University CNRS/INSERM, DMU Neurosciences, Pitié-Salpétrièren, APHP, Paris, France",
    "LWL-Klinik Dortmund, Marsbruchstraße 179, Dortmund, 44287 Germany",
    "Department of Data Science & Biostatistics, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands"
  ],
  "article_type": "research article",
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  "author_total": 121,
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  "bibtex": "https://research.draconitic.com/paper/60c5ehh1nb962.bib",
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  "doi": "10.1186/s13063-026-09861-7",
  "fulltext_url": "https://europepmc.org/articles/PMC13725940",
  "id": "60c5ehh1nb962",
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  "landing_url": "https://europepmc.org/article/MED/42968118",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Study Protocol"
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      "openalex",
      "2736|Treatment of Major Depression"
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  "openalex": "W7172511445",
  "pdf_url": "https://europepmc.org/articles/PMC13725940?pdf=render",
  "pmcid": "PMC13725940",
  "pmid": "42968118",
  "published": "2026-08-05",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/60c5ehh1nb962.ris",
  "sources": [
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      "first_seen": "2026-11-03T15:20:53Z",
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      "url": "https://europepmc.org/article/MED/42968118"
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      "origin": "openalex:2736|Treatment of Major Depression",
      "subfield": "pharmacology-toxicology"
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  "title": "INTENSIFY-a randomized, controlled trial to investigate the effect of an early intensified pharmacological treatment for major psychiatric disorders after treatment failure in the current episode: a study protocol.",
  "title_text": "INTENSIFY-a randomized, controlled trial to investigate the effect of an early intensified pharmacological treatment for major psychiatric disorders after treatment failure in the current episode: a study protocol.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:22:01Z",
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