Biomarkers of treatment outcome in schizophrenia: Defining a benchmark for clinical significance

Stephen Z. Levine, Jonathan Rabinowitz, Rudolf Uher, Shitij Kapur

Research output: Contribution to journalArticlepeer-review


Emerging data from on imaging and genetic studies have generated interest in "clinically significant" biomarkers to predict response and prognosis. What constitutes "clinical significance" and how a biomarker would reach that threshold are unclear. To develop a benchmark we reviewed different approaches for defining "clinical significance" applied in schizophrenia research and identified that an improvement of 15 points on the PANSS Total is considered meaningful in clinical settings. Using this benchmark and we simulated thousands of schizophrenia trials, using characteristics derived from the NEWMEDS database with over 8000 patients with schizophrenia, to the kind of imaging, genetic, and other biomarkers that could attain clinical significance. We plotted the interaction between frequency-of-occurrence, the effect size of biomarkers and their relationship to the clinical significance threshold. Results show that categorical biomarkers are likely to attain clinical significance when they occur in 20-50% of the clinical population, and can predict at least a 8-10 point PANSS scale difference. Genetic markers are likely to have clinical significance when they occur in 20-50% of the population and can predict 7-9 points on the PANSS scale. A marker with a lower frequency or lesser effect size would find it hard to meet clinical significance thresholds for schizophrenia. The assumptions and limitations of this approach are discussed. Compared with standards in the rest of medicine, biomarkers that can attain this benchmark will be cost-effective and are likely to be adopted by clinical systems.

Original languageEnglish
Pages (from-to)1578-1585
Number of pages8
JournalEuropean Neuropsychopharmacology
Issue number10
StatePublished - Oct 2015

Bibliographical note

Funding Information:
Dr. Uher is supported by the Canada Research Chairs program, the Canadian Institutes of Health Research and the Nova Scotia Health Research Foundation. Dr. Levine has received research support, and/or consultancy fees and/or travel support from Shire, F. Hoffmann-LaRoche, and Eli Lilly. Dr. Rabinowitz has served as a consultant to Janssen (J&J), Eli Lilly, Pfizer, BiolineRx, Roche and Amgen, and is on scientific advisory board at MedAvante. Dr. Kapur has received recent grant support from Lundbeck and Roche and has served as a one-off consultant and/or speaker for Otsuka and Takeda and served on the Scientific Advisory Boards for Acadia, Lundbeck and Roche

Funding Information:
Dr. Kapur's involvement is supported by an MRC UK Award, STRATA and by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London .

Publisher Copyright:
© 2015 Elsevier B.V. and ECNP.


  • Biological markers
  • Biological psychiatry
  • Translational medical research
  • Treatment response

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Pharmacology (medical)


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