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Identification and validation of biomarkers for autism spectrum disorders

Nature Reviews Drug Discovery volume 15, page 70 (2016)Cite this article

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Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders, but effective medical treatments for the core symptoms of the disorder are still lacking. According to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), the core symptoms of ASD comprise deficits in social communication and interaction, and repetitive and restricted behaviours, which include sensory abnormalities. Novel genetic and preclinical approaches now provide unprecedented opportunities to identify the underpinning pathophysiological mechanisms and aetiology-based treatment targets, as discussed in a Review article by Ghosh et al. (Drug discovery for autism spectrum disorder: challenges and opportunities. Nat. Rev. Drug Discov. 12, 777–790 (2013)1. This has led to more interest from the pharmaceutical industry in an area in which the overall risk of failure is seen as very high because key parameters of drug efficiency are not yet established and the regulatory environment is uncertain. For example, industry has recently invested in several pre-competitive projects, such as the European Union (EU) Innovative Medicines Initiative (IMI)-brokered public–private partnership EU-AIMS (European Autism Interventions — A Multicentre Study for Developing New Medications)2.

However, even when new compounds that show preclinical promise for ASD are found, there are still considerable challenges in testing them in clinical trials. For instance, the current practice of testing treatments in clinically and biologically heterogeneous patient groups hampers the ability of investigators to detect potentially significant efficacy signals in specific subgroups who 'respond'. Therefore, we need biomarkers that stratify patient populations according to distinct biological subtypes. So far, the identification and validation of biomarkers has been limited by studies with small sample sizes that have insufficient power and/or because studies use different (and often not standardized) measures. We also need quantifiable, reproducible outcome measures — including surrogate end points — that are sensitive to change, in order to assess treatment efficacy.

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Figure 1: Examples of biomarker stratification approaches.

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Author information

Author notes

  1. Eva Loth, Will Spooren, Jan K. Buitelaar and Declan G. M. Murphy: These authors contributed equally to this work

Authors and Affiliations

  1. Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK

    Eva Loth

  2. Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Pharmaceuticals, Grenzacherstrasse 124, Basel, CH-4070, Switzerland

    Will Spooren

  3. Regulatory Affairs, Pharmaceutical Development, F. Hoffmann-La Roche Pharmaceuticals, Grenzacherstrasse 124, Basel, CH-4070, Switzerland

    Lindsay M. Ham

  4. European Medicines Agency, 30 Churchill Place, London, E14 5EU, UK

    Maria B. Isaac

  5. Agence Nationale de Sécurité du Médicament et des Produits de Santé, 143–147 Boulevard Anatole France, Saint-Denis Cedex, 93285, France

    Caroline Auriche-Benichou

  6. Child and Adolescent Psychiatry, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, 68159, Germany

    Tobias Banaschewski

  7. Department of Psychiatry, Autism Research Centre, University of Cambridge, Douglas House, 18b Trumpington Road, Cambridge, CB2 8AH, UK

    Simon Baron-Cohen

  8. Bundesinstitut für Arzneimittel und Medizinprodukte, Kurt-Georg-Kiesinger Allee 3, Bonn, 53175, Germany

    Karl Broich

  9. Department of Women's and Children's Health, Center of Neurodevelopmental Disorders, Karolinska Institutet, CAP Research Center, Gävlegatan 22B, Floor 8, Stockholm, SE-113 30, Sweden

    Sven Bölte

  10. Institut Pasteur, Unité Génétique Humaine et Fonctions Cognitives, 25 Rue du Docteur Roux, Paris Cedex 15, 75015, France

    Thomas Bourgeron

  11. Department of Psychology, Clinical Child Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK

    Tony Charman

  12. Discovery Neuroscience Research, Erl Wood, Lilly UK, Erl Wood Manor, Windlesham, GU20 6PH, UK

    David Collier

  13. Agencia Española de Medicamentos y Productos Sanitarios, Parque Empresarial Las Mercedes, Edifico 8, Calle Campezo 1, Madrid, 28022, Spain

    Fernando de Andres-Trelles

  14. Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, Utrecht, 3584 CG, The Netherlands

    Sarah Durston

  15. Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK

    Christine Ecker

  16. College ter Beoordeling van Geneesmiddelen (Medicines Evaluation Board), Graadt van Roggenweg 500, Utrecht, 3531 AH, The Netherlands

    Andre Elferink

  17. Bundesinstitut für Arzneimittel und Medizinprodukte, Kurt-Georg-Kiesinger Allee 3, Bonn, 53175, Germany

    Marion Haberkamp

  18. Medicines and Healthcare Products Regulatory Agency, 151 Buckingham Palace Road, London, SW1W 9SZ, UK

    Robert Hemmings

  19. Centre for Brain and Cognitive Development, Birkbeck, University of London, 32 Torrington Square, London, WC1E 7JL, UK

    Mark H. Johnson

  20. Centre for Brain and Cognitive Development, Birkbeck, University of London, 32 Torrington Square, London, WC1E 7JL, UK

    Emily J. H. Jones

  21. Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Pharmaceuticals, Grenzacherstrasse 124, Basel, CH-4070, Switzerland

    Omar S. Khwaja

  22. College ter Beoordeling van Geneesmiddelen (Medicines Evaluation Board), Graadt van Roggenweg 500, Utrecht, 3531 AH, The Netherlands

    Sabine Lenton

  23. Centre for Brain and Cognitive Development, Birkbeck, University of London, 32 Torrington Square, London, WC1E 7JL, UK

    Luke Mason

  24. Agenzia Italiana del Farmaco, Via del Tritone, 181, Rome, 00187, Italy

    Valentina Mantua

  25. Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, 68159, Germany

    Andreas Meyer-Lindenberg

  26. Department of Psychiatry, Autism Research Centre, University of Cambridge, Douglas House, 18b Trumpington Road, Cambridge, CB2 8AH, UK

    Michael V. Lombardo

  27. Department of Psychology, University of Cyprus, PO Box 20537, Nicosia, 1678, Cyprus

    Michael V. Lombardo

  28. Center for Applied Neuroscience, University of Cyprus, PO Box 20537, Nicosia, 1678, Cyprus

    Michael V. Lombardo

  29. Donders Center for Cognitive Neuroimaging, Radboud University Nijmegen Medical Centre, Kapittelweg 29, Nijmegen, 6525 EN, The Netherlands

    Laurence O'Dwyer

  30. Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Pharmaceuticals, Grenzacherstrasse 124, Basel, CH-4070, Switzerland

    Koichi Okamoto

  31. Janssen Research & Development, 1125 Trenton Harbourton Road, Titusville, 08560, New Jersey, USA

    Gahan J. Pandina

  32. Agenzia Italiana del Farmaco, Via del Tritone, 181, Rome, 00187, Italy

    Luca Pani

  33. University Campus Bio-Medico, Via Álvaro del Portillo, 21, Rome, 00128, Italy

    Antonio M. Persico

  34. Mafalda Luce Center for Pervasive Developmental Disorders, Via Bernardo Rucellai, 36, Milan, 20126, Italy

    Antonio M. Persico

  35. Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK

    Emily Simonoff

  36. Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, 46285, Indiana, USA

    Sitra Tauscher-Wisniewski

  37. European Medicines Agency, 30 Churchill Place, London, E14 5EU, UK

    Jordi Llinares-Garcia

  38. European Medicines Agency, 30 Churchill Place, London, E14 5EU, UK

    Spiros Vamvakas

  39. Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neurosciences, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK

    Steve Williams

  40. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Kapittelweg 29, Nijmegen, 6525 EN, The Netherlands

    Jan K. Buitelaar

  41. Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK

    Declan G. M. Murphy

  42. The views expressed in this article are the personal views of the author and may not be understood nor quoted as being made on behalf of or reflecting the position of the European Medicines Agency (EMA) or one of its committees or working parties or any of the national agencies.,

    Maria B. Isaac, Karl Broich, Andre Elferink, Marion Haberkamp, Robert Hemmings, Sabine Lenton, Valentina Mantua, Luca Pani, Jordi Llinares-Garcia & Spiros Vamvakas

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Corresponding author

Correspondence to Eva Loth.

Ethics declarations

Competing interests

W.S., K.O., L.M.H. and O.S.K. are employees at F. Hoffmann-La Roche. D.C. and S.T.-W. are employees at Eli Lilly. G.J.P. is an employee at Janssen Research & Development, LLC. A.M.-L. has received consultant fees and travel expenses from Alexza Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Defined Health, Decision Resources, Desitin Arzneimittel, Elsevier, F. Hoffmann-La Roche, Gerson Lehrman Group, Grupo Ferrer, Les Laboratoires Servier, Lilly Deutschland, Lundbeck Foundation, Outcome Sciences, Outcome Europe, PriceSpective and Roche Pharma and has received speaker's fees from Abbott, AstraZeneca, BASF, Bristol-Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Pfizer Pharma and Servier Deutschland. J.K.B. has been a consultant to, or member of advisory board of, and/or speaker for, Janssen Cilag BV, Eli Lilly, Shire, Lundbeck, Roche and Servier. D.G.M.M. has been a consultant to Roche.

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Summary of Study Protocol According to Schedule (PDF 308 kb)

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Members of the EU-AIMS LEAP Project (PDF 99 kb)

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Loth, E., Spooren, W., Ham, L. et al. Identification and validation of biomarkers for autism spectrum disorders. Nat Rev Drug Discov 15, 70 (2016). https://doi.org/10.1038/nrd.2015.7

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