A state-of-the-art overview of candidate diagnostic biomarkers for Attention-deficit/hyperactivity disorder (ADHD)

ABSTRACT

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental conditions and is highly heterogeneous in terms of symptom profile, associated cognitive deficits, comorbidities, and outcomes. Heterogeneity may also affect the ability to recognize and diagnose this condition. The diagnosis of ADHD is primarily clinical but there are increasing research efforts aiming at identifying biomarkers that can aid the diagnosis.

Areas covered

We first discuss the definition of biomarkers and the necessary research steps from discovery to implementation. We then provide a broad overview of research studies on candidate diagnostic biomarkers in ADHD encompassing genetic/epigenetic, biochemical, neuroimaging, neurophysiological and neuropsychological techniques. Finally, we critically appraise current limitations in the field and suggest possible ways forward.

Expert opinion

Despite the large number of studies and variety of techniques used, no promising biomarkers have been identified so far. Clinical and biological heterogeneity as well as methodological limitations, including small sample size, lack of standardization, confounding factors, and poor replicability, have hampered progress in the field. Going forward, increased international collaborative efforts are warranted to support larger and more robustly designed studies, develop multimodal datasets to combine biomarkers and improve diagnostic accuracy, and ensure reproducibility and meaningful clinical translation.

KEYWORDS:

• Attention-deficit/hyperactivity disorder (ADHD)
• biochemistry
• diagnostic biomarker
• genetics
• neuroimaging
• neurophysiology
• neuropsychology

Article highlights

• Attention-deficit/hyperactivity disorder (ADHD) is a very common neurodevelopmental condition and is highly clinically and biologically heterogenous.

• Diagnostic biomarkers may support clinical diagnosis while informing on the underlying etiological mechanisms, which could help individualize ADHD treatment.

• Several lines of studies have investigated case–control differences in an attempt to identify diagnostic biomarkers, encompassing genetic/epigenetic, biochemical, neuroimaging, neurophysiological, and neuropsychological techniques.

• No clinically valid candidate diagnostic biomarker for ADHD has been identified to date, based on the criteria set by the World Federation of ADHD and the World Federation of Societies of Biological Psychiatry (i.e. being confirmed by at least two independent studies and having specificity and sensitivity of at least 80%).

• Clinical and biological heterogeneity as well as methodological limitations and differences among studies have hampered advances in the field.

• Collaborative efforts are warranted to develop larger and more robustly designed studies, integrate multiple biomarkers through multimodal datasets, validate the identified measures in independent samples, and test their clinical utility.

Declaration of interest

S Cortese declares honoraria and reimbursement for travel and accommodation expenses for lectures from the following nonprofit associations: Association for Child and Adolescent Central Health (ACAMH), Canadian ADHD Alliance Resource (CADDRA), British Association of Pharmacology (BAP), and from Healthcare Convention for educational activity on ADHD. Prof. Cortese has served on the advisory board of the Association for Child and Adolescent Mental Health, and the British Association for Psychopharmacology. M Solmi has received honoraria/has been a consultant for AbbVie, Angelini, Lundbeck, Otsuka, all unrelated to this work. CU Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Tolmar, Vertex, and Viatris; He provided expert testimony for Janssen and Otsuka; He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; He has received grant support from Janssen and Takeda; He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript was recruited by Research Square. Reviewers with declared or apparent competing interests are not utilized for these reviews. This reviewer was paid a small honorarium for completing the review within a specified timeframe. Honoraria for reviews such as this are paid regardless of the reviewer recommendation. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.