The future of child and adolescent clinical psychopharmacology: A systematic review of phase 2, 3, or 4 randomized controlled trials of pharmacologic agents without regulatory approval or for unapproved indications.

We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010-08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes.

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Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest S Cortese declares honoraria and reimbursement for travel and accommodation expenses for lectures from the following non-profit 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. M Højlund has been a consultant to or has received honoraria from the Lundbeck Foundation, H. Lundbeck, and Otsuka. C Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. I Baeza has received honoraria and travel support from Angelini, Otsuka-Lundbeck and Janssen. T Banaschewski served in an advisory or consultancy role for eye level, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche, and Takeda. He received conference support or speaker’s fee by Janssen, Medice and Takeda. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. JK Buitelaar has been a consultant to / member of advisory board of / and/or speaker for Takeda, Medice, Angelini, Janssen, Boehringer-Ingelheim and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. D Coghill served in an advisory or consultancy role for Medice, Novartis, Servier, and Shire/Takeda. He received conference support or speaker’s fee from Medice, Servier, and Shire/Takeda. He received royalties from Cambridge University Press and Oxford University Press; He is not an employee of any of these companies, and not a stock shareholder of any of these companies and the present work is unrelated to these relationships. D Cohen has been a consultant or has received honoraria from Janssen/J&J and Otsuka; he served on a Data Safety Monitoring Board for Lundbeck. CU Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for 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, Mindpax, LB Pharma and Quantic. E Grunblatt received grant support from MEDICE Arzneimittel Pütter GmbH & Co KG. C Moreno has received honoraria as a consultant and/or advisor and/or for lectures from Angelini, Esteve, Exeltis, Janssen, Lundbeck, Neuraxpharm, Nuvelution, Otsuka, Pfizer, Servier and Sunovion outside the submitted work. M Parellada has been a consultant to or has received honoraria or grants from Angelini, Janssen Cilag, Exeltis, Lundbeck, Otsuka, Pfizer, Roche, Sage, Servier. A.M. Persico has been a consultant to and/or speaker for and has received honoraria from Servier, Sanofi, and Healx Limited. In the last 3 years, D. Purper-Ouakil reports honoraria/non-financial support from Medice and Shire/Takeda, non-financial support from HAC Pharma, and has worked as an unpaid scientific coordinator for Mensia, all outside the submitted work. In the last 2 years, B Vitiello was a paid consultant for Medice, Menarini, Angelini, and Alkermes Pharmaceuticals. ICKW reports research funding outside the submitted work from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Takeda, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, the Hong Kong Innovation and Technology Commission, the NIHR, the European Commission, and the Australian National Health and Medical Research Council, and has also received expert testimony payment from the Hong Kong Court of Final Appeal in the previous 3 years and consultancy fee from IQVIA and World Health Organization. In the last 3 years, V Roessner received no honoraria from pharmaceutical companies. He received royalties from Hogrefe, Oxford University Press; the present work is unrelated to these relationships. The other authors have no conflicts of interest to declare.