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

Samuele Cortese*, Katherine McGinn, Mikkel Højlund, Alan Apter, Celso Arango, Immaculada Baeza, Tobias Banaschewski, Jan Buitelaar, Josefina Castro-Fornieles, David Coghill, David Cohen, Edna Grünblatt, Pieter J. Hoekstra, Anthony James, Pia Jeppesen, Péter Nagy, Anne Katrine Pagsberg, Mara Parellada, Antonio M. Persico, Diane Purper-OuakilVeit Roessner, Paramala Santosh, Emily Simonoff, Dejan Stevanovic, Argyris Stringaris, Benedetto Vitiello, Susanne Walitza, Abraham Weizman, Tamar Wohlfarth, Ian C.K. Wong, Gil Zalsman, Alessandro Zuddas, Carmen Moreno, Marco Solmi, Christoph U. Correll

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched and (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.

Original languageEnglish
Article number105149
JournalNeuroscience and Biobehavioral Reviews
StatePublished - Jun 2023


FundersFunder number
Consorcio Centro de Investigación Biomédica en RedCB/07/09/0023
European Union's FP7
European Union’s FP7
Fondazione di Modena & UNIMORE
Fundación Familia Alonso
H2020 Program
Innovation Fund of the Federal Joint Committee01VSF19027, 01NVF17046
Italian Autism Foundation
MSE Pharma
Madrid Regional GovernmentB2017/BMD-3740 AGES-CM-2
National Institutes of Health5P50MH115846-03, 1U01MH124639-01
National Institute of Mental Health
Center for International Business Education and Research, University of Illinois at Urbana-Champaign
Fundación Alicia Koplowitz
Takeda Pharmaceutical CompanyIIR-DEU-002258
Horizon 2020 Framework Programme
European Federation of Pharmaceutical Industries and Associations
Simons Foundation Autism Research Initiative847879
Social Science Research Institute, Duke University
HORIZON EUROPE Framework Programme101057454
European CommissionPI19/01024, PI18/0242/PI21/0391, PMP21/00051, PI21/01929, 777394
Deutsche ForschungsgemeinschaftFR 2069/8-1, TE 280\18-1, RO 3876/11-2, RO 3876/11-1
Bundesministerium für Bildung und Forschung01GL1741C
Ministero della Salute
Instituto de Salud Carlos III
Ministerio de Ciencia e Innovación
Seventh Framework Programme
Centro de Investigación Biomédica en Red de Salud Mental
Horizon 2020
European Regional Development Fund
Consejería de Salud y Familias, Junta de Andalucía
Innovative Medicines Initiative101034377, 115300, 777389, AIMS-2-TRIALS


    • Adolescents
    • Children
    • Dietary interventions
    • Medications
    • Probiotics
    • Psychopharmacology


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