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
Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Forlagets udgivne version, 1,79 MB, PDF-dokument
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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 105149 |
| Tidsskrift | Neuroscience and Biobehavioral Reviews |
| Vol/bind | 149 |
| Antal sider | 30 |
| ISSN | 0149-7634 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Five RCTs were identified, recruiting exclusively individuals aged 17 or younger and testing pharmacological compounds. Of these trials, 60% were funded by drug companies and 40% were sponsored by universities/hospitals. Five modes of action were assessed, including 5 compounds. Mechanisms of action of the compounds assessed in RCTs in schizophrenia included:
Funding Information:
I Baeza has received grants from the Spanish Ministry of Health, Instituto de Salud Carlos III supported by ERDF Funds from the European Commission ( PI18/0242/PI21/0391 ) “A way of making Europe”, Plan Nacional sobre Drogas and Fundación Alicia Koplowitz.
Funding Information:
J Castro-Fornieles has received funding from the Spanish Ministry of Science and Innovation , Instituto de Salud Carlos III (ISCIII), co-financed by the European Union , CIBERSAM , European Union Structural Funds, European Union Seventh Framework Program , European Union H2020 Program under the Innovative Medicines I Project AIMS-2-TRIALS (Grant agreement No 777394 ), PERIS and SGR program from de Catalonia Governement, Fundació Marató de TV3 and Fundación Alicia Koplowitz.
Funding Information:
We retained 12 RCTs, including 1 RCT on a Chinese medicine formula. About 67% (73% when limiting to RCTs of pharmacological agents) were funded by drug companies, the rest were sponsored by universities/hospitals. Six modes of action were assessed, including 7 compounds. Mechanisms of action of the compounds assessed in RCTs in Tourette’s syndrome included:
Funding Information:
C Moreno has received funding from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), CIBER -Consorcio Centro de Investigación Biomédica en Red - ( CB/07/09/0023 ), co-financed by the European Union and ERDF Funds from the European Commission, “A way of making Europe”, financed by the European Union - NextGenerationEU (PMP21/00051, PI21/01929), Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, EU Seventh Framework Program , H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking : Project c4c (Grant agreement No. 777389 ), and Horizon Europe (Project FAMILY, Grant agreement: No 101057529; Project Psych-STRATA , Grant agreement: No 101057454 ), National Institute of Mental Health of the National Institutes of Health, Fundación Familia Alonso, and Fundación Alicia Koplowitz.
Funding Information:
C Arango has received funding from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII) , co-financed by the European Union, ERDF Funds from the European Commission , “A way of making Europe”, financed by the European Union - NextGenerationEU ( PMP21/00051 ), PI19/01024 . CIBERSAM , Madrid Regional Government ( B2017/BMD-3740 AGES-CM-2 ), European Union Structural Funds , European Union Seventh Framework Program , European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project PRISM-2 (Grant agreement No. 101034377 ), Project AIMS-2-TRIALS (Grant agreement No 777394 ), Horizon Europe , the National Institute of Mental Health of the National Institutes of Health under Award Number 1U01MH124639-01 (Project ProNET) and Award Number 5P50MH115846-03 (project FEP-CAUSAL ), Fundación Familia Alonso, and Fundación Alicia Koplowitz .
Funding Information:
We found three RCTs: one, testing sertraline (SSRI) funded by a drug company and two, assessing propranolol (beta-blocker) combined with memory consolidation and reactivation, respectively, sponsored by universities/hospitals. The only RCT with reported results, the one on sertraline, failed to find any significant effect of sertraline vs placebo.
Funding Information:
This paper is dedicated to the memory of our beloved colleague and friend Professor Alessandro Zuddas, who suddenly passed away in July 2022. C Arango has received funding from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), co-financed by the European Union, ERDF Funds from the European Commission, “A way of making Europe”, financed by the European Union - NextGenerationEU (PMP21/00051), PI19/01024. CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project PRISM-2 (Grant agreement No. 101034377), Project AIMS-2-TRIALS (Grant agreement No 777394), Horizon Europe, the National Institute of Mental Health of the National Institutes of Health under Award Number 1U01MH124639-01 (Project ProNET) and Award Number 5P50MH115846-03 (project FEP-CAUSAL), Fundación Familia Alonso, and Fundación Alicia Koplowitz. I Baeza has received grants from the Spanish Ministry of Health, Instituto de Salud Carlos III supported by ERDF Funds from the European Commission (PI18/0242/PI21/0391) “A way of making Europe”, Plan Nacional sobre Drogas and Fundación Alicia Koplowitz. J Buitelaar has been supported by the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programmes which receive support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394, the resources of which are composed of financial contributions from the European Union's FP7 and Horizon2020 Programmes, and from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI; and by the Horizon2020 supported programmes PRIME (Grant No. 847879) and CANDY (Grant No. 847818). J Castro-Fornieles has received funding from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), co-financed by the European Union, CIBERSAM, European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines I Project AIMS-2-TRIALS (Grant agreement No 777394), PERIS and SGR program from de Catalonia Governement, Fundació Marató de TV3 and Fundación Alicia Koplowitz. C Moreno has received funding from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), CIBER -Consorcio Centro de Investigación Biomédica en Red- (CB/07/09/0023), co-financed by the European Union and ERDF Funds from the European Commission, “A way of making Europe”, financed by the European Union - NextGenerationEU (PMP21/00051, PI21/01929), Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, EU Seventh Framework Program, H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project c4c (Grant agreement No. 777389), and Horizon Europe (Project FAMILY, Grant agreement: No 101057529; Project Psych-STRATA, Grant agreement: No 101057454), National Institute of Mental Health of the National Institutes of Health, Fundación Familia Alonso, and Fundación Alicia Koplowitz. P Nagy has been a consultant to and/or speaker for Medice, Servier, and Egis Pharmaceuticals for work that is unrelated to the present paper. M Parellada has received funding from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), CIBER -Consorcio Centro de Investigación Biomédica en Red- (CB/07/09/0023), co-financed by the European Union and ERDF Funds from the European Commission, “A way of making Europe”, financed by the European Union - NextGenerationEU (PMP21/00051), Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, EU Seventh Framework Program, H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project AIMS-2-TRIALS (Grant agreement No 777394), and Horizon Europe, National Institute of Mental Health of the National Institutes of Health, Fundación Familia Alonso, and Fundación Alicia Koplowitz. D Purper-Ouakil reports non-financial support from HAC Pharma and Lundbeck, honoraria and non-financial support from Medice in the last 3 years. She also collaborated in FP7 and Horizon 2020 projects and a Horizon 2020 SME project sponsored by Mensia without financial interests. She has received several national public grants (DGOS-PHRC-N and equivalent). AM Persico's work is funded by the Italian Ministry of Health, the Fondazione di Modena & UNIMORE (Mission-oriented), and the Italian Autism Foundation. V Roessner has received funding from the Federal Ministry of Education and Research (01GL1741C), the Innovation Fund of the Federal Joint Committee (01NVF17046, 01VSF19027), the German Research Foundation (RO 3876/11-1, RO 3876/11-2, TE 280\18-1, FR 2069/8-1), MSE Pharma, and Takeda (IIR-DEU-002258).
Funding Information:
M Parellada has received funding from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), CIBER -Consorcio Centro de Investigación Biomédica en Red- ( CB/07/09/0023 ), co-financed by the European Union and ERDF Funds from the European Commission, “A way of making Europe”, financed by the European Union - NextGenerationEU (PMP21/00051), Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, EU Seventh Framework Program, H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project AIMS-2-TRIALS (Grant agreement No 777394 ), and Horizon Europe, National Institute of Mental Health of the National Institutes of Health, Fundación Familia Alonso , and Fundación Alicia Koplowitz.
Funding Information:
D Purper-Ouakil reports non-financial support from HAC Pharma and Lundbeck , honoraria and non-financial support from Medice in the last 3 years. She also collaborated in FP7 and Horizon 2020 projects and a Horizon 2020 SME project sponsored by Mensia without financial interests. She has received several national public grants (DGOS-PHRC-N and equivalent).
Funding Information:
J Buitelaar has been supported by the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programmes which receive support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394 , the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon2020 Programmes , and from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions, and AUTISM SPEAKS , Autistica and SFARI ; and by the Horizon2020 supported programmes PRIME (Grant No. 847879 ) and CANDY (Grant No. 847818 ).
Publisher Copyright:
© 2023 The Authors
ID: 367259056