RESIDENT: Pharmacological Interventions for Aggressive and Agitative Behaviors in Youth with Developmental Disorders: A Literature Review (UofA)
Presenting Author(s): Dr. Usama MalikCo-Author(s): Dr. Daniel Moreno De Luca
Date and time: 22 Mar 2025 from 15:30 to 15:45
Location: Hawthorn C
Abstract
Background:
Youth with neurodevelopmental disorders, such as intellectual disability (ID) and autism spectrum disorder (ASD), often exhibit aggressive, agitative, and self-harming behaviors that significantly impact their quality of life and burden caregivers. While non-pharmacological approaches are preferred as first-line treatments, pharmacological interventions are frequently used in severe or refractory cases. However, evidence on their efficacy and safety remains fragmented.
Objectives:
This study evaluated the efficacy and safety of pharmacological treatments for managing aggression, agitation, and related behaviors in youth with neurodevelopmental disorders, while identifying research gaps and suggesting future directions.
Methods:
A systematic review of systematic reviews, meta-analyses, and randomized controlled trials (RCTs) published between 2019 and 2024 was conducted. Studies involving youth (up to 25 years) with ID, IDD, ASD, or unspecified developmental disorders receiving pharmacological treatment for aggression, agitation, or self-injury were included. Primary outcomes were reductions in challenging behaviors; secondary outcomes included safety profiles and quality of life. Subgroup analyses explored variations by disorder type, medication class, and age group.
Results:
Out of 60 identified articles, 31 met inclusion criteria. Atypical antipsychotics demonstrated the most evidence for reducing aggression, while other pharmacotherapies, including antidepressants and methylphenidate, showed less robust results.
Conclusion:
Pharmacological interventions play a critical role in managing challenging behaviors in youth with neurodevelopmental disorders. While certain medications, like atypical antipsychotics, are effective, safety concerns remain paramount. High-quality research is needed to optimize care and improve outcomes for this population.
Learning Objectives
1. Explore the role of pharmacological treatments in managing challenging behaviors in youth with neurodevelopmental disorders;
2. Evaluate the effectiveness and limitations of current pharmacological therapies for this patient population; and
3. Identify research gaps and prioritize future directions to improve treatment outcomes and care quality.
Literature References
1. Andel, Dorinde M. van, Jan J. Sprengers, Mandy G. Keijzer-Veen, Annelien J. A. Schulp, Marc R. Lillien, Floortje E. Scheepers, and Hilgo Bruining. “Bumetanide for Irritability in Children With Sensory Processing Problems Across Neurodevelopmental Disorders: A Pilot Randomized Controlled Trial.” Frontiers in Psychiatry 13 (2022): 780281. https://doi.org/10.3389/fpsyt.2022.780281.
2. Bahji, Anees, Evan Forth, Amina Nasar, Ahmed Waqas, Emily R. Hawken, and Muhammad Ayub. “Navigating Agitation in Neurodevelopmental Disorders: A Comparative Study of Pharmacotherapies via Network Meta-Analysis in Children and Adults with Autism Spectrum Disorder or Intellectual Disabilities.” Journal of Psychopharmacology (Oxford, England), December 17, 2024, 2698811241303654. https://doi.org/10.1177/02698811241303654.
3. Breaux, Rosanna, Raman Baweja, Hana-May Eadeh, Delshad M. Shroff, Annah R. Cash, Courtney S. Swanson, Amy Knehans, and James G. Waxmonsky. “Systematic Review and Meta-Analysis: Pharmacological and Nonpharmacological Interventions for Persistent Nonepisodic Irritability.” Journal of the American Academy of Child and Adolescent Psychiatry 62, no. 3 (March 2023): 318–34. https://doi.org/10.1016/j.jaac.2022.05.012.
4. Brignell, Amanda, Catherine Marraffa, Katrina Williams, and Tamara May. “Memantine for Autism Spectrum Disorder.” The Cochrane Database of Systematic Reviews 8, no. 8 (August 25, 2022): CD013845. https://doi.org/10.1002/14651858.CD013845.pub2.
5. Choi, Hangnyoung, Jae Han Kim, Hee Sang Yang, Jong Yeob Kim, Samuele Cortese, Lee Smith, Ai Koyanagi, et al. “Pharmacological and Non-Pharmacological Interventions for Irritability in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis with the GRADE Assessment.” Molecular Autism 15, no. 1 (January 23, 2024): 7. https://doi.org/10.1186/s13229-024-00585-6.
6. Cortese, Samuele, Fang Wang, Marco Angriman, Gabriele Masi, and Oliviero Bruni. “Sleep Disorders in Children and Adolescents with Autism Spectrum Disorder: Diagnosis, Epidemiology, and Management.” CNS Drugs 34, no. 4 (April 2020): 415–23. https://doi.org/10.1007/s40263-020-00710-y.
7. Cukier, Sebastián, and Natalia Barrios. “[Pharmacological interventions for intellectual disability and autism].” Vertex (Buenos Aires, Argentina) XXX, no. 143 (2019): 52–63.
8. Deb, Shoumitro, Meera Roy, Bharati Limbu, Basma Akrout Brizard, Meena Murugan, Ashok Roy, and Jacopo Santambrogio. “Randomised Controlled Trials of Antipsychotics for People with Autism Spectrum Disorder: A Systematic Review and a Meta-Analysis.” Psychological Medicine 53, no. 16 (December 2023): 7964–72. https://doi.org/10.1017/S003329172300212X.
9. Fallah, Merrick S., Mateen R. Shaikh, Binod Neupane, Daniel Rusiecki, Teresa A. Bennett, and Joseph Beyene. “Atypical Antipsychotics for Irritability in Pediatric Autism: A Systematic Review and Network Meta-Analysis.” Journal of Child and Adolescent Psychopharmacology 29, no. 3 (April 2019): 168–80. https://doi.org/10.1089/cap.2018.0115.
10. Ghanizadeh, Ahmad, Mohammed Molla, and Garth Jon Olango. “The Effect of Stimulants on Irritability in Autism Comorbid with ADHD: A Systematic Review.” Neuropsychiatric Disease and Treatment 15 (2019): 1547–55. https://doi.org/10.2147/NDT.S194022.
11. Gogou, M., and G. Kolios. “[Is there place for nutrition in the treatment of children with autism spectrum disorder?].” Psychiatrike = Psychiatriki 31, no. 1 (2020): 57–69. https://doi.org/10.22365/jpsych.2020.311.57.
12. Groof, C. de, W. De La Marche, and M. Danckaerts. “[Effectiveness of guanfacin on comorbid disorders in children and adolescents with adhd: a systematic literature review].” Tijdschrift Voor Psychiatrie 61, no. 12 (2019): 845–53.
13. Groves, Laura, Chris Jones, Alice Welham, Anna Hamilton, Ashley Liew, and Caroline Richards. “Non-Pharmacological and Pharmacological Interventions for the Reduction or Prevention of Topographies of Behaviours That Challenge in People with Intellectual Disabilities: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.” The Lancet. Psychiatry 10, no. 9 (September 2023): 682–92. https://doi.org/10.1016/S2215-0366(23)00197-9.
14. Iffland, Michelle, Nuala Livingstone, Mikaela Jorgensen, Philip Hazell, and Donna Gillies. “Pharmacological Intervention for Irritability, Aggression, and Self-Injury in Autism Spectrum Disorder (ASD).” The Cochrane Database of Systematic Reviews 10, no. 10 (October 9, 2023): CD011769. https://doi.org/10.1002/14651858.CD011769.pub2.
15. Jawed, Bilal, Jessica Elisabetta Esposito, Riccardo Pulcini, Syed Khuram Zakir, Matteo Botteghi, Francesco Gaudio, Daniele Savio, Caterina Martinotti, Stefano Martinotti, and Elena Toniato. “The Evolving Role of Cannabidiol-Rich Cannabis in People with Autism Spectrum Disorder: A Systematic Review.” International Journal of Molecular Sciences 25, no. 22 (November 20, 2024): 12453. https://doi.org/10.3390/ijms252212453.
16. Joshi, Gagan, Timothy Wilens, Elizabeth S. Firmin, Barbora Hoskova, and Joseph Biederman. “Pharmacotherapy of Attention Deficit/Hyperactivity Disorder in Individuals with Autism Spectrum Disorder: A Systematic Review of the Literature.” Journal of Psychopharmacology (Oxford, England) 35, no. 3 (March 2021): 203–10. https://doi.org/10.1177/0269881120972336.
17. Lee, Tsung-Min, Kuan-Min Lee, Chuan-Ya Lee, Hsin-Chien Lee, Ka-Wai Tam, and El-Wui Loh. “Effectiveness of N-Acetylcysteine in Autism Spectrum Disorders: A Meta-Analysis of Randomized Controlled Trials.” The Australian and New Zealand Journal of Psychiatry 55, no. 2 (February 2021): 196–206. https://doi.org/10.1177/0004867420952540.
18. Liang, Shun-Chin, Cheuk-Kwan Sun, Hsin-Yi Fan, Weilun Chung, Ruu-Fen Tzang, Kuo-Chuan Hung, Hsien-Jane Chiu, Yu-Shian Cheng, and Pin-Yang Yeh. “Therapeutic Effects of Antidepressants for Global Improvement and Subdomain Symptoms of Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.” Journal of Psychiatry & Neuroscience: JPN 47, no. 4 (2022): E299–310. https://doi.org/10.1503/jpn.210191.
19. Persico, Antonio M., Arianna Ricciardello, Marco Lamberti, Laura Turriziani, Francesca Cucinotta, Claudia Brogna, Benedetto Vitiello, and Celso Arango. “The Pediatric Psychopharmacology of Autism Spectrum Disorder: A Systematic Review - Part I: The Past and the Present.” Progress in Neuro-Psychopharmacology & Biological Psychiatry 110 (August 30, 2021): 110326. https://doi.org/10.1016/j.pnpbp.2021.110326.
20. Ramerman, L., G. de Kuijper, T. Scheers, M. Vink, P. Vrijmoeth, and P. J. Hoekstra. “Is Risperidone Effective in Reducing Challenging Behaviours in Individuals with Intellectual Disabilities after 1 Year or Longer Use? A Placebo-Controlled, Randomised, Double-Blind Discontinuation Study.” Journal of Intellectual Disability Research: JIDR 63, no. 5 (May 2019): 418–28. https://doi.org/10.1111/jir.12584.
21. Ritter, Chantel, Katherine Hewitt, and Carly A. McMorris. “Psychotropic Polypharmacy Among Children and Youth with Autism: A Systematic Review.” Journal of Child and Adolescent Psychopharmacology 31, no. 4 (May 2021): 244–58. https://doi.org/10.1089/cap.2020.0110.
22. Rossignol, Daniel A., and Richard E. Frye. “A Systematic Review and Meta-Analysis of Immunoglobulin G Abnormalities and the Therapeutic Use of Intravenous Immunoglobulins (IVIG) in Autism Spectrum Disorder.” Journal of Personalized Medicine 11, no. 6 (May 30, 2021): 488. https://doi.org/10.3390/jpm11060488.
23. Rossignol, Daniel A., and Richard E. Frye. “Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.” Journal of Personalized Medicine 11, no. 11 (November 3, 2021): 1141. https://doi.org/10.3390/jpm11111141.
24. Rossignol, Daniel A., and Richard E. Frye. “The Effectiveness of Cobalamin (B12) Treatment for Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.” Journal of Personalized Medicine 11, no. 8 (August 11, 2021): 784. https://doi.org/10.3390/jpm11080784.
25. Salazar de Pablo, Gonzalo, Carolina Pastor Jordá, Julio Vaquerizo-Serrano, Carmen Moreno, Anna Cabras, Celso Arango, Patricia Hernández, et al. “Systematic Review and Meta-Analysis: Efficacy of Pharmacological Interventions for Irritability and Emotional Dysregulation in Autism Spectrum Disorder and Predictors of Response.” Journal of the American Academy of Child and Adolescent Psychiatry 62, no. 2 (February 2023): 151–68. https://doi.org/10.1016/j.jaac.2022.03.033.
26. Siafis, Spyridon, Oğulcan Çıray, Johannes Schneider-Thoma, Irene Bighelli, Marc Krause, Alessandro Rodolico, Anna Ceraso, et al. “Placebo Response in Pharmacological and Dietary Supplement Trials of Autism Spectrum Disorder (ASD): Systematic Review and Meta-Regression Analysis.” Molecular Autism 11, no. 1 (August 26, 2020): 66. https://doi.org/10.1186/s13229-020-00372-z.
27. Siafis, Spyridon, Oğulcan Çıray, Hui Wu, Johannes Schneider-Thoma, Irene Bighelli, Marc Krause, Alessandro Rodolico, et al. “Pharmacological and Dietary-Supplement Treatments for Autism Spectrum Disorder: A Systematic Review and Network Meta-Analysis.” Molecular Autism 13, no. 1 (March 4, 2022): 10. https://doi.org/10.1186/s13229-022-00488-4.
28. Siegel, Matthew, Kelly McGuire, Jeremy Veenstra-VanderWeele, Katharine Stratigos, Bryan King, Christopher Bellonci, Munya Hayek et al. "Practice parameter for the assessment and treatment of psychiatric disorders in children and adolescents with intellectual disability (intellectual developmental disorder)." Journal of the American Academy of Child & Adolescent Psychiatry 59, no. 4 (2020): 468-496.
29. Silva, Estácio Amaro da, Wandersonia Moreira Brito Medeiros, João Paulo Mendes Dos Santos, João Marçal Medeiros de Sousa, Filipe Barbosa da Costa, Katiúscia Moreira Pontes, Thaís Cavalcanti Borges, et al. “Evaluation of the Efficacy and Safety of Cannabidiol-Rich Cannabis Extract in Children with Autism Spectrum Disorder: Randomized, Double-Blind, and Placebo-Controlled Clinical Trial.” Trends in Psychiatry and Psychotherapy 46 (2024): e20210396. https://doi.org/10.47626/2237-6089-2021-0396.
30. Sprengers, Jan J., Dorinde M. van Andel, Nicolaas P. A. Zuithoff, Mandy G. Keijzer-Veen, Annelien J. A. Schulp, Floortje E. Scheepers, Marc R. Lilien, Bob Oranje, and Hilgo Bruining. “Bumetanide for Core Symptoms of Autism Spectrum Disorder (BAMBI): A Single Center, Double-Blinded, Participant-Randomized, Placebo-Controlled, Phase-2 Superiority Trial.” Journal of the American Academy of Child and Adolescent Psychiatry 60, no. 7 (July 2021): 865–76. https://doi.org/10.1016/j.jaac.2020.07.888.
31. Tsujii, Noa, Masahide Usami, Noriyuki Naya, Toshinaga Tsuji, Hirokazu Mishima, Junko Horie, Masakazu Fujiwara, and Junzo Iida. “Efficacy and Safety of Medication for Attention-Deficit Hyperactivity Disorder in Children and Adolescents with Common Comorbidities: A Systematic Review.” Neurology and Therapy 10, no. 2 (December 2021): 499–522. https://doi.org/10.1007/s40120-021-00249-0.
32. Ure, Alexandra, Georgina R. Cox, Richard Haslam, and Katrina Williams. “Acetylcholinesterase Inhibitors for Autistic Spectrum Disorders.” The Cochrane Database of Systematic Reviews 6, no. 6 (June 1, 2023): CD013851. https://doi.org/10.1002/14651858.CD013851.pub2.