PMID- 37811711 OWN - NLM STAT- MEDLINE DCOM- 20231101 LR - 20240515 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 10 IP - 10 DP - 2023 Oct 9 TI - Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD). PG - CD011769 LID - 10.1002/14651858.CD011769.pub2 [doi] LID - CD011769 AB - BACKGROUND: Pharmacological interventions are frequently used for people with autism spectrum disorder (ASD) to manage behaviours of concern, including irritability, aggression, and self-injury. Some pharmacological interventions might help treat some behaviours of concern, but can also have adverse effects (AEs). OBJECTIVES: To assess the effectiveness and AEs of pharmacological interventions for managing the behaviours of irritability, aggression, and self-injury in ASD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, 11 other databases and two trials registers up to June 2022. We also searched reference lists of relevant studies, and contacted study authors, experts and pharmaceutical companies. SELECTION CRITERIA: We included randomised controlled trials of participants of any age with a clinical diagnosis of ASD, that compared any pharmacological intervention to an alternative drug, standard care, placebo, or wait-list control. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Primary outcomes were behaviours of concern in ASD, (irritability, aggression and self-injury); and AEs. Secondary outcomes were quality of life, and tolerability and acceptability. Two review authors independently assessed each study for risk of bias, and used GRADE to judge the certainty of the evidence for each outcome. MAIN RESULTS: We included 131 studies involving 7014 participants in this review. We identified 26 studies as awaiting classification and 25 as ongoing. Most studies involved children (53 studies involved only children under 13 years), children and adolescents (37 studies), adolescents only (2 studies) children and adults (16 studies), or adults only (23 studies). All included studies compared a pharmacological intervention to a placebo or to another pharmacological intervention. Atypical antipsychotics versus placebo At short-term follow-up (up to 6 months), atypical antipsychotics probably reduce irritability compared to placebo (standardised mean difference (SMD) -0.90, 95% confidence interval (CI) -1.25 to -0.55, 12 studies, 973 participants; moderate-certainty evidence), which may indicate a large effect. However, there was no clear evidence of a difference in aggression between groups (SMD -0.44, 95% CI -0.89 to 0.01; 1 study, 77 participants; very low-certainty evidence). Atypical antipsychotics may also reduce self-injury (SMD -1.43, 95% CI -2.24 to -0.61; 1 study, 30 participants; low-certainty evidence), possibly indicating a large effect. There may be higher rates of neurological AEs (dizziness, fatigue, sedation, somnolence, and tremor) in the intervention group (low-certainty evidence), but there was no clear evidence of an effect on other neurological AEs. Increased appetite may be higher in the intervention group (low-certainty evidence), but we found no clear evidence of an effect on other metabolic AEs. There was no clear evidence of differences between groups in musculoskeletal or psychological AEs. Neurohormones versus placebo At short-term follow-up, neurohormones may have minimal to no clear effect on irritability when compared to placebo (SMD -0.18, 95% CI -0.37 to -0.00; 8 studies; 466 participants; very low-certainty evidence), although the evidence is very uncertain. No data were reported for aggression or self -injury. Neurohormones may reduce the risk of headaches slightly in the intervention group, although the evidence is very uncertain. There was no clear evidence of an effect of neurohormones on any other neurological AEs, nor on any psychological, metabolic, or musculoskeletal AEs (low- and very low-certainty evidence). Attention-deficit hyperactivity disorder (ADHD)-related medications versus placebo At short-term follow-up, ADHD-related medications may reduce irritability slightly (SMD -0.20, 95% CI -0.40 to -0.01; 10 studies, 400 participants; low-certainty evidence), which may indicate a small effect. However, there was no clear evidence that ADHD-related medications have an effect on self-injury (SMD -0.62, 95% CI -1.63 to 0.39; 1 study, 16 participants; very low-certainty evidence). No data were reported for aggression. Rates of neurological AEs (drowsiness, emotional AEs, fatigue, headache, insomnia, and irritability), metabolic AEs (decreased appetite) and psychological AEs (depression) may be higher in the intervention group, although the evidence is very uncertain (very low-certainty evidence). There was no evidence of a difference between groups for any other metabolic, neurological, or psychological AEs (very low-certainty evidence). No data were reported for musculoskeletal AEs. Antidepressants versus placebo At short-term follow-up, there was no clear evidence that antidepressants have an effect on irritability (SMD -0.06, 95% CI -0.30 to 0.18; 3 studies, 267 participants; low-certainty evidence). No data for aggression or self-injury were reported or could be included in the analysis. Rates of metabolic AEs (decreased energy) may be higher in participants receiving antidepressants (very low-certainty evidence), although no other metabolic AEs showed clear evidence of a difference. Rates of neurological AEs (decreased attention) and psychological AEs (impulsive behaviour and stereotypy) may also be higher in the intervention group (very low-certainty evidence) although the evidence is very uncertain. There was no clear evidence of any difference in the other metabolic, neurological, or psychological AEs (very low-certainty evidence), nor between groups in musculoskeletal AEs (very low-certainty evidence). Risk of bias We rated most of the studies across the four comparisons at unclear overall risk of bias due to having multiple domains rated as unclear, very few rated as low across all domains, and most having at least one domain rated as high risk of bias. AUTHORS' CONCLUSIONS: Evidence suggests that atypical antipsychotics probably reduce irritability, ADHD-related medications may reduce irritability slightly, and neurohormones may have little to no effect on irritability in the short term in people with ASD. There was some evidence that atypical antipsychotics may reduce self-injury in the short term, although the evidence is uncertain. There was no clear evidence that antidepressants had an effect on irritability. There was also little to no difference in aggression between atypical antipsychotics and placebo, or self-injury between ADHD-related medications and placebo. However, there was some evidence that atypical antipsychotics may result in a large reduction in self-injury, although the evidence is uncertain. No data were reported (or could be used) for self-injury or aggression for neurohormones versus placebo. Studies reported a wide range of potential AEs. Atypical antipsychotics and ADHD-related medications in particular were associated with an increased risk of metabolic and neurological AEs, although the evidence is uncertain for atypical antipsychotics and very uncertain for ADHD-related medications. The other drug classes had minimal or no associated AEs. CI - Copyright (c) 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Iffland, Michelle AU - Iffland M AD - Senior Practitioner Branch, NDIS Quality and Safeguards Commission, Penrith, Australia. FAU - Livingstone, Nuala AU - Livingstone N AD - Cochrane Evidence Production and Methods Directorate , Cochrane, London, UK. FAU - Jorgensen, Mikaela AU - Jorgensen M AD - Senior Practitioner Branch, NDIS Quality and Safeguards Commission, Penrith, Australia. FAU - Hazell, Philip AU - Hazell P AD - Speciality of Psychiatry, University of Sydney School of Medicine, Sydney, Australia. FAU - Gillies, Donna AU - Gillies D AD - Senior Practitioner Branch, NDIS Quality and Safeguards Commission, Penrith, Australia. AD - Sydney, Australia. LA - eng SI - ClinicalTrials.gov/NCT00872898 SI - ClinicalTrials.gov/NCT00490802 SI - ClinicalTrials.gov/NCT00773812 SI - ClinicalTrials.gov/NCT00873509 SI - ClinicalTrials.gov/NCT01333072 SI - ClinicalTrials.gov/NCT01227668 SI - ClinicalTrials.gov/NCT00844753 SI - ClinicalTrials.gov/NCT01592747 SI - ClinicalTrials.gov/NCT00380692 SI - ClinicalTrials.gov/NCT00515320 SI - ClinicalTrials.gov/NCT00004486 SI - ClinicalTrials.gov/NCT00211757 SI - ClinicalTrials.gov/NCT01040221 SI - ClinicalTrials.gov/NCT01617447 SI - ClinicalTrials.gov/NCT00576732 SI - ClinicalTrials.gov/NCT00086645 SI - ClinicalTrials.gov/NCT02552147 SI - ClinicalTrials.gov/NCT01911442 SI - ClinicalTrials.gov/NCT00005014 SI - ClinicalTrials.gov/NCT01086475 SI - ClinicalTrials.gov/NCT00183339 SI - ClinicalTrials.gov/NCT00198107 SI - ClinicalTrials.gov/NCT00468130 SI - ClinicalTrials.gov/NCT00498173 SI - ClinicalTrials.gov/NCT01337687 SI - ClinicalTrials.gov/NCT01624675 SI - ClinicalTrials.gov/NCT01908205 SI - ClinicalTrials.gov/NCT01972074 SI - ClinicalTrials.gov/NCT02940574 SI - ClinicalTrials.gov/NCT00365859 SI - ClinicalTrials.gov/NCT01624194 SI - ClinicalTrials.gov/NCT01962870 SI - ClinicalTrials.gov/NCT00178503 SI - ClinicalTrials.gov/NCT00025779 SI - ClinicalTrials.gov/NCT01238575 SI - ClinicalTrials.gov/NCT01944046 SI - ClinicalTrials.gov/NCT01793441 SI - ClinicalTrials.gov/NCT00065962 SI - ClinicalTrials.gov/NCT00453180 SI - ClinicalTrials.gov/NCT01098383 SI - ClinicalTrials.gov/NCT00057408 SI - ClinicalTrials.gov/NCT00198120 SI - ClinicalTrials.gov/NCT01914939 SI - ClinicalTrials.gov/NCT01970345 SI - ClinicalTrials.gov/NCT03553875 SI - ClinicalTrials.gov/NCT04520685 SI - ClinicalTrials.gov/NCT03887676 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PT - Systematic Review DEP - 20231009 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Antipsychotic Agents) RN - 0 (Antidepressive Agents) RN - 0 (Neurotransmitter Agents) SB - IM UOF - doi: 10.1002/14651858.CD011769 MH - Child MH - Adult MH - Adolescent MH - Humans MH - *Autism Spectrum Disorder/drug therapy MH - Quality of Life MH - *Antipsychotic Agents/therapeutic use MH - Antidepressive Agents/therapeutic use MH - Aggression MH - *Self-Injurious Behavior/drug therapy MH - Fatigue MH - Neurotransmitter Agents/pharmacology PMC - PMC10561353 COIS- Michelle Iffland is a Research Officer with the NDIS Quality and Safeguards Commission, NSW. The NDIS Quality and Safeguards Commission is committed to reducing and eliminating the use of restrictive practices in people with a disability. Donna Gillies is the Director for Research and Practice Evidence with the NDIS Quality and Safeguards Commission, Penrith, NSW. The NDIS Quality and Safeguards Commission is committed to reducing and eliminating the use of restrictive practices in people with a disability. Nuala Livingstone is a Quality Assurance Editor with the Cochrane Evidence Production and Methods Directorate, Central Editorial Service, and an Editor with Cochrane Developmental, Psychosocial and Developmental Problems (DPLP); UK. Nuala Livingstone was not involved in the editorial process for this article Mikaela Jorgensen is the Assistant Director of Research with the NDIS Quality and Safeguards Commission, NSW, which is committed to the reduction and elimination of restrictive practices for people with disability. Philip Hazell (PH) reports payments for lectures, for Lilly, Janssen, Pfizer and Shire, and advisory boards for Lilly, Janssen and Shire related to the pharmacological management of child and adolescent mental disorders in general; paid to Sydney Local Health District; PH is a Consultant Psychiatrist for Sydney Local Health District, NSW, and an Editor with Cochrane Developmental, Psychosocial and Learning Problems, UK. PH reports being involved in a study eligible for inclusion in this review: Multisite randomised control trail of fluoxetine for children and adolescents with autism; the study was funded by NHMRC and hosted by Murdoch Children's Research Institute, VIC. The researchers retained complete control over the study design, methods, data analysis and reporting. PH was not involved in assessing the studies for eligibility, extracting data from the studies, or assessing the risk of bias or grading the certainty of the evidence; these methods were completed by two independent review authors (DG, MI, MJ, NL). EDAT- 2023/10/09 12:42 MHDA- 2023/11/01 12:43 PMCR- 2024/10/09 CRDT- 2023/10/09 06:43 PHST- 2024/10/09 00:00 [pmc-release] PHST- 2023/11/01 12:43 [medline] PHST- 2023/10/09 12:42 [pubmed] PHST- 2023/10/09 06:43 [entrez] AID - CD011769.pub2 [pii] AID - 10.1002/14651858.CD011769.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2023 Oct 9;10(10):CD011769. doi: 10.1002/14651858.CD011769.pub2.