Title: Comparing pharmacological and non-pharmacological interventions for adults with Attention-Deficit/Hyperactivity Disorder (ADHD): systematic review and network meta-analysis
Funder: Department of Health and Social Care

Abstract: Research question: How do pharmacological treatments, non-pharmacological interventions, or their combinations compare with each other in terms of efficacy in treating core symptoms and related dysfunctions (e.g., emotional dysregulation), as well as tolerability, in adults with Attention-Deficit/Hyperactivity Disorder (ADHD)? Background: ADHD is the most common neurodevelopmental condition in children, and its impairing symptoms persist into adulthood in more than 70% of childhood cases, with an estimated prevalence at &sim;2.5% in the general adult population. If untreated, adult ADHD is associated with substantial societal burden, estimated at around &pound;20,000/person/yr. Provision of care for adults with ADHD in the UK is currently under-resourced, patchy and heterogeneous in terms of treatments offered. Rigorous evidence synthesis on the efficacy and tolerability of available treatment options is crucial to inform clinical decision-making and improve the quality of care and effectiveness of NHS provision for adults with ADHD. In fact, the implementation of ineffective treatments would ultimately lead to additional burden for already overstretched NHS adult mental health and primary care systems. Aims and objectives: To conduct the first network meta-analysis (NMA) including, in the same network, randomised controlled trials (RCTs) of pharmacological and non-pharmacological interventions (or their combinations) in adults with ADHD. Methods: We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and its extension for NMAs. The protocol is registered in PROSPERO (CRD42021265576). We will search a broad set of electronic databases/registries and contact drug companies and experts in the field to retrieve published and unpublished RCTs (parallel or cross-over) of medications (UK licensed or unlicensed) and any non-pharmacological intervention in adults (&ge; 18 years) with ADHD. Primary outcomes will be: 1) change in severity of ADHD core symptoms, and 2) acceptability (all-cause discontinuation). Secondary outcomes will include tolerability (drop-out due to side effects) and change in the severity of emotional dysregulation, executive dysfunctions, and quality of life. The risk of bias in each individual RCT included in the NMA will be assessed using the Cochrane Risk of Bias tool-version 2. We will evaluate the transitivity assumption comparing the distribution of possible effect modifiers across treatment comparisons. We will perform Bayesian network meta-analysis for each outcome with random-effects model in OpenBUGS. Pooled estimates of network meta-analysis will be obtained using the Markov Chains Monte Carlo method. We will judge the credibility in the evidence derived from the NMA using the CINeMA tool. We will conduct a series of sensitivity analyses to assess the robustness of the findings. Anticipated Impact and Dissemination: We anticipate formal peer-reviewed publication by December 2024. By June 2025, the findings will be disseminated to NICE, other guidelines groups (e.g., SIGN) and other relevant stakeholders. Based on the temporal lag between the current and previous version of the NICE guidelines, we expect that a dissemination of the findings to NICE in June 2025 will be extremely timely to inform the next revision of the NICE guidelines. We expect NICE and other guidelines to impact clinical practice in the NHS soon after their publication.

Lay abstract: Aim: We want to understand which are the best treatments for adults with ADHD. Background: Children with ADHD have problems with attention. They also need to move more than most children. Many children with ADHD continue to have ADHD as adults. When not treated, each adult with ADHD costs to society more than &pound;20,000 per year. Experts and ADHD support groups think that the NHS does not meet the needs of adults with ADHD. There are long waiting lists for many adults who seek help for ADHD in the NHS: up to several years in many parts of the UK. We need to make sure that the NHS offer treatments that work well. Based on studies up to 2017, NICE recommended medicines as the main treatment for adults with ADHD. However, some people need additional treatments. Also, some people do not feel well with medicines and need alternative treatments. In 2017, there were only a few studies on treatments other than medicines for adults with ADHD. Since then, new studies have found that some treatments, such as talking therapy, work well for several problems that adults with ADHD have. So, we need to understand how the different treatments compare with each other. We also need to know which aspects of ADHD available treatments can improve. Methods: We will not do a new study of people with ADHD to see how well treatments for ADHD work. This would be very expensive. Rather, we will use studies that are already available. We will search for studies of medicines, talk therapies, and brain therapies for adults with ADHD. We will then use a new method to put together the information from these studies. We are well known experts in this type of research. We will understand what is the best treatment for adults with ADHD. We will also understand how different treatments improve different difficulties in people ADHD. Patient and public involvement: We have worked with the president of a group of patients with ADHD in the UK, other experts, and people with lived experience of ADHD. Adults with ADHD and their families will help us understanding better the results of our research. Dissemination: We will communicate our results to people working in the NHS, patients, and their families. With their help, we will make recommendations on how best to treat ADHD.

Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH