It's been over two years since I wrote Mental Elf blog with my pediatrician colleague (Suetani S and Panagoda G, 2022) on the findings from the evidence in the treatment of attention-deficit/hyperactivity disorder (ADHD). We thought ADHD was a hot topic at the time, but two and a half years later, it remains very hot.
Since then, several important Mental Elf blogs on ADHD (eg ADHD and intimate partner violence (Bhavsar V and Duggal J, 2023), ADHD and truancy (Fielding C, 2022), ADHD and academic performance (Badenoch D, 2022)). Although the evidence base for ADHD is growing rapidly, many key questions remain unanswered (Chaulagain A et al., 2023), including how to assess the utility of interventions with low/no evidence of clinical evidence – the subject of another Mental Elf blog (Karmakar S). 2022).
An emerging priority in ADHD: How relevant is the research evidence we have to the patient sitting in front of me?
A new study published today by Lancet Psychiatry Garcia-Argibay et al (2025) explores this question.
ADHD is a “hot topic” in mental health science right now, and rightfully so, as there are many unanswered questions that research can actually improve people's lives.
Methods
Using data from multiple Swedish national registries, the authors identified everyone with a diagnosis of ADHD who had received ADHD medication. Based on their analysis of 164 RCTs of ADHD medications, they divided the cohort into those eligible and those not eligible for a typical ADHD randomized controlled trial (RCT).
The most common exclusion criteria include: antidepressant use, psychosis, bipolar disorder, substance use disorder, cardiovascular disorder, learning disability/low IQ, anxiety disorder, and autism spectrum disorder.
The study compared two groups:
Preliminary results
- Changing treatment
- Discontinuation of treatment.
Secondary outcomes
- Number of inpatient psychiatric hospitalizations
- Number of emergency department visits or hospitalizations for accidental injuries or accidents
- Experience specialist care for an alcohol or drug-related diagnosis, depression or anxiety.
Results
Of the 189,699 subjects included in this study, just over half (53%) were classified as ineligible for a typical ADHD medication RCT. The proportion of ineligible individuals was higher for adults aged 17 and older (74%) than for adolescents (35%) or children (21%).
Let me repeat that for emphasis: more than 70% of adults were ineligible for a typical ADHD medication RCT.
In terms of preliminary results;
- The noncompliant group had a higher risk of transition to treatment than the compliant group (hazard ratio (HR) 1.14, 95% confidence interval (CI) 1.12–1.16)
- The nonadherent group had a slightly lower risk of drug discontinuation (HR 0.96 with 95% CI 0.94–0.98)
In terms of secondary outcomes:
- The noncompliant group had a higher risk
- inpatient psychiatric hospitalizations (incidence ratio (IRR) 9.68 with 95% CI 9.57–9.78)
- Emergency department visits or hospitalizations for accidental injuries or accidents (IRR 1.31, 95% CI 1.27–1.35)
- Specialist care for an alcohol or drug-related diagnosis (IRR 14.78, 95% CI 14.64–14.91), depression (IRR 6.00, 95% CI 5.94–6.06) or anxiety (IRR 11.63, 95% CI 11.5–11.5)
Of note, the mean age for the eligible group was 13 (age range 10–16) compared to 26 (age range 17–37) for the ineligible group. For adults (age 17 and older), the median age for the eligible group was 20 (age range 17–29) compared to 30 (age range 23–40) for the ineligible group.
This study found that more than 70% of adults are not eligible for a typical ADHD drug research trial (RCT). Can we trust the evidence we produce if we exclude such a large proportion of people from our research?
Results
The authors concluded that:
(the) study showed that a significant part People with ADHD, especially adultsthere is not suitable for standard RCTsand there are these individuals higher rates of adverse clinical outcomes compared to their matched counterparts.
As the authors point out in the discussion section, we have a paradox especially for adults with ADHD;
the patients most likely to benefit from evidence-based guidance are the most underrepresented in clinical trials designed to inform management.
These ADHD researchers conclude that “patients most likely to benefit from evidence-based guidance are underrepresented in clinical trials designed to inform guidance.”
Strengths and limitations
This is an exceptional study. The authors proposed a key question, collected a large amount of data, and analyzed it to obtain relevant findings. All studies were elegant in design and elegant in delivery.
As the authors acknowledge, the study has the usual limitations associated with cohort studies. There is especially lack of fine-grained clinical data at the individual patient level. This meant that the study used sharper instruments to assess clinical parameters, as was most evident in the study's secondary outcomes.
For example, the number of inpatient psychiatric hospitalizations has been used as a proxy for overall psychiatric burden. At least in Australia I've never seen anyone go to a public hospital for a relapse of ADHD. The number of emergency department visits or hospitalizations for accidental injuries or accidents has been used as an objective measure of functional impairment, but it is an unusual way to assess someone's daily functioning. Although comorbidity is the rule, not the exception, among adults with ADHD and the clinical approach can be difficult (Katzman MA et al, 2017), I am not convinced that many of them will need specialist care for their disease.
Finally, I know very little about Sweden, but I think the legal framework for prescribing psychostimulant drugs will be different to Australia, where I have experience. ADHD drug prescriptions are also very high in Sweden Compared to places like the UK or Australia. However, this rate is much lower than that seen in North America (Chan AYL et al., 2023). I also suspect that many cultural factors outside of the health system, such as per capita gross domestic product and societal attitudes toward the concept of ADHD, will play a large role in how you view the condition in different countries.
This study was conducted in Sweden. When considering the relevance of research, we must always ask ourselves whether patients and settings are so different that we cannot apply this evidence to our own situation.
Implications for practice
As a clinician, I want to know the answer to the question; “Will this medication help my patient get better in this condition?“no”How well does this drug work under ideal conditions?“
As an adult psychiatrist, most of my patients present for ADHD evaluation in their 30s and 40s. How much confidence would you have in your evidence-based guidance if you knew that more than 70% of your patients were not eligible to participate in a typical RCT? To misquote Winston Churchill, is RCT the worst form of evidence (except for all the other forms that have been tested from time to time)?
The authors suggest a more comprehensive approach to clinical research in ADHD. Given that this is not a problem unique to ADHD, I would argue that we should consider a similar approach for all psychiatric conditions. They offer Combining results from RCTs, pragmatic trials, observational studies and targeted trials in commonly excluded populations to triangulate data to provide clinicians with a better understanding of the effectiveness of each intervention in different cohorts. I would also add local service level information to the mix. In certain circumstances, a small amount of fine-grained clinical information about a given population may be more valuable than a large amount of high-level data.
We also need to agree on what to measure. How do we measure results at the individual level? What do we mean by functional impairment? Do we want our patients to be less distracted or do we want them to be employed? How do we measure results at the population level? If we adequately treat ADHD in a population, will we as a society see a reduction in lost productivity? And is population-level productivity a legitimate reason and measurable outcome to treat the patient sitting in front of me?
This is an opportunity to take the results of this exceptional research to move the field forward. All that glitters is not gold; RCTs may no longer be the gold standard of clinical research in psychiatry. We urgently need to build the bridge that takes us from effectiveness to effectiveness.
All that glitters is not gold. Should we rely less on RCTs and be more open-minded about different types of evidence?
Statement of interest
Shuichi is a member of the Royal Australian and New Zealand College of Psychiatrists' ADHD Network and the Australian Association of ADHD Professionals.
Connections
Primary paper
Garcia-Argibay M, Chang Z, Brickell I. et al (2025) Assessing ADHD medication trial representativeness: a Swedish population-based study comparing hypothetical trial eligible and non-trial eligible individuals. Lancet Psychiatry (in press)
Other references
Badenoch D. ADHD is a significant risk factor for poor academic performance, according to new research from Norway's #CAMHScampfire. Mental Elf, 23 September 2022.
Bhavsar V and Duggal J. What is the evidence for ADHD as a risk factor for intimate partner violence or sexual violence? Mental Elf, November 6, 2023.
Chan AYL, Ma TT, Lau WCY et al (2023). Consumption of attention-deficit/hyperactivity disorder medications in 64 countries and regions from 2015 to 2019: a longitudinal study. EClinical Medicine. 2023 Mar 20;58:101780. doi: 10.1016/j.eclinm.2022.101780. PMID: 37181411; PMCID: PMC10166776.
Chaulagain A, Lyhmann I, Halmøy A. et al (2023) A systematic meta-review of systematic reviews of attention deficit hyperactivity disorder. Eur Psychiatry. 2023 Nov 17;66(1):e90. doi: 10.1192/j.eurpsy.2023.2451. PMID: 37974470; PMCID: PMC10755583.
Fielding C. What is the relationship between neurodevelopmental or mental disorders and truancy or exclusion from school? Mental Elf, November 10, 2022.
Karmakar S. Behavior therapy can reduce symptoms of inattention in adults with ADHD. Mental Elf, 24 Jan 2022.
Katzman MA, Bilkey TS, Chokka PR. et al (2017) Adult ADHD and comorbid disorders: clinical implications of a dimensional approach. BMC Psychiatry. 2017 Aug 22;17(1):302. doi: 10.1186/s12888-017-1463-3. PMID: 28830387; PMCID: PMC5567978.
Suetani S and Pangoda G. 1999. Criticizing the evidence behind “evidence-based conclusions” about ADHD. Mental Elf, 21 September 2022.