Taiwanese Population Study Finds Strong Association Between Cleft Lip and Palate and Subsequent ADHD

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Stimulant medications have long been considered the default first-line treatment for attention-deficit/hyperactivity disorder (ADHD). Clinical guidelines, prescribing practices, and public narratives all reinforce the idea that stimulants should be tried first, with non-stimulants reserved for cases where stimulants fail or are poorly tolerated.

I recently partnered with leading ADHD researcher Jeffrey Newcorn for a Nature Mental Health commentary on the subject. We argue that this hierarchy deserves reexamination. It is important to note that our position is not anti-stimulant. Rather, we call into question whether the evidence truly supports treating non-stimulants as secondary options, and we propose that both classes should be considered equal first-line treatments.

What the Evidence Really Shows

Stimulants have earned their reputation as the go-to drug of choice for ADHD. They are among the most effective medications in psychiatry, reliably reducing core ADHD symptoms and improving daily functioning when properly titrated and monitored. However, when stimulant and non-stimulant medications are compared more closely, the gap between them appears smaller than commonly assumed.

Meta-analyses often report slightly higher average response rates for stimulants, but head-to-head trials where patients are directly randomized to one medication versus another frequently find no statistically significant differences in symptom improvement or tolerability. Network meta-analyses similarly show that while some stimulant formulations have modest advantages, these differences are small and inconsistent, particularly in adults.

When translated into clinical terms, the advantage of stimulants becomes even more modest. Based on existing data, approximately eight patients would need to be treated with a stimulant rather than a non-stimulant for one additional person to experience a meaningful benefit. This corresponds to only a 56% probability that a given patient will respond better to a stimulant than to a non-stimulant. This difference is not what we would refer to as “clinically significant.” 

How The Numbers Can Be Misleading

One reason non-stimulants may appear less effective is the way efficacy is typically reported. Most comparisons rely on standardized mean differences, a method of averages that may mask heterogeneity of treatment effects. In reality, ADHD medications do not work uniformly across patients.

For example, evidence suggests that response to some non-stimulants, such as atomoxetine, is bimodal: this means that many patients respond extremely well, while others respond poorly, with few in between. When this happens, average effect sizes can obscure the fact that a substantial subgroup benefits just as much as they would from a stimulant. In other words, non-stimulants are not necessarily less effective across the board, but that they are simply different in who they help.

Limitations of Clinical Trials

In our commentary, we also highlight structural issues in ADHD research. Stimulant trials are particularly vulnerable to unblinding, as their immediate and observable physiological effects can reveal treatment assignment, potentially inflating perceived efficacy. Non-stimulants, with slower onset and subtler effects, are less prone to this bias.

Additionally, many randomized trials exclude patients with common psychiatric comorbidities such as anxiety, depression, or substance-use disorders. Using co-diagnoses as exclusion criteria for clinical trials on ADHD medications is nonviable when considering the large number of ADHD patients who also have other diagnoses. Real-world data suggest that a large proportion of individuals with ADHD would not qualify for typical trials, limiting how well results generalize to everyday clinical practice.

Considering the Broader Impact

Standard evaluations of medication tolerability focus on side effects experienced by patients, but this narrow lens misses broader societal consequences. Stimulants are Schedule II controlled substances, which introduces logistical barriers, regulatory burdens, supply vulnerabilities, and administrative strain for both patients and clinicians.

When used as directed, stimulant medications do not increase risk of substance-use disorders (and, in fact, tend to reduce these rates); however, as ADHD awareness has spread and stimulants are more widely prescribed, non-medical use of prescription stimulants has become more widespread, particularly among adolescents and young adults. Non-stimulants do not carry these risks.

Toward Parallel First-Line Options

Non-stimulants are not without drawbacks themselves, however. They typically take longer to work and have higher non-response rates, making them less suitable in situations where rapid results are essential. These limitations, however, do not justify relegating them to second-line status across the board.

This is a call for abandoning a one-size-fits-all approach. Instead, future guidelines should present stimulant and non-stimulant medications as equally valid starting points, clearly outlining trade-offs related to onset, efficacy, misuse risk, and practical burden.

The evidence already supports this shift. The remaining challenge is aligning clinical practice and policy with what the data, and patient-centered care, are increasingly telling us.

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Today, most treatment guidelines recommend starting ADHD treatment with stimulant medications. These medicines often work quickly and can be very effective, but they do not help every child, and they can have bothersome side effects, such as appetite loss, sleep problems, or mood changes. Families also worry about long-term effects, the possibility of misuse or abuse, as well as the recent nationwide stimulant shortages. Non-stimulant medications are available, but they are usually used only after stimulants have not been effective.

This stimulant-first approach means that many patients who would respond well to a non-stimulant will end up on a stimulant medication anyway. This study addresses this issue by testing two different ways of starting medication treatment for school-age children with attention-deficit/hyperactivity disorder (ADHD). We want to know whether beginning with a non-stimulant medicine can work as well as the  “stimulant-first” approach, which is currently used by most prescribers.

From this study, we hope to learn:

• Is starting with a non-stimulant medication “good enough” compared with starting with a stimulant?
  In other words, when we look at overall improvement in a child’s daily life, not just ADHD symptoms, does a non-stimulant-first approach perform similarly to a stimulant-first approach?
• Which children do better with which approach?
  Children with ADHD are very different from one another. Some have anxiety, depression, learning problems, or autism spectrum conditions. We want to know whether certain groups of children benefit more from starting with stimulants, and others from starting with non-stimulants.
• How do the two strategies compare for side effects, treatment satisfaction, and staying on medication?
  We will compare how often children stop or switch medications because of side effects or lack of benefit, and how satisfied children, parents, and clinicians are with care under each strategy.
• What are the longer-term outcomes over a year?
  We are interested not only in short-term symptom relief, but also in how children are doing months later in school, at home, with friends, and emotionally.

Our goal is to give families and clinicians clear, practical evidence to support a truly shared decision: “Given this specific child, should we start with a stimulant or a non-stimulant?”

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Who will be in the study?

We will enroll about 1,000 children and adolescents, ages 6 to 16, who:

• Have ADHD and are starting or restarting medication treatment, and
• Are being treated in everyday pediatric and mental health clinics at large children’s hospitals and health systems across the United States.

We will include children with common co-occurring conditions (such as anxiety, depression, learning or developmental disorders) so that the results reflect the “real-world” children seen in clinics, not just highly selected research volunteers.

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How will the treatments be assigned?

This is a randomized comparative effectiveness trial, which means:

• Each child will be randomly assigned (like flipping a coin) to one of two strategies:
  
  
  
  1. Stimulant-first strategy – the clinician starts treatment with a stimulant medication.
  2. Non-stimulant-first strategy – the clinician starts treatment with a non-stimulant medication.
• Within the assigned class, the clinician and family still choose the specific medicine and dose, and can adjust treatment as they normally would. This keeps the study as close as possible to real-world practice.
• The randomization is 1:1, so about half the participants will start with stimulants and half with non-stimulants.

Parents and clinicians will know which type of medicine the child is taking, as in usual care. However, the experts who rate how much each child has improved using our main outcome measure will not be told which treatment strategy the child received. This helps keep their ratings unbiased.

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What will participants be asked to do?

Each family will be followed for 12 months. We will collect information at:

• Baseline (before or just as medication is started)
• Early follow-up (about weeks 3 and 6)
• Later follow-up (about 3 months, 6 months, and 12 months)

At these times:

• Parents will complete questionnaires about ADHD symptoms, behavior, emotions, and daily functioning at home and in the community.
• Teachers will complete brief forms about the child’s behavior and performance at school.
• Children and teens (when old enough) will complete age-appropriate questionnaires about their own mood, behavior, and quality of life.
• A specially trained clinical rater, using all available information but blinded to treatment strategy, will give a global rating of how much the child has improved overall, not just in ADHD symptoms.

We will also track:

• Medication changes (stopping, switching, or adding medicines)
• Reasons for any changes (side effects, lack of benefit, or other reasons)
• Any serious side effects or safety concerns

Data will be entered into a secure, HIPAA-compliant research database. Study staff at each site will work closely with families to make participation as convenient as possible, including offering flexible visit schedules and electronic options for completing forms when feasible.

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How will we analyze the results?

Using standard statistical methods, we will:

• Compare the overall improvement of children in the stimulant-first group versus the non-stimulant-first group after 12 months.
• Look at differences in side effects, discontinuation rates, and treatment satisfaction between the two strategies.
• Examine which child characteristics (such as age, sex, co-occurring conditions, and baseline severity) are linked to better results with one strategy versus the other.
• Analyze long-term outcomes, including functioning at home, school, and with peers, and emotional well-being.

All analyses will follow the “intention-to-treat” principle, meaning we compare children based on the strategy they were originally assigned to, even if their medication is later changed. This mirrors real-world decision-making: once you choose a starting strategy, what tends to happen over time?

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Why is this study necessary now?

This study addresses a critical, timely gap in ADHD care:

• Guidelines are ahead of the evidence.
  Existing guidelines almost always recommend stimulants as the first-line medication, yet careful reviews of the evidence show that direct comparisons of stimulant-first versus non-stimulant-first strategies are limited. We do not have strong data to say that starting with stimulants is clearly superior for all children.
• Real-world children are more complex than those in past trials.
  Most prior medication trials have excluded children with multiple conditions, serious family stressors, or other complexities that are very common in everyday practice. Our pragmatic, multi-site design will include these children and thus produce findings that are directly relevant to front-line clinicians and families.
• Families and clinicians are asking for alternatives.
  Parents often express worries about stimulant side effects, long-term use, and stigma. Clinicians would like clearer guidance about when a non-stimulant is a reasonable first choice. At the same time, stimulant shortages and concerns about misuse and diversion have exposed the risks of relying almost entirely on one class of medications.
• The timing is right to influence practice and policy.
  Our team includes parents, youth advocates, frontline clinicians, and national networks that link major children’s hospitals. These partners have helped shape the study from the beginning and will help interpret and share the results. This means that if starting with non-stimulants is found to be similarly effective and safer or more acceptable for some children, practice patterns and guidelines can change rapidly.

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In short, this study is needed now to move ADHD medication decisions beyond “one-size-fits-all.” By rigorously comparing stimulant-first and non-stimulant-first strategies in real-world settings, and by focusing on what matters most to children and families overall functioning, side effects, and long-term well-being, we aim to give patients, parents, and clinicians the information they need to choose the best starting treatment for each child.

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This project was conceived by Professor Stephen V. Faraone, PhD (SUNY Upstate Medical University, Department of Psychiatry, Syracuse, NY) and Professor Jeffrey H. Newcorn, MD (Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, NY).   It will be conducted at nine sites across the USA.

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EBI-ADHD: 

If you live with ADHD, treat ADHD, or write about ADHD, you’ve probably run into the same problem: there’s a ton of research on treatments, but it’s scattered across hundreds of papers that don’t talk to each other.  The EBI-ADHD website fixes that. 

EBI-ADHD (Evidence-Based Interventions for ADHD) is a free, interactive platform that pulls together the best available research on how ADHD treatments work and how safe they are. It’s built for clinicians, people with ADHD and their families, and guideline developers who need clear, comparable information rather than a pile of PDFs. EBI-ADHD Database  The site is powered by 200+ meta-analyses covering 50,000+ participants and more than 30 different interventions.  These include medications, psychological therapies, brain-stimulation approaches, and lifestyle or “complementary” options. 

The heart of the site is an interactive dashboard.  You can: 

1. Choose an age group: children (6–17), adolescents (13–17), or adults (18+). 

2. Choose a time frame: results at 12, 26, or 52 weeks. 

3. Choose whether to explore by intervention (e.g., methylphenidate, CBT, mindfulness, diet, neurofeedback) or by outcome (e.g., ADHD symptoms, functioning, adverse events), depending on what’s available. EBI-ADHD Database 

The dashboard then shows an evidence matrix: a table where each cell is a specific treatment–outcome–time-point combination. Each cell tells you two things at a glance: 

1. How big the effect is, compared to placebo or another control (large benefit, small benefit, no effect, small negative impact, large negative impact). 

2. How confident we can be in that result (high, moderate, low, or very low certainty).  

Clicking a cell opens more detail: effect sizes, the underlying meta-analysis, and how the certainty rating was decided. 

EBI-ADHD is not just a curated list of papers. It’s built on a formal umbrella review of ADHD interventions, published in The BMJ in 2025. That review re-analyzed 221 meta-analyses using a standardized statistical pipeline and rating system. 

The platform was co-created with 100+ clinicians and 100+ people with lived ADHD experience from around 30 countries and follows the broader U-REACH framework for turning complex evidence into accessible digital tools.  

Why it Matters 

ADHD is one of the most studied conditions in mental health, yet decisions in everyday practice are still often driven by habit, marketing, or selective reading of the literature. EBI-ADHD offers something different: a transparent, continuously updated map of what we actually know about ADHD treatments and how sure we are about it. 

In short, it’s a tool to move conversations about ADHD care from “I heard this works” to “Here’s what the best current evidence shows, and let’s decide together what matters most for you.” 

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