How Epigenetics Could Revolutionize ADHD Care

What if we could improve early detection of ADHD before symptoms emerged?

What if we could more accurately predict someone’s response to a medication and use that information to prescribe a personalized ADHD treatment plan, instead of going through unnecessary trial and error?

These are among the exciting possibilities associated with epigenetic research. As scientists uncover and better understand the epigenetic markers associated with ADHD, the hope is that this information will contribute to the development of new precision medicine toolkits for better detection, monitoring, and treatment formulation. Still, today, we have more questions than answers about epigenetics and its potential utility for ADHD care.

A 101 on Epigenetics

Reading Genes

Genes play an important role in shaping a wide range of traits and characteristics, from hair and eye color to susceptibility to mental health conditions. Yet, genetic influences are less ‘fixed’ than one might think. Epigenetics refers to the study of the biological processes that regulate gene activity during our lifetime, and the array of factors that can impact it.

Think of epigenetic processes as collections of chemical “tags” that regulate where, when, and to what extent genes are activated or deactivated in the body. One of these types of tags, called methyl groups, can stick to the DNA sequence (a process called DNA methylation) and affect how cells “read” genes, without changing the underlying DNA sequence itself.

[Read: Preconception Experiences of Moms — and Dads — May Influence Babies’ Development]

Consider cell differentiation. All cells have access to the same DNA sequence, yet over 200 cell types exist in the body that look and work very differently from one another. Epigenetic tags allow each of these cells to “read” only the parts of the DNA sequence that are relevant to them, in order to become skin cells, liver cells, brain cells, muscle cells, and other unique cells with the right structure and functions for their specific role.

Environment Matters

Our environment and what we experience in life affects where and how many of these tags attach to our DNA, impacting gene expression. Though identical twins share the same DNA sequence, research shows that they become less and less similar in their epigenetic patterns over time, partly because of unique environmental experiences. As twins get progressively exposed to different environments and make different lifestyle choices, for example, these accumulated experiences become “embedded” at the level of gene functioning.

We care about epigenetics because changes in the ways cells read genes can cause lasting effects on an individual’s development, functions and behaviors. Epigenetic alterations have been linked to numerous poor health outcomes. The field of environmental epigenetics is exploding as researchers race to determine what kind of factors might modulate the way our genes work.

ADHD and Epigenetics: What Could the Future Hold?

Could We Detect ADHD Before Symptoms Emerge?

Today, we are only able to detect ADHD through the subjective evaluation of symptoms, which limits opportunities for very early or even preventive interventions. Far off into the future, we could reach a point where ADHD and epigenetics research will offer us ways to detect risk for the condition well before symptoms emerge. Hypothetically, we’d combine information on epigenetic markers with other genetic and environmental information to build more sensitive risk-prediction models that could be used in clinical settings.

[Read: Prenatal and Early Life Risk Factors of ADHD]

We’re not there yet, but we are developing an ever-growing understanding of epigenetic factors associated with an increased risk for ADHD, including but not limited to the following:

• maternal metabolic conditions in pregnancy^{1 2 3 4 5}
• lower gestational age and birth weight^{6 7}
• stress exposure^{8 9}
• inflammation^{10 11}
• smoking¹²
• nutritional factors such as folate exposure¹³
• exposure to lead and other chemicals^{14 15}

The extent to which these factors are causal – and mediated by epigenetic changes – remains unclear. Another complication is that these risk factors are not exclusive to ADHD; they are associated with other cognitive and neuropsychiatric outcomes.

Findings from recent epigenome-wide studies point in exciting directions. One study found that epigenetic patterns at birth associate prospectively with the severity of ADHD symptoms in mid to late childhood.¹⁶ That is, at birth, there appears to be a relationship between the chemical tags present on certain genes, including those involved in neurodevelopment and cognition, and the severity of ADHD symptoms 6 to 10 years later — an “epigenetic signal” that warrants further exploration for its potential in detecting ADHD, including its course and chronicity, before symptoms emerge.

Could We Prevent or Reverse ADHD?

Even if scientists can map the epigenetic markers associated with ADHD well enough to build sophisticated risk-prediction models, there are important ethical considerations. As with any form of prediction, risk of false positives exists. It’s also possible that an existing risk factor may not materialize into any impairment.

The big question is one of action: What should we actually do if there is a positive screen for ADHD? And what obligation to act may exist for parents, clinicians, and the ADHD community at large, among other stakeholders?

Some studies show evidence that lifestyle interventions — improvements to diet, exercise, and sleep — might help to generally restore epigenetic patterns.^{17 18} Animal studies also show interesting findings: enriching environments and appropriate care can help reverse some epigenetic changes in animals that were exposed to severe stress in early life.^{19 20} Might we be able to target and reverse the chemical tags on DNA through similar interventions? Perhaps, but there’s a lot to consider first, like the high potential for off-target effects. Because the constitution of normal epigenetic patterns remains somewhat unclear, manipulating tags could have unintended consequences.

Could Epigenetics Unlock Precision Treatment for ADHD?

Identifying ADHD Subtypes

To say that ADHD is a heterogeneous condition is an understatement; there is huge variability in onset, clinical presentation, presence of comorbidities, developmental course, level of impairment, and chronicity among individuals. While we’ve attempted to specify presentations of ADHD — predominantly inattentive, predominantly hyperactive/impulsive, and combined presentation — we are simply not yet good at separating and understanding why individuals with ADHD follow such different courses and clinical presentations. Future findings on epigenetic patterns may help to identify more narrow subgroups or subtypes and stratified interventions.

Predicting Treatment Response

Today’s ADHD medications work well for many patients, but a sizable minority — up to 35% — don’t respond to them at all.²¹ The current approach across psychiatry — a trial-and-error process that starts with first-line treatments before moving into second-line approaches — can be tremendously burdensome, time-intensive, and stressful.

In the future, epigenetic profiling may help clinicians predict and monitor therapeutic responses to different types and classes of medications and with greater specificity. What’s more, if epigenetic markers can point to potential causal mechanisms for ADHD, future research could lead to entirely new types of interventions for ADHD.

ADHD and Epigenetic Research: Early Days, Great Potential Ahead

Epigenetics offers a promising, unifying framework for understanding how genes and environment come together at the biological level to shape development and health. Thanks to recent research, we know more about particular genes that might be responsive to the environment and implicated in ADHD. We also know that these are dynamic processes; the specific time during which epigenetic marks are measured might make a huge difference in determining if such marks serve as signals of future ADHD.

As we continue to unravel the epigenetic landscape that contributes to ADHD, we remain hopeful that this knowledge will lead to better strategies for diagnosis and treatment, ultimately improving the lives of those affected by this complex condition.

Epigenetics and ADHD: Next Steps

• Read: The Future of ADHD Research Looks Like This
• Read: Mapping the ADHD Brain — MRI Scans May Unlock Better Treatment and Even Symptom Prevention
• Read: Epigenetics and ADHD — The Impacts of Environment, Lifestyle, and Stress
  

The content for this article was derived from the ADDitude ADHD Experts webinar titled, “Epigenetics: Understanding its Role in ADHD and Future Applications” [Video Replay & Podcast #473] with Charlotte Cecil, Ph.D., which was broadcast on September 28, 2023.

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