Providers are handling an overwhelming number of cases involving genetic and social complexities, and various challenges of modern healthcare. Many children come from diverse family structures, making it difficult to gather accurate genetic or family history, which complicates treatment. One patient’s genetic profile revealed they were a poor metabolizer of all ADHD medications, leaving them with limited options. When faced with medication failures and financial barriers, a recommended an unconventional, but practical approach included using small doses of coffee to improve focus, along with other accessible sources of caffeine like tea and sugar-free drinks. While unconventional, this highlights the need for creative and individualized treatment solutions in the face of limited resources and evolving societal challenges.
About Gene Testing for ADHD
Treating ADHD can be complex, as reactions to medications vary widely among individuals. Someone once told me that stimulants are like salts— suggesting how it’s unlikely to cause interactions—but this isn’t entirely accurate. Just as salt can cause swelling or elevate blood pressure in some people, stimulants may lead to insomnia, increased heart rate, weight loss, or other side effects, though not universally. Adverse reactions, like tics or rashes, are real concerns, and I had a young patient with extremely rare symptoms: body-jumping tics, out-of-body sensations, and even requiring intubation. These reactions highlight the importance of discontinuing medications that aren’t tolerated and avoiding repeated trials of ineffective treatments. ADHD mainly medications fall into 5 main categories, their use requires careful tailoring to the individual, balancing efficacy and safety so here are some quick notes:
- Amphetamine Salts (Adderall, Dexedrine, Vyvanse): metabolized mainly via 2D6 but undergoes such as hydroxylation, oxidation, and glucuronidation. About 30-40% is excreted in the urine unchanged.
- Atomoxetine (Straterra): metabolized mainly via 2D6 and some 2C19. The FDA has specific instructions for patients based on their CYP2D6 metabolizer phenotype and/or in the presence of known inhibitors of CYP2d6.
- Clonidine (Kapvay): no mention of CYP enzymes but a study has found CYP2d6 plays a role in metabolizing (Claessens et al.)
- Guanfacine (Intuniv): metabolized via CYP 3A4, ~40-75% is renally excreted unchanged. The maximum dose shouldn’t exceed 4mg for small kids.
- Methylphenidate Derivatives (Ritalin, Concerta, Metadate, Daytrana, Focalin): Possibly 2D6 but is primarily metabolized via CES1A1.
If I had to use a stimulant on someone who can’t metabolize ANY ADHD medication, then I’ll trial something that’s off-label, like Modafinil, which was pulled from FDA approval due to SJS risks (-Springer) but it may work in rare situations. In practice, I’m a strong advocate for micro-dosing with patients, as I’ve seen incredible results. For example, one patient on 0.5 mg of Haldol and another on a small dose of risperidone experienced significant improvements, such as the cessation of hallucinations, without side effects. Additionally, I always recommend collaborating with peers and physicians to ensure patient safety, genetic specialist consultations and avoid navigating risky situations alone.
Sidebar: For ADHD patients on atomoxetine, dosing should align with its weight-based range, as increasing the dose too quickly or excessively is not recommended. Atomoxetine takes 4-6 weeks for full effect, so adjustments should be gradual and evidence-based. In severe cases, I may go to the higher end of the range or discontinue after at least six weeks if there’s no improvement. However, it’s crucial not to treat atomoxetine dosing like antidepressants, where frequent dose changes are common. Always seek reliable, evidence-based guidance or have a sound reason for deviating from standard practice and document it well:
- <70kg: 0.5mg/kg x 3d, then 1.2mg/kg (max: 1.4mg/kg, not to exceed 100mg)
- >70kg: 40mg/kg x3d, then 80mg (max: 100mg) -Cohen Children’s Medical Center by Northwell Health
Additional Information
- ADHD Rollercoaster: a 7-part blog series: Genetic Testing for ADHD Medications: What Your Genes Might Tell You That Your Doctor Cannot. The series does a great job discussing the significance of genetic testing but it’s heavy reading. The website also talked about the difference btw generic and brand name Concerta, which is interesting because I have a patient where I have to write *brand name only due to a bad rxn to generics. Quick side-note, some insurances will ONLY pay for generics :((
- Are Your Genes Responsible for Your Unhappiness? & What is the COMT Gene? by Psychology Today. Some insight about how genetics can affect your lifestyle. I normally don’t look at the COMT/MTHER gene because I just about tell all my patients to get their labs regularly checked, make sure there are no vitamin deficits, eat vegetables..etc Like I base deficiencies on labs not on genetics because you can have kids with COMT/MTHER reduced but have no behavior problems.
I probably listed this somewhere else but wanted to make a note of the limitations of gene testing to make everyone happy:
- One single pharmacogenomic test cannot be used to determine how you will respond to all medications. You may need more than one pharmacogenomic test if you are taking more than one medication.
- Pharmacogenomic tests are not available for all medications. Because pharmacogenomic tests are available only for certain medications, your doctor determines if you need to have a pharmacogenomic test prior to beginning a specific treatment.
- There are currently no pharmacogenomic tests for aspirin and many over-the-counter pain relievers.
A nice chart about which enzyme is metabolizing psych medications
Update
After speaking with a genetic specialist, I wanted to add some key points:
- Advancements and Challenges in Genomic Testing: Retesting was recommended as interpretations of DNA can evolve due to new research and updated literature, even though DNA itself does not change. This highlights the dynamic nature of genomics and its reliance on continuous scientific updates. I retested the patient with the same company (offered free) or exploring alternatives to compare results, emphasizing the need for stronger support in this emerging field.
- Limitations in Understanding Drug Metabolism: There are no definitive biomarkers for clonidine and amphetamines. For instance, while CYP2D6 is implicated in amphetamine metabolism, its role isn’t fully understood, reflecting population-level variations. This incomplete understanding challenges clinicians to integrate genetic reports with the broader clinical context, as seen with a patient who reported an allergy and a genetic interaction but required individualized care beyond the report’s findings.
More research needs to be done: In summary, the specialist explained that while studies are exploring how the COMT genotype affects medication metabolism, there’s insufficient evidence to make it a reliable guide for treatment. Given the patient’s interactions with 3A4 enzymes, amphetamines were recommended. Additionally, the specialist shared insights about two genetic findings worth considering:
- ADRA2A: ADRA2A encodes the α-2A adrenergic receptor, which is a norepinephrine receptor. This genetic testing screens for the polymorphism which is a single G>C substitution at position -1291 (rs1800544) in the promoter region of ADRA2A. Patients with the C/C genotype may have a moderately reduced response to methylphenidates compared to G allele carriers.
- CES1A1: CES1A1, encodes for carboxylesterase 1, the primary enzyme responsible for metabolizing methylphenidate. Gly143Glu polymorphism results in reduced enzyme activity of carboxylesterase 1. Studies have consistently shown that the Gly143Glu variation decreases methylphenidate metabolism.
Additional Options: using a patch wouldn’t be effective due to genetic interactions and noted that modafinil, metabolized by CYP3A4, should be started at a low dose due to patient-specific factors. Although the patient’s use of coffee wasn’t addressed in depth, it remains a practical choice for now. The plan includes retesting and, if a stimulant is still desired, pursuing modafinil despite the challenges of obtaining prior authorization, especially since it isn’t FDA-approved for ADHD. However, with thorough documentation, such as genetic reports, studies, and second opinions, the process should be manageable. The experience highlights the value of collaboration and staying informed, as the specialist’s understanding approach turned a hectic day into a productive one, emphasizing the beauty of seeking help when needed.
2nd Update
The repeated genetic test yielded similar results, confirming no significant genetic markers for non-stimulants or amphetamines. A second opinion or using a different testing company might provide more insight but doesn’t seem worth the effort. Pursuing a prior authorization (PA) for modafinil also feels futile, as it’s unlikely to be metabolized effectively. The child is managing “okay” on a non-stimulant, and the family is advised to stay prepared with a latte for an extra boost when needed.
Additional References & Resources
- About Genetic Reports and Myths
- CYP450 & Medications
- How Genetic Testing can Improve the Outcomes of Depression
- Plus I briefly spoke about it in the ADHD pearls section
