Welcome, I know I’ve beaten the poor genetic horse multiple times:
- 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
I can’t control it, our clinic has tested hundreds of kids and you’ll be surprised how many interactions we are dealing with! Sometimes I have to completely change a regimen ASAP. Some providers are still against gene testing and I listed the limitations below but overall, I want people to understand what’s going on in society and how it’s affecting treatment.
We have blended extra families, kids that have 3 plus daddies known and unknown, grandparents raising children and can’t remember last week, kids being adopted/broken families due to substance abuse…etc. So how else can you get accurate genetic/family hx information, I gave up on genograms in middle school. With mental health, the struggle for decent treatment and stability is REAL.
Time for a (Clinical) Story
I had a patient whose genetic report came back as a poor metabolizer of ALL ADHD medications. Yes even non-stimulants! No 2D6 so atomoxetine and basically all the other meds, including bupropion was in the red bin, nothing in the green but desvenlafaxine, which is in everyone’s green bin due to going through the kidneys… Poor guy is failing everything in school and overall scared to trial anything else due to a horrific response to medications.
You can try a patch, Modafinil, or the FDA-approved Qelbree, a new non-stimulant medication for ADHD (–Single Care) but GOODLUCK with coverage! so what did I recommend? What’s cheap, tastes good, improves focus, and acts as a stimulant? Yup, you’ve guessed correctly, coffee!
Of course, the family looked at me like I just grew a horn but in actuality, I’ve been recommending it also in my substance abuse population. I know adults would say I already drink coffee like water! but not KIDS. Don’t forget about the simple things in life.
I told the father, to try a small shot of black coffee (1/2 cup) in the morning. I also mentioned, vitamin b’s, tea, caffeine also comes in pill forms (but usually for weight loss), and don’t forget carbonated drinks…etc Stuff that the body usually tolerates. No one is allergic to Mountain Dew, yes the sugar content is horrible but there are also sugar-free drinks. If the child receives scheduled medications, families are usually open to other options.
The dad asked for something in writing, I just responded do you get prescriptions for Dunkin Donuts and candy? We all laugh because I’m like that’s not happening but if the family was serious or concerned, complementary health isn’t FDA approved so it doesn’t have to be in the form of a “prescription”.
About Gene Testing for ADHD
I gave that quick story to introduce the difficulty of treating ADHD and some pearls. Someone told me stimulants are like salts (as in no one is allergic to salt) so there shouldn’t be any interactions, which is not true. Think about how salt can make some people swell, BP increase, etc. Stimulants are similar, sometimes they cause insomnia, palpitations/increased HR, weight loss … but not for everyone.
Adverse reactions are a real concern such as tics, rash…My patient actually had very atypical symptoms including getting intubated, body jumping tics, and feeling like he was out of his body and this was in elementary school. This is the reason to not only stopped the stimulant but definitely don’t keep prescribing it and again he’s not allergic, just can’t tolerate the medications so when doctors put him on the same stuff that wasn’t working it was no response even at high doses. ADHD medications are mainly in 5 categories and I usually carry this info with my 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 Derivative (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. Another option I’ll do is micro-dosing…It’s another blog topic but I do talk about it a lot on the website -long story short, I LOVE micro-dosing with my patients. I have someone on 0.5 Haldol and another patient on a small dose of risperidone that stopped having hallucinations and with no side effects. If there’s still a concern, companies usually have a number to call to speak with a genetic specialist. And yes def speak with peers and physicians, don’t deal with a risky situation alone.
Side note: my ADHD patient was previously on atomoxetine and the prescriber kept increasing the dose like within months and it’s not recommended. Atomoxetine has a weight-based range, you don’t just go up or assume it’ll make it better and it takes 4-6 for the full effects. If the ADHD symptoms are severe I’ll go to the highest-end of the range or d/c (after > 6 weeks) but don’t start increasing the dose like an antidepressant. So if you do ask for help, make sure the source/advice is reliable, EBP, or truly have a sound reason to do something unconventional 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:
- Retesting was recommended: and this was when my head started to hurt, because your DNA doesn’t “technically change” but additional research, literature, and things outdated can change how it’s “interpreted”. They offered to retest for free but another option I contemplated was going to a different company (if it was affordable) and compare/contrast…my only point with this is how genomics is still a relatively new field and wish this area was more supported.
- There are no biomarkers for clonidine and amphetamines: per the specialist, “Although the enzymes involved in amphetamine metabolism have not yet been clearly defined, CYP2D6 is known to be involved with the formation of 4-hydroxy (OH)-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility” so it’s still not completely understood because I have people who have genetic reports as clean as a whistle and still don’t respond to clonidine or amphetamines. My patient here said he’s allergic to clonidine and had a genetic interaction on the report. I’m not basing medications on the report alone but continue looking at the whole clinical picture because….
More research needs to be done: long story short, the specialist was discussing how studies are looking at how the COMT genotype metabolizes medications but “lacks evidence” to be reliable. Simply put, the data isn’t advanced enough to understand these intricacies in the body…Therefore, it was recommended to use amphetamines due to the interactions with 3a4 the patient had in the report. She also gave me some interesting additional information about 2 genetic findings to consider:
- ADRA2A: ADRA2A encodes the α-2A adrenergic receptor, which is a norepinephrine receptor. GeneSight 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.
Remainder Options: the specialist explained how a patch wouldn’t be helpful because of another genetic interaction and she reported how modafinil is metabolized by 3a4 so it was recommended to start low because of the patient interactions. She somewhat ignored me putting the patient on coffee but it’s still the best option after all this MESS.
I’m going to retest and if the patient still wants to use a stimulant, I will still try modafinil and hope to get a PA before the next century. It’s not FDA approved for ADHD so you know it’ll be an automatic problem. However, with solid documentation, i.e. the genetic reports, studies, past records, following recommendations such as retesting or getting a second opinion, etc. the battle with getting coverage shouldn’t be too painful.
The moral of the story is how collaborating and staying current is so important. I enjoyed my quick conversation with the specialist because I was somewhere in between psych evals and volcanoes. I actually forgot I scheduled the meeting until I got a message. The person was very nice and understanding so if you’re struggling with an issue or anything crazy, getting that extra help is beautiful!
2nd Update
The repeated genetic test had about the same results (duh!). Non-stimulants and amphetamines had no proven genetic markers (in general) and that was the extent of the update per another specialist. A 2nd opinion or a different company may be helpful but it’s not worth the fuss. Trying to get a PA for modafinil isn’t worth the fight either, he probably can’t metabolize it anyway. The kid is doing “okay” with a non-stimulant and hopefully, the family keep a latte on stand by :))
