Clinicians have numerous pharmacotherapy options available to treat ADHD in their toolbox. How do you know which formulation or combination of therapies is right for your patient with ADHD?
Dr. Jeffrey Strawn
According to Jeffrey R. Strawn, MD, the answer depends on onset and duration of the medication and how that fits in to the patient’s current needs.
The most common treatment for ADHD, stimulants, are amphetamine-based and methylphenidate-based compounds known for improving core symptoms of inattention, impulsivity, and hyperactivity and are “probably associated with the most efficacy relative to the other interventions,” Dr. Strawn, associate professor of psychiatry, pediatrics, and clinical pharmacology at Cincinnati Children’s Hospital Medical Center, said at Psychopharmacology Update presented by Current Psychiatry and Global Academy for Medical Education. “But what I think is also really important for us to remember as clinicians is that they improve adherence, social interactions, [and] academic efficiency as well as accuracy.”
Other ADHD pharmacotherapy options include nonstimulant norepinephrine reuptake inhibitors (NRIs) like atomoxetine, and alpha-2 agonists like the extended-release forms of guanfacine and clonidine. All are Food and Drug Administration–approved for the treatment of ADHD, and the FDA has approved some combination alpha-2 agonists and stimulants treatments for ADHD as well.
When making decisions about formulations for ADHD pharmacotherapy, clinicians should think about whether the patient has issues swallowing tablets or capsules. Tablets, capsules, and chewable tablets may be appropriate for patients who can easily take these medications, while patients who have problems with swallowing pills may benefit from dissolvable tablets, solutions, and transdermal applications. Each of these options “have differences in terms of absorption, also differences in terms of intestinal transit time in younger children, as well as patients perhaps with irritable bowel, as well as other conditions that may affect absorption,” Dr. Strawn said. Different formulations have unique considerations: liquid formulations have the benefit of making precise adjustments, sublingual formulations may have quick absorption and onset, and oral dissolvable tablets can improve treatment adherence and reduce misuse of medication.
Formulations can be available as a delayed release, extended release, pulsatile release, targeted release, or a combination of immediate, delayed, and/or extended release. “Ultimately, what this gives rise to is differences in onset of action and duration, as well as differences in the elimination profile of the medication,” he said.
Transdermal formulations “avoid the first-pass metabolism, which may reduce side effects or increase efficacy,” but patients converting from an oral formulation may require reducing the dose. “It’s always important to remember, for example, with something like Daytrana, the transdermal methylphenidate formulation, if we’re converting a patient from an oral methylphenidate, we roughly need to use half the dose for the transdermal formulation,” Dr. Strawn explained. Transdermal formulations can carry benefits of steady plasma concentrations and longer duration of action but may cause skin irritation or accidentally be removed. “It’s really important they’re properly disposed of because oftentimes they do contain some active medication within the residual matrix.”
Methylphenidate, mixed amphetamine salt–based preparations
Modified-release formulations include matrix- or reservoir-based formulations and are most importantly differentiated from other formulations by their gastrointestinal (GI) transit time and the permeation through the GI membrane. When considering what formulation to choose, “it’s important to consider that, even with an ‘extended release formulation,’ all of these medications have some percentage that is immediately released, and that percentage varies considerably from formulation to formulation,” Dr. Strawn said.
He noted that brand names are sometimes used for formulations “because it’s often very difficult for us as clinicians and even for pharmacists to distinguish between these various formulations of the medication, which often have the same ‘extended’ or ‘delayed release’ modifying term within the name of the medication.”
Examples of medications that have greater immediate release include Metadate CD (30%), Aptensio XR (37%), long-acting methylphenidate (50%), dexmethylphenidate extended-release (50%), and Mixed Salts amphetamine extended release (50%). Formulations with a less immediate release include Quillivant solution or Quillichew chewable tablets (20%), Dyanaval XR solution (20%), OROS methylphenidate (22%), Daytrana that begins within 1 or 2 hours and lasts for 9 hours, or lisdexamfetamine that begins within 1 hour and lasts for 9 hours.
Depending on a patient’s needs, one particular formulation may work better than another. Dexmethylphenidate (Focalin XR) has a 50% immediate release and 50% extended release formulation, which “may be really important for a high school student who has first period precalculus followed by second period human geography,” Dr. Strawn said, while “a patient who may have first period study hall and second period art” may benefit from OROS methylphenidate.
Clinicians should also consider the effect of counterclockwise hysteresis when adding a short-acting stimulant later in the day. “There seems to be something really magic about having that ascending concentration time curve that, when we’re on the descending loop of that concentration time curve, we really seem to get a dramatic waning of the effect of the medication, even though technically the concentration is within the ‘therapeutic range,’ ” Dr. Strawn said. “With counterclockwise hysteresis, we see that the effect increases with time for a given concentration of the medication.”
Combining ADHD pharmacotherapies
For children and adolescents with ADHD, atomoxetine is a nonstimulant, FDA-approved treatment option. “It seems to be effective not just in terms of total ADHD symptoms, but also in terms of hyperactive and impulsive symptoms as well as the inattentive symptoms,” Dr. Strawn said.
Pharmacogenetics can be a guide for selecting an atomoxetine for a patient with ADHD, he noted. “What I think is most relevant here is the way in which pharmacogenetics can actually help guide our dosing, which then optimizes tolerability, potentially efficacy of atomoxetine,” he said. “Atomoxetine is pretty extensively metabolized by [CYP]2D6, and it’s one of about 300 medications that actually has specific labeling from the FDA on dosing based on genotype. It recommends a slower titration, as well as a lower target dose of atomoxetine in individuals who are P450 2D6 poor metabolizers relative to those patients who are ultra-rapid or normal metabolizers.”
Atomoxetine is most often combined with methylphenidate and has some evidence of benefit in children or adolescents who do not have an adequate response to stimulants alone. When combining stimulants with the alpha-2 agonists guanfacine or clonidine, “there are some improvements in terms of the combination treatment relative to the monotherapy,” Dr. Strawn said. He also emphasized that patients taking guanfacine immediate release tend to have better absorption and faster onset, compared with the extended release formulation. “This is something that potentially is very important when we think beyond steady state and we think about the practical use of this medication,” he said.
Baseline history is important
Overall, taking a baseline history of a patient with ADHD is “critically important” before starting them on stimulants, Dr. Strawn said. “Specifically, I would recommend documenting a negative history of syncope, family history of sudden cardiac death, as well as the lack of any known history of structural cardiac abnormalities,” he said. “Without a consultation with the cardiologist specifically around this question, I’m very, very, very hesitant – as in I don’t – use stimulants in patients who have histories of aortic stenosis, Wolff-Parkinson-White, as well as arrhythmogenic right ventricular dysplasia.”
Although patients with ADHD were typically followed with routine hemodynamic monitoring every 3 months prior to the COVID-19 pandemic, some clinicians see their patients with ADHD less frequently if they have been stabilized on a stimulant. , particularly in young children. In adults, it may also be very helpful to talk with spouses,” Dr. Strawn said.
Dr. Strawn also called attention to a recommendation to perform a routine electrocardiogram (EKG) in patients with ADHD who might receive stimulants. “At present, there is no recommendation to obtain a routine screening EKG in these patients, provided that we have an absence of those other red flags on the history,” he said. “Certainly, I would consider it in situations where I do have persistent tachycardia or hypertension, or there are other treatment-emergent symptoms, although really in many of these situations, I’m actually speaking on the phone with my pediatric or adult cardiology colleagues.”
Global Academy and this news organization are owned by the same parent company. Dr. Strawn reported receiving research support from Allergan, the FDA, the National Institutes of Health, Neuronetics, and Otsuka; serving as a consultant and receiving material support from Myriad; receiving royalties from Springer Publishing; and serving as a consultant for Intra-Cellular Therapies. In addition, he has been on the speaker’s bureau for the Neuroscience Education Institute and CMEology, and Medscape.