Stimulants work by increasing the levels of norepinephrine and dopamine in the frontal cortex. They also stimulate adrenergic receptors in the heart and blood vessels, leading to small increases in resting heart rate and blood pressure—on average, an increase of <10 beats per minute for heart rate and <5 mm Hg for both systolic and diastolic blood pressure. A minority (5-15%) of patients experience larger increases. The existing evidence on long-term cardiovascular risks of stimulants is mixed. Some studies have shown no increased risk, while others have cited an increased risk for arrhythmias, cerebrovascular disease, hypertension, ischemic heart disease, heart failure, pulmonary hypertension, and/or sudden cardiac death. Overall, existing studies are of limited quality and relatively short duration.

A 2024 case-control study by Zhang et al. examined the long-term (up to 14 years) cardiovascular effects of stimulants in 278, 027 individuals aged 6–64 years in Sweden. The results suggested that long-term use of ADHD medications was associated with an increased risk of hypertension and arterial disease. Each additional year of medication use was associated with an average of 4% increased risk of cardiovascular disease. The increase in risk was highest during the first three years of treatment and thereafter stabilized. Reassuringly, the study did not observe any statistically significant increases in the risk for arrhythmias, heart failure, ischemic heart disease, thromboembolic disease, or cerebrovascular disease.

When determining whether a stimulant is the right course of action for a particular patient with ADHD, providers must balance the potential benefits against these risks. Proper treatment of ADHD can improve educational, occupational, and social outcomes. Additionally, stimulants are associated with a decrease in unintentional physical injuries and deaths, substance use disorders, and criminal acts. These medications are highly effective, with response rates of 65-75% and an effect size of 1.0. Therefore, in a generally healthy child or adolescent without cardiac risk factors, stimulant medication should still be considered the first-line treatment for ADHD, and no routine cardiac evaluation is necessary. Consultation with cardiology may be warranted prior to stimulant initiation in cases of complex congenital heart disease or symptoms suggesting significant cardiovascular issues, such as severe palpitations, fainting, exercise intolerance (not accounted for by obesity), or a strong family history of sudden death.

To improve the cardiovascular safety of stimulant use, providers should have an extensive discussion with patients and parents about the risks, including cardiovascular risks, benefits, and alternatives of the medication. Screening each child for factors that increase cardiovascular risk, including personal and family cardiovascular history, is essential. Additionally, monitoring pulse and blood pressure at baseline and regularly throughout treatment is recommended. Psychopharmacology should be just one part of a comprehensive treatment plan, which may also include psychoeducation, behavioral therapy, lifestyle modifications including diet and exercise, linkage with community supports, and school resources. If stimulants are not an option, providers can explore alternative treatment options, such as nonstimulant medications (though selective norepinephrine receptor inhibitors and alpha 2 agonists also have cardiovascular risks to consider) or behavioral therapy without medications. Omega-3 fatty acids, video game treatment (e.g., Endeavor Rx), trigeminal nerve stimulation, or biofeedback also have some evidence for the treatment of ADHD.

References

Cortese S, Fava C. Long-term cardiovascular effects of medications for attention-deficit/hyperactivity disorder-Balancing benefits and risks of treatment. JAMA Psychiatry. 2024;81(2):123–24. https://doi.org/10.1001/jamapsychiatry.2023.4126

Dopheide JA, Stutzman DL. Five steps to improve cardiac safety of attention deficit hyperactivity disorder treatment. The Journal of Pediatric Pharmacology and Therapeutics. 2024;29.6:670-673.

Pliszka S. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry. 2007;46(7):894-921.

Torres-Acosta N, O’Keefe J, O’Keefe C. et al. Cardiovascular effects of ADHD therapies: JACC review topic of the week. JACC. 2020;76(7): 858–866. https://doi.org/10.1016/j.jacc.2020.05.081

Wolraich, Mark L., et al. Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2019;144(4).

Zhang L, Li L, Andell P, et al. Attention-deficit/hyperactivity disorder medications and long-term risk of cardiovascular diseases. JAMA Psychiatry. 2024;81(2):178–187. doi:10.1001/jamapsychiatry.2023.4294

AUTHOR:

Dr. Kristen Kim, MD

Child, Adolescent and Adult Psychiatrist

Vista Hill Foundation

When compared to non-stimulant FDA approved medications (atomoxetine, alpha agonists) stimulants, such as methylphenidate and amphetamine have a larger effect size (1.0 vs. ~0.7). As a result, these medications are often first line treatment for ADHD.  When prescribed and monitored appropriately, stimulant medications rarely induce major psychiatric side effects such as psychosis and/or exacerbate other disorders, but for some vulnerable youth, particularly adolescents, and in circumstances where the medications are misused (including in combination with illicit substances such as other stimulants or high potency marijuana, amongst others) serious problems can arise.

Whether the ongoing stressors associated with the Covid pandemic, including familial loss, financial strain and other issues, either on their own or in combination with co-occurring substance use  (legal as with ADHD stimulant agents or with illicit drugs) will lead to increased incidence of psychotic and/or other major potentially persisting psychiatric disorders remains to be evaluated.  Clearly as the pandemic has gone on there have been increased symptoms of anxiety and depression in children and adolescents generally (Zeytinoglu et al., 2021; Twenge, 2021) and those challenged with attentional difficulties have been additionally stressed by the challenges of remote learning and the distanced interpersonal environment.

While for some, efforts to enhance the capacities of youth who have challenges with focusing and attentiveness with prescriptions for stimulant or other ADHD medications, ongoing careful oversight, reassessment and monitoring for risk behaviors are recommended approaches.  What impact the pandemic has had and will have on the emergence of psychotic and/or major affective symptoms and pathologies in youth remains to be studied and better understood.  Historically, stressful life changes can exacerbate psychosis and other emotional disorders in vulnerable and at-risk populations, and we likely have seen and will continue to see instances of this among our youth in 2021 and beyond.

In summary, stimulant misuse and abuse is a common cause of psychotic symptoms (Henning et al., 2019) and it is important to consider that stimulant overuse, including higher therapeutic doses of FDA approved stimulants, can also cause these symptoms, as Henning, Kurtom and Espiridion’s referenced case below.  This also reminds us to screen for family history of psychotic and other mental illness in all of our ADHD patients.  Caution with the use of stimulants with youth at risk of experiencing psychotic symptoms is strongly recommended, and psychiatric consultation would be recommended for situations of concern.

References:

Henning, A., Kurtom, M., & Espiridion, E. D. (2019). A Case Study of Acute Stimulant-induced Psychosis. Cureus, 11(2), e4126. https://doi.org/10.7759/cureus.4126

Wolraich ML, Hagan JF, Allan C, et al; Subcommittee on Children and Adolescents with Attention-Deficit/Hyperactive Disorder. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. 2019;144(4):e20192528. Pediatrics. 2020 Mar;145(3):e20193997. doi: 10.1542/peds.2019-3997. Erratum for: Pediatrics. 2019 Oct;144(4): PMID: 32111626.

Zeytinoglu, S., Morales, S., Lorenzo, N. E., Chronis-Tuscano, A., Degnan, K. A., Almas, A. N., Henderson, H., Pine, D. S., Fox, N. A. (2021) A Developmental Pathway from Early Behavioral Inhibition to Young Adults’ Anxiety During the COVID-19 Pandemic. Journal of the American Academy of Child and Adolescent Psychiatry. doi: 10.1016/j.jaac.2021.01.021

Twenge, J; The mental health of youth and their parents during the pandemic; presentation at 6^th Annual CICAMH conference, 3/19/21; San Diego

Decreased appetite:
If your patient’s appetite decreases after taking ADHD medicine, advise the parent to give the morning dose after breakfast so that the youth will eat better in the morning. Also advise them to serve a large dinner in the evening when the medication is beginning to wear off. Have them keep healthy, high-calorie, protein snacks on hand for whenever a child asks for food, even if it is before bedtime. Discuss with parents that it is more important to monitor the child’s weight than his day-to-day appetite. Advise them to let you know if the child’s poor appetite lasts for a long period, and consider reducing the dose or stopping the drug on weekends or summer breaks to allow appetite and food intake to return to normal.

Stomach pain or upset:
Advise parents not to give the medication on an empty stomach. Taking the medication with or immediately after food can be helpful for this side effect.

Sleep problems:
Parents should set up a regular bedtime routine that includes calming activities, such as bathing or reading.  Makes sure that a long-acting stimulant is only given in the mornings, typically no later than 10am, and an afternoon dose of a short-acting stimulant should typically not be given later than 3pm. If the sleep disturbance persists, the provider could consider switching from a long-acting to a shorter-acting form or reducing the dose or stopping an afternoon dose.

Daytime drowsiness:
If a child is taking atomoxetine (Strattera) or guanfacine (Tenex/Intuniv) or clonidine (Catapres/Kapvay) and experiences daytime sleepiness, consider giving the medication at bedtime instead of in the morning.  The provider could also consider lowering the dose or dividing the dose and giving it twice a day. 

Rebounding effects:
When an ADHD medication wears off in the afternoon or evening, some children have a period of more ADHD symptoms or irritability and moodiness.  This is more common with the stimulant medications than the non-stimulant medications. To prevent this “rebounding” consider using a longer-lasting medication or prescribing a small dose of fast-acting stimulant later in the day.

Mood Changes:
Make sure the parents are keeping an eye out for changes in the child’s mood and anxiety.  Stimulant medications can negatively affect mood symptoms and anxiety. If that does occur, consider using a non-stimulant medication instead to address the ADHD symptoms.

Finally, it is often advisable to schedule medication initiation or dosage changes to occur on weekends when parents can better monitor for side effect emergence

It is our hope that this practical primer on addressing the common side effects for ADHD medications is helpful to address problems that may arise in the primary care office. And remember providers can contact is at SmartCare for real-time consultation on particular cases.

Case Presentation:

10 yo boy with history of motor tic disorder (eye blinking, shoulder shrugging) who was then diagnosed with ADHD combined type. He was started on Concerta and titrated to 36 mg qAM, which has been helpful for his ADHD symptoms but has led to an increase in his motor tics. The question is what to do next?

Discussion:

ADHD is a common issue that presents in the primary care setting. Some children who present with ADHD have co-morbid mental health concerns, including tic disorders, anxiety disorder and depression, which can impact the treatment plan. There are some medications that are used to treat ADHD that can worsen other mental health symptoms, namely tics, anxiety, agitation, and sleep disturbance. Generally, in these situations, the options are to reduce the dose of the medication to see if that helps vs. change to a different medication that does not worsen the other symptoms vs continue the original medication at the current dose and add a second medication to treat the other worsening symptoms.

In the case of co-morbid ADHD and tic disorder, it can be a little bit complicated. There are certainly cases where stimulant medications can worsen tics, but there are also cases where families report an improvement in the tics when the child is started on a stimulant medication or at the very least not a worsening of the tics. So if a child has ADHD and one is considering medication treatment, the presence of the tic disorder is not a contraindication to using a stimulant medication, but if one starts with a stimulant medication, it is important to make sure to be monitoring closely for worsening tics. It is helpful to use the lowest

possible dose of the stimulant to target the ADHD symptoms effectively, to minimize the risk of

worsening the tics. If a medication trial from one class of stimulants causes a worsening in the tics but a robust response for the ADHD, consider trying a medication from the other class of stimulants next. Alternatively, one could try a non-stimulant medication. The alpha-agonists guanfacine (Tenex), guanfacine XR (Intuniv), clonidine (Catapres), and clonidine XR (Kapvay)) are good options because they can treat both the ADHD symptoms as well as the tics. Atomoxetine (Strattera) and bupropion (Wellbutrin) are alternative options for ADHD and certainly should not worsen tics but also would most likely not reduce the tics either. Another option is to use a stimulant as the primary treatment for the ADHD and adjunctive guanfacine or clonidine for the tic disorder.

Case Conclusion:

For this particular case, first, consider reducing the dose of Concerta to see if a lower dose reduces the negative effect on the tics, making sure that the positive effect on his ADHD symptoms continues. If that does not work, consider either changing to a different stimulant (consider Adderall or Vyvanse which are from a different class) or a non-stimulant (consider Tenex or Intuniv) which could help with the tic disorder. If the family wants to continue with Concerta because of the positive effect on his ADHD, consider adding adjunctive Tenex to target the tics. Also, the child can be referred for habit reversal, which is CBT for tics.

It is our hope that this detailed discussion about a clinical case is helpful for similar situations that might come up in your primary care practices.