When Stimulants “Fail” for Children With Attention-Deficit/Hyperactivity Disorder
Zakia Alavi, MD1,2 • Isabella Theresa Felzer-Kim, PhD2 • Heide Hullsiek Rollins, MD2,3
1Mid-State Health Network, Lansing, Michigan
2Michigan State University, East Lansing, Michigan
3Pine Rest Christian Mental Health Services, Grand Rapids, Michigan
Alavi Z, Felzer-Kim IT, Rollins HH. When stimulants “fail” for children with attention-deficit/hyperactivity disorder. Consultant. 2020;6(8):3-5. doi:10.25270/con.2020.07.00005
Received February 24, 2020. Accepted June 1, 2020.
The authors report no relevant financial relationships.
Zakia Alavi, MD, Assistant Professor, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, 1355 Bogue St, B240, East Lansing, MI 48824 (firstname.lastname@example.org)
Attention-deficit/hyperactivity disorder (ADHD) is the childhood mental health condition for which pharmacotherapy is best understood. This abundance of research allows for positive responses to pharmacotherapy for many patients. In fact, in a systematic literature review, pharmacotherapy of any type for ADHD was found to be more cost-effective than behavioral therapy, community care, placebo, or no treatment at all.1 Brain imaging studies even suggest that medication can reduce many functional brain abnormalities in children with ADHD.2 Thus, although modern ADHD pharmacotherapy does not completely normalize patients, it can reduce symptoms for many as part of a holistic treatment program.3
The American Academy of Pediatrics recommends stimulants (methylphenidate [MPH] and amphetamine [AMPH]) as the first-line pharmacologic intervention for ADHD, often secondary to or in conjunction with behavioral therapy.4 The recommendations note that the evidence is stronger for stimulants (MPH is mentioned most) than for other ADHD medications such as atomoxetine (ATX), extended-release guanfacine (GXR), and extended-release clonidine.4 The mechanism of action of stimulants is to enhance the availability of dopamine and norepinephrine in various ways—blocking dopamine and norepinephrine transporters, inhibiting monoamine oxidase, or enhancing the release of catecholamines.5 In a meta-analysis of 32 double-blind, placebo-controlled trials in persons aged 6 to 18 years with ADHD, effect sizes were higher for stimulants than for nonstimulants.6
But stimulants “fail” to assist many patients with ADHD, and this presents a clinical challenge.
From 10% to 35% of patients do not respond to stimulants, according to best estimates from the American Academy of Child and Adolescent Psychiatry (AACAP) and the Centers for Disease Control and Prevention.7-9 The AACAP recommends that clinicians titrate doses of medication to “achieve maximum benefit with minimum adverse effects”9,10 However, many clinicians may have trouble interpreting these guidelines. They might not know why stimulants might “fail” and what to do next. Thus, this article explores potential reasons that stimulants “fail” and offers suggestions for managing these situations.
HETEROGENOUS OUTCOME MEASURES
There is considerable variability in outcome measures used to assess ADHD pharmacotherapy effectiveness, including the observer and the timing of assessment. In a review of double-blind trials comparing ATX, stimulants, and placebo effectiveness on two different scales (the ADHD Rating Scale-IV parent version and the Life Participation Scale for ADHD), any change of less than 30% on one scale did not register as any functional improvement on the other scale.11
Even in research, predetermined criteria for response are often not even used at all—Rostain and colleagues12 searched 102 publications presenting data on response to ADHD pharmacology and found that only 5 offered predefined criteria for “normalization” and that only 13 offered predefined criteria for “remission”; some of these criteria were vague and individual.7
Timing is also important: In a recent study concerned with rates of switching from MPH to ATX, the mean duration of stimulant therapy before switching was 11.2 months.5 In other studies, 6 months and 12 months are used as thresholds at which to determine whether patients have “failed” stimulants.13,14
In summary, we know that an ADHD treatment plan should be designed according to practice guidelines and adjusted with goals of remission of symptoms and functional improvement,7 but in clinical practice, a lot of clinical judgment is involved in defining “remission” and “improvement.”
DIAGNOSTIC ERROR OR COMORBID DIAGNOSES
Stimulants may “fail” due to incorrect ADHD diagnoses or undiagnosed comorbid conditions in patients with ADHD. Estimates of comorbid psychiatric diagnoses in children with ADHD are 50% to 90%,15,16 emphasizing the high prevalence of complex patients labeled with ADHD. Many of these complex patients may be misdiagnosed or their comorbidities may be undiagnosed at the onset of stimulant therapy. Naguy offers an excellent comprehensive review on ADHD medications interacting with comorbidities including depression and oppositional defiant disorder.17 A few examples are provided below.
Autism spectrum disorder (ASD). According to a 2019 systematic review, there is insufficient evidence to recommend or dissuade the use of stimulants to reduce irritability in children with ADHD and ASD.18 There are instances when stimulants might actually increase irritability; the stimulant response rate to for those with concomitant ADHD and ASD is lower and the rate of discontinuation higher than for those with ADHD alone.19 However, many patients respond: in one study, 65 (52.4%) of 124 children with autism took stimulants for a mean of 4.0 years with a favorable responses rate of 69.4% (reduction in hyperactivity, impulsivity, disinhibition, and inattention).20 The adverse effects are not trivial, however, as this same study showed that 66% of the patients experienced at least one adverse effect.20 In another study, patients with Asperger syndrome responded more often to stimulants than patients with autism,21 so the severity of ASD also appears to be important.
Schizophrenia. Patients who have undiagnosed or asymptomatic schizophrenia but who are labeled with ADHD can react very poorly to stimulants. AMPH can cause behavioral sensitization, in which AMPH triggers psychosis, and once it is resolved, the psychosis can be triggered again simply by psychosocial stress.22,23 The effect of stimulants on dopamine levels is the opposite of that of antipsychotic therapy. Clinicians should remain cautious regarding the use of stimulants for patients at risk for psychosis; there are few controlled studies regarding stimulants and psychosis, and there are no clear guidelines for clinicians.24
Bipolar disorder (BPD). Stimulants can be ineffective or harmful for patients with BPD.25 Some studies suggest a risk of stimulants triggering mania in children with undiagnosed BPD; the diagnosis of BPD is more common in children with ADHD who have taken MPH for long periods of time prior to the first diagnosis of mania.26 Other studies show no evidence for MPH triggering mania.
Tourette syndrome and tic disorders. Therapeutic doses of MPH have no adverse effect and may actually improve tics, but supratherapeutic doses may worsen tics.27,28
Certain environmental characteristics may influence the effectiveness of stimulants in ADHD. In one study, parental depressive symptoms, the severity of ADHD, and below-average IQ moderated the effectiveness of MPH.29 There is some evidence that ADHD pharmacotherapies can show differential effectiveness based on socioeconomic status.30,31 The subtype of ADHD could also dictate response rates.32 Other studies have found different volumes of certain brain regions in persons who do not respond to MPH.33 Finally, sleep disturbances can alter the effectiveness of treatments.34,35
WHEN STIMULANTS “FAIL”
What next? An underappreciated action point is removing prescriptions and observing consequent behavior changes, particularly when the diagnosis is questioned. Otherwise, many clinicians choose to add another medication, or prescribe a nonstimulant alone (in cases of strong adverse effects, absolutely no meaningful effect, or an interaction). There is some evidence that the addition of a nonstimulant to a stimulant can have better efficacy compared with a stimulant alone.36 Options include ATX, a serotonin-norepinephrine reuptake inhibitor, and guanfacine or clonidine (both α2-adrenergic agonists). Antidepressants can be useful, especially for patients with excessive hyperactivity or aggression. Atypical antipsychotics could also be considered, but in one study, children who had these medications added to their regimen had higher health care costs, more medication switching, more hospitalizations, more emergency department visits, and more outpatient visits, compared with children on monotherapy.37
CALL FOR GUIDELINES
In summary, stimulants can “fail” for many patients with ADHD. However, clinicians should recognize that “failure” is often a clinically complex judgment call. It could be that the diagnosis is incorrect or that an undiagnosed comorbid condition in present. It could also be that various environmental factors are influencing the success of the medication. Guidelines for success should also include how long to wait and how exactly to measure outcomes.
- Wu EQ, Hodgkins P, Ben-Hamadi R, et al. Cost effectiveness of pharmacotherapies for attention-deficit hyperactivity disorder: a systematic literature review. CNS Drugs. 2012;26(7):581‐600. doi:10.2165/11633900-000000000-00000
- An L, Cao X-H, Cao Q-J, et al. Methylphenidate normalizes resting-state brain dysfunction in boys with attention deficit hyperactivity disorder. Neuropsychopharmacology. 2013;38(7):1287‐1295. doi:10.1038/npp.2013.27
- Shaw M, Hodgkins P, Caci H, et al. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. BMC Med. 2012;10:99. doi:10.1186/1741-7015-10-99
- Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007‐1022. doi:10.1542/peds.2011-2654
- Warrer P, Thomsen PH, Dalsgaard S, et al. Switch in therapy from methylphenidate to atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: an analysis of patient records. J Child Adolesc Psychopharmacol. 2016;26(4):354‐361. doi:10.1089/cap.2015.0060
- Faraone SV. Using Meta-analysis to compare the efficacy of medications for attention-deficit/hyperactivity disorder in youths. P T. 2009;34(12):678‐694.
- Childress AC, Sallee FR. Attention-deficit/hyperactivity disorder with inadequate response to stimulants: approaches to management. CNS Drugs. 2014;28(2):121‐129. doi:10.1007/s40263-013-0130-6
- Centers for Disease Control and Prevention. Treatment of ADHD. Reviewed October 8, 2019. Accessed May 28, 2020. https://www.cdc.gov/ncbddd/adhd/treatment.html
- Pliszka S; AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894‐921. doi:10.1097/chi.0b013e318054e724
- Practice parameters for the assessment and treatment of attention-deficit hyperactivity disorder. American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry. 1991;30(3):I‐III. doi:10.1097/00004583-199105000-00038
- Buitelaar JK, Wilens TE, Zhang S, Ning Y, Feldman PD. Comparison of symptomatic versus functional changes in children and adolescents with ADHD during randomized, double-blind treatment with psychostimulants, atomoxetine, or placebo. J Child Psychol Psychiatry. 2009;50(3):335‐342. doi:10.1111/j.1469-7610.2008.01960.x
- Rostain A, Jensen PS, Connor DF, Miesle LM, Faraone SV. Toward quality care in ADHD: defining the goals of treatment. J Atten Disord. 2015;19(2):99-117. doi:10.1177/1087054712473835
- Ben Amor L, Sikirica V, Cloutier M, et al. Combination and switching of stimulants in children and adolescents with attention deficit/hyperactivity disorder in Quebec. J Can Acad Child Adolesc Psychiatry. 2014;23(3):157‐166. Accessed May 28, 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197516/
- Sanchez RJ, Crismon ML, Barner JC, Bettinger T, Wilson JP. Assessment of adherence measures with different stimulants among children and adolescents. Pharmacotherapy. 2005;25(7):909‐917. doi:10.1592/phco.2005.25.7.909
- Pliszka SR. Comorbidity of attention-deficit/hyperactivity disorder with psychiatric disorder: an overview. J Clin Psychiatry. 1998;59(suppl 7):50‐58. Accessed May 28, 2020. http://www.psychiatrist.com/jcp/article/pages/1998/v59s07/v59s0707.aspx
- Wilens TE, Biederman J, Brown S, et al. Psychiatric comorbidity and functioning in clinically referred preschool children and school-age youths with ADHD. J Am Acad Child Adolesc Psychiatry. 2002;41(3):262‐268. doi:10.1097/00004583-200203000-00005
- Naguy A. Psychopharmacotherapy of attention deficit-hyperactivity disorder in children with comorbid conditions. Pediatr Neurol. 2018;82:7‐12. doi:10.1016/j.pediatrneurol.2017.09.010
- Ghanizadeh A, Molla M, Olango GJ. The effect of stimulants on irritability in autism comorbid with ADHD: a systematic review. Neuropsychiatr Dis Treat. 2019;15:1547‐1555. doi:10.2147/NDT.S194022
- Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry. 2005;62(11):1266‐1274. doi:10.1001/archpsyc.62.11.1266
- Nickels K, Katusic SK, Colligan RC, Weaver AL, Voigt RG, Barbaresi WJ. Stimulant medication treatment of target behaviors in children with autism: a population-based study. J Dev Behav Pediatr. 2008;29(2):75‐81. doi:10.1097/dbp.0b013e31815f24f7
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- Marangoni C, De Chiara L, Faedda GL. Bipolar disorder and ADHD: comorbidity and diagnostic distinctions. Curr Psychiatry Rep. 2015;17(8):604. doi:10.1007/s11920-015-0604-y
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- Jerrell JM, McIntyre RS, Park Y-MM. Correlates of incident bipolar disorder in children and adolescents diagnosed with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2014;75(11):e1278‐e1283. doi:10.4088/JCP.14m09046
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