Polypharmacy in the Management of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Review and Update

Abstract

Objective: Prescription of multiple medications concurrently for children and adolescents has increased in recent years. Examination of this practice has been undervalued relative to its incidence. This article reviews studies investigating effectiveness of medication combinations for youth with attention-deficit/hyperactivity disorder (ADHD). Methods: A literature search identified studies that combined two or more prescribed medications for the treatment of ADHD. Included studies focused on youth; had study design of randomized controlled trial (RCT), nonrandomized trial, or case review (n > 10); and included an outcome measure of treatment effectiveness. Results: Thirty-nine pertinent studies were identified. All studies combined two medications, with the vast majority including a stimulant (n = 37). The largest group (n = 16) combined stimulant and alpha-agonist, finding greater efficacy than alphaagonist alone but not stimulant alone in all cases. A few RCTs found benefit from the addition of risperidone or divalproex to stimulant for comorbid aggression. Four studies adding atomoxetine found mixed reports of benefit, including the only small RCT showing no benefit. RCTs with selective serotonin reuptake inhibitors found minimal evidence of benefit for mood or anxiety comorbidities. Conclusion:The best studied combination is stimulant and alpha-agonist; addition of alpha-agonist to stimulant seems effective for residual symptoms of ADHD. Stimulant plus risperidone has the most evidence of efficacy for comorbid aggression or disruptive behavior. Limited support exists for the effectiveness of other medication combinations, including no trials studying three or more medications concurrently. Combinations frequently yielded more side effects, leaving monotherapy preferable if a sufficient treatment response can be achieved.

Drivers and Barriers to Tolerable and Effective Treatment for ADHD: The Importance of Treatment Perseverance and Duration of Effect

“…Multivariable analyses also revealed that both adolescent and adult patients in the ER only group experienced significantly fewer AEs than those in the ER + IR cohort. A recent study examining the effects of polypharmacy in children and adolescents treated for ADHD also concluded that monotherapy is preferable to reduce the number of AEs, when it yields an adequate response (Baker et al, 2021). It is important to consider that tolerability was identified by HCPs as a cardinal goal in treatment management in the current study, thus these two findings highlight another potential advantage of ER monotherapy over combination regimens: reduction in adverse events.…”

Impact of a national audit on child and adolescent psychiatrists’ prescribing practices

“…Using more than one medication at any one time may be necessary, advantageous, and supported by various clinical guidelines, especially for hard to treat or comorbid cases. This is the case especially for ADHD, one of the most common reasons for attendance in CAMHS and a disorder with the largest amount of evidence for effective medication use (Baker et al 2021).…”

Change in Striatal Functional Connectivity Networks Across Two Years Due to Stimulant Exposure in Childhood ADHD: Results from the ABCD Sample

“…Indeed, prospective longitudinal studies are consistent with that dismal prognosis; symptoms persist into adolescence and adulthood, stimulants have no demonstrable benefit beyond the controlled trial period (8), and stimulant use is positively associated with symptom persistence (9,10). While findings from carefully controlled prospective studies are useful, it is unclear how well they generalize to the context of community-based treatment, which is marked by high medication nonadherence, intermittent stimulant exposure (11–13), and polypharmacy (14). While long needed, there have not been available community datasets that allow examination of real-world neural and symptom changes longitudinally in children being treated for ADHD with stimulants.…”

“…Carefully controlled prospective studies investigating stimulant exposure in ADHD have identified modulation in resting-state functional connectivity (rs-FC), measured by the temporal correlation of neural activity in a taskfree state, which is associated with chronic stimulant exposure and can partially explain symptom reduction among stimulant-treated children and adolescents (5)(6)(7). While controlled prospective studies are essential for teasing apart the relationships between stimulant exposure, functional characteristics of the brain, and heterogeneous symptom trajectories, the study protocols of controlled trials do not exactly match circumstances of real-world community treatment, which are marked by high nonadherence leading to intermittent stimulant exposure (8)(9)(10) and multiple psychotropic medication prescriptions (11). Medication adherence, described as taking medication in a way "corresponding to agreed recommendations from a clinician" (12), is particularly poor for adolescents with ADHD, with estimations ranging from 13.2% to 64% (8,13).…”