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

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 alpha-agonist 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.