REVIEW OF: Baker M et al, J Child Adolesc Psychopharmacol 2021;31(3):148–163

TYPE of Study: Literature review

Psychotropic polypharmacy is increasingly the norm in clinical practice. We use it to address persistent symptoms or to target comorbid conditions, though we do so at the risk of increased side effects, more drug interactions, and worsened patient compliance. This review examines the evidence base for polypharmacy in the treatment of ADHD in children and adolescents.

The authors’ literature search found 39 studies and 17 randomized controlled trials (RCTs), a “relatively limited evidence base … to support a practice that occurred in 20% of outpatient visits in 2007 and is likely higher today.”

Nearly all trials included a stimulant. The most common additions were alpha-agonists, followed by risperidone and atomoxetine.

Sixteen of the 37 studies combined a stimulant and an alpha-agonist. RCT data showed that for stimulant partial responders, the combination of stimulant and alpha-agonist was superior to alpha-agonist alone in reducing residual ADHD symptoms, and superior to stimulant alone if there was a history of partial response to stimulant monotherapy, with an effect size of about 0.4. Combination treatment was associated with bradycardia, sedation, somnolence, and hypotension.

For ADHD with comorbid aggression and disruptive behavior, RCT data found that stimulants alone had a large effect size. Combination treatment with divalproex or risperidone did improve response beyond stimulant monotherapy, with the greatest support for risperidone; however, there was a price to pay. Despite the short study durations and the low dosages of risperidone (<2 mg/day) in all the studies, significant prolactin elevations and weight gain were seen.

One RCT of atomoxetine found no evidence of improvement with added MPH, with the suggestion that “optimizing dose and allowing adequate duration for response is favorable to adding medications.”

For management of comorbid anxiety, depression, and disruptive mood dysregulation disorder, data from four RCTs of SSRIs with stimulants showed this very common combination, while safe, had minimal benefit for anxiety and mood comorbidities.

The authors conclude the data support existing guidelines to start with stimulant monotherapy for ADHD. Still, antipsychotics are worth considering, despite their side effects, when aggression is severe or persistent. The authors recommend using measurement-based care to determine if the benefit of an added medication is worth the risk.

CCPR’s Take: Combination treatment for ADHD may be beneficial, though it comes at the cost of more side effects. Adding an alpha-agonist is helpful in partial responders to stimulants, and, in line with clinical lore, adding risperidone can be helpful for aggression. Remember that side effects can differ based on pubertal ­status.