Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients

R. Cunill, X. Castells, A. Tobias, D. Capellà

The factors underlying the variability in the results of randomized, placebo-controlled clinical trials (RPCCT) assessing pharmacological interventions for adults with attention deficit hyperactivity disorder (ADHD) are not fully understood. A systematic review and meta-analysis of RPCCT comparing pharmacological treatment and placebo in adults with ADHD was carried out. The study outcomes were all-cause treatment discontinuation, efficacy on ADHD symptoms, and safety. Patient-, intervention-, and study design-related covariates were collected. Meta-regression methods were applied. Forty-four studies involving 9952 patients were included. All-cause treatment discontinuation was slightly higher with pharmacological treatment than with placebo (odds ratio (OR) = 1.18; 95 % confidence interval (CI) 1.02, 1.36; p = 0.003). A better outcome on all-cause treatment discontinuation was observed in studies that provided concomitant psychotherapy when compared to those that did not (rate of OR (ROR) = 0.68, p = 0.048). Pharmacological treatment was efficacious for reducing ADHD symptoms (standardized mean difference (SMD) = 0.45; 95 % CI 0.37, 0.52; p < 0.00001), with stronger intervention effects found in studies investigating stimulant drugs (difference of SMD (Diff SMD) = 0.18, p = 0.017), in shorter studies (Diff SMD = -0.01, p = 0.044), and when clinician-rated scales were used (Diff SMD = 0.44, p < 0.0001). Pharmacological treatment was associated with more frequent adverse events (AEs) (OR = 2.29; 95 % CI 1.97, 2.66; p = 0.006). Studies with a lead-in phase and with a higher proportion of patients previously treated with stimulants were associated with a better safety outcome (ROR = 0.59, p = 0.017; ROR = 0.98, p = 0.036, respectively). Pharmacological treatment provides mild symptom improvement but is associated with frequent AEs and higher treatment discontinuation than placebo, particularly when no concomitant psychotherapy is administered. Stimulants appear more efficacious than non-stimulant drugs and the former should be preferred over the latter. The efficacy of pharmacological treatment should be monitored over time because it may decrease progressively.