Development of bipolar disorder in patients with attention-deficit/hyperactivity disorder: A systematic review and meta-analysis of prospective studies

•Co-occurrence of ADHD and bipolar disorder is frequently reported.•About 10% of ADHD children and adolescents develops bipolar disorder.•ADHD patients exhibit greater prospective risk of bipolar disorder than controls.•Great clinical attention should be paid to ADHD as precursor of bipolar disorder.•The recognition of pre-bipolar ADHD has relevant clinical implications. Increasing attention has been recently paid to precursors of bipolar disorder (BD). Symptoms of attention-deficit/hyperactivity disorder (ADHD) have been reported among the most common prodromes of BD. The aim of this study was to estimate the risk of BD in youths affected by ADHD based on prospective studies. A systematic review was conducted according to the PRISMA guidelines. A meta-analysis of single proportions was performed to compute the overall occurrence of BD in ADHD individuals. Binary outcome data were used to calculate risk estimates of BD occurrence in ADHD subjects versus Healthy Controls (HC). An overall proportion of BD occurrence of 10.01% (95%-confidence interval [CI]: 6.47%-15.19%; I2 = 82.0%) was found among 1248 patients with ADHD over 10 prospective studies. A slightly higher proportion was found when excluding one study based on jack-knife sensitivity analysis (11.96%, 95%-CI: 9.15%-15.49%; I2 = 54.1%) and in three offspring studies (12.87%, 95%-CI: 8.91%-18.23%). BD occurrence was not significantly associated with mean follow-up duration (p-value = 0.2118). A greater risk of BD occurrence in ADHD versus HC from six studies was found (risk ratio: 8.97, 95%-CI: 4.26-18.87, p-value < 0.0001). Few prospective studies have been retrieved in our search and most were not specifically aimed at assessing BD in followed-up ADHD patients. Greater clinical attention should be paid to ADHD as an early precursor of BD since a substantial proportion of ADHD patients is expected to be diagnosed with BD during the developmental age.