How Fast should we Titrate Methylphenidate in Adults with ADHD? A Meta-analysis of Dose Titration Regimens in RCTs

Rationale: Methylphenidate (MPH) is recommended as first-line treatment for ADHD in adults by all evidence-based treatment guidelines (1,2). Randomised controlled trials (RCTs) have time constraints and tend to favour fast titration regimens. We analysed titration regimens in 31 RCTs of MPH in order to review the evidence for fast versus slow titration of MPH.

Methods: We included all 17 RCTs that were selected for the largest published meta-analysis (3) and found 14 more RCTs published 2004-17 in PubMed using similar inclusion criteria. Most studies (20 of 31) were performed in the US, 9 studies (mainly) in Europe. The older studies were single centre studies, had smaller samples, used IR MPH and had mainly cross-over designs.

Results: 31 RCTs used a total of 32 titration regimens. 12 studies used fixed and 19 studies used flexible dose titration, which meant no further dose increases once a good clinical response was achieved. The time of titration varied considerably from 3 days to 6 weeks (mean±SD = 19.3±9.9 days). The lowest starting dose was 10mg (or two doses of 5mg IR MPH) and the highest starting dose was 40mg per day. The lowest maximum dose was 45mg and the highest 180mg per day.

Conclusions: Published RCTs of MPH in adult ADHD use fast titration regimens with relative high starting doses and 1-3 dose increases per week. In everyday clinical practice the speed of titration is often slower, and is influenced by availability of follow-up appointments, box sizes of MPH preparations (30 tablets or capsules per box), prescriber choice and patient preference (4). Fast titration regimens may result in prescribing unnecessarily high doses of MPH.