Background:

There is growing recognition that ADHD persists into adulthood and the incidence of diagnosis increases. First-line treatment includes central stimulating drugs such as methylphenidate (MPH). Critical appraisal of current trials for national clinical guidelines encouraged us to review existing trials in more detail with a focus on study design and systematic restrictions on study populations.

Objectives:

To identify factors that influence effect estimates such as restrictions in study population and features of study design, such as responder selection.

Methods:

We used the systematic search in the Danish Health and Medicine Authorities’ recently published national guideline for references. Each trial was assessed independently for study design features and results by two researchers. We aimed to clarify the effect of bias introduced by:
1. exclusion of participants with psychiatric comorbidity;
2. exclusion of non-responders to MPH; and
3. effect of wash-out period (abstinence symptoms).

Results:

We assessed 28 trials: 39% allowed psychiatric comorbidity, while 36% did not and 25% were unclear about this; 32% of trials excluded previous non-responders (so called 'enriched design'); 14% of trials had a MPH-naïve population, while the remaining 54% were unclear about this; 75% of trials used a wash-out period with withdrawal of current psychotropic medication, while 7% did not have a wash-out period, and 18% were unclear about this. ADHD symptoms improved; standardised mean difference (SMD) 1.39 (95% confidence interval (CI) 0.84 to 1.94) when rated by investigator and SMD 0.62 (95% CI 0.33 to 0.91) when self-rated, both in favour of MPH. No study was free of restrictions on the study population.

Conclusions:

The effect size of MPH in a clinical setting is essentially unknown. Current evidence is unreliable and estimated effect sizes are potentially misleading.