Neuropsychological functioning and OROS® methylphenidate in an Adult Attention-Deficit/Hyperactivity Disorder (ADHD) population

Objective: Neuropsychological tests have been used in attention-deficit/hyperactivity disorder (ADHD) to compare ADHD patients with normal subjects, to assess drug-placebo differences in clinical trials and to identify appropriate medication levels via test dose paradigms. While clinical studies have generally been positive1 with moderate effect sizes, outcomes have been inconsistent, particularly in adults. This analysis examined a neurocognitive battery in a sample of adult ADHD subjects during a clinical trial of OROS® methylphenidate (OROS MPH; Concerta®).2 Methods:This 8-week crossover study utilized OROS MPH in 41 subjects who met DSM-IV criteria and the Utah Criteria for ADHD. ADHD symptoms were assessed using the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS)3 and the ADHD-Rating Scale (ADHD-RS). (The primary efficacy and safety results were previously reported.2) The CNS Vital Signs (CNSVS) is a computer-based neurocognitive battery with tests of Verbal and Visual Memory, Finger Tapping, Symbol Digit Coding (SDC), the Stroop Test, the Shifting Attention Test (SAT), and the Continuous Performance Test (CPT). The developer has reported average scores for both normal and ADHD subjects on these tests.4 Baseline scores on this population were compared with the normative data. The impact of treatment (OROS MPH vs placebo) on test scores was assessed via paired t-tests. Results: OROS MPH was superior to placebo for all clinical ADHD measures, including total WRAADDS (44% vs 13% improvement; P=0.001), plus the subscales addressing inattention, hyperactivity/impulsivity, and emotional dysregulation. At baseline, our ADHD patients had CNSVS scores midway between the developer's ADHD and normal samples. However, on errors in the Stroop and CTP commission errors, the ADHD patients scored worse than either comparison group. Although OROS MPH was usually associated with better scores than placebo, this difference only achieved significance for 4 of the tests: SDC number correct (P=0.041), Stroop complex reaction time (P=0.009), SAT number correct (P=0.018), and CPT reaction time (P=0.034). Conclusions: Baseline scores were consistently worse than the test developer's normative data, and endpoint scores on OROS MPH were consistently better than placebo. The tests that reached or approached significance were all test scores that had previously reached significance in test dose paradigms. The longer period between testing in this clinical trial (4 weeks) compared with a test dose paradigm (1 hour) may contribute to the weaker relationship. Conversely, actual clinical trials in adults with ADHD have frequently failed to find drug-placebo differences on cognitive testing.