Tolcapone's effect on neurocognition and neurophysiological measures in COMT-genotyped healthy adults

Background: Tolcapone, a reversible catechol O-methyl transferase (COMT) enzyme inhibitor has been shown to improve neurocognitive performance in healthy subjects carrying the Val/ Val genotype of the COMT gene (SNP rs4680). However, the anatomical basis for tolcapone's action and the neurocognitive targets engaged by it are still unclear. Studies will identify the latter by investigating tolcapone's effect on MATRICS Consensus Cognitive Battery (MCCB) performance, and the anatomical basis for its action will be assessed by electroencephalography recording during 5 Choice-Continuous performance test (5C-CPT). Methods: 40 Carefully screened, COMT-genotyped, medically and psychiatrically healthy males and females aged 18-35 years will receive a single dose of tolcapone (200 mg or placebo p.o.) across 2 test days separated by 1 week in a double-blind, randomized, counterbalanced, crossover design. The main effect of tolcapone will be analyzed using repeated measures ANOVA. Results: 15 subjects (Met/Met:Val/Val= 3:12) have completed the study thus far. Overall, tolcapone was well tolerated however it mildly elevated systolic blood pressure and decreased heart rate (effect size (d)=0.5) in a time-dependent manner. Tolcapone significantly improved verbal fluency task performance (F= 8.79, df (1,14), p=0.01), decreased false alarm rate (FlA) on 5C-CPT (F=4.58, df(1,14), p=0.01) and tended to activate frontal electrodes during “non-target trials” (p=0.16) compared to placebo. Conclusions: Our preliminary findings suggest that tolcapone (200 mg) is biologically active, and significantly improves verbal fluency task performance and response inhibition measured by FlA during non-target trials. Tolcapone activated frontal electrodes during non-target trials, consistent with its behavioral effects, suggesting a frontal locus of bioactivity for this drug.