25. Cortical Information Processing in Patients With Schizophrenia is Modulated by Tolcapone: Role of COMT val158met Genotype
Year: 2017
Type: conference-abstract
Abstract: Background: Dopamine (DA) dysfunction is involved in deficits underlying working memory (WM) and prefrontal cortical (PFC) physiology in patients with schizophrenia. Evidence indicates that DA stabilizes and focuses the prefrontal cortical web by modulating NMDA, non-NMDA, and GABAergic networks. Catechol-O-methyl transferase (COMT) plays a role in regulating dopamine release in the PFC. Val[158]Met, a common COMT functional polymorphism, affects PFC function and WM capacity and has been associated with cognitive deficits in schizophrenia. Tolcapone, a COMT inhibitor that minimally penetrates the blood–brain barrier, has been shown to improve executive function and PFC efficiency as observed in BOLD fMRI studies in normal volunteers. We also previously found that tolcapone’s effect on neuropsychological tasks was modulated by COMT val-met genotype. Methods: In the current study, we sought to determine whether tolcapone (100 mg three times a day on the first day and 200 mg 3 times a day for the next 6 days) or placebo would have an effect on PFC recruitment of neuronal resources in patients with schizophrenia. We randomized 33 subjects following a within-subjects, counterbalanced study design and enrolled them to participate in a double-blinded, cross-over, placebo-controlled trial. Subjects underwent BOLD fMRI on the seventh day of each arm while performing the N-Back working memory task (1-Back, 2-Back, and 3-Back). Comparing the three COMT genotypes, the 33 subjects (6 women) are not different in age, gender, IQ or race. We performed a 3-way ANCOVA on percentage accuracy with Drug, Load, and Genotype as factors in SAS 9.3. Results: There was a significant main effect of drug (tolcapone > placebo, P = .0034) and load (P < .0001) on N-Back performance test. We processed the fMRI data in SPM12 and obtained the placebo-tolcapone contrast map for each participant with first level analysis. These first-level contrast maps were entered into group analysis using a 2-way ANCOVA with load and genotype as factors and accuracy as a covariate of no interest. In parallel to the performance results, there were significant effects of drug in WM load on prefrontal BOLD signal change. Although all genotypes showed decreased bilateral DLPFC activation on tolcapone compared to the placebo condition, post-hoc analysis showed that Val/Val homozygotes had the strongest reduction (P = .045) in the right DLPFC compared to the other two genotype groups when the signal was extracted from the placebo > tolcapone contrast with all genotypes and all load effects combined. Conclusion: Our results are consistent with previous findings in healthy volunteers of tolcapone’s COMT inhibitory effect improving information processing, especially in Val/Val homozygotes. These findings suggest that in patients with schizophrenia also, tolcapone improves PFC efficiency during working memory and its effect is most likely modulated by COMT Val-Met genotype.
Source: Schizophrenia Bulletin
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2600021654