Beneficial and adverse effects of antipsychotic medication on cognitive flexibility are related to COMT genotype in first episode psychosis
Introduction
The ability to flexibly adjust behavior to changing environmental demands (cognitive flexibility), and to maintain newly learned behavioral preferences without regressing to previous, and no longer adaptive, response preferences (cognitive stability) form important complementary components of executive function (Diamond, 2013). Patients with schizophrenia and affective disorders have well-established disturbances in cognitive flexibility and stability evident in many studies using the Wisconsin Card Sorting Test (WCST) (Heaton et al., 1994; Merriam et al., 1999). Similar deficits have been reported on a computerized analog of the WCST, the Penn Conditional Exclusion Test (PCET) (Hill et al., 2015). Utilizing translational models of cognition evaluating discrete components of behavioral set shifting mediated by different brain regions may improve the sensitivity of set-shifting tasks for understanding cognitive deficits in psychotic disorders and for evaluating treatment outcomes and genetic associations.
Research using animal models has indicated a critical role for the interaction between dopaminergic activity in the prefrontal cortex and striatum in set-shifting. Specifically, cognitive flexibility is impaired by a combination of decreased prefrontal dopamine (DA) and elevated striatal DA, while cognitive stability is impaired in the context of increased prefrontal DA and decreased striatal dopaminergic activity (Amodeo et al., 2014; Ragozzino et al., 2002; Roberts et al., 1994).
Animal studies investigating the role of D1 dopamine receptors in the PFC have focused on delayed response tasks, which require online maintenance of a previously presented stimulus. Striatal dopamine is thought to be important for flexibility and updating goal representations when new information is pertinent (Cools and D'Esposito, 2011). Research using non-human primates revealed that destruction of dopamine neurons in the PFC resulted in enhanced distractibility (poor cognitive stability), while dopamine depletion in the striatum resulted in reduced distractibility (poor cognitive flexibility) (Crofts et al., 2001). These opposing effects of PFC and striatal lesions on dopamine systems highlight the possible competition between the PFC and the striatum, and suggest that a dynamic balance between stabilization and flexible updating depends on balanced dopamine transmission within the PFC and striatum respectively. This functional opposition between flexibility and stability is consistent with the model of neurochemical reciprocity between dopamine in the PFC and the striatum in which variability in PFC dopaminergic activity leads to corresponding changes in striatal dopamine activity (Cools and D'Esposito, 2011; Tunbridge et al., 2006).
Catechol-O-methyltransferase (COMT) enzyme activity is a significant regulator of synaptic DA in the prefrontal cortex (Chen et al., 2004). The rs4680 A>G polymorphism in COMT results in a valine to methionine amino acid change which decreases the in vivo stability of the COMT enzyme, reducing DA catabolism, thus increasing synaptic DA. COMT activity in Val/Val homozygotes is approximately 38% higher than Met/Met homozygotes and 29% higher than Val/Met heterozygotes in the dorsolateral prefrontal cortex (DLPFC) (Chen et al., 2004). Thus, COMT genotype may be an important factor in mediating cognitive flexibility and stability supported by dopamine activity in the PFC and striatum respectively. Further, the Met allele is hypothesized to be associated with more tonic than phasic dopamine release in subcortical regions, and higher dopamine concentrations in the cortex that leads to greater cognitive stability and more limited cognitive flexibility (Bilder et al., 2004). In contrast, the Val allele is believed to be associated with more phasic dopamine activity in subcortical regions and lower dopamine concentrations in the cortex, leading to greater cognitive flexibility and reduced behavioral stability, particularly in Val homozygotes (Bilder et al., 2004).
In this study we examined the role of a well characterized genetic polymorphism in the COMT gene in mediating cognitive antipsychotic treatment effects in first episode psychosis (FEP). We considered catechol-O-methyltransferase (COMT) to be a potentially important baseline consideration in a pharmacogenomic context because Met carriers and Val homozygotes respond differently to antipsychotic therapy (Huang et al., 2016). In previous studies, Met carriers have demonstrated improved performance on the N-back task compared to Val homozygotes following antipsychotic pharmacotherapy (Bertolino et al., 2004; Weickert et al., 2004). Because COMT modulates dopaminergic systems differently in the PFC and striatum due to limited DA transporter (DAT) expression in PFC (Cools and D'Esposito, 2011; Tunbridge et al., 2006), evaluating the relation between COMT genotype and components of set-shifting that are differentially dependent on prefrontal and striatal function before and after treatment with antipsychotics may shed light on mechanisms underlying variable cognitive outcomes following antipsychotic therapy.
Section snippets
Participants
FEP participants (54.8% schizophrenia spectrum disorder, 29.0% bipolar disorder with psychosis, 12.9% major depressive disorder with psychosis, 3.2% psychotic disorder NOS) were evaluated, performed cognitive testing and then treated at the University of Illinois at Chicago (UIC). Participants were considered first episode if this were their first hospitalization for acute psychotic symptoms and had limited prior exposure to antipsychotic medication. Individuals presenting to emergency rooms
Baseline comparison of patients and controls
Group performance on the PCET before and after treatment is summarized in Table 2. For perseverative errors the Poisson regression indicated significant main effects of group [χ2 = 7.24, p = .007] and genotype [χ2 = 14.50, p < .001] as well as a significant group by genotype interaction effect [χ2 = 16.29, p < .001]. Analysis of regressive errors revealed significant main effects of group [χ2 = 3.99, p = .046] and genotype [χ2 = 8.74, p = .003], as well as a significant group by genotype
Discussion
This study demonstrated differential cognitive change after acute antipsychotic therapy in untreated first episode patients with psychotic disorders based on COMT genotype. Met carriers with FEP showed cognitive improvement after antipsychotic treatment characterized by a significant reduction of both perseverative and regressive errors. These findings indicate enhanced cognitive flexibility and stability for Met carriers, respectively, following antipsychotic treatment. These observations
Acknowledgements
We thank Drs. Ovidio DeLeon, Margret Harris, Hugo Solari, Peter Weiden, and the clinical core staff of the UIC Center for Cognitive Medicine for their contributions to diagnostic and psychopathological assessments. We also thank Shitalben Patel for her contributions to the genotyping portions of this work. This study was supported in part by NARSAD, NIMH Grants MH077862, MH083888, MH062134, MH080066, and MH072767 and American College of Clinical Pharmacy.
Conflicts of interest
Dr. Sweeney has received support from Takeda. The other authors have no conflicts of interest at this time.
Role of the funding source
This project was supported by the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) and the National Institutes of Health (NIMH: MH077862, MH062134, MH080066, and MH072767).
Contributors
Courtney Nelson is the lead author and was responsible for data analysis and manuscript preparation. Dr. Hill is the corresponding author and he was involved in all aspects of the report. Hayley Amsbaugh was involved in writing portions of the report. Dr. Reilly was responsible for data management and supervision of clinical and cognitive assessments. Dr. Bishop was responsible for handling genetic data and contributed to writing the report. Drs. Rosen and Marvin were involved in recruitment
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