COMT and 5-HT1A-receptor genotypes potentially affect executive functions improvement after cognitive remediation in schizophrenia

Abstract

Cognitive remediation therapy (CRT) has been proved to improve cognitive deficits in schizophrenia and to enhance functional outcomes of classical rehabilitation. However, CRT outcomes are heterogeneous and predictors of response are still unknown. Genetic variability, especially in the dopaminergic system, has been hypothesized to affect CRT. We previously reported that rs4680 of the catechol-O-methyltrasferase (COMT) influences improvements in executive functions in patients treated with CRT, but this result was not confirmed by other studies. Such inconsistent findings may depend, other than on clinical variables, also on other genes involved in cognition. Recent studies proved that serotonin 1A receptor (5-HT1A-R) regulates dopamine in the prefrontal cortex (PFC), and clinical works suggested a 5-HT1A-R role in cognition. We then analysed possible effects of COMT rs4680 and 5-HT1A-R rs6295 on CRT outcomes, taking into account also clinical and demographic factors. Eighty-six clinically stabilized schizophrenia patients treated with three months CRT were assessed with the Wisconsin Card Sorting Test, as a measure of executive functions, at enrolment and after CRT treatment, and underwent COMT and 5-HT1A-R genotyping. We found a significant main effect of COMT genotype and an interaction with 5-HT1A-R on executive function improvement after CRT. The results suggest that these two polymorphisms may have an additive effect on individual capacity to recover from cognitive deficit, probably through their role on PFC dopaminergic transmission modulation, known to be critical for modulating cognitive functions.

Factors Associated With Response and Resistance to Cognitive Remediation in Schizophrenia: A Critical Review

“…In contrast to these positive findings other studies did not find such a great association (or no association) between COMT Met/Met genotype and greater improvement after CR (Greenwood et al, 2011; Twamley et al, 2014). Moreover, further investigation provided new awareness of the role of COMT in CR response, pointing out a potential interaction between COMT polymorphism and antipsychotic drugs (Bosia et al, 2014a) and serotonin 1A receptor (5-HT1A-R) (Bosia et al, 2014b). Overall, these data suggest how COMT genotype could provide useful information in the selection of an appropriate and personalized pharmacological and rehabilitative treatment in schizophrenia (Medalia et al, 2018).…”

COMT genotype and response to cognitive remediation in schizophrenia

“…Second, other than examining the interaction of COMT genotype with CRT response of subjects on clozapine, we were not able to examine the interaction of specific antipsychotics with both the COMT polymorphism and the effects of CRT as the subjects were on various antipsychotics preventing a systematic analysis. Finally, our results may also be affected by other loci in the genome (Bosia et al, 2014a; Wonodi et al, 2003). Associations between single genes and single cognitive processes may be more complex.…”

“…The differential COMT genotype effects on working memory functions have been used as a predictor of pharmacological treatment response in subjects with schizophrenia(Bertolino et al, 2004; Weickert et al, 2004), but few studies have examined the COMT genotype as predictor of cognitive interventions (Bosia et al, 2014a; Panizzutti et al, 2013) and results have been inconsistent(Greenwood et al, 2011). Hence, the question of this possible association requires further examination.…”

Cognitive training improves the disturbed behavioral architecture of schizophrenia-like rats, “Wisket”

“…dopaminergic, glutamatergic, serotoninergic and GABAergic) disturbed in schizophrenia, are involved in the cognitive functions, too. The beneficial effects of cognitive training might be associated with changes in these systems, and their disruption in schizophrenia may be improved by cognitive remediation [17,18,38,[40][41][42]. Therefore, further imaging, electrophysiological and/or molecular biological studies are warranted to explore the structural and functional changes in Wisket rats, and their potential improvements after cognitive training.…”