2025-04-28
096_ Drugs Capable of Remyelination and Cognitive Performance in Psychosis and Affective Disorders (Amendment to 094)
Research Question and Aims
Analyzing the data of our original PsyCourse proposal entitled “Drugs Capable of Remyelination and Cognitive Performance in Psychosis and Affective Disorders”, we were able to demonstrate that psychotic patients receiving quetiapine treatment showed superior cognitive performance in two verbal memory tasks, the Digit-Span-Test Backwards (DST-B) and the Verbal Learning and Memory Test (VLMT). Both tests are assumed to proxy hippocampal memory function, a brain region, where demyelination is observed in later stages of psychotic disorders (PMID: 27460617, 31552495). Quetiapine has been shown to induce oligodendrocyte differentiation (in-vitro, PMID: 27592856) and remyelination (in-vivo, PMID: 24997607), which could be the neuropharmacological link to the observed treatment effects. These findings are so far in agreement with our hypotheses.
However, we also observe a large variability between patients suggesting the potential involvement of moderating genetic effects. Indeed, we recently could show that cell type-specific polygenic burden scores reflecting the polygenic schizophrenia risk based on variants of the top 5% genes expressed in mouse radial glia-like cells (RAD), oligodendrocyte precursor cells (OPC), and mature oligodendrocytes (OLI), could predict therapeutic effects on hippocampal volume (PMID: 31712617, 38965091). Thus, we would like to suggest evaluating potentially moderating effects of the three cell type-specific polygenic burden scores RAD, OPC, and OLI on the observed quetiapine effects on verbal memory in psychotic patients using genome-wide genetic data.
Analytic Plan
We hypothesize that the observed quetiapine effects on verbal memory are moderated by cell type-specific polygenic burden scores RAD, OPC, and OLI (PMID: 31712617, 38965091). We wish to calculate the individual burden scores of the PsyCourse patients based on the available Illumina GSA genotypes. Then, we intend to re-analyze the effects of quetiapine on cognitive function in psychotic patients by additionally including each of the three polygenic burden scores, RAD, OPC, and OLI, as main effect and interaction term, respectively. The overall schizophrenia risk score will also be calculated to benchmark our results.
Resources needed
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