Antipsychotic and pharmacogenomic effects on cross-sectional symptom severity and cognitive ability in schizophrenia

Lock, Siobhan K., Kappel, Djenifer B., Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Walters, James T.R. ORCID: https://orcid.org/0000-0002-6980-4053, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Pardinas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590 and Legge, Sophie E. 2025. Antipsychotic and pharmacogenomic effects on cross-sectional symptom severity and cognitive ability in schizophrenia. EBioMedicine 116 , 105745. 10.1016/j.ebiom.2025.105745

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Abstract

Background People with schizophrenia differ in the type and severity of symptoms experienced, as well as their response to medication. A better understanding of the factors that influence this heterogeneity is necessary for the development of individualised patient care. Here, we sought to investigate the relationships between phenotypic severity and both medication and pharmacogenomic variables in a cross-sectional sample of people with schizophrenia or schizoaffective disorder depressed type. Methods Confirmatory factor analysis derived five dimensions relating to current symptom severity (positive symptoms, negative symptoms of diminished expressivity, negative symptoms of reduced motivation and pleasure, depression and suicide) and cognitive ability in participants prescribed with antipsychotic medication. Linear models were fit to test for associations between medication and pharmacogenomic variables with dimension scores in the full sample (N = 585), and in a sub-sample of participants prescribed clozapine (N = 215). Findings Lower cognitive ability was associated with higher chlorpromazine-equivalent daily antipsychotic dose (β = −0.12; 95% CI, −0.19 to −0.05; p = 0.001) and with the prescription of clozapine (β = −0.498; 95% CI, −0.65 to −0.35; p = 3 × 10−10) and anticholinergic medication (β = −0.345; 95% CI, −0.55 to −0.14; p = 8 × 10−4). We also found associations between pharmacogenomics-inferred cytochrome P450 (CYP) enzyme activity and symptom dimensions. Increased genotype-predicted CYP2C19 and CYP3A5 activity were associated with reduced severity of the positive (β = −0.108; 95% CI, −0.19 to −0.03; p = 0.009) and both negative symptom dimensions (β = −0.113; 95% CI, −0.19 to −0.03; p = 0.007; β = −0.106; 95% CI, −0.19 to −0.02; p = 0.012), respectively. Faster predicted CYP1A2 activity was associated with higher cognitive dimension scores in people taking clozapine (β = 0.17; 95% CI, 0.05–0.29; p = 0.005). Interpretation Our results confirm the importance of taking account of medication history (and particularly antipsychotic type and dose) in assessing potential correlates of cognitive impairment or poor functioning in patients with schizophrenia. We also highlight the potential for pharmacogenomic variation to be a useful tool to help guide drug prescription, although these findings require further validation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Elsevier
ISSN:	2352-3964
Date of First Compliant Deposit:	24 April 2025
Date of Acceptance:	23 April 2025
Last Modified:	28 May 2025 14:45
URI:	https://orca.cardiff.ac.uk/id/eprint/177876

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