Pharmacogenomics: A road ahead for precision medicine in psychiatry

Pardiñas, Antonio F.; Walters, James

doi:10.1016/j.neuron.2021.09.011

Cited by 32 publications

(34 citation statements)

References 202 publications

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“…Individual differences in response to psychopharmacology are known to be influenced by genetic and environmental factors (7,8). Pharmacogenomics research aims to identify genetic variants that contribute to this variability and is one of the most promising pillars of precision medicine strategies (9).…”

Section: Introductionmentioning

confidence: 99%

Genomic Stratification of Clozapine Prescription Patterns Using Schizophrenia Polygenic Scores

Kappel

Legge²,

Hubbard³

et al. 2023

Biological Psychiatry

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Section: Introductionmentioning

confidence: 99%

Genomic Stratification of Clozapine Prescription Patterns Using Schizophrenia Polygenic Scores

Kappel

Legge²,

Hubbard³

et al. 2023

Biological Psychiatry

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“…Individual differences in response to pharmacological treatment are known to be influenced by genetic and environmental factors (8,9). Pharmacogenomic research aims to identify genetic variants that contribute to this variability and is one of the most promising pillars of precision medicine strategies (10). To date, while most known pharmacogenomic variants are associated with ADME processes (absorption, distribution, metabolism, and excretion), markers associated with disease and disorder risk can also be assessed to investigate treatment outcomes (11).…”

Section: Introductionmentioning

confidence: 99%

“…This suggests that investigating the association between genetic liability to the disorder and response to antipsychotics might be fruitful, with a hypothesis being that heavier genetic burden could be associated with poorer treatment response. As treatment outcomes in schizophrenia are multifaceted and depend on complex factors including treatment adherence (10), many studies on this matter have investigated treatment response by focusing on individuals with the most severe symptomatology, often using samples of those with TRS (16). However, the evidence for schizophrenia risk alleles being predictors of TRS is inconclusive, and the largest study on this topic suggests that the schizophrenia PRS is not substantially elevated in those with this diagnosis (17).…”

Section: Introductionmentioning

confidence: 99%

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Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores

Kappel

Legge

Hubbard

et al. 2022

Preprint

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BACKGROUND: Treatment-resistant schizophrenia (TRS) affects ~30% of individuals with the disorder. Clozapine is the medication of choice in TRS but optimizing administration and dose titration are complex. The identification of predictive factors that influence clozapine prescription and response, including genetics, is of clinical interest in a precision psychiatry framework. We aimed to determine if a polygenic risk score (PRS) for schizophrenia is associated with the highest drug dose an individual received during clozapine treatment. METHODS: We used generalized linear regression models accounting for demographic, pharmacological, and clinical covariates to determine the relationship between PRS and highest daily dose of clozapine. We used two independent multi-ancestry samples of individuals from the UK from a clozapine monitoring system, CLOZUK2 (N= 3133) and CLOZUK3 (N= 909). Schizophrenia PRS were calculated using the latest available GWAS summary statistics from the Psychiatric Genomics Consortium. In a secondary analysis of the two merged cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRS and clozapine doses classified as low, standard, or high (>600 mg/day). RESULTS: After controlling for relevant available covariates, schizophrenia PRS were correlated with the highest clozapine dose ever prescribed, in both CLOZUK2 (β= 12.217, s.e= 3.776, P= 0.001) and CLOZUK3 (β= 12.730, s.e= 5.987, P= 0.034). In the secondary analysis, the schizophrenia PRS was specifically associated with taking a clozapine dose greater than 600 mg/day (OR= 1.279, P= 0.006). CONCLUSIONS: Schizophrenia PRS is associated with the highest clozapine dose ever prescribed in two independent multi-ancestry samples from the UK, suggesting that the genetic liability to schizophrenia might index factors associated with therapeutic decisions in TRS cohorts.

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“…Recent genome-wide association studies (GWAS) have pointed towards a small number of variants that could explain between 1% and 10% of the variance in clozapine pharmacokinetics after accounting for non-genetic factors 14,15 , and these may also have downstream relevance for ADRs 16 . Unfortunately, these studies have only been carried out in individuals of European ancestry, a clear limitation given the known diversity of drug-metabolising enzyme alleles worldwide, and the potential lack of transferability of genomic predictors across populations 13 . The Eurocentrism of clozapine pharmacogenomics studies is also particularly problematic as the prescription patterns and outcomes of this drug seem to be ancestrally stratified to some extent: For example, doses recommended for individuals of East Asian ancestry and indigenous populations of the Americas are lower than those typically prescribed to Europeans, to compensate for a generally slower clozapine metabolism in those populations 17 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: A longitudinal analysis and GWAS using clinical monitoring data from the UK

Pardiñas

Kappel

Roberts

et al. 2022

Preprint

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BackgroundThe antipsychotic clozapine is the only drug with proven effectiveness against the treatment-resistant symptoms that affect 20-30% of those with schizophrenia. Despite this, clozapine is markedly under-prescribed, partly due to concerns about its narrow therapeutic range and adverse drug reaction profile. Both concerns are linked to drug metabolism, which varies across worldwide populations and is partially genetically determined. There is, however, a lack of clozapine pharmacogenomic data based on study participants of multiple ancestries.MethodsWe analysed data from 4,495 individuals linked to 16,068 assays from a clozapine monitoring service in the UK. Genomic information was used to identify five biogeographical ancestries (European, Sub-Saharan African, North African, Southwest Asian and East Asian) as well as admixed individuals. Pharmacokinetic modelling, GWAS, and a polygenic score association analysis were conducted on this longitudinal dataset using three outcome variables: two metabolite plasma concentrations (clozapine and norclozapine) and their ratio.FindingsA faster average clozapine metabolism was seen in those of Sub-Saharan African ancestry compared to Europeans. In contrast, East and Southwest Asians were more likely to be slow clozapine metabolisers. Eight pharmacogenomic loci were identified in the GWAS, with consistent cross-ancestral effects. Polygenic scores generated from these loci led to significant associations with clozapine outcome variables in the whole sample and within individual ancestries, with variances explained between 0.61%-7.26%.InterpretationLongitudinal cross-ancestry GWAS can discover pharmacogenomic markers of clozapine metabolism that, individually or as polygenic scores, have consistent effects across ancestries. While the potential clinical role of these predictors is evaluated, we provide strong evidence that ancestral differences in clozapine metabolism should be incorporated into clozapine dosing and managing protocols to optimise their utility for diverse populations.FundingMedical Research Council (MRC).

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Pharmacogenomics: A road ahead for precision medicine in psychiatry

Cited by 32 publications

References 202 publications

Genomic Stratification of Clozapine Prescription Patterns Using Schizophrenia Polygenic Scores

Genomic Stratification of Clozapine Prescription Patterns Using Schizophrenia Polygenic Scores

Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores

Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: A longitudinal analysis and GWAS using clinical monitoring data from the UK

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