A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam.

2022-06

Campbell, Ciarán

McCormack, Mark

Patel, Sonn

Stapleton, Caragh

Bobbili, Dheeraj

Krause, Roland

Depondt, Chantal

Sills, Graeme J

Koeleman, Bobby P

Striano, Pasquale

Zara, Federico

Sander, Josemir W

Lerche, Holger

Kunz, Wolfram S

Stefansson, Kari

Stefansson, Hreinn

Doherty, Colin P

Heinzen, Erin L

Scheffer, Ingrid E

Goldstein, David B

O'Brien, Terence

Cotter, David

Berkovic, Samuel F

Sisodiya, Sanjay M

Delanty, Norman

Cavalleri, Gianpiero L

Journal Article

https://orcid.org/0000-0001-8267-5252

https://orcid.org/0000-0002-8213-6141

https://orcid.org/0000-0001-5141-3591

https://orcid.org/0000-0001-9938-7126

https://orcid.org/0000-0002-8452-5319

https://orcid.org/0000-0002-6065-1476

https://orcid.org/0000-0001-6041-9661

https://orcid.org/0000-0002-7268-8559

https://orcid.org/0000-0002-2311-2174

https://orcid.org/0000-0003-4580-841X

https://orcid.org/0000-0002-1511-5893

https://orcid.org/0000-0002-3953-9842

https://orcid.org/0000-0002-9802-0506

10.1111/epi.17228

Levetiracetam (LEV) is an effective anti-seizure medicine, but 10-20% of people treated with LEV report psychiatric side-effects and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioural ADRs associated with LEV. This case-control study compared cases of LEV-associated behavioural disorder (n=149) or psychotic reaction (n=37) to LEV-exposed people with no history of psychiatric ADRs (n=920). All samples were of European ancestry. We performed GWAS analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n=18) and controls (n=122). Univariate GWAS found no significant associations with either LEV-ADR. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to controls (p = 0.0097, estimate = 0.4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV-ADRs.

link

Epilepsia 2022; 63(3): 1563-1570

Epilepsia