Hyponatremic Cognitive Dysfunction Resulting from Drug-Drug-Gene Interaction between Sertraline and Cannabidiol in an Intermediate CYP2C19 Metabolizer Patient

Abstract

Background: Pharmacogenomics (PGx) can provide more precision in determining causation of adverse drug reactions (ADRs) from drug-drug-gene interaction clinical application. Case Summary: Patient was an intermediate CYP2C19 metabolizer on stable therapy taking a low but therapeutic dose of sertraline for depression and anxiety over a period of 20 years. The patient then became hyponatremic and cognitively impaired after addition of cannabidiol (CBD) to this sertraline regimen. The proposed mechanism was drug-drug-gene interaction of CBD further inhibiting the CYP2C19 metabolism of sertraline and increasing drug exposure to produce moderate to severe hyponatremia and subsequent cognitive dysfunction. Practice Implications: Pharmacogenomics (PGx) testing may assist in etiology of patient symptoms from adverse drug reactions (ADRs) or drug-drug interactions by combining these with detection and application of drug-gene interactions. This case shows inhibition of CYP2C19 by CBD to further increase sertraline exposure, producing hyponatremia and subsequent cognitive dysfunction through CYP2C19 phenoconversion by CBD.

Unveiling behavioral and molecular neuroadaptations related to the antidepressant action of cannabidiol in the unpredictable chronic mild stress model

“…A recent case report showed a pharmacokinetic interaction between CBD and STR in a patient treated with STR for depression and anxiety. CBD inhibited CYP2C19 increasing STR exposure, producing hyponatremia and subsequent cognitive dysfunction ( Nanan et al, 2022 ). This fact may be critical since the behaviors related to an excess of serotonin are similar to symptoms of anxiety and depressive disorders ( Jukic et al, 2018 ).…”

From genes to drugs: CYP2C19 and pharmacogenetics in clinical practice

“…In particular, the concomitant use of CYP2C19 inhibitors and psychiatric medications may commonly lead to phenotype conversion from nonpoor metabolizer phenotype to poor metabolizer phenotype ( Klieber et al, 2015 ). In a recently published case report, a patient with intermediate CYP2C19 phenotype who was on sertraline for 20 years developed cognitive dysfunction and hyponatremia due to an increase in sertraline plasma concertation after addition of CBD to their treatment regimen ( Nanan et al, 2022 ). In another clinical case report, a patient complained of inadequate depression control despite several attempts with multiple antidepressants, including escitalopram, venlafaxine, and bupropion.…”

“…The patient was phenotypically a CYP2C19 IM and a CYP2D6 PM, and genetic variants in CYP2D6 and CYP2C19 increased his venlafaxine plasma concentration. In addition, the metabolism of other concomitant medications was impacted by the strong CYP2C19 inhibitor, bupropion, which contributed to the treatment failure ( Nanan et al, 2022 ).…”