Characterizing the Effect of CYP2C19/CYP2D6 Genotype on Plasma Drug Exposure to Antidepressant, Antipsychotic Medications

The researchers of this study sought to quantify the difference in antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers.

Results from a systematic review and meta-analysis published in JAMA Psychiatry support the clinical relevance of personalized antidepressant and antipsychotic dosing based on the CYP2C19/CYP2D6 genotype. Pooled data from nearly 100 unique studies indicated that CYP2C19 and CYP2D6 genotypes were significantly associated with plasma levels of several antidepressant and antipsychotic agents. To achieve optimal blood drug levels, the investigators wrote, clinicians may need to account for CYP2C19/CYP2D6 enzyme capacity.

Antidepressant and antipsychotic drugs are metabolized by the CYP2C19 and CYP2D6 enzymes. The capacities of these enzymes are genetically determined; “normal” metabolizers (NM) have normal enzymatic capacity, while “poor” metabolizers (PM) do not possess the active enzyme. “Intermediate” metabolizers (IM) have reduced, though not absent, enzymatic capacity. Prior studies have indicated that patients in the IM and PM category experience higher plasma concentration and greater adverse events following drug exposure.

The investigators sought to better define the optimal dosing of psychiatric drugs for patients based on CYP2C19/CYP2D6 genotype. PubMed,,, the International Clinical Trials Registry Platform, and CENTRAL databases were searched for studies published between January 1, 1990, and June 30, 2020.

Eligible studies had available CYP2C19/CYP2D6 genotype data such that classification into NM, IM, and PM categories was possible. The primary outcome was drug exposure, measured using 1 of the following metrics, based on availability: (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady state plasma level, or (3) reciprocal apparent total drug clearance. Ratio of means (RoM) was used to compare drug exposure in the PM and IM groups compared to the NM group.

Data were extracted from 94 unique studies, comprising a total cohort of 8379 patients. The CYP2D6 genotype was associated with significant exposure differences for aripiprazole, haloperidol, and risperidone. Specifically, patients in the CYP2D6 IM and CYP2D6 PM categories had significantly greater mean drug exposure compared to patients in the CYP2D6 NM category when given aripiprazole (RoM, 1.48; 95% confidence interval [CI], 1.41-1.57; 12 studies; n=1038) or risperidone (RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; n=1492). Exposure to haloperidol lactate was associated with greater exposure in CYP2D6 PM vs CYP2D6 NM, though not in CYP2D6 IM (RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; n=423).

Escitalopram oxalate and sertraline hydrochloride exposure differed across CYP2C19 genotypes. Specifically, escitalopram oxalate exposure was much larger in CYP2C19 PM vs CYP2C19 NM (RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; n=1262). Sertraline hydrochloride levels were higher in CYP2C19 IM vs NM patients (RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; n=917).

Exposure differences were also observed across genotypes for the following drugs: clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride. However, not enough data were available to verify the significance of these differences.

In this systematic review and meta-analysis, the CYP2C19/CYP2D6 genotype was significantly associated with drug levels of certain antipsychotic and antidepressant medications. Results support the personalization of psychiatric drug regimens based on genotype. The primary limitations of this study are due to its meta-analytic design, which prevented adjustment for confounders. Between-study heterogeneity also limits the robustness of conclusions.

“[M]ore representative studies focused on these specific gene-drug associations are necessary for an adequate quantification of the magnitude of drug level changes and for representative evaluation of the relevance of these changes,” the investigators wrote.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry.

Please see the original reference for a full list of authors’ disclosures.


Milosavljević F, Bukvić N, Pavlović Z, et al. Association of CYP2C19 and CYP2D6 poor and intermediate metabolizer status with antidepressant and antipsychotic exposure: A systematic review and meta-analysis. JAMA Psychiatry. Published online November 25, 2020. doi:10.1001/jamapsychiatry.2020.3643