Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for Psychiatric Precision Medicine

Abstract

Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration-approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (eg, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19.

Pharmacogenomics‐Driven Prediction of Antidepressant Treatment Outcomes: A Machine‐Learning Approach With Multi‐trial Replication

“…Our observation that the CYP2C19 metabolizer phenotype was not significantly associated with citalopram/escitalopram treatment outcomes or depression severity clusters is similar to findings from previous research. Although functional CYP2C19 allele variants are associated with citalopram/escitalopram metabolism and some drug side effects, the impact of CYP P450 genotypes, including CYP2C19 , on therapeutic outcomes has been less clear . Some studies in depressed patients have found a significant association between the CYP2C19 genotype and treatment response to citalopram or escitalopram, whereas other studies have failed to demonstrate such an association .…”

“…The lack of improved predictability of treatment outcomes through use of the CYP2C19 genotype does not mean that pharmacokinetic mechanisms and the CYP2C19 genotype are not clinically relevant. That is especially true with respect to adverse responses, such as dose‐dependent risk for corrected QT interval prolongation with citalopram …”

“…Although functional CYP2C19 allele variants are associated with citalopram/escitalopram metabolism and some drug side effects, 38 the impact of CYP P450 genotypes, including CYP2C19, on therapeutic outcomes has been less clear. 39 Some studies in depressed patients have found a significant association between the CYP2C19 genotype and treatment response to citalopram or escitalopram, 40,41 whereas other studies have failed to demonstrate such an association. 42,43 There are similar inconsistencies in the results of studies attempting to link serum concentrations of antidepressants, including citalopram, with antidepressant response.…”

“…That is especially true with respect to adverse responses, such as dose-dependent risk for corrected QT interval prolongation with citalopram. 39…”

A path to precision in the ICU

“…Enthusiasm for precision medicine can be seen across the spectrum of biomedical research, not only in oncology but also in cardiology [5], pulmonology [6], allergy [7], psychiatry [8], and public health [9]. Recently, a potential role for precision medicine in the ICU has also been discussed [10–18].…”