Pharmacogenetic‐Guided Treatment of Depression: Real‐World Clinical Applications, Challenges, and Perspectives

Abstract

Depression is a leading cause of disability worldwide and, despite the availability of numerous antidepressants, the lack of standardized criteria to apply personalized prescription is still a major issue. Pharmacogenetic (PGx) markers in cytochrome P450 (CYP450) genes are already usable to guide antidepressant choice/titration according to clinical guidelines; they are an important step toward personalized psychiatry as they can reduce the time to identify an effective and tolerated treatment. Clinical application is still limited due to the financial and organizational challenges, but the number of services providing genotyping of pharmacogenes is increasing, with encouraging projections of cost‐effectiveness. Critical aspects that emerged from the available studies are the importance of integration of genotyping results in electronic medical records, standardization, and regular updates of decision support systems, training and collaboration of different professionals, need of longer follow‐ups to estimate cost‐effectiveness, and importance of avoiding inequalities in access to genotyping. Diversities exist among the groups of patients to whom genotyping is offered (pre‐emptive or reactive testing) and the type of clinical services (e.g., hospitals and primary care), currently without a consensus on which is the best approach. Future studies should aim to clarify these issues, as well as consider and compare PGx applications among different countries and healthcare systems. Finally, the extension of genotyping outside pharmacokinetic genes should be considered as a key step to improve the clinical impact of PGx, as this could significantly increase the variance explained in treatment outcomes.

Genetics of nonpharmacological treatments of depression

“…The polygenicity of treatment response requires large samples to identify genetic factors that show stable associations among samples, and these genetic factors cannot be identified a priori, leading to the substantial unsuccess of candidate gene studies (Fabbri et al, 2020). However, there are a few exceptions, primarily regarding the role of haplotypes in CYP450 genes in response to antidepressant drugs, as these were largely replicated and are included in prescribing guidelines (Zanardi et al, 2021a(Zanardi et al, , 2021b, though an equivalent successful result is lacking for nonpharmacological treatments of depression.…”

“…Genetic variants and gene expression levels are possible biomarkers for guiding therapy, contributing to the implementation of precision medicine in the treatment of depression (Dall'Aglio et al, 2021;Zanardi et al, 2021a). Pharmacogenetics of antidepressants has been widely studied, and variants in cytochrome P450 genes (CYP450) have recommendations for clinical use, according to prescribing guidelines (Zanardi et al, 2021a). On the other hand, nonpharmacological treatments have been far less investigated in terms of genetic markers of efficacy.…”

Evaluating study designs and treatment outcomes of antidepressant pharmacogenetic clinical trials - Challenges and future perspectives. A critical review

“…Previous reviews on PG tests for antidepressants have mainly taken into consideration the limitations concerning the PG test mechanisms in terms of choices of genetic variants in accordance with drug labels and international guidelines ( Bousman et al, 2019 ;Fabbri et al, 2018 ;Fabbri and Serretti, 2020 ;Zanardi et al, 2021a ). None has been focused on clinical and assessment methodological characterization as possible sources of errors.…”

Pharmacogenomic Testing for Major Depression: A Qualitative Study of the Perceptions of People with Lived Experience and Professional Stakeholders

“…Regardless of which provider PWLE wanted to facilitate testing, this was often based on the existence of a trusting relationship, echoing previous reports in the PGx for depression 24 and general PGx literature. 36 P/HCP participants repeatedly discussed the need for conclusive economic analyseswhich has been called for numerous times both in the context of PGx for depression 9,20 and PGx testing more generally. 33,36 We agree that further investigation into the accessibility, effectiveness, and costeffectiveness (including societal costs) of different implementation strategies for PGx testing is needed.…”