Progress and prospects in pharmacogenetics of antidepressant drugs

ABSTRACT

Introduction: Depression is responsible for the most part of the personal and socio-economic burden due to psychiatric disorders. Since antidepressant response clusters in families, pharmacogenetics represents a meaningful tool to provide tailored treatments and improve the prognosis of depression.

Areas covered: This review aims to summarize and discuss the pharmacogenetics of antidepressant drugs in major depressive disorder, with a focus on the most replicated genes, genome-wide association studies (GWAS), but also on the findings provided by new and promising analysis methods. In particular, multimarker tests such as pathway analysis and polygenic risk scores increase the power of detecting associations compared to the analysis of individual polymorphisms. Since genetic variants are not necessarily associated with a change in protein level, gene expression studies may provide complementary information to genetic studies. Finally, the pharmacogenetic tests that have been investigated for clinical application are discussed.

Expert opinion: Despite the lack of widespread clinical applications, preliminary results suggest that pharmacogenetics may be useful to guide antidepressant treatment. The US Food and Drug Administration included pharmacogenetic indications in the labeling of several antidepressants. This represented an important official recognition of the clinical relevance of genetic polymorphisms in antidepressant treatment.

KEYWORDS:

• Major depression
• antidepressant
• gene
• polymorphism
• pharmacogenomics
• GWAS
• tailored treatment

Article highlights

• Antidepressant pharmacogenetics may improve depression prognosis providing personalized treatments since currently up to 2/3 of patients treated with antidepressants do not reach complete remission.

• Polymorphisms in some candidate genes (including SLC6A4, HTR2A, CYP2C19, CYP2D6, ABCB1 and FKBP5) have been tested for guiding antidepressant treatment compared to treatment as usual and interesting results were reported.

• Genome-wide association studies (GWAS) represent the current frontier of research and they allow to study genetic modulators of antidepressant response both at single polymorphisms level and multimarker level (pathway analysis, polygenic risk scores).

• Peripheral gene expression levels represent easily accessible biomarkers that could provide complementary information to pharmacogenetics.

• GWAS may allow the development of tests based on a number of genetic polymorphisms throughout the genome (in specific genes or pathways) able to classify patients within a spectrum of risk to be non-responder or develop side effects.

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Declaration of interest

A Serretti is or has been consultant/speaker for: Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers, Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Supplementary material

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