Searching beyond the genome: SSRI pharmacogenomics

The discovery of biomarkers has revolutionized the treatment of various cancers, making individualized treatment possible. Researchers at Mayo Clinic in Rochester, Minnesota, are making progress in efforts to provide similarly individualized treatment for major depressive disorder (MDD). Key to the success of this work is genome-wide association studies that go beyond genomic variations to incorporate variations in metabolomes, proteomes and transcriptomes.

"We're beginning to gain insights with regard to individual variation that we could never have had without linking genomics and these other, multiple '-omics,' " says Richard Weinshilboum, M.D., the director of the Pharmacogenomics Research Program at Mayo Clinic's Center for Individualized Medicine. "One size does not fit all. We want to determine the underlying mechanisms, and eventually to translate that understanding into enhanced diagnosis, treatment and ultimately prevention of psychiatric disease."

Heterogeneity and molecular probes

Dr. Weinshilboum has devoted decades to researching the mechanisms responsible for large individual variation in drug toxicity or efficacy for diseases as diverse as depression, childhood leukemia and breast cancer. His remarks were made at Mayo Medical School during the second annual Mrazek Lecture, titled "SSRI Pharmacogenomics."

Dr. Weinshilboum notes that the greatest challenge in treating a mental illness such as MDD is phenotypic heterogeneity among patients. "There are probably multiple underlying pathophysiologies that have the same symptom complex, just as they do with breast cancer," he says.

However, breast cancer researchers have access to laboratory cell lines representing various molecular subtypes and genotypes. "We don't have anything like that yet for serotonergic neurons," Dr. Weinshilboum says. SSRI researchers must undertake the lengthy process of generating induced pluripotent stem cells from skin biopsies, and then converting the stem cells into neurons that can be used in the laboratory.

Adding metabolomic analysis to genomic data provides essential information for understanding phenotypic heterogeneity. Metabolomic profiling is far more complex than characterizing the four nucleotides in the genome, involving a variety of platforms such as liquid chromatography electrical chemical assay and gas chromatography time-of-flight mass spectrometry. "Each platform sees different metabolites, so using a variety of platforms is necessary," Dr. Weinshilboum says.

He presented new data indicating that novel biology involved in response to antidepressant drugs might be uncovered by combining metabolomics with genome-wide genomic studies. "If we investigate the metabolomics or some other '-omic,' together with the genomics, we begin to see things we couldn't see with just the DNA sequence," Dr. Weinshilboum says.

A key aspect of Mayo Clinic's work is the use of SSRI therapies as "molecular probes" for MDD molecular mechanisms. Dr. Weinshilboum credits the late David A. Mrazek, M.D., a consultant and chair of the Mayo Clinic Department of Psychiatry and Psychology, with the idea of using SSRIs in a way similar to the use of a variety of drugs in attacking breast cancer.

Genome-wide significance

The benefits of these approaches are demonstrated in research published in the August 2014 issue of the British Journal of Clinical Pharmacology, in which Mayo Clinic researchers and colleagues performed the first genome-wide association study for plasma concentrations of escitalopram (S-CT) and its metabolites in MDD patients treated with the medication. MDD is the most common psychiatric disorder, and selective serotonin reuptake inhibitors (SSRIs), such as citalopram (CT) and S-CT, are commonly prescribed antidepressants. However, a large proportion of patients do not respond or fail to respond adequately to treatment with these drugs.

The aim of the genome-wide study was to learn more about SSRI action at the molecular level — specifically, characterizing the contribution of genetic variation to individual variation in plasma concentrations of S-CT and its metabolites. Using samples from 435 MDD patients treated with CT or S-CT, plasma drug and metabolite concentrations were measured at baseline and at four and eight weeks after the start of drug therapy.

Previous studies have indicated that a major factor affecting CT and S-CT plasma concentrations is biotransformation catalyzed by the cytochrome P450 enzymes CYP2C19 and CYP2D6. Confirming those observations, the Mayo Clinic study demonstrated that single-nucleotide polymorphisms in or near the CYP2C19 and CYP2D6 genes were significantly associated with plasma S-CT and the S-didesmethylcitalopram metabolite, respectively. The study also identified novel associations that the researchers say warrant further investigation.

Mayo Clinic is part of the Pharmacogenomics Research Network, established more than a decade ago by the National Institutes of Health. Dr. Weinshilboum is hopeful about the ability of network researchers to discover individualized treatment for patients with MDD: "What's happened in breast cancer treatment is going to happen in psychiatric disease, without a doubt."

For more information

Ji Y, et al. Citalopram and escitalopram plasma drug and metabolite concentrations: Genome-wide associations. British Journal of Clinical Pharmacology. 2014;78:373.