Journal of Psychosocial Nursing and Mental Health Services

Psychopharmacology 

Where Are We Today with Personalized Medicine?

Robert H. Howland, MD

Abstract

The use of pharmacogenetics information is central to the concept of personalized medicine. Understanding pharmacogenetic differences in drug response and tolerability has been investigated mainly through the study of pharmacokinetic and pharmacodynamic processes. The hope and promise of pharmacogenetic testing has led to the commercial availability of several testing products. With the exception of the relationship between certain types of adverse drug reactions and immune response genes such as the human leukocyte antigen, a growing body of research has not yet established the clinical utility of pharmacogenetics testing. Variance in findings from pharmacogenetics studies conducted to date may be due to epistasis (gene-gene and gene-environment interactions), epigenetics (non-DNA sequence-related heredity), or other genetic factors, which have been largely unexplored in pharmacogenetics research.

Abstract

The use of pharmacogenetics information is central to the concept of personalized medicine. Understanding pharmacogenetic differences in drug response and tolerability has been investigated mainly through the study of pharmacokinetic and pharmacodynamic processes. The hope and promise of pharmacogenetic testing has led to the commercial availability of several testing products. With the exception of the relationship between certain types of adverse drug reactions and immune response genes such as the human leukocyte antigen, a growing body of research has not yet established the clinical utility of pharmacogenetics testing. Variance in findings from pharmacogenetics studies conducted to date may be due to epistasis (gene-gene and gene-environment interactions), epigenetics (non-DNA sequence-related heredity), or other genetic factors, which have been largely unexplored in pharmacogenetics research.

That some patients respond to a particular drug and others do not respond, or that some patients tolerate a drug well and others are intolerant of the same drug, has suggested that genetic differences among patients may contribute to differences in medication response or the development of adverse effects (Evans & McLeod, 2003; Weinshilboum, 2003). Pharmacogenomics and pharmacogenetics are terms that refer to the use of molecular genetic approaches to understand differences in drug response and tolerability. Although the two terms are sometimes used interchangeably, pharmacogenetics more specifically is the study of specific single nucleotide polymorphisms (SNPs) in specific genes with known functions that could plausibly be linked to drug response. Pharmacogenomics refers to whole genome scanning to find SNPs that might be associated with a drug response, but without necessarily knowing the specific function of the identified SNPs. Slight variations in a particular gene are referred to as genetic polymorphisms.

Understanding pharmacogenetic differences in drug response and tolerability has been investigated mainly through the study of pharmacokinetic and pharmacodynamic processes (Weinshilboum, 2003). Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of drugs in the body, but the metabolism of drugs through the liver is the most clinically relevant pharmacokinetic process. The cytochrome P-450 (CYP450) system is a group of different drug-metabolizing enzymes (DMEs), each produced by a different gene, which metabolize drugs in the liver. Various DMEs account for the metabolism of the majority of commonly prescribed drugs. Genetic polymorphisms occur with each of these CYP450 genes, which affect the activity of the enzyme and can influence how a person metabolizes certain drugs.

Pharmacodynamics refers to the mechanism of action of a drug at its particular target(s). Psychotropic drug targets typically are enzymes (e.g., monoamine oxidase), transporters (e.g., serotonin reuptake transporter), or receptors (e.g., dopamine receptors) that regulate the synthesis, transmission, or degradation of different chemical neurotransmitters in the brain. The various enzymes, transporters, and receptors that are found throughout the nervous system each exist as a protein that is produced by a different gene. Multiple genetic polymorphisms have been identified for many of the neurotransmitter enzymes, transporters, and receptors of interest in clinical psychopharmacology. These polymorphisms may result in alterations of the amount, structure, binding, or function of these proteins, which can affect how drugs interact with them and therefore influence the therapeutic effects or adverse effects of the drug.

Pharmacogenetics and Personalized Medicine

The use of pharmacogenetics information is central to the concept of personalized medicine. Despite the hope and promise of pharmacogenetics, and the commercial availability of several testing products (de Leon, 2009), a growing body of research has not established the clinical utility of this approach.

Because of the high prevalence of depression, the common use of selective serotonin reuptake inhibitor (SSRI) drugs, and the commercial availability of DME genetic tests, the Agency for Healthcare Research and Quality (AHRQ) reviewed existing studies to determine whether testing for CYP450 polymorphisms in adults taking SSRI drugs for depression leads to improvement in outcomes or whether testing results are useful in medical, personal, or public health decision making (Thakur et al., 2007). The AHRQ working group identified 37 relevant studies for their analysis. Their literature review revealed a paucity of high-quality clinical studies addressing their main objectives. The studies they detailed had several limitations, including non-randomized design, inadequate power, and not accounting for other genetic factors that may influence SSRI response or tolerability (e.g., genetic variations in serotonin receptor proteins). Most important, there were no prospective studies of CYP450 genotyping and its relationship to clinical outcomes. The data failed to support a clear correlation between CYP450 polymorphisms and SSRI drug levels, efficacy, or tolerability. There were no data regarding whether testing leads to improved outcomes versus not testing in the treatment of depression; whether testing influences medical, personal, or public health decision making; or whether any harms are associated with testing itself or with subsequent management options.

Similar to the findings from this AHRQ review, the clinical utility of genotyping DMEs or pharmacodynamic drug targets for other psychotropic drugs also has not been established (de Leon, 2009; Tomalik-Scharte, Lazar, Fuhr, & Kirchheiner, 2008). An exception to these disappointing findings is the relationship between certain types of adverse drug reactions and immune response genes (e.g., human leukocyte antigen [HLA]). Approximately 20% of adverse drug reactions may have an immunological etiology (Knowles, Uetrecht, & Shear, 2000). One recent example is the identification of a genetic risk factor for allergic reactions to carbamazepine (Tegretol®, Equetro®, Carbatrol®) and phenytoin (Dilantin®) (Locharernkul et al., 2008). Serious and sometimes fatal dermatologic reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in patients of Asian ancestry who have the inherited allelic variant HLA-B*1502. Such genetically at-risk patients should be screened prior to taking these drugs, and these drugs should not be started in patients who test positive for this allele.

Summary

The current clinical utility of pharmacogenetics information is likely limited by our developing knowledge of the sheer complexity of the human genome. The importance of epistasis (gene-gene and gene-environment interactions) (Motsinger, Ritchie, & Reif, 2007), epigenetics (non-DNA sequence-related heredity) (Feinberg, 2008), copy number variations (Redon et al., 2006), and so-called “junk DNA” (Pennisi, 2012) in genomics research is growing rapidly, but these are largely unexplored in pharmacogenetic studies. Because some or even much of the variance in findings from pharmacogenetics studies conducted to date may be due to these genetic factors, I will describe them in more detail in next month’s article. Nurses should be familiar with the current status of pharmacogenetics technology in the care of patients receiving drug therapy, as this information will be important for educating patients and their families about the few benefits and common limitations of pharmacogenetic testing in their treatment.

References

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Authors

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author has disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

Posted Online: October 15, 2012

10.3928/02793695-20121005-01

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