In psychiatry, personalization is largely based on “pharmacogenetics,” the selection of medications based on genetic factors associated with drug response and tolerability. Could your patient’s genetic code predict which medications you prescribe?
It’s important to point out that some genes affect pharmacokinetics while others involve pharmacodynamic while others involve pharmacodynamic processes. Pharmacokinetics refers to how quickly and efficiently a drug reaches its target and how quickly it leaves the body: drug absorption, distribution, metabolism, and excretion. Clinically, the most important contributor is the cytochrome P-450 (CYP450) system, which accounts for the metabolism of approximately 60% of prescribed drugs.
Multiple CYP450 enzymes exist and are classified according to a standardized nomenclature. The major enzymes of interest in clinical psychopharmacology are 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4. For instance, fluoxetine is a substrate of 2D6; increased activity of this enzyme means lower blood levels of fluoxetine, while decreased activity corresponds to higher blood levels.
Pharmacodynamics, on the other hand, refers to the mechanism of action of a drug at its particular target(s). Whenever you prescribe a psychotropic drug, you are (most likely) thinking about the drug’s targets: receptors, transporters, or enzymes. Each of these directly or indirectly regulates the synthesis, transmission, or degradation of neurotransmitters such as serotonin and dopamine. Similar to the enzymes mentioned above, pharmacodynamic targets exist as proteins produced by different genes. Slight variations in the coding for a particular gene are referred to as polymorphisms, and these can alter the amount, structure, binding, or function of these proteins. In turn, these differences in the protein targets can influence the therapeutic or adverse effects of the drugs you prescribe.
For a well-known example of pharmacodynamic variation, consider the serotonin reuptake transporter (SERT). SERT regulates the reuptake of serotonin into neurons, and is the main site of action of selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Multiple genetic polymorphisms in SERT have been identified. Some research suggests that patients carrying certain SERT polymorphisms (such as the S or “short” allele) may respond less well to SSRI drugs and may experience more adverse effects of SSRIs, but the correlation is not absolute.
Polymorphisms of other genes involved in the pharmacodynamics of drug response, such as serotonin (5-HT) receptors, dopamine receptors, and other transporters, have been studied. But no single genetic difference, as of now, is significant enough to predict an outcome when you prescribe a drug.
Pharmacogenetic Tools
This article originally appeared in The Carlat Psychiatry Report -- an unbiased monthly covering all things psychiatry.
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In recent years, numerous products have come on the market to analyze genetic polymorphisms. The first commercially available product was the AmpliChip CYP450 Test, developed by Roche Diagnostics and approved by the FDA in 2004. Using a small blood sample from the patient, it analyzes genetic polymorphisms associated with two metabolizing enzymes (2D6 and 2C19). Based on the patient’s 2D6 and 2C19 polymorphisms, his or her 2D6 metabolic activity is characterized as poor, intermediate, extensive, or ultra-rapid, and 2C19 activity as poor or extensive. This information can theoretically be used to make clinical decisions about drugs that are 2D6 or 2C19 substrates.
Many newer pharmacogenetic tests, based on similar technology, are currently available on the market. The most popular ones include Genecept and GeneSight. These tests analyze the majority of the known 450 enzyme polymorphisms, as well as various combinations of pharmacodynamic genes.
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