Genome-wide association studies have made it clear that patients respond very differently to drug treatment due to polymorphism, or genetic variation. Between 25 and 50 percent of patients don’t respond as expected to prescriptions, especially to drugs for mental disorders. When compounded alongside inter-individual variability in drug response, this creates a major clinical problem (1).
Antidepressants are one of the most common drugs prescribed to treat disorders, ranging from depression and social anxiety disorder to seasonal affective disorder and dysthymia. The actual metabolism of 90% of drugs is actually limited to just seven different cytochrome enzymes. With this group of proteins in mind, scientists have begun to explore the role of genetics in the efficiency of treatment. Antidepressants have been linked to cytochrome P450 (CYP) enzymes, and it is the natural variation in the activity of these enzymes that can contribute to a range in efficacy of treatment, at times resulting in more harm than good (2).
Pharmacogenomics and pharmacogenetics are new fields which seek, firstly, to uncover genetic variants that influence drug response, and, secondly, to study DNA structural variations and their impact on drug metabolism, efficacy and tolerability. According to the Federal Drug Administration (FDA), “pharmacogenetics and pharmacogenomics are important key tools in development and testing of new drugs and their impact in treating individuals with human disease” (3). By understanding variations, researchers can create treatment options specific to an individual.
For antidepressants, the problem lies in the rate of metabolism in the enzyme P450 system. The primary function of P450 is to metabolize drugs and break down toxic compounds including metabolic byproducts (4). Normal metabolizers inherit two copies of the normal wild-type allele from each parent and thus respond normally to drugs at standard doses; however, when a person inherits dysfunctional or abnormal numbers of the allele, the treatment can go awry. For example, if a person carries a loss-of-function allele but is heterozygous they would experience reduced activity of this enzyme and lower drug metabolism. If a person is homozygous for the loss of function allele, the drug metabolism would be even lower. Both scenarios would mean that a person would have unmetabolized forms of the drug remaining in their system, and wouldn’t experience the drug’s effects. On the other hand, carrying multiple copies of the wild type allele is associated with increased activity and would cause enhanced drug degradation, requiring a higher drug dosage (3). In the past, patient genotypes would not even be considered in understanding why certain dosages were not having the desired effects. It is pharmacogenomics that is now enabling us to understand the complex interactions between drugs and our genome.
Beyond cytochrome enzymes, pharmacogenomics has also uncovered other genetic variants that contribute to antidepressant efficiency, such as Receptor 5-HT1A , which has been linked to a delayed clinical response with Selective serotonin reuptake inhibitor therapy (antidepressant). Researchers believe that polymorphisms associated with this receptor contribute to the delay (5).
The studies that link cytochrome P450 enzymes to antidepressant metabolization are now being taken into consideration when antidepressants are administered. The FDA has even approved of the AmpliChip CYP450 test, which assesses the genotype for CYP2d6, the gene responsible for encoding the CYP450 enzyme, to aid in proper prescription of medication to psychiatric patients (6).
With pharmacogenetics and pharmacogenomics studies continuing to uncover the links between how genes truly influence our reactions to different drugs, personalized therapy seems closer than ever.
References
- Harper, Andrew R, and Eric J Topol. “Pharmacogenomics in clinical practice and drug development.” Nature biotechnology vol. 30,11 (2012): 1117-24. doi:10.1038/nbt.2424
- T P, Aneesh et al. “Pharmacogenomics: the right drug to the right person.” Journal of clinical medicine research vol. 1,4 (2009): 191-4. doi:10.4021/jocmr2009.08.1255
- Butler, Merlin G. “Pharmacogenetics and Psychiatric Care: A Review and Commentary.” Journal of mental health & clinical psychology vol. 2,2 (2018): 17-24.
- Lee JW, Aminkeng F, Bhavsar AP, et al. The emerging era of pharmacogenomics: Current successes, future potential, and challenges. Clin Genet. 2014; 86(1): 21–28.
- Jonathan F. Lister (2016) Pharmacogenomics: A focus on antidepressants and atypical antipsychotics. Mental Health Clinician: January 2016, Vol. 6, No. 1, pp. 48-53.
- Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther. 2013;93(5):402-8.