CNS Spectr. 2008;13(2):115-118
Faculty Affiliation and Disclosure
Dr. Stahl is adjunct professor of psychiatry in the Department of Psychiatry at the University of California-San Diego in La Jolla.
Disclosures: Dr. Stahl receives grant/research support from AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Neurocrine Bioscience, Organon, Pfizer, Sepracor, Shire, Somaxon, and Wyeth; is a consultant to Acadia, Amylin, Asahi, AstraZeneca, Biolaunch, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, CSC Pharma, Cyberonics, Cypress Bioscience, Eli Lilly, Epix, Fabre Kramer, Forest, GlaxoSmithKline, Jazz, Neurocrine Bioscience, Neuromolecular, Neuronetics, Nova Del Pharma, Novartis, Organon, Otsuka, PamLab, Pfizer, Pierre Fabre, Sanofi Synthelabo, Schering Plough, Sepracor, Shire, Solvay, Somaxon, Takeda, Tetragenix, and Wyeth; and is on the speaker’s bureau of Pfizer.
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New Trend in Psychopharmacology
Personalizing medicine by understanding the unique properties of each patient’s genome has the potential of predicting what drug to prescribe for that individual. This approach has already proven useful for several drugs in medicine and promises to become a strategy for selection of therapeutics in psychiatry soon. Understanding some of the key concepts, strategies, and advances in the field of pharmacogenomics can set the stage for adapting emerging findings to the practice of psychopharmacology.
What is Pharmacogenetics, or is it Pharmacogenomics?
Some key terms in this field are defined in Table 1.1,2 DNA polymorphisms are the unique changes in DNA sequence that are considered to be the mediators of variations in drug response to treatment, susceptibility to disease, and other differences among individuals. Single nucleotide polymorphisms (SNPs) are the most common type of DNA variation, and are intensely investigated as causes of variations in drug responsivity among individuals (Table 1).1-3
Figure 1 attempts to show the link between a gene and drug response.3 Therefore, the specific type of gene that an individual expresses will dictate the molecular subtype of protein that gene expresses. Depending upon subtle molecular variations in that protein (eg, for an enzyme, receptor, or growth factor), this hypothetically alters the efficiency of information processing in brain circuits and, thus, dictates differences in behaviors mediated by those circuits.3 Changing neurotransmission at these circuits with drugs acting by specific mechanisms may have different functional interactions within these circuits; this can theoretically determine whether the drug alters information processing there and, subsequently, whether it works to reduce symptoms.1-3
Although some experts use the terms “pharmacogenetics” and “pharmacogenomics” interchangeably, many consider pharmacogenetics to be the study of specific SNPs at specific genes with known functions that could plausibly be linked to drug response, whereas pharmacogenomics scans the whole human genome to find SNPs empirically associated with a drug response, without necessarily knowing the function of the SNP (Table 2).1,2 Pharmacogenetics tests SNPs identified in advance, such as those linked to various neurotransmitters, receptors, or growth factors, whereas pharmacogenomics scans the entire genome to determine SNPs that are associated with drug response and often identifies genes whose functions are not known or would not have been predicted in advance to be linked to drug response.
In either case, SNPs (on the left in Figure 2) alter protein synthesis by making subtle molecular changes in the amino acid sequence of these proteins (middle of Figure 2), hypothetically leading to changes within brain circuits that alter function, including causing symptoms of psychiatric disorders.3 SNPs may also determine whether these circuits will respond to specific drugs by determining the capability of various molecular targets within specific brain circuits to alter the efficiency of information processing and thereby reduce psychiatric symptoms (on the right in Figure 2; Figure 1).
Status of Pharmacogenomics in Medicine Today
Several examples exist where knowing which genetic variant of specific genes that a patient expresses will dictate either the dose of a drug to be given (eg, warfarin) or whether the drug will work or not (eg, pertuzumab and imatinib chemotherapies) (Table 3).1,4 What about psychiatry? Can pharmacogenomics lead to individualized treatments for psychiatric disorders (Figure 3)? Some of the key challenges to implementing clinically useful pharmacogenomics in psychiatry today are listed in Table 4 and include the fact that there are generally only preliminary and unconfirmed results for many specific genes with hypothesized links to drug response (Table 5).5-8 However, the promising leads shown in Table 5, coupled with proven advances in other fields (Table 3) pave the way for psychiatry. Soon there may be clinically applicable pharmacogenomic markers for psychopharmacologic management.
The key question we want answered is: “Does testing for genetic polymorphisms in subjects undergoing psychiatric drug treatment lead to improvement in outcome, or are testing results useful in medical, personal, or public health decision making?”1 When that answer is “yes,” pharmacogenomics will come of age in psychiatry. Until then, stay tuned and stay informed.
1. Grossman I. Routine pharmacogenetic testing in clinical practice: dream or reality? Pharmacogenomics. 2007;8:1449-1459.
2. Gordon E. Integrating genomics and neuromarkers for the era of brain-related personalized medicine. Personalized Medicine. 2007;4:201-215.
3. Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; 2008.
4. Pander J, Gelderblom H, Guchelaar HJ. Insights into the role of heritable genetic variation in the pharmacokinetics and pharmacodynamics of anticancer drugs. Expert Opin Pharmacother. 2007;8:1197-1210.
5. Arranz MJ. de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry. 2007;12:707-747.
6. Malhotra AK, Murphy GM, Kennedy JL. Pharmacogenetics of psychotropic drug response. Am J Psychiatry. 2004;161:780-796.
7. Hu XZ, Rush AJ, Charney D, et al. Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry. 2007;64:783-792
8. Licamele L, Volpi S, Heaton C, et al. Pharmacogenomic study of iloperidone treatment in patients with schizophrenia identifies markers associated with efficacy. Poster presented at: the Annual Meeting of the American Society of Human Genetics. October 23-27, 2007; San Diego, Calif.