Frontiers in Psychiatric Research
By Ma-Li Wong, MD, Mauricio Arcos-Burgos MD, PhD and Julio Licinio, MD |
June 1, 2008
Dr Wong is Miller Professor and vice-chair for translational research and Dr Arcos-Burgos is research associate professor in the department of psychiatry and behavioral sciences at the Leonard M. Miller School of Medicine, University of Miami, in Florida; Dr Licinio is Miller Professor and chair in the department of psychiatry and behavioral sciences and chief executive officer, University of Miami Behavioral Health.
What will these new discoveries bring to psychiatry? We may quickly transition from having a few candidate genes of known functions, to a plethora of candidate genes/gene regions in several chromosomes, to a handful of replicated genes/gene regions of poorly defined functions. To make matters worse, it is believed that most genetic variations probably contribute incremental increases in disease risk. Thus, most genes that increase the risk for a psychiatric dis- order may not have the same effect as the recently described macular degeneration variant that raises the risk for macular degeneration by 2 to 3 times in those carrying 1 copy of the gene variant. (The Table shows that most genes associated with psychiatric conditions would only slightly raise the odds ratio above 1.)
Depending on disease frequency, an increase of 50% may cause a modest increase in actual individual risk of about 3% to 4%. Genetic risk is likely to act in combination with lifestyle and chronic stressors, such as trauma, and to affect total disease risk, but the size of the combined effect is unclear and most likely varies from case to case. For example, someone with several gene variants that predispose to posttraumatic stress disorder (PTSD) may have a full-blown case of PTSD in the context of a single traumatic event, while another person without genetic predisposition to PTSD may have the full-blown disorder in the context of chronic and repeated abuse.
It is difficult to predict how long it will take before genetic findings alter the way psychiatrists treat patients. In many cases, it has taken several years for genetic findings to lead to changes in therapeutics, even for single-mutation diseases (also called mendelian diseases).
Pharmacogenetic findings and clinical psychiatry
The field of pharmacogenetics has contributed useful tools to the clinical setting. In the past few years, the FDA has added genetic information to the package inserts of drugs in other areas of medicine. In 2003, it changed package insert information for azathioprine(Drug information on azathioprine) and mercaptopurine(Drug information on mercaptopurine) to include the genetic risk of neutropenia.21 In 2005, it included UGT1A1 genotype information and clinical testing of the UGT1A1*28 allele for the drug irinotecan(Drug information on irinotecan).22,23 In 2006, it added genetic information to the warfarin(Drug information on warfarin) label.24 The future may soon bring an integration of pharmacogenomics into clinical practice, similar to that which is happening in cancer research. Discovery of clinically predictive genotypes, haplotypes, and somatic mutations have resulted in FDA-approved pharmacogenetic tests and the initiation of a genotype-guided cancer therapy trial.25
In 2004, the FDA approved the first gene chip for genotyping variations in the genes of 2 metabolizing enzymes of the cytochrome P-450 (CYP) system.26 The 2 genes are the CYP2D6 (29 variations) and CYP2C19 (2 variations) genes, which influence the plasma levels of a significant number (about 25%) of widely prescribed drugs, including most psychiatric drugs. This genotyping test is intended to help clinicians select optimal drug and dosing regimens in conjunction with clinical evaluations and other diagnostic tools. For instance, adherent patients taking standard doses who have low or elevated plasma drug levels may be, respectively, ultrarapid or poor metabolizers because of genetic variations in their CYP enzymes. It is important to take into consideration that about 10% of white persons and 20% of Asian persons are poor metabolizers, and these individuals may be at increased risk for developing a toxic reaction to a drug and/or severe adverse effects.
Clinical guidelines for CYP2D6 and CYP2C19 genotype testing in psychiatry have already been summarized, but no clear indications have been described.27 Genotyping costs are still high in the clinical setting, and information about the impact of genetic variants is imprecise because there are limited controlled (for the effects of diet, medication adherence, and lifestyle) study results on the impact of genetic variants.28 Currently, it remains unclear whether the use of available pharmacogenetic testing is cost-effective in psychiatry, but a patient who is intolerant to several drugs could potentially derive tremendous benefit from CYP genotyping.
Ethical issues in genetics and genomics
A crucial element in genetic research is the debate on the ethics of genetics, because genetic information may be used to discriminate against individuals, which could result in negative financial consequences and privacy infringements. Another sensitive issue is the likely influence of race and ethnicity on genetics and pharmacogenetics. Disease susceptibility might involve different polymorphisms in different populations and personalized medicine may be affected by ethnicity. Genetic research in particular and also clinical research at large may need to focus on individuals of specific ethnic backgrounds. This will change the framework of clinical research and require closer ties with diverse communities.
Ethical principles were formulated by the Human Genetics Commission in 2002: "Each individual is entitled to lead a life in which genetic characteristics will not be the basis of unjust discrimination or inhuman treatment." It is to be hoped that those principles will be sanctioned when the Genetic Information Non-Discrimination Act is approved by Congress and the Senate and signed into law by the president. This act will prohibit insurers from using genetic information to deny benefits or raise premiums, and it will prohibit the use of genetic information to make employment or compensation decisions. Until then, patients will worry about genetic testing and fear disclosing genetic information that could be crucial for their medical care.
Genetic research brings the hope that we may be closer to understanding the pathophysiology of complex disorders and ultimately improve treatment modalities, understand outcomes, and facilitate prevention. Identifying new genes for psychiatric disorders may open up the possibility of novel drug treatments targeted at previously unknown biological pathways. The foremost goal of genetic research is prevention, and genetic information is expected to have a major impact on public health by its use in the prevention of disease or the adverse effects of drugs.
Genomics can improve the practice of psychiatry in 2 ways: by personalizing existing treatments for psychiatric patients and by identifying new targets for the development of novel therapeutic strategies that go beyond the monoamine approaches in current use. Ethical issues need to be addressed at the levels of ethnically targeted genetic testing and at the individual level in terms of ensuring that access to health care is not restricted in any way by a person's genetic makeup. Clinicians need to have a good level of understanding of pharmacogenetics to talk to well- informed inquisitive patients, and clearly, that requirement will increase as this field matures
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