Polymorphisms, or genetic variations, can lead to savings in lives and costs
Orlando, FL – The thousands of Americans who are clinically depressed seek therapeutic treatment. Their treatment consists of the most advanced prescription drugs – yet for a great number of these patients, treatment is ineffective leading to greater morbidity and mortality caused by this mental disorder.
The evidence is borne out by clinical findings. Drug therapy is available, but 30 to 50 percent of clinically depressed patients will not respond to treatment. According to current treatment guidelines, identifying these non-responders can take three to six weeks. There are some 2.2 million cases of severe side effects from correctly applied drug therapy in the United States. The cost of these side effects is estimated at $4.3 billion and causes 106,000 deaths a year. A substantial share of this can be expected to be due to psychoactive drugs.
The answer may lie in how an individual’s physiological make-up affects the efficacy of pharmaceutical therapy. Pharmacogenetics is an emerging field of study that assesses the genetically determined variations in responses to drugs in humans or in laboratory organisms. The wide range of reactions is due to polymorphisms, or variations of the same genes. Phramacogenetics encompasses the concepts of Pharmacokinetics, disposition of drugs in the body (i.e., their absorption, distribution, metabolism, and elimination), or what a body does to a drug; and Pharmcodynamics, the uptake, movement, binding, and interactions of pharmacologically active molecules at their tissue site(s) of action, or what a drug does to the body.
Cytochrome P450 CYP2D6 is responsible for the metabolism of approximately 20 to 25 percent of prescription medicines. These include carvedilol, S-metoprolol, propafenone, timolol, tricyclic antidepressants, haloperidol, perphenazine, rispiradone, and thioridazine. Mutations in the CYP2D6 gene can result in ultra rapid (UM), extensive (EM), intermediate (IM) and poor metabolizer (PM) phenotypes. Clinically important are the UM, PM and probably IM phenotypes. On average, 7 to 10 percent of Caucasians are PMs.
An overview of how these polymorphisms are related to successful drug therapy will be offered to the managers of the nation’s clinical laboratories. The presentation, “CYP2D6 Polymorphisms as Predictors of Patient Response to Antidepressant Drugs,” by Dr. Werner Steimer, from the Institut für Klinische Chemie und Pathobiochemie Klinkum rechts der Isar, Technische Universsität München (Munich), will be given at the 54th Annual Meeting of the American Association for Clinical Chemistry (AACC). AACC (http://www.aacc.org/) is the scientific organization for clinical laboratory professionals, physicians, and research scientists. Their primary commitment is the understanding of laboratory testing to identify, monitor and treat human disease. More than 11,000 attendees are expected for the meeting, which is being held at the Orange County Convention Center, Orlando, FL, July 28-August 1, 2002.
Dr. Steimer will discuss how individualizing clinical therapy can be accomplished through one of three ways: Therapeutic drug monitoring (TDM) guides the administration of safe and effective drug therapy in the individual patient. Monitoring can be used to confirm a plasma drug concentration that is above or below the therapeutic range, thus minimizing the time that elapses before corrective measures can be implemented in the patient. Phenotyping assesses the manifestation of one or more genotypes; Genotyping accounts for the genetic disposition of an individual.
The presenter’s research focused on CYP2D6 as related to pharmacokinetics and pharmacodynamics. He will offer the following conclusions:
The influence of CYP2D6 polymorphisms on the pharmacokinetics of many antidepressants is proven.
Relevant deviations from normal metabolism, due to genetic variation of CYP206.
In certain clinical situations, genotyping of CYP2D6 might prove useful in addition to TDM.
There is a lack of studies to prove the medical and economic effectiveness of screening for drug-metabolizing enzymes (DMEs).
The necessary study of the genetic basis of parmacodynamic variability has just started.