Pharmacogenetics: a new diagnostic tool in the management of antidepressive drug therapy.
Pharmacogenetics studies the genetic basis of an individual's ability to respond to pharmacotherapy. Variability of this response is a major problem. Fatal adverse drug reactions have been reported to be the fourth leading cause of death in the US. In depression, 30-40% of all patients do not respond sufficiently to the initial treatment and it can take up to 6 weeks for them to be identified. Much knowledge has been gathered throughout the last 3 decades about the genetic basis of pharmacokinetic variability. Genetic tests suitable for the routine laboratory are now available for some important metabolizing enzymes (e.g., CYP2D6, CYP2C19) identifying those individuals who are slow or fast metabolizers of certain drugs, many of which are widely used in the treatment of depression (e.g., tricyclic antidepressants). The possible use of these tests in the clinical practice of monitoring antidepressant therapy is discussed in relation to older phenotyping methods and therapeutic drug monitoring.Less well studied than the genetics of pharmacokinetics is the genetic basis of pharmacodynamic variability. As selective serotonin reuptake inhibitors (SSRI) have a wide therapeutic index, pharmacokinetic variability usually does not explain insufficient response to therapy. Recently, some excitement was caused by reports on serotonin transporter gene polymorphisms and their influence on the response to antidepressive therapy with SSRIs as this could provide an interesting diagnostic tool in assessing the chances of response to the most popular group of antidepressants at present. Current knowledge in this young field of research is summarized.
Steimer
W
W
Institute for Clinical Chemistry and Pathobiochemistry, Munich University of Technology, Ismaninger Str. 22, 81675 Munich, Germany. steimer@klinchem.med.tu-muenchen.de
Müller
B
B
Leucht
S
S
Kissling
W
W
D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology / Q000627:therapeutic use; D002352:Carrier Proteins / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003863:Depression / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D002352:Carrier Proteins; D019389:Cytochrome P-450 CYP2D6; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human