12 - Functional gene-linked polymorphic regions in pharmacogenetics

Summary

OVERVIEW

Starting from the complexity of neural pathways and their close integration, this chapter focuses on the possible advantages of investigating polymorphisms involved in the regulation of gene expression or in variation of enzymatic activity, using examples related to neurotransmitter pathway modulation (namely, uptake and metabolism). These examples (i.e., serotonin transporter-linked polymorphic region, monoamine oxidase A (MAO-A) promoter region, and catechol-O-methyltransferase (COMT)) are also used to support the hypothesis that quantitative variations of expression and functional levels would be better than structural changes at single receptor sites to identify differences in both treatment response and, likely, psychopathology. The possible influence of the serotonin (5-HT) transporter variants on the efficacy of fluvoxamine, paroxetine, pindolol augmentation, and on the effects of total sleep deprivation, is described in depression. The possible importance of this functional polymorphism in obsessive-compulsive disorder (OCD), stress reactivity and panic disorder (PD) is also discussed. Variations in MAO-A activity in female patients are discussed in relation to the pharmacogenetics of panic disorder, together with some hypotheses regarding the chromosomal location of the gene. Some preliminary results are described linking a functional polymorphism in the coding sequence of the gene COMT and antidepressant response in unipolar depression and bipolar mood disorder. Finally, the expected impact of new approaches (i.e., orphan receptor research, nucleic acid chips, and single nucleotide polymorphisms) is discussed in terms of the advantages and pitfalls (e.g., many new exciting data but also a stronger need for very careful replications and analysis).