Current Pharmacogenomics - Volume 4, Issue 3, 2006

Genetic factors are supposed to play a major role for the differences in response to treatment or the incidence of adverse drug effects in psychopharmacotherapy. The aim of pharmacogenetics is to elucidate this variability due to hereditary differences. According to the currently known hypotheses on the mechanisms of drug action, several mutations in genes coding for neurotransmitter-receptors, -degrading enzymes, transport proteins or enzymes of the drug metabolizing system have been identified and investigated in terms of efficacy and adverse drug effects. Although there exists considerable controversy among the results, many studies are supportive for the hypothesis, that psychopharmacogenetics will be helpful in predicting an individual's drug response and identify persons at risk for serious side effects on the basis of the genetic make up. The introduction and inclusion of pharmacogenomics, which is a powerful tool to identify genes affected by drugs, will most likely help to delineate so far unknown drug targets, predict drug responsiveness and adverse reactions and finally propose new hypotheses for both the pathophysiological basis of psychiatric disorders and the mechanisms of psychotropic drug action. This paper briefly overviews the present status of pharmacokinetic and pharmacodynamic aspects in the pharmacogenetics of antipsychotics, antidepressants and lithium ions. Further, a summary on the work investigating genes of the signal transduction cascade, neuronal plasticity and stress response is given.

Affective disorders, including unipolar (UP) disorder and bipolar (BP) disorder are among the most important causes of death and disability worldwide and result in high costs in terms of morbidity as well as mortality. Although the etiology and pathophysiology is widely unknown, family-, twin- and adoption studies argue for a strong genetic determination of these disorders. These studies indicate that there is between 40-85% heritability for these disorders but point also to the importance of environmental factors. Despite the availability of a wide range of different drugs, about 30-50% of patients do not respond properly to acute treatment. Here we provide an overview of genetic drug response markers for affective disorder. Central in review is the question if individual therapeutic outcome for a given treatment can be predicted using genetic markers? An overview of pharmacogenetic and pharmacogenomic approaches is described for selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and mood stabilizing drugs in relation to each of the major candidate genes for affective disorders.

Microarrays have become one of the leading technologies used for gene expression analysis and functional genomics in many biological fields. Potential applications of microarrays can facilitate advances in molecular biology, systems biology, functional genomics, clinical medicine, and pharmacogenomics. However, microarray data can also lead to inaccurate and irreproducible conclusions. Here, we present a critical review of current computational tools used for normalization, statistical analysis, cluster analysis, and mathematical modeling-based analysis. Despite the pitfalls and challenges that still encompass the computational analysis of microarray data, the use of this technology remains very promising. In our opinion, achieving the full potential of microarray technology requires additional theoretical advances.

This paper will review the literature on the most recent advances of pharmacogenomics of essential hypertension. Specifically, the hypotheses regarding the responsibility of gene polymorphisms in hypertension and whether the pathophysiological mechanisms underlying hypertension can be translated in pharmacogenomic evidence will be analyzed. In particular, the present review will cover the role of genes in blood pressure regulation (mostly, sodiumsensitivity and vasoconstriction) as well as in the antihypertensive response to drugs: associations, lack of associations and contradictory results will be evaluated, and the reasons for discrepancies examined. Emphasis will be placed on the methodologies used so far to conceive and develop pharmacogenomic hypotheses to improve our capability to achieve solid, unequivocal results to be translated in the day-by-day clinical practice.

Attention deficit hyperactivity disorder (ADHD) is a common childhood disorder, symptoms of which include inattentiveness, impulsiveness, distractibility and hyperactivity. Although the etiology of ADHD is not known, high heritability estimates (ranging from 60-90%) have been reported. The mode of inheritance is also unknown, however, it is widely believed that multiple susceptibility genes (each of small effect) are contributing to the liability of the disorder. Animal, pharmacological and molecular studies have implicated disruption in catecholamine neurotransmission (dopaminergic, serotonergic, and noradrenergic) in the etiology of ADHD. Recent genetic studies have identified ADHD susceptibility genes including DAT1, DRD4 and DRD5. In addition, there is evidence that DNA variation at the serotonin transporter (5-HTT), serotonin receptor 1B (5-HT1B) and the synaptosomal associated protein-25 (SNAP-25) genes contribute to susceptibility for ADHD. Genetic variants at these and other candidate genes have been examined for their potential to predict medication response in ADHD. Preliminary results are conflicting with no clear pattern emerging. However, the numbers of pharmacogenetic studies to date are limited and are mainly focused on methylphenidate and variants at the dopaminergic system genes. A more focused approach is required, examining genetic variation in genes involved kinetically and dynamically in medications used to treat ADHD. In this context, studies should be extended to include atomoxetine, a selective inhibitor of the noradrenergic transporter used in the treatment of ADHD. These studies might include a range a noradrenergic system genes.

Although microarray analysis is a highly promising technology in the genome era, its application for gene expression profiling to characterize various phenomes, including genetic phenotypes, diseases, responses to chemicals and clinical annotations, is far from being a real use. One of the obstacles is the quality of the data, which needs to be enough to be able to solely use microarrays for these purposes. For this, selecting a set of genes as a molecular signature, based on transcriptomics, proteomics or metabolomics, and the use of the selected set of genes in focused microarrays has great merits. Here, we summarize how sets of genes were selected, what types of genes were used and what kind of statistics will be needed for focused microarrays, to distinguish them from genome-wide microarrays and to explain why focused microarray analysis is advantageous in gene expression profiling.

Pharmacogenetics is a rapidly expanding area of research focussed on the relationship between drug response and genetic variation. Due to the broad range of potential applications its influence on the process of drug development and on the practice of medicine, but also on society could be enormous. Therefore, the ethical, social and legal issues connected to the field are the subject of a number of recent publications. This review summarizes the key ethical implications of pharmacogenetics concerning both research and potential clinical applications, such as the stratification of patients and research participants, the establishment and use of biobanks, the use of racial identifiers in research, the problem of secondary information, informed consent issues, the potential for discrimination and stigmatisation, possible changes to the doctor-patient relationship and issues of access to and allocation of pharmacogenetic services. The study of the literature shows that there is no fundamental opposition to the field, even though a large number of potential problems have been identified. Most discussions are aimed to partake in the shaping of the field and its implementation into clinical practice, pointing at potential pitfalls. Ethical evaluations of putative future developments and their consequences are based on the anticipation of different future scenarios and thus tied to actual developments in the field. Thus, specifications and possibly revisions will be necessary as the field progresses.