Pharmacogenomics and Therapeutic Strategies for Dementia

Ramón Cacabelos


Expert Rev Mol Diagn. 2009;9(6):567-611. 

In This Article

Expert Commentary

The great variability in the therapeutic response of AD patients to conventional treatments (<20% effective responders), the heterogeneity of the disease and its complex pathogenesis, the occurrence of neuropsychiatric disorders associated with cognitive deterioration, as well as the presence of other age-related disorders in patients with dementia, seem to suggest that: it is very unlikely that a single drug may be able to halt disease progression after the onset of the disease. Multifactorial interventions (as in other complex disorders, e.g., cardiovascular disease, cancer and AIDS) might be an alternative strategy; however, drug–drug interactions in elderly patients who receive over six different drugs per day can represent a serious drawback in terms of safety. The coadministration of many different drugs in patients with concomitant pathologies (i.e., coronary disease, hypertension, atherosclerosis, hyperlipidemia and dementia) may represent an obstacle for an effective pharmacological management of dementia since some drugs effective for a peripheral medical condition can exert a deleterious effect on brain function and brain perfusion with severe effects on cognition, behavior and psychomotor function. The fact that approximately 50–60% of patients with dementia exhibit a marked cerebrovascular dysfunction recommends that cerebrovascular protection should not be neglected in the treatment of AD; the co-administration of psychotropic drugs should be carried out with extreme care as most psychotropics deteriorate cognitive function, psychomotor activity and cerebrovascular function; the conventional procedures currently used in drug development (i.e., trial-and-error) and serendipity are not cost effective nowadays. In addition, the bimodal fashion of the amyloid–tau hypothesis of AD as a major target for future drug developments is a focus of controversy with unpredictable consequences for the industry and the public; the reluctant attitude of the medical community to incorporate genomic procedures as diagnostic aids and disease biomarkers is not contributing to accelerating our understanding of the dementia syndrome and its biological diversity; and the underdeveloped field of pharmacogenetics and pharmacogenomics is delaying the possibility of optimizing our limited therapeutic resources for the treatment of AD.

The introduction of novel procedures into an integral genomic medicine protocol for CNS disorders is an imperative requirement in drug development and in clinical practice in order to improve diagnostic accuracy and to optimize therapeutics. This kind of protocol should integrate the following components: clinical history, laboratory tests, neuropsychological assessment, cardiovascular evaluation, conventional x-ray technology and structural neuroimaging, functional neuroimaging, computerized brain electrophysiology, cerebrovascular evaluation, structural genomics, functional genomics, pharmacogenetics, pharmacogenomics, nutrigenetics, nutrigenomics, bioinformatics for data management, and artificial intelligence procedures for diagnostic assignments and probabilistic therapeutic options.[4] All of these procedures, under personalized strategies adapted to the complexity of each case, are essential in order to depict a clinical profile based on specific biomarkers correlating with individual genomic profiles.

Our understanding of the pathophysiology of CNS disorders has advanced dramatically during the last 30 years, especially in terms of their molecular pathogenesis and genetics. The drug treatment of CNS disorders has also made remarkable strides, with the introduction of many new drugs for the treatment of schizophrenia, depression, anxiety, epilepsy, Parkinson's disease, and AD, among many other quantitatively and qualitatively important neuropsychiatric disorders. Improvement in terms of clinical outcome, however, has fallen short of expectations, with up to a third of the patients continuing to experience clinical relapse or unacceptable medication-related side effects in spite of efforts to identify optimal treatment regimes with one or more drugs. Potential reasons to explain this historical setback might be that the molecular pathology of most CNS disorders is still poorly understood, drug targets are inappropriate (not fitting into the real etiology of the disease), most treatments are symptomatic but not anti-pathogenic, the genetic component of most CNS disorders is poorly defined, and the understanding of genome–drug interactions is very limited.

Assuming that the human genome contains approximately 20,000–30,000 genes, only 0.31% of commercial drugs have currently been assigned to corresponding genes whose gene products might be involved in pharmacokinetic and pharmacodynamic activities of a given drug, and only 4% of the human genes have been assigned to a particular drug metabolic pathway. Supposing a theoretical number of 100,000 chemicals in current use worldwide, and assuming that practically all human genes can interact with drugs taken by human beings, each gene in the human genome should be involved in the metabolism and/or biopharmacological effect of 30–40 drugs; however, assuming that most xenobiotic substances in contact with our organism can influence genomic function, it might be possible that for 1 million xenobiotics in daily contact with humans, an average of 350–500 xenobiotics have to be assigned to each one of the genes potentially involved in drug metabolism and/or the processing of xenobiotics. To fulfil this task, a single gene has to possess the capacity of metabolizing many different xenobiotic substances and, at the same time, many different genes have to cooperate in orchestrated networks in order to metabolize a particular drug or xenobiotic under sequential biotransformation steps (Figure 12). Numerous chemicals increase the metabolic capability of organisms by their ability to activate genes encoding various xenochemical-metabolizing enzymes, such as CYPs, transferases and transporters. Many natural and artificial substances induce the hepatic CYP subfamilies in humans, and these inductions might lead to clinically important drug–drug interactions. Some of the key cellular receptors that mediate such inductions have been identified recently, including nuclear receptors, such as the constitutive androstane receptor (constitutive androstane receptor, NR1I3), the retinoid X receptor (NR2B1), the pregnane X receptor (NR1I3), and the vitamin D receptor (NR1I1) and steroid receptors, such as the glucocorticoid receptor (NR3C1).[78] There is a wide promiscuity of these receptors in the induction of CYPs in response to xenobiotics. Indeed, this adaptive system acts as an effective network where receptors share partners, ligands, DNA response elements and target genes, influencing their mutual relative expression.[78,79]

Figure 12.

Pharmacogenetic and pharmacogenomic components of the therapeutic process in dementia.

The optimization of CNS therapeutics requires the establishment of new postulates regarding the costs of medicines, the assessment of protocols for multifactorial treatment in chronic disorders, the implementation of novel therapeutics addressing causative factors, and the setting-up of pharmacogenetic/pharmacogenomic strategies for drug development.

The cost of medicines is a very important issue in many countries owing to the growing of the aging population (>5% disability), neuropsychiatric and demented patients (>5% of the population) belonging to an unproductive sector with low income, and the high cost of healthcare systems and new health technologies in developed countries. Despite the effort of the pharmaceutical industry to demonstrate the benefits and cost–effectiveness of available drugs, the general impression in the medical community and in some governments is that some psychotropics and most antidementia drugs present in the market are not cost effective.[2] Conventional drugs for neuropsychiatric disorders are relatively simple compounds with unreasonable prices. Some new products are not superior to conventional antidepressants, neuroleptics and anxiolytics. There is an urgent need to assess the costs of new trials with pharmacogenetic and pharmacogenomic strategies, and to implement pharmacogenetic procedures for the prediction of drug-related adverse events. Pharmacogenomics can also help to reduce costs in drug development, as well as the number of patients in clinical trials with high risk of toxicity. It has been suggested that the two critical strategies for pipeline genetics must make use of fewer patients: the early identification of efficacy signals so that they can be applied early in development for targeted therapies, and identification of safety signals that can subsequently be validated prospectively during development using the least number of patients with adverse responses.[75]

Cost–effectiveness analysis has been the most commonly applied framework for evaluating pharmacogenetics. Pharmacogenetic testing is potentially relevant to large populations that incur in high costs. For instance, the most common drugs metabolized by CYP2D6 account for 189 million prescriptions and $12.8 billion annually in expenditures in the USA, which represent 5–10% of total utilization and expenditures for outpatient prescription drugs.[80] Pharmacogenomics offer great potential to improve patients' health in a cost-effective manner; however, pharmacogenetics/pharmacogenomics will not be applied to all drugs available in the market, and careful evaluations should be made prior to investing resources in research and development of pharmacogenomic-based therapeutics and making reimbursement decisions.[81]

In performing pharmacogenomic studies in dementia, it is necessary to rethink the therapeutic expectations of novel drugs, redesign the protocols for drug clinical trials, and incorporate biological markers as assessable parameters of efficacy and prevention. In addition to the characterization of genomic profiles, phenotypic profiling of responders and nonresponders to conventional drugs is also important (and currently neglected).

An important issue in AD therapeutics is that antidementia drugs should be effective in covering the clinical spectrum of dementia symptoms represented by memory deficits, behavioral changes and functional decline. It is difficult (or impossible) for a single drug to be able to fulfil these criteria. A potential solution to this problem is the implementation of cost-effective, multifactorial (combination) treatments integrating several drugs, taking into consideration that traditional neuroleptics and novel antipsychotics (and many other psychotropics) deteriorate both cognitive and psychomotor functions in the elderly and may also increase the risk of stroke.[82] Few studies with combination treatments have been reported and most of them are poorly designed. We also have to realize that the vast majority of dementia cases in people older than 75–80% are of a mixed type, in which the cerebrovascular component associated with neurodegeneration cannot be therapeutically neglected. In most cases of dementia, the multifactorial (combination) therapy appears to be the most effective strategy.[10,42–47] The combination of several drugs increases the direct costs (e.g., medication) by 5–10% but, in turn, annual global costs are reduced by approximately 18–20% and the average survival rate increases approximately 30% (from 8 to 12 years postdiagnosis).

There are major concerns regarding the validity of clinical trials in patients with severe dementia. If we assume that AD is a complex disorder where genomic and environmental factors interact to induce the premature death of neurons (which begins 30 years prior to the onset of the disease), it seems clear that future therapeutic strategies must be addressed toward the prevention of neurodegeneration because when the first symptoms appear thousands of millions of neurons have already died, and under these circumstances the possibility of being therapeutically effective is very remote.

Major impact factors associated with drug efficacy and safety include: the mechanisms of action of drugs, drug-specific adverse reactions, drug–drug interactions, nutritional factors, vascular factors, social factors and genomic factors (nutrigenetics, nutrigenomics, pharmacogenetics, pharmacogenomics). Among genomic factors, nutrigenetics/nutrigenomics and pharmacogenetics/pharmacogenomics account for more than 80% of efficacy–safety outcomes in current therapeutics.[9,10,45,47]

To achieve a mature discipline of pharmacogenetics and pharmacogenomics in CNS disorders and dementia, it would be convenient to accelerate the following processes: educate physicians and the public on the use of genetic/genomic screening in the daily clinical practice; standardize genetic testing for major categories of drugs; to validate pharmacogenetic and pharmacogenomic procedures according to drug category and pathology; regulate ethical, social and economic issues; and incorporate pharmacogenetic and pharmacogenomic procedures to both drugs in development and drugs on the market in order to optimize therapeutics.[9,10,42–47]


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