9. Practical Considerations
The great variability in the therapeutic response of patients with CNS disorders 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, seem to suggest that: (i) it is very unlikely that a single drug may be able to halt disease progression after the onset of the disease; (ii) multifactorial interventions (as in other complex disorders, such as cardiovascular disease, cancer, AIDS, etc.) might be an alternative strategy; however, drug-drug interactions in patients who receive over 6 different drugs per day can represent a serious drawback in terms of safety; (iii) the co-administration of many different drugs in patients with concomitant pathologies (i.e., coronary disease, hypertension, atherosclerosis, hyperlipidemia, dementia) may represent an obstacle for an effective pharmacological management of CNS disorders 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; (iv) 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; (v) the co-administration of psychotropic drugs should be carried out with extreme care as most psychotropics deteriorate cognitive function, psychomotor activity, and cerebrovascular function; (vi) the conventional procedures currently used in drug development (i.e., trial-and-error) and serendipity are not cost-effective nowadays; (vii) 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; (viii) 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 CNS disorders and their biological diversity; and (ix) the underdeveloped field of pharmacogenetics and pharmacogenomics is delaying the possibility of optimizing our limited therapeutic resources for the treatment of neuropsychiatric disorders and dementia [7]. 
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: (i) clinical history; (ii) laboratory tests; (iii) neuropsychological assessment; (iv) cardiovascular evaluation; (v) conventional X-ray technology; (vi) structural neuroimaging; (vii) functional neuroimaging; (viii) computerized brain electrophysiology; (ix) cerebrovascular evaluation; (x) structural genomics; (xi) functional genomics; (xii) pharmacogenetics; (xiii) pharmacogenomics; (xiv) nutrigenetics; (xv) nutrigenomics; (xvi) bioinformatics for data management; and (xvii) artificial intelligence procedures for diagnostic assignments and probabilistic therapeutic options [6]. All 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 taken remarkable strides, with the introduction of many new drugs for the treatment of SCZ, 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 one 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: (i) the molecular pathology of most CNS disorders is still poorly understood; (ii) drug targets are inappropriate, not fitting into the real etiology of the disease; (iii) most treatments are symptomatic, but not anti-pathogenic; (iv) the genetic component of most CNS disorders is poorly defined; and (v) the understanding of genome-drug interactions is very limited [6,7].
The optimization of CNS therapeutics requires the establishment of new postulates regarding (i) the costs of medicines; (ii) the assessment of protocols for multifactorial treatment in chronic disorders; (iii) the implementation of novel therapeutics addressing causative factors; and (iv) the setting-up of pharmacogenetic/pharmacogenomic strategies for drug development [7].
The cost of medicines is a highly important issue in many countries due to (i) the growth of the aging population (>5% disability), (ii) neuropsychiatric and demented patients (>5% of the population) belonging to an unproductive sector with low income, and (iii) the high cost of healthcare systems and new health technologies in developed countries. Despite the efforts 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 anti-dementia drugs present in the market are not cost-effective [4]. 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: (i) the early identification of efficacy signals so that they can be applied early in development for targeted therapies; and (ii) identification of safety signals which can subsequently be validated prospectively during development using the least number of patients with adverse responses [190]. 
Cost-effectiveness analysis has been the most commonly applied framework for evaluating pharmacogenetics. Pharmacogenetic testing is potentially relevant to large populations which incur in high costs. For instance, the most common drugs metabolized by CYP2D6 account for 189 million prescriptions and US$12.8 billion annually in expenditures in the US, which represent 5–10% of total utilization and expenditures for outpatient prescription drugs [196]. 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 R&D of pharmacogenomic-based therapeutics and making reimbursement decisions [197].
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 non-responders to conventional drugs is also important (and currently neglected). 
An important issue in AD therapeutics is that anti-dementia 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 [198]. Few studies with combination treatments have been reported and most of them are poorly designed. We must also realize that the vast majority of dementia cases in people older than 75–80 years 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 [6,7,99,100,101,102]. 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 by about 30% (from 8 to 12 years post-diagnosis) [4,7]. 
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 towards 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 following: (i) the mechanisms of action of drugs; (ii) drug-specific adverse reactions; (iii) drug-drug interactions; (iv) nutritional factors; (v) vascular factors; (vi) social factors; and (vii) genomic factors (nutrigenetics, nutrigenomics, pharmacogenetics, pharmacogenomics). Among genomic factors, nutrigenetics/nutrigenomics and pharmacogenetics/pharmacogenomics account for over 80% of efficacy-safety outcomes in current therapeutics [6,7,11,102,104].
To achieve a mature discipline of pharmacogenetics and pharmacogenomics in CNS disorders and dementia it would be convenient to accelerate the following processes: (i) to educate physicians and the public on the use of genetic/genomic screening in the daily clinical practice; (ii) to standardize genetic testing for major categories of drugs; (iii) to validate pharmacogenetic and pharmacogenomic procedures according to drug category and pathology; (iv) to regulate ethical, social, and economic issues; and (v) to incorporate pharmacogenetic and pharmacogenomic procedures to both drugs in development and drugs on the market in order to optimize therapeutics [6,7,8,9,10,11,12,13,14,15,16,100,101,102,104].