1. Introduction
From an epidemiological perspective, central nervous system (CNS) disorders are the third largest health problem in developed countries, representing 10–15% of deaths, after cardiovascular disorders (25–30%) and cancer (20–25%). Approximately 127 million Europeans suffer brain disorders. The total annual cost of brain disorders in Europe is about €386 billion, with €135 billion of direct medical expenditures (€78 billion, inpatients; €45 billion, outpatients; €13 billion, pharmacological treatment), €179 billion of indirect costs (lost workdays, productivity loss, permanent disability), and €72 billion of direct non-medical costs. Mental disorders represent €240 billion (62% of the total cost, excluding dementia), followed by neurological diseases (€84 billion, 22%) [1]. In low- and middle-income countries, dementia makes the largest contribution to disability with a median population-attributable prevalence fraction (PAPF) of 25.1%, followed by stroke (11.4%), limb impairment (10.5%), arthritis (9.9%), depression (8.3%), eyesight problems (6.8%), and gastrointestinal impairments (6.5%) [2]. Alzheimer’s disease (AD) is the most frequent form of dementia (50–70%), followed by vascular dementia (30–40%), and mixed dementia (15–20%). These prevalent forms of age-related neurodegeneration affect over 25 million people at present, and probably over 75 million people will be at risk in the next 20–25 years worldwide. The prevalence of dementia increases exponentially from approximately 1% at 60–65 years of age to over 30–35% in people of over 80 years. It is likely that in patients older than 75–80 years of age most cases of dementia are mixed in nature (degenerative + vascular), whereas pure AD cases are very rare after 80 years of age. The average annual cost per person with dementia ranges from €10,000 to €40,000, depending upon disease stage and country, with a lifetime cost per patient of more than €150,000. In some countries, approximately 80% of the global costs of dementia (direct + indirect costs) are assumed by the patients and/or their families. About 10–20% of the costs in dementia are attributed to pharmacological treatment, including anti-dementia drugs, psychotropics (antidepressants, neuroleptics, anxiolytics), and other drugs currently prescribed in the elderly (antiparkinsonians, anticonvulsants, vasoactive compounds, anti-inflammatory drugs, etc.). In addition, during the past 20 years over 300 drugs have been partially or totally developed for AD, with the subsequent costs for the pharmaceutical industry, and only five drugs with moderate-to-poor efficacy and questionable cost-effectiveness have been approved in developed countries [3,4,5].

1.1. Towards a Personalized Medicine in Neuropsychiatric Disorders
Common features in CNS disorders include the following: (i) polygenic/complex disorders in which genomic and environmental factors are involved; (ii) deterioration of higher activities of the CNS; (iii) multifactorial dysfunctions in several brain circuits; and (iv) accumulation of toxic proteins in the nervous tissue in cases of neurodegeneration. For instance, the neuropathological hallmark of AD (amyloid deposition in senile plaques, neurofibrillary tangle formation, and neuronal loss) is but the phenotypic expression of a pathogenic process in which different gene clusters and their products are potentially involved [6,7]. 
Extensive molecular genetics studies carried out in the past two decades have demonstrated that most CNS disorders are multifactorial, polygenic/complex disorders in which hundreds of genes distributed across the human genome might be involved. For example, 255 genes have been associated with dementia (Table 1), 205 with schizophrenia, 106 with depression, 107 with anxiety, 103 with stroke, 385 with different types of ataxia, 155 with epilepsia, 83 with meningioma, 105 with glioblastoma, 27 with astrocytoma, 73 with Parkinson’s disease, and over 30 genes with cerebrovascular disorders. Many of these genetic associations could not be replicated in different settings and different populations due to many complex (methodological, technological) factors [8,9,10]. Furthermore, the same genomic defect can give rise to apparently diverse phenotypes, and different genomic defects can converge in an apparently common phenotype, this increasing the complexity of genomic studies (e.g., patient recruitment, pure controls, concomitant pathology, epigenetic factors, environmental factors) [10].
pharmaceuticals-03-03040-t001_Table 1 Table 1  Selected human genes investigated as potential candidate genes associated with dementia and age-related neurodegenerative disorders [4,5,6,9,20,21,22].   Drug metabolism, and the mechanisms underlying drug efficacy and safety, are also genetically-regulated complex traits in which hundreds of genes cooperatively participate. Disease-associated genomics, transcriptomics, proteomics and metabolomics are essential components of the therapeutic outcome [11]. Pharmacogenetic and pharmacogenomic factors may account for 60–90% of drug variability in drug disposition and pharmacodynamics. About 10–20% of Caucasians are carriers of defective CYP2D6 polymorphic variants which alter the metabolism of many psychotropic agents. The incorporation of pharmacogenetic/pharmacogenomic protocols into CNS research and clinical practice can foster the optimization of therapeutics by helping to develop cost-effective pharmaceuticals and improving drug efficacy and safety [6,7,8,11,12,13,14,15,16,17,18,19,20,21].