Open Journal of Psychiatry, 2013, 3, 46-139 OJPsych http://dx.doi.org/10.4236/ojpsych.2013.31008 Published Online January 2013 (http://www.scirp.org/journal/ojpsych/) Genomics of schizophrenia and pharmacogenomics of antipsychotic drugs Ramón Cacabelos1*, Pablo Cacabelos1, Gjumrakch Aliev1,2 1EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, EuroEspes Chair of Biotechnology and Genomics, Camilo José Cela University, Corunna, Spain 2Gally International Biomedical Research Consulting LLC, San Antonio, USA Email: *[email protected] Received 13 October 2012; revised 15 November 2012; accepted 24 November 2012 ABSTRACT procedures both to drugs under development and drugs on the market would help to optimize thera- Antipsychotic drugs are the neuroleptics currently peutics in SCZ and other central nervous system dis- used in the treatment of schizophrenia (SCZ) and orders. psychotic disorders. SCZ has a heritability estimated at 70% - 90%; and pharmacogenomics accounts for Keywords: Genomics; Antipsychotic Drugs; 60% - 90% variability in the pharmacokinetics and Schizophrenia pharmacodynamics of psychotropic drugs. Personal- ized therapeutics based on individual genomic pro- files in SCZ entails the characterization of 5 types of 1. INTRODUCTION gene clusters and their related metabolomic profiles: Central nervous system (CNS) disorders are the third 1) genes associated with disease pathogenesis; 2) greatest problem of health in developed countries, repre- genes associated with the mechanism of action of senting 10% - 15% of deaths after cardiovascular disor- drugs; 3) genes associated with drug metabolism ders (25%) and cancer (20%). CNS disorders pose sev- (phase I and II reactions); 4) genes associated with eral challenges to our society and the scientific commu- drug transporters; and 5) pleiotropic genes involved nity: 1) they represent an epidemiological problem and a in multifaceted cascades and metabolic reactions. socio-economic, psychological and family burden; 2) Genetic studies in SCZ have revealed the presence of most of them have an obscure/complex pathogenesis; 3) chromosome anomalies, copy number variants, mul- their diagnosis is not easy and lacks specific biomarkers; tiple single-nucleotide polymorphisms of susceptibil- and 4) their treatment is difficult and inefficient. In terms ity distributed across the human genome, aberrant of economic burden, approximately 10% - 20% of direct single-nucleotide polymorphisms in microRNA genes, costs are associated with their pharmacological treatment, mitochondrial DNA mutations, and epigenetic phe- with a gradual increase in parallel with the severity of the nomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the rela- disease [1,2]. tionship between variation in specific candidate genes Approximately 127 million Europeans suffer brain and the positive and adverse effects of drug treatment. disorders. The total annual cost of brain disorders in Approximately 18% of neuroleptics are major sub- Europe is about €386 billion, with €135 billion in direct strates of CYP1A2 enzymes, 40% of CYP2D6, and medical expenditures (€78 billion, inpatients; €45 billion, 23% of CYP3A4. About 10% - 20% of Western outpatients; €13 billion, pharmacological treatment), populations are defective in genes of the CYP super- €179 billion in indirect costs (lost workdays, loss of family. Only 26% of Southern Europeans are pure productivity, permanent disability), and €72 billion in extensive metabolizers for the trigenic cluster inte- direct non-medical costs. Mental disorders represent grated by the CYP2D6 + CYP2C19 + CYP2C9 genes. €240 billion (62% of the total cost, excluding dementia), Efficacy and safety issues in the pharmacological followed by neurological diseases (€84 billion, 22%) [3]. treatment of SCZ are directly linked to genetic clus- Common features in CNS disorders include the fol- ters involved in the pharmacogenomics of antipsy- lowing: 1) polygenic/complex disorders in which genetic, chotic drugs and also to environmental factors. Con- epigenetic and environmental factors are involved; 2) sequently, the incorporation of pharmacogenomic deterioration of higher activities of the CNS; 3) multi- factorial dysfunctions in several metabolomic networks *Corresponding author. leading to functional damage to specific brain circuits; OPEN ACCESS R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 47 and 4) accumulation of toxic proteins in the nervous tis- phasis was on the role of hyperdopaminergia in the eti- sue in cases of neurodegeneration [1,2]. ology of SCZ, but it was subsequently reconceptualized Our understanding of the pathophysiology of CNS to specify subcortical hyperdopaminergia with prefrontal disorders has advanced dramatically during the last 30 hypodopaminergia [18]. Carlsson’s hypothesis postulates years, especially in terms of their molecular pathogenesis that the positive and negative symptoms of SCZ are due and genetics. Drug treatment has also made remarkable to failure of mesolimbic and mesocortical projections strides, with the introduction of many new drugs; how- consequent on hypofunction of the glutamate N-methyl- ever, improvement in terms of clinical outcome has D-aspartate (NMDA) receptor. The emergence of posi- fallen short of expectations, with up to one third of pa- tive symptoms (hallucinations), and synapse regression tients continuing to experience clinical relapse or unac- involves molecules such as neuregulin and its receptor ceptable medication-related side-effects in spite of efforts ErbB4, which have been implicated in SCZ [19]. While to identify optimal treatment regimens. Potential reasons multiple theories have been put forth regarding the origin to explain this historical setback might be that: 1) the of SCZ, by far the vast majority of evidence points to the molecular pathology of brain disorders is still poorly neurodevelopmental model in which developmental in- understood; 2) drug targets are inappropriate, not fitting sults as early as late first or early second trimester lead to into the real etiology of the disease; 3) most treatments the activation of pathologic neural circuits during ado- are symptomatic, but not anti-pathogenic; 4) the genetic lescence or young adulthood, leading to the emergence component of CNS disorders is poorly defined; and 5) of positive or negative symptoms. There is evidence the understanding of genome-drug interactions is very from brain pathology (enlargement of the cerebroven- limited [2,4-6]. tricular system, changes in gray and white matters, and The pharmacological management of CNS disorders is abnormal laminar organization), genetics (changes in the an issue of special concern due to the polymedication normal expression of proteins involved in early migra- required to modulate the symptomatic complexity of tion of neurons and glia, cell proliferation, axonal out- brain disorders. The introduction of novel procedures growth, synaptogenesis, and apoptosis), environmental into an integral genomic medicine protocol in CNS dis- factors (increased frequency of obstetric complications orders is an imperative requirement for clinical practice and increased rates of schizophrenic births due to prena- and drug development in order to improve diagnostic tal viral or bacterial infections), and gene-environmental accuracy (disease-specific biomarkers) and to optimize interactions (a disproportionate number of SCZ candi- therapeutics (pharmacogenomics) [7-12]. A growing date genes are regulated by hypoxia, microdeletions and body of fresh knowledge on the pathogenesis of CNS microduplications, the overrepresentation of pathogen- disorders, together with data on neurogenomics and related genes among SCZ candidate genes) in support of pharmacogenomics, is emerging in recent times. The the neurodevelopmental model [20]. Dean [21] reviewed incorporation of this new armamentarium of molecular evidence to assess the hypothesis that SCZ is a hu- pathology and genomic medicine to daily medical prac- man-specific disorder associated with the need for highly tice, together with educational programs for the correct complex CNS development. Changes in the size of the use of drugs, must help to: 1) understand brain patho- frontal lobe, increases in numbers of specific cell types, genesis; 2) establish an early diagnosis; and 3) optimize changes in gene expression and changes in genome se- therapeutics either as a preventive strategy or as a formal quence all seem to be involved in the evolution of the symptomatic treatment [2,5,6,13,14]. human CNS. Human-specific changes in CNS develop- Schizophrenia (SCZ) is a typical paradigm of mental ment are wide-ranging. The modification in CNS struc- disorder with a prevalence of 1% and a high socioeco- ture and function that has resulted from these changes nomic impact in our society. SCZ and related disorders affects many pathways and behaviors that also appear to are highly heritable but cannot be explained by currently be affected in subjects with SCZ. Therefore, there is evi- known genetic risk factors. SCZ has a heritability esti- dence to support the hypothesis that SCZ is a disease that mated at 70% - 90% [1,15-17]. Several neurobiological develops due to derangements to human-specific CNS hypotheses have been postulated as responsible for SCZ functions that have emerged since our species diverged pathogenesis: polygenic/multifactorial genomic defects, from non-human primates. intrauterine