Optimization of Antidepressant use with Pharmacogenetic Strategies.

BACKGROUND: The response rate in the pharmacological treatment of depression has been estimated to be around 50%, achieving a remission in symptomatology in only one third of the patients. Suboptimal prescription of antidepressants has been proposed as a significant explanatory factor for this therapeutic inefficacy. The use of pharmacogenetic testing might favor the optimization of pharmacotherapy in emotional disorders. However, its implementation in the clinical routine requires studies which prove its efficacy. OBJECTIVE: The aim is to explore the clinical effects obtained by means of the personalization of antidepressant treatment derived from the pharmacogenetic profile of the individual. METHOD: A sample of 291 patients under antidepressant treatment was selected, and these patients were genotyped for the most common polymorphisms of the CYP2D6, CYP2C9, CYP2C19 and CYP3A4/5 genes using RT-PCR and TaqMan® technology. 30 of them were subjected to psycho-affective assessment using the HDRS scale before and after a process of individualization of their psychopharmacological treatment in accordance with the genotype obtained. RESULTS: 70% of the individuals treated using the traditional criterion of trial-and-error were not taking the active ingredient most suited to their pharmacogenetic profile. The inclusion of this genetic information in the choice of drug and its dosage entailed a significant, progressive reduction in depressive symptomatology, with an efficacy ratio of 80% and a remission of the pathology in almost 30% of the cases. CONCLUSION: These results suggest that the prescription of pharmacogenetic profile-based strategies has a positive effect on the therapeutic response to antidepressants.

Pharmacogenetic considerations in the treatment of Alzheimer's disease.

The practical pharmacogenetics of Alzheimer's disease (AD) is circumscribed to acetylcholinesterase inhibitors (AChEIs) and memantine. However, pharmacogenetic procedures should be applied to novel strategies in AD therapeutics including: novel AChEIs and neurotransmitter regulators, anti-Aß treatments, anti-tau treatments, pleiotropic products, epigenetic drugs and combination therapies. Genes involved in the pharmacogenetic network are under the influence of the epigenetic machinery which regulates gene expression transcriptionally and post-transcriptionally, configuring the fundamentals of pharmacoepigenomics. Over 60% of AD patients present concomitant pathologies demanding additional treatments which increase the likelihood of drug-drug interactions. Lipid metabolism dysfunction is a pathogenic mechanism inherent to AD neurodegeneration. The therapeutic response to hypolipidemic compounds is influenced by the APOE and CYP genotypes. The development of novel compounds and the use of combination/multifactorial treatments require the implantation of pharmacogenomic procedures for the avoidance of ADRs and the optimization of therapeutics.

Histamine and Immune Biomarkers in CNS Disorders.

Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS) disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56) which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA) is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimer's disease (AD). Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic) in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1ß, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death.

Novel Therapeutic Strategies for Dementia.

Dementia represents a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. Alzheimer disease (AD), the most prevalent form of dementia, is a polygenic/multifactorial/complex disorder in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions lead to amyloid deposition, neurofibrillary tangle formation and premature neuronal death, the major neuropathological hallmarks of AD. For the past 20 years, over 1,000 different compounds have been studied as potential candidate drugs for the treatment of AD. About 50% of these substances are novel molecules obtained from natural sources. The candidate compounds can be classified according to their pharmacological properties and/or the AD-related pathogenic cascade to which they are addressed to halt disease progression. In addition to the Food and Drug Administration (FDA)-approved drugs since 1993 (tacrine, donepezil, rivastigmine, galantamine, memantine), most candidate strategies fall into 6 major categories: (i) novel cholinesterase inhibitors and neurotransmitter regulators, (ii) anti-amyloid beta (Aß) treatments (amyloid-ß protein precursor (APP) regulators, Aß breakers, active and passive immunotherapy with vaccines and antibodies, ß - and γ - secretase inhibitors or modulators), (iii) anti-tau treatments, (iv) pleiotropic products (most of them of natural origin), (v) epigenetic intervention, and (vi) combination therapies. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.

Neuroimmune Crosstalk in CNS Disorders: The Histamine Connection.

The neuroimmune system represents a dense network of biochemical signals associated with neurotransmitters, neuropeptides, neurohormones, cytokines, chemokines, and growth factors synthesized in neurons, glial cells and immune cells, to maintain systemic homeostasis. Endogenous and/or exogenous, noxious stimuli in any tissue are captured by sensor cells to inform the brain; likewise, signals originating at the central nervous system (CNS) level are transmitted to peripheral immune effectors which react to central stimuli. This multidirectional information system makes it possible for the CNS to respond to peripheral damage and for alterations in brain function to be reflected in peripheral immune changes. Different CNS disorders, such as anxiety, depression, psychosis, stroke, Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation and post-traumatic brain injury exhibit changes in CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56 immune markers. Histamine is an important pleiotropic factor in neuroimmune regulation. This biogenic amine shows age-and sex-dependent changes in the CNS, and is significantly altered, together with interleukin- 1ß and TNF-α, in Alzheimer's disease and other neurodegenerative disorders in which neuroinflammation appears to be an aggravating phenotype. Therapeutic intervention to halt progression of deleterious neuroinflammatory reactions in CNS disorders is a major challenge for molecular pharmacology in the future.

Epigenetics of Aging and Alzheimer's Disease: Implications for Pharmacogenomics and Drug Response.

Epigenetic variability (DNA methylation/demethylation, histone modifications, microRNA regulation) is common in physiological and pathological conditions. Epigenetic alterations are present in different tissues along the aging process and in neurodegenerative disorders, such as Alzheimer's disease (AD). Epigenetics affect life span and longevity. AD-related genes exhibit epigenetic changes, indicating that epigenetics might exert a pathogenic role in dementia. Epigenetic modifications are reversible and can potentially be targeted by pharmacological intervention. Epigenetic drugs may be useful for the treatment of major problems of health (e.g., cancer, cardiovascular disorders, brain disorders). The efficacy and safety of these and other medications depend upon the efficiency of the pharmacogenetic process in which different clusters of genes (pathogenic, mechanistic, metabolic, transporter, pleiotropic) are involved. Most of these genes are also under the influence of the epigenetic machinery. The information available on the pharmacoepigenomics of most drugs is very limited; however, growing evidence indicates that epigenetic changes are determinant in the pathogenesis of many medical conditions and in drug response and drug resistance. Consequently, pharmacoepigenetic studies should be incorporated in drug development and personalized treatments.

Pharmacogenomics of Alzheimer's disease: novel therapeutic strategies for drug development.

Alzheimer's disease (AD) is a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis, and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. As a complex disorder, AD is a polygenic and multifactorial clinical entity in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions, lead to amyloid deposition, neurofibrillary tangle formation, and premature neuronal death, the major neuropathological hallmarks of AD. Future perspectives for the global management of AD predict that genomics and proteomics may help in the search for reliable biomarkers. In practical terms, the therapeutic response to conventional drugs (cholinesterase inhibitors, multifactorial strategies) is genotype-specific. Genomic factors potentially involved in AD pharmacogenomics include at least five categories of gene clusters: (1) genes associated with disease pathogenesis; (2) genes associated with the mechanism of action of drugs; (3) genes associated with drug metabolism (phase I and II reactions); (4) genes associated with drug transporters; and (5) pleiotropic genes involved in multifaceted cascades and metabolic reactions. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.

Epigenetic drug discovery for Alzheimer's disease.

INTRODUCTION: It is assumed that epigenetic modifications are reversible and could potentially be targeted by pharmacological and dietary interventions. Epigenetic drugs are gaining particular interest as potential candidates for the treatment of Alzheimer's disease (AD). AREAS COVERED: This article covers relevant information from over 50 different epigenetic drugs including: DNA methyltransferase inhibitors; histone deacetylase inhibitors; histone acetyltransferase modulators; histone methyltransferase inhibitors; histone demethylase inhibitors; non-coding RNAs (microRNAs) and dietary regimes. The authors also review the pharmacoepigenomics and the pharmacogenomics of epigenetic drugs. The readers will gain insight into i) the classification of epigenetic drugs; ii) the mechanisms by which these drugs might be useful in AD; iii) the pharmacological properties of selected epigenetic drugs; iv) pharmacoepigenomics and the influence of epigenetic drugs on genes encoding CYP enzymes, transporters and nuclear receptors; and v) the genes associated with the pharmacogenomics of anti-dementia drugs. EXPERT OPINION: Epigenetic drugs reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Unfortunately, clinical trials with this category of drugs are lacking in AD. The authors highlight the need for pharmacogenetic and pharmacoepigenetic studies to properly evaluate any efficacy and safety issues.

Cognitive reserve and lifestyle in Spanish individuals with sporadic Alzheimer's disease.

BACKGROUND: Some authors suggest that besides the fundamental components, cognitive reserve (CR) also reflects the influence of a combination of factors that improve mental health. METHOD: After obtaining the sociodemographic profile of each participant and evaluating their neurologic and neuropsychologic abilities, first, homogeneity analysis was used as a technique to select variables and reduce the number of categories with similar behavior; then CR construct was identified through a latent class analysis model. It was then possible to categorize participants according to their level in this construct and compare the neuropsychological performance of the subgroups that emerged, using a t test of differences of means for independent samples. RESULTS: Participants with Alzheimer's disease with low CR scores exhibited significantly greater deficits in measures of memory, attention, and language than patients with high CR. CONCLUSIONS: Our results ratify the effect of higher education, higher professional performance, and ludic activities on CR.

Study of sociodemographic variables linked to lifestyle and their possible influence on cognitive reserve.

Cognitive reserve is an active mechanism based on the application of resources learned thanks to a good education, profession, or premorbid intelligence. The aim of this research is to study whether the inclusion of sociodemographic variables linked to lifestyle can discriminate individuals more effectively regarding their level of cognitive reserve. Results show the importance of educational, intellectual, and professional type variables, which can contribute to a deeper knowledge of this construct. In our view, a broad number of variables should be used to assess cognitive reserve effectively.