Several reasons underlie this relative failure, such as, for example, 1 lack of knowledge of the mechanisms involved, 2 heterogeneity of most psychiatric disorders that have good inter-rater validity but weak relationship with specific neurobiological mechanisms , 3 variable tolerance that leads to poor compliance, and 4 insufficient prediction for a specific treated patient of the efficacy, side effects, and outcome associated with the prescribed treatments. G proteins are a family of trimeric proteins, consisting of α, β, and γ subunits. Data to date on psychopharmacogenomics is reviewed in this article. The overall mortality of TdP is between 10 and 17% Salle et al 1985; Fung et al 2000. These prevalence rates appear to be unrelated to ethnicity, education, income, or marital status, but culture may influence the experience and the communication of depressive symptoms. Antipsychotic therapy still remains try and error to a considerable degree.
The urgency to develop new treatments that may have better efficacy and tolerance is explained by the fact that none of the treatments currently available can be considered completely satisfying. Treatment response to antidepressant, anxiolytic, and antipsychotic drugs is influenced by genetic factors and depends on the structure or functional expression of gene products. The situation improved profoundly with the advent of antipsychotic medication in the 1950's, later called the typical antipsychotics or neuroleptics. Specifically, pharmacodynamics describes the drug concentration versus effect relationships in an organism Greenblatt et al. Psychopharmacogenetics relies on the analyses of the genes involved in treatment response — adverse effects, efficacy, and their mechanisms. This has opened new avenues towards the identification of drug targets to treat eating disorders and obesity.
Notably, a wealth of novel information has been gained from the identification of highly selective ligands for some dopamine receptor subtypes, the generation of dopamine receptor subtype-targeted mutant mice and subtypespecific antibodies, and the advances of molecular genetics. What are the efficacy and side effects of the available treatments? Movement disorders constitute a group of neurological diagnoses characterized by changes in muscle tone, the presence of inappropriate movements, the impairment in timing and sequencing of normal movements, and the absence of weakness. This chapter will provide an overview of the variety of G protein subtypes and their associated proteins. These pharmacological substances are very potent in their antipsychotic efficacy but often inducing severe side effects, for the most part extrapyramidal motor disorders like akathisia, parkinsonism, and early and late onset dyskinesias, beyond else. This volume presents information on the psychopharmacogenetic, representing an area of research that is based on various specialities including clinical psychiatry, pharmacology, neurobiology and genetics. Several reasons underlie this relative failure, such as, for example, 1 lack of knowledge of the mechanisms involved, 2 heterogeneity of most psychiatric disorders that have good inter-rater validity but weak relationship with specific neurobiological mechanisms , 3 variable tolerance that leads to poor compliance, and 4 insufficient prediction for a specific treated patient of the efficacy, side effects, and outcome associated with the prescribed treatments.
Whereas no markers applicable to patient screening have yet been identified, the discussion highlights areas of current research and provides a context for future studies in this domain. Unfortunately, none of these questions can be answered as of yet. In addition, they are implicated in various physiological and pathological conditions. The last decade, the knowledge on the neural circuitry underlying regulation of food intake and energy balance, has increased enormously with the discovery of leptin and its downstream targets. Linkage studies indicate that there are still genes to be discovered that play an important role in the aetiology of eating disorders and obesity. Still, concentration-dependent adverse effects do exist even for these compounds. What are the core symptoms? The mean age of onset is in the third decade of life, although onset in adolescence is rising common.
Clozapine was a big success, improving psychotic conditions in patients that were hitherto refractory to treatment. What are the core symptoms? The utility of psychopharmacogenetics may be substantial. Structure and functions of dopamine receptors, and their implications to pathological conditions have been reviewed earlier Civelli et al. The rapidly developing molecular genetic techniques contributed the advance in this field. Psychiatric and substance-abuse co-morbidities are the most common complications, and mortality rates are increased in the population of depressed subjects, as a result of high suicidal risks, accidents, complications of substance abuse and increased fatality of stress-sensitive medical illnesses. In fact, considering less severe forms such as Minor Depression or Brief Recurrent Depression, the lifetime rate may reach up to one third of the population.
More recent, clinical and neuropathological studies have distinguished a second major form of dementia, frontotemporal dementia, although less frequent. Interestingly, both Alzheimer's disease and frontotemporal dementia have features in common, such as neuronal loss in a number of brain structures and the intra or extracellular accumulation of misfolded proteins which constitute markers for the diseases. The psychopharmacogenetic field represents an important area of research that is based on various specialties including clinical psychiatry. Prediction of efficacy, prevention of major side effects, and selection of the most appropriate treatment should thus have major medical and economical impacts. However, only one week after publication of the reports on cloning of the D1 receptor, a novel dopamine receptor subtype was identified, the D3 receptor Sokoloff et al. Still others are clear genetic conditions, like Huntington's disease and familial tremor.
It also poses a major problem for adults who were either first diagnosed later in life or have suffered from persisting symptoms from childhood Faraone et al. Pharmacogenomic knowledge of psychiatric treatments will improve outcome by determining most beneficial drug according to the individual's genetic information. Minor depression in older men and major depression in both older men and women was shown to increase the risk of dying, even after adjustment for sociodemographic variables, health status and health behaviours Penninx 1999. In addition to these primary movement disorders, similar movement impairments can occur as a reflection of metabolic disturbances, infectious diseases, and cerebrovascular accidents. Should I pay a subscription fee to always have free shipping? What are the risk factors? A final category of secondary movement disorders is composed of the syndromes directly related to medication side effects, collectively termed drug-induced movement disorders. Dopamine is an important neurotransmitter in the brain and controls various functions, including motor activity, cognition, motivation, emotion, food intake and endocrine secretions. Therefore, the possibility to start the therapy at the right dosage, according to the patient's metabolic capacity, would be expected to improve treatment outcome by decreasing the occurrence of concentration-dependent adverse effects and therapeutic failure or delayed response.
In this book, the basic and advanced knowledge on psychiatric disorders is provided for non-clinicians: What is schizophrenia? Although no drugs have been developed, so far, that specifically act on G proteins, G proteins are potential pharmaceutical targets as changes in G proteins and their associated regulatory proteins have been implicated in a number of pathological conditions. Among the numerous risk factors involved, the importance of a genetic vulnerability has been demonstrated, and the heritability, in the broad sense, has being estimated to be between 50 and 70%. This enables G proteins to be intracellular transducers of a variety of extracellular signals such as hormones, neurotransmitters, odorants, and photons. Are there already some psychopharmacogenetic data useful in clinical practice? It has long been thought that only two receptor subtypes, the D1 and D 2 receptors, which were initially defined on the basis of their distinct transduction mechanisms and pharmacological profiles Spano et al. Psychopharmacogenetics was born with the development of psychotropic drugs in psychiatry, that is, slightly after the discovery of the role of lithium in bipolar disorders and of antipsychotic agents in schizophrenia. These symptom clusters may coexist or may occur individually and must significantly interfere with academic, family, and social functioning of the afflicted individual.
G proteins associate with a variety of receptors See Table 1. Almost all insights into the pharmacogenetics of psychosis are derived from schizophrenic patients therefore all the following comments will generally refer to this disorder. Thus, dosage optimisation is an important issue for all compounds used in psychiatry. Psychotic disorders are severe psychiatric conditions, frequent, disabling, with patients at high risk for suicide, for addiction and social decline. What are the efficacy and side effects of the available treatments and their mechanisms? Also, depression represent a frequent complication of diabetes, and other metabolic illnesses Lynch 1994.
The questions considered include: What is schizophrenia? Pharmacogenetic research on sexual dysfunctions could be productive in answering several important questions: How much positive predictive power could genetic information provide in forecasting sexual sideeffects? This step limits the temporal persistence and the spatial spread of monoamines at their presynaptic and postsynaptic receptors and thus allow fine-tuningof neurotransmitter actions. The targets may include a variety of proteins, such as receptors, enzymes, transporters, ion channels, second messengers, among others. Subsequently, this pharmacokinetic variability can partly explain the wide range of doses required for optimal therapeutic effect. Being able to give each patient the appropriate dosage of the right treatment should enhance not only its immediate efficacy, but also compliance and therefore long-term efficacy. Despite considerable efforts there has been no success so far in determining predictive factors for treatment response and relapse.