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doi: 10.1007/s00406-008-1002-9pmid: 18344043
Personalized medicine is still in its infancy concerning drug development in neuropsychopharmacology. Adequate biomarkers with clinical relevance to drug response and/or tolerability and safety largely remain to be identified. Possibly, this kind of personalized medicine will first gain clinical relevance in the dementias. The clinical relevance of the genotyping of drug-metabolizing enzymes as suggested by drug licencing authorities for the pharmacokinetic evaluation of medicinal products needs to be proven in sound clinical trials.
doi: 10.1007/s00406-007-1003-0pmid: 18344044
Knowledge concerning the classification of mental disorders progressed substantially with the use of DSM III-IV and IDCD 10 because it was based on observed data, with precise definitions. These classifications a priori avoided to generate definitions related to etiology or treatment response. They are based on a categorical approach where diagnostic entities share common phenomenological features. Modifications proposed or discussed are related to the weak validity of the classification strategy described above. (a) Disorders are supposed to be independent but the current coexistence of two or more disorders is the rule; (b) They also are supposed to have stability, however anxiety disorders most of the time precede major depression. For GAD age at onset, family history, biology and symptomatology are close to those of depression. As a consequence broader entities such as depression-GAD spectrum, panic-phobias spectrum and OCD spectrum including eating disorders and pathological gambling are taken into consideration; (c) Diagnostic categories use thresholds to delimitate a border with normals. This creates “subthreshold” conditions. The relevance of such conditions is well documented. Measuring the presence and severity of different dimensions, independent from a threshold, will improve the relevance of the description of patients pathology. In addition, this dimensional approach will improve the problems posed by the mutually exclusive diagnoses (depression and GAD, schizophrenia and depression); (d) Some disorders are based on the coexistence of different dimensions. Patients may present only one set of symptoms and have different characteristics, evolution and response to treatment. An example would be negative symptoms in Schizophrenia; (e) Because no etiological model is available and most measures are subjective, objective measures (cognitive, biological) and genetics progresses created important hopes. None of these measures is pathognomonic and most appear to be related to risk factors especially at certain periods when associated with environmental events. One of the major aims for a classification of patients is to identify groups to whom a best possible therapeutic strategy can be proposed. Drugs may improve fear extinction while the genetic and/or acquired avoidance may be called phobia. The basic mechanism and or the corresponding phenotype should appear in the classification. Progresses in early identification of disturbances by taking into account all the information available (prodromal symptoms, cognitive, biological, imaging, genetic, family information) are crucial for the future therapeutic strategy: prevention.
Maier, Wolfgang; Zobel, Astrid
doi: 10.1007/s00406-007-1004-zpmid: 18344045
Individualized medicine through molecular pharmacogenetics is one of the major future goals in clinical medicine. In psychopharmacology, pharmacogenetics became an expanding research component. Major research results were already attained: first, it is now feasible to predict a major proportion of the interindividual variation of plasma levels of most antidepressants and antipsychotics by using the DNA-sequence variation in genes for crucial CYP P450-enzymes as CYP2D6. Second, it is now possible to relate serious side effects (tardive dyskinesia, weight gain) of antipsychotics to specific genetic variants of genes for target proteins. Third, a long list of mainly functional variants in target protein genes was explored for their predictive power for the beneficial and adverse treatment outcome. Although specific results transferable into clinical practice were not yet obtained in this respect, the proof of principle could be demonstrated.
doi: 10.1007/s00406-007-1005-ypmid: 18344046
To produce its characteristic effects, a drug must be present in appropriate concentrations at its sites of action. The latter is not only a function of the dose administered, but also of the extent and rate of drug absorption, distribution, tissue binding, biotransformation, and excretion, which can vary markedly between individual patients due to differences in gender, age, morbidity, smoking or eating habits, differential expression of drug metabolising enzymes or drug transporters or other factors. Therefore drug concentrations in blood resulting after a given dose differ by tenfold or more between individual patients. For psychoactive drugs, animal studies have shown that plasma concentrations of psychotropic drugs correlate well with concentrations in the target organ, the brain. In the brain of patients treated with antipsychotic or antidepressant drugs clear-cut relationships were found between plasma concentrations of the drug and occupancy of dopamine receptors or serotonin uptake sites by positron emission tomography (PET). Monitoring concentrations of psychoactive drugs in plasma of patients, so called therapeutic drug monitoring (TDM), is therefore useful to adjust dosages for optimal “receptor” blockade. TDM is well established for mood stabilizers and anticonvulsant drugs. For other neuropsychiatric drugs, however, “routine” TDM is rare. Optimal target concentrations are unclear for many drugs, and the number of laboratories that use reliable methods to measure the low concentrations of the drugs within a single day is quite limited. Moreover, the use of TDM in pratice is far from optimal. The TDM group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP see http://www.agnp.de/ ) has published literature-based guidelines for optimal use of TDM in psychiatry. TDM can be most informative to solve problems underlying the treatment of an individual patient. It can be clarified if suggested non-compliance or insufficient response in spite of recommended doses is due to rapid metabolism of the drug. Moreover, many drug interactions have been detected by using TDM. In conclusion, TDM is a reliable tool to optimise psychopharmacotherapy. When used adequately it is helpful for many psychiatric patients and in many situations.
doi: 10.1007/s00406-007-1006-xpmid: 18344047
Dementia is a major problem of health in developed countries. Alzheimer’s disease (AD) is the main cause of dementia, accounting for 50–70% of the cases, followed by vascular dementia (30–40%) and mixed dementia (15–20%). Approximately 10–15% of direct costs in dementia are attributed to pharmacological treatment, and only 10–20% of the patients are moderate responders to conventional anti-dementia drugs, with questionable cost-effectiveness. Primary pathogenic events underlying the dementia process include genetic factors in which more than 200 different genes distributed across the human genome are involved, accompanied by progressive cerebrovascular dysfunction and diverse environmental factors. Mutations in genes directly associated with the amyloid cascade (APP, PS1, PS2) are only present in less than 5% of the AD population; however, the presence of the APOE-4 allele in the apolipoprotein E (APOE) gene represents a major risk factor for more than 40% of patients with dementia. Genotype–phenotype correlation studies and functional genomics studies have revealed the association of specific mutations in primary loci (APP, PS1, PS2) and/or APOE-related polymorphic variants with the phenotypic expression of biological traits. It is estimated that genetics accounts for 20–95% of variability in drug disposition and pharmacodynamics. Recent studies indicate that the therapeutic response in AD is genotype-specific depending upon genes associated with AD pathogenesis and/or genes responsible for drug metabolism (CYPs). In monogenic-related studies, APOE-4/4 carriers are the worst responders. In trigenic (APOE-PS1-PS2 clusters)-related studies the best responders are those patients carrying the 331222-, 341122-, 341222-, and 441112- genomic profiles. The worst responders in all genomic clusters are patients with the 441122+ genotype, indicating the powerful, deleterious effect of the APOE-4/4 genotype on therapeutics in networking activity with other AD-related genes. Cholinesterase inhibitors of current use in AD are metabolized via CYP-related enzymes. These drugs can interact with many other drugs which are substrates, inhibitors or inducers of the cytochrome P-450 system; this interaction elicits liver toxicity and other adverse drug reactions. CYP2D6-related enzymes are involved in the metabolism of more than 20% of CNS drugs. The distribution of the CYP2D6 genotypes differentiates four major categories of CYP2D6-related metabolyzer types: (a) Extensive Metabolizers (EM)(*1/*1, *1/*10)(51.61%); (b) Intermediate Metabolizers (IM) (*1/*3, *1/*4, *1/*5, *1/*6, *1/*7, *10/*10, *4/*10, *6/*10, *7/*10) (32.26%); (c) Poor Metabolizers (PM) (*4/*4, *5/*5) (9.03%); and (d) Ultra-rapid Metabolizers (UM) (*1xN/*1, *1xN/*4, Dupl) (7.10%). PMs and UMs tend to show higher transaminase activity than EMs and IMs. EMs and IMs are the best responders, and PMs and UMs are the worst responders to pharmacological treatments in AD. It seems very plausible that the pharmacogenetic response in AD depends upon the interaction of genes involved in drug metabolism and genes associated with AD pathogenesis. The establishment of clinical protocols for the practical application of pharmacogenetic strategies in AD will foster important advances in drug development, pharmacological optimization and cost-effectiveness of drugs, and personalized treatments in dementia.
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