Several reasons for Selleck JQ1 nonresponse to treatment, have been considered. The main issue is the heterogeneity of schizophrenic disorders, which can result, in different, clinical pictures. The existing theories discussed for schizophrenia (Figure 1) may be only a small part of the existing mechanisms causing schizophrenia. Consequently, the research strategy is to focus on the effects of alterations in drug target proteins. In addition, the duration of the untreated psychosis seems to adversely affect, acute treatment, response and short-term Inhibitors,research,lifescience,medical outcome.2 Here, we will focus on the pharmacokinetic and pharmacodynamic aspects of nonresponse to treatment,

in schizophrenia. The atypical antipsychotic clozapine, which was licensed in the USA especially for the treatment of so-called treatment-resistant schizophrenia3 (after having been available in Europe since 19684), is not, effective in all patients and 20% to Inhibitors,research,lifescience,medical 30% are known to be nonresponders. In a naturalistic study in the psychiatric clinic of the University of Munich, responders with no relapse were compared with responders with partial relapse. The response rate was only partially dependent on dose and plasma levels. Figure 1. Theories for schizophrenia, NMDA, N-methyl-D-aspartate. Responders received an average dosage of 225 mg/day clozapine and had

a plasma level of 205 ng/mL clozapine on average and 120 ng/ml , Inhibitors,research,lifescience,medical desmethylclozapine per day. Responders with partial relapse received lower dosages (125 mg/day) and also Inhibitors,research,lifescience,medical had lower plasma levels (100 ng/mL clozapine, 55 ng/mL desmethylclozapine, respectively). Nonresponders received higher dosages (250 mg/day) and generally also showed considerably higher plasma levels (290 ng/mL clozapine and 225 ng/mL desmethylclozapine, respectively). Therefore the nonresponders did not respond to therapy even though

they received higher dosages and had higher plasma levels (Messer T, personal communication), and that additional factors are involved. Inhibitors,research,lifescience,medical Pharmacogenomics Pharmacogenomics is the study of how an individual’s genetic inheritance affects the body’s response to drugs (Figure 2). This includes both the interindividual sideeffect profile and the therapeutic outcome. Single nucleotide polymorphisms (SNPs) occur every 100 to 300 bases in the human genome, leading to a large number of possible associations with response to pharmacotherapy. Keeping this in mind, current, research activities Thiamine-diphosphate kinase mainly focus on pharmacokinetic and pharmacodynamic alterations. Most, notably, genes coding for the metabolizing and transport proteins and drug target, structures (receptors, transporters, and signal transduction pathways) are being investigated. Figure 2. Pharmacogenomics: the study of how genetic inheritance affects the body’s response to drugs. Pharmacokinetics Various reasons have been discussed for nonresponse (Table I).