The study confirms that D(2) occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a "target and trigger" hypothesis of antipsychotic action, i.e., that the D(2) receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D(2) occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.

The distribution and abundance of Ixodes scapularis were studied in Wisconsin, northern Illinois, and portions of the Upper Peninsula of Michigan by inspecting small mammals for ticks and by collecting questing ticks at 138 locations in state parks and natural areas. Environmental data were gathered at a local level (i.e., micro and meso levels), and a geographic information system (GIS) was used with several digitized coverages of environmental data to create a habitat profile for each site and a grid map for Wisconsin and Illinois. Results showed that the presence and abundance of I. scapularis varied, even when the host population was adequate. Tick presence was positively associated with deciduous, dry to mesic forests and alfisol-type soils of sandy or loam-sand textures overlying sedimentary rock. Tick absence was associated with grasslands, conifer forests, wet to wet/mesic forests, acidic soils of low fertility and a clay soil texture, and Precambrian bedrock. We performed a discriminant analysis to determine environmental differences between positive and negative tick sites and a regression equation to examine the probability of I. scapularis presence per grid. Both analyses indicated that soil order and land cover were the dominant contributors to tick presence. We then constructed a risk map indicating suitable habitats within areas where I. scapularis is already established. The risk map also shows areas of high probability the tick will become established if introduced. Thus, this risk analysis has both explanatory power and predictive capability.

Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.

This article argues for a new way of studying executive-coaching outcomes, which is illustrated with a study based on data from 156 client-coach pairs. The argument accepts that we are unlikely to get robust data on coaching outcomes in the near future but assumes that we can expect similar effectiveness for coaching as that demonstrated in rigorous psychotherapy outcome research. Therefore, it is argued that it is more important now to (a) identify the "active ingredients" that predict the effectiveness of executive coaching, and (b) to determine the difference in predictive value of these active ingredients on coaching effectiveness. The outcome study examined some of these active ingredients, such as the working alliance between coach and client, the self-efficacy of the client, the personality of the client, and the "personality match" between client and coach. The results show that client perceptions of coaching outcome were significantly related to their perceptions of the working alliance, client self-efficacy, and to client perceptions of the range of techniques of the coach. The client-coach relationship mediated the impact of self-efficacy and range of techniques on coaching outcomes, suggesting that this relationship is the key factor in determining how clients perceive the outcome of coaching.

In vivo D2 occupancy measurements in rats using [3H]-raclopride is analogous to using [11C]-raclopride in human PET scanning. Suppression of CAR occurred at a D2 occupancy of around 70-75%, and catalepsy at D2 occupancy >80%. Results closely resembled human studies where 65-70% D2 occupancy was required for antipsychotic response, while > or = 80% D2 occupancy led to EPS. Brain mechanisms involved in mediation of catalepsy in rats and EPS in humans might indeed be similar. Both suppression of CAR in rats and antipsychotic response in humans might share an underlying construct, i.e. the need for around 70% D2 receptor blockade.

The 20S proteasome is the main protease for the degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceeds proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disorders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity. Chemical manipulation of chlorpromazine abrogated its D2R receptor binding affinity while retaining its ability to enhance 20S mediated proteolysis at low micromolar concentrations. The resulting small molecule enhancers of 20S proteasome activity induced the degradation of intrinsically disordered proteins, α-synuclein, and tau but not structured proteins. These small molecule 20S agonists can serve as leads to explore the therapeutic potential of 20S activation or as new tools to provide insight into the yet unclear mechanics of 20S-gate regulation.

Current dosing regimens of psychotropic drugs are based on plasma kinetic considerations, although it is unclear whether plasma levels faithfully reflect brain kinetics of drugs. 1,2 To examine this, we compared the kinetics of plasma levels of two widely used antipsychotics, olanzapine and risperidone, vs the time course of their effects in the brain. We used positron emission tomography (PET) and Novel antipsychotics are currently used to treat diverse medical conditions such as schizophrenia, mania, depression, and dementia. It is well established that antagonism of D 2 receptors is critical for antipsychotic efficacy, 3,4 and that at clinical doses antipsychotics block a substantial proportion of D 2 receptors in vivo. 5 Positron emission tomography and selective ligands such as [ 11 C]raclopride have provided valuable insights regarding receptor occupancy during treatment with olanzapine and risperidone. 6,7 However, in most studies PET scans were obtained only at a single time point after medication intake, typically 12 h post-dose. Hence, little is known about the time course of brain receptor blockade with these atypical antipsychotics. This is of particular interest as it has been shown that D 2 receptor occupancy can persist up to 15 days after withdrawal from oral doses of conventional neuroleptics, 8 and up to 6 months after depot injection of haloperidol decanoate. 9 We measured the time course of drug plasma levels and brain D 2 receptor occupancy in healthy volunteers after a single dose of 3-4 mg risperidone (n = 4) or 15 mg olanzapine (n = 4). We used [ 11 C]raclopride as a PET-ligand to estimate central D 2 receptor occupancy in the striatum, 1 and [ 11 C]FLB457 for quantification of extra-striatal D 2 blockade in the thalamus. 10 Additionally, we investigated the time course of plasma levels and striatal D 2 occupancy in five stable patients suffering from schizophrenia. These patients had received a monotherapy with olanzapine 15-20 mg day −1 (n = 3) or risperidone 3 mg day −1 (n = 2) for at least one month. We scanned them immediately after withdrawal from their antipsychotic medication, and again after 24 and 48 h.In the single-dose experiments in healthy volunteers, mean peak olanzapine plasma levels occurred 6 h after intake (23 ng ml −1 ± 4 SD). The plasma elimination half-life time (t 1/2 ) was 24.2 h (95% confidence interval (CI): 21.2-28.1). After 72 h, plasma levels declined on Figure 1 Single dose experiments in controls. Time course of plasma levels (olanzapine: , grey dashed line; risperidone plus 9-OH-risperidone: , grey solid line), and striatal D 2 receptor occupancy (olanzapine: , black dashed line; risperidone: , black solid line). All results are normalized to 100% of their peak value. Error bars denote one standard deviation.

Shedding light on the design strategies used to make structurally photoactive metal–organic frameworks.