The NIMH-MATRICS project for developing cognition-enhancing agents for schizophrenia

The US National Institute of Mental Health supported an initiative to facilitate the development of pharmacological agents for enhancing neurocognition in patients with schizophrenia. This has been accomplished through a consensus-building process that has included representatives from academia, the pharmaceutical industry, and government. The group has addressed obstacles to drug development that include (i) the lack of a well-accepted instrument for measuring neurocognition in clinical trials; (ii) the lack of a consensus on the best molecular target or targets for drug development; (iii) the lack of a consensus regarding the optimal trial design for either comedication that improves cognition when added to an antipsychotic or a broad spectrum agent that improves cognition and treats psychosis; and (iv) the approaches of regulatory agencies such as the US Food and Drug Administration to approving and labeling a new agent

History of Psychopharmacology.

We live in an age of psychopharmacology. One in six persons currently takes a psychotropic drug. These drugs have profoundly shaped our scientific and cultural understanding of psychiatric disease. By way of a historical review, we try to make sense of psychiatry's dependency on psychiatric drugs in the care of patients. Modern psychopharmacology began in 1950 with the synthesis of chlorpromazine. Over the course of the next 50 years, the psychiatric understanding and treatment of mental illness radically changed. Psychotropic drugs played a major part in these changes as state hospitals closed and psychotherapy gave way to drug prescriptions. Our review suggests that the success of psychopharmacology was not the consequence of increasingly more effective drugs for discrete psychiatric diseases. Instead, a complex mix of political economic realities, pharmaceutical marketing, basic science advances, and changes in the mental health-care system have led to our current infatuation with psychopharmacology

The one-electron oxidation product of a metallocenyl-terminated cyanine

The 1-(2,3,4,5,1',2',3',4'-octa­methyl­ferrocen-1-yl)-3-(ruth­eno­cen­yl)­allylium cation readily undergoes one-electron oxidation to a dication in which an octa­methyl­ferrocenium moiety is bridged by a vinyl­ene group to a [(η^6-fulvene)(η^5-cyclo­penta­dienyl)­ruthenium]+ moiety. In the title compound, 1-(2,3,4,5,1',2',3',4'-octa­methyl­ferrocen-1-yl)-3-(ruth­eno­cen­ylidene)prop-1-enium(2+) bis­(tetra­fluoro­borate), [Fe­Ru­(C_5H_5)(C_9H_(13))(C_(17)H_(19))]­(BF_4)_2, the C-C bond lengths in the bridge (average for two independent mol­ecules) are, starting from the ipso octa­methyl­ferrocenium carbon and ending at the exo carbon of the coordinated fulvene, 1.455 (6), 1.344 (3) and 1.449 (8) Å, indicating a localized electronic structure

Clinical trials of potential cognitive-enhancing drugs in schizophrenia: what have we learned so far?

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website "www.clinicaltrials.gov" using the terms "schizophrenia AND cognition," "schizophrenia AND neurocognition," "schizophrenia AND neurocognitive tests," "schizophrenia AND MATRICS," "schizophrenia AND MCCB," "schizophrenia AND BACS," "schizophrenia AND COGSTATE," and "schizophrenia AND CANTAB" and "first-episode schizophrenia AND cognition." The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia

Disparity between General Symptom Relief and Remission Criteria in the Positive and Negative Syndrome Scale (PANSS): A Post-treatment Bifactor Item Response Theory Model.

Objective: Total scale scores derived by summing ratings from the 30-item PANSS are commonly used in clinical trial research to measure overall symptom severity, and percentage reductions in the total scores are sometimes used to document the efficacy of treatment. Acknowledging that some patients may have substantial changes in PANSS total scores but still be sufficiently symptomatic to warrant diagnosis, ratings on a subset of 8 items, referred to here as the "Remission set," are sometimes used to determine if patients' symptoms no longer satisfy diagnostic criteria. An unanswered question remains: is the goal of treatment better conceptualized as reduction in overall symptom severity, or reduction in symptoms below the threshold for diagnosis? We evaluated the psychometric properties of PANSS total scores, to assess whether having low symptom severity post-treatment is equivalent to attaining Remission. Design: We applied a bifactor item response theory (IRT) model to post-treatment PANSS ratings of 3,647 subjects diagnosed with schizophrenia assessed at the termination of 11 clinical trials. The bifactor model specified one general dimension to reflect overall symptom severity, and five domain-specific dimensions. We assessed how PANSS item discrimination and information parameters varied across the range of overall symptom severity (θ), with a special focus on low levels of symptoms (i.e., θ<-1), which we refer to as "Relief" from symptoms. A score of θ=-1 corresponds to an expected PANSS item score of 1.83, a rating between "Absent" and "Minimal" for a PANSS symptom. Results: The application of the bifactor IRT model revealed: (1) 88% of total score variation was attributable to variation in general symptom severity, and only 8% reflected secondary domain factors. This implies that a general factor may provide a good indicator of symptom severity, and that interpretation is not overly complicated by multidimensionality; (2) Post-treatment, 534 individuals (about 15% of the whole sample) scored in the "Relief" range of general symptom severity, but more than twice that number (n = 1351) satisfied Remission criteria (37%). 2 in 3 Remitted patients had scores that were not in a low symptom range (corresponding to Absent or Minimal item scores); (3) PANSS items vary greatly in their ability to measure the general symptom severity dimension; while many items are highly discriminating and relatively "pure" indicators of general symptom severity (delusions, conceptual disorganization), others are better indicators of specific dimensions (blunted affect, depression). The utility of a given PANSS item for assessing a patient depended on the illness level of the patient. Conclusion: Satisfying conventional Remission criteria was not strongly associated with low levels of symptoms. The items providing the most information for patients in the symptom Relief range were Delusions, Preoccupation, Suspiciousness Persecution, Unusual Thought Content, Conceptual Disorganization, Stereotyped Thinking, Active Social Avoidance, and Lack of Judgment and Insight. Lower scores on these items (item scores ≤2) were strongly associated with having a low latent trait θ or experiencing overall symptom relief. The inter-rater agreement between Remission and Relief subjects suggested that these criteria identified different subsets of patients. Alternative subsets of items may offer better indicators of general symptom severity and provide better discrimination (and lower standard errors) for scaling individuals and judging symptom relief, where the "best" subset of items ultimately depends on the illness range and treatment phase being evaluated

Synthesis and Properties of a (Diarylamino)ferrocene and Its Radical Cation

(Di-p-tolylamino)ferrocene (1) was synthesized using Pd-catalyzed C−N bond formation; it is oxidized at −250 mV vs ferrocene in THF. Magnetic susceptibility measurements show the unpaired electron of [1]^+[BF_4]^- (2) to be principally ferrocene-localized; however, the diarylamino moiety leads to a substantial red shift of the ligand-to-metal charge-transfer transition of 2 relative to that of ferrocenium

Application of a single-objective, hybrid genetic algorithm approach to pharmacokinetic model building.

A limitation in traditional stepwise population pharmacokinetic model building is the difficulty in handling interactions between model components. To address this issue, a method was previously introduced which couples NONMEM parameter estimation and model fitness evaluation to a single-objective, hybrid genetic algorithm for global optimization of the model structure. In this study, the generalizability of this approach for pharmacokinetic model building is evaluated by comparing (1) correct and spurious covariate relationships in a simulated dataset resulting from automated stepwise covariate modeling, Lasso methods, and single-objective hybrid genetic algorithm approaches to covariate identification and (2) information criteria values, model structures, convergence, and model parameter values resulting from manual stepwise versus single-objective, hybrid genetic algorithm approaches to model building for seven compounds. Both manual stepwise and single-objective, hybrid genetic algorithm approaches to model building were applied, blinded to the results of the other approach, for selection of the compartment structure as well as inclusion and model form of inter-individual and inter-occasion variability, residual error, and covariates from a common set of model options. For the simulated dataset, stepwise covariate modeling identified three of four true covariates and two spurious covariates; Lasso identified two of four true and 0 spurious covariates; and the single-objective, hybrid genetic algorithm identified three of four true covariates and one spurious covariate. For the clinical datasets, the Akaike information criterion was a median of 22.3 points lower (range of 470.5 point decrease to 0.1 point decrease) for the best single-objective hybrid genetic-algorithm candidate model versus the final manual stepwise model: the Akaike information criterion was lower by greater than 10 points for four compounds and differed by less than 10 points for three compounds. The root mean squared error and absolute mean prediction error of the best single-objective hybrid genetic algorithm candidates were a median of 0.2 points higher (range of 38.9 point decrease to 27.3 point increase) and 0.02 points lower (range of 0.98 point decrease to 0.74 point increase), respectively, than that of the final stepwise models. In addition, the best single-objective, hybrid genetic algorithm candidate models had successful convergence and covariance steps for each compound, used the same compartment structure as the manual stepwise approach for 6 of 7 (86 %) compounds, and identified 54 % (7 of 13) of covariates included by the manual stepwise approach and 16 covariate relationships not included by manual stepwise models. The model parameter values between the final manual stepwise and best single-objective, hybrid genetic algorithm models differed by a median of 26.7 % (q₁ = 4.9 % and q₃ = 57.1 %). Finally, the single-objective, hybrid genetic algorithm approach was able to identify models capable of estimating absorption rate parameters for four compounds that the manual stepwise approach did not identify. The single-objective, hybrid genetic algorithm represents a general pharmacokinetic model building methodology whose ability to rapidly search the feasible solution space leads to nearly equivalent or superior model fits to pharmacokinetic data

Trends in Optical Nonlinearity and Thermal Stability in Electrooptic Chromophores Based upon the 3-(Dicyanomethylene)-2,3-dihydrobenzothiophene-1, 1-dioxide Acceptor

A series of new thiophene-bridged chromophores based on the powerful heterocyclic acceptor 3-(dicyanomethylene)-2,3-dihydrobenzothiophene-1,1-dioxide has been synthesized; the dependence of the linear and second-order nonlinear optical properties and thermal stability of these species upon the donor group and the bridging group have been studied. In addition, the synthesis of a related new acceptor, not containing the fused benzene ring, is described and a chromophore based upon this acceptor is studied

Double Doping of a Low-Ionization-Energy Polythiophene with a Molybdenum Dithiolene Complex

Doping of organic semiconductors is crucial for tuning the charge-carrier density of conjugated polymers. The exchange of more than one electron between a monomeric dopant and an organic semiconductor allows the polaron density to be increased relative to the number of counterions that are introduced into the host matrix. Here, a molybdenum dithiolene complex with a high electron affinity of 5.5 eV is shown to accept two electrons from a polythiophene that has a low ionization energy of 4.7 eV. Double p-doping is consistent with the ability of the monoanion salt of the molybdenum dithiolene complex to dope the polymer. The transfer of two electrons to the neutral dopant was also confirmed by electron paramagnetic resonance spectroscopy since the monoanion, but not the dianion, of the molybdenum dithiolene complex features an unpaired electron. Double doping allowed an ionization efficiency of 200% to be reached, which facilitates the design of strongly doped semiconductors while lessening any counterion-induced disruption of the nanostructure