Direct and Indirect Cost Burden and Change of Employment Status in Treatment-Resistant Depression: A Matched-Cohort Study Using a US Commercial Claims Database.

BACKGROUND: Treatment-resistant depression (TRD) poses a substantial burden to health care payers including employers, costing an estimated $29 billion-$48 billion yearly in the United States. Furthermore, variation of burden across increasing levels of resistance and the potential impact of TRD on employment status remain largely unexplored. OBJECTIVE: To evaluate health care resource utilization (HRU) and costs, work loss, indirect costs, and employment status change in TRD. METHODS: A claims-based algorithm identified adults with TRD from a US claims database of privately insured employees and dependents (January 2010-March 2015). TRD patients were matched 1:1 on demographics to patients with major depressive disorder (MDD) (non-TRD MDD) and without MDD (non-MDD), who were identified using ICD-9-CM codes. Costs, HRU, and employment status change were compared over 2 years following the first antidepressant (randomly imputed date for non-MDD), adjusting for baseline comorbidity index and costs. RESULTS: TRD patients (N = 6,411) had more HRU than either matched control cohort, translating into higher per patient per year (PPPY) health care costs: $6,709 and $9,917 more than non-TRD MDD and non-MDD patients, respectively (P < .001 for both). TRD patients with work loss data (N = 1,908) had 35.8 work loss days PPPY (1.7 and 6.2 times the work loss rate in non-TRD MDD and non-MDD patients, respectively). Work loss-related costs in TRD patients were $1,811 higher than non-TRD MDD and $3,460 higher than in non-MDD patients (P < .001). TRD patients had 1.3-1.4 times the rate of employment status change versus control cohorts (all P < .05). CONCLUSIONS: TRD, even compared to MDD, poses a significant direct and indirect cost burden to US employers and may be associated with higher rates of employment status change.

Treatment patterns in Medicaid patients with schizophrenia initiated on a first- or second-generation long-acting injectable versus oral antipsychotic.

BACKGROUND: Poor antipsychotic (AP) adherence is a key issue in patients with schizophrenia. First-generation antipsychotic (FGA) and second-generation antipsychotic (SGA) long-acting injectable therapies (LAI) may improve adherence compared to oral antipsychotics (OAP). The objective of the study was to compare treatment adherence and persistence in Medicaid patients with schizophrenia initiated on first-generation long-acting injectable therapies (FGA-LAI) or second-generation long-acting injectable therapies (SGA-LAI) versus OAP. METHODS: Adults with schizophrenia initiated on FGA-LAI, SGA-LAI, or OAP on or after January 2010 were identified using a six-state Medicaid database (January 2009-March 2015). Outcomes were assessed during the 12 months following treatment initiation. Index medication adherence was assessed using the proportion of days covered ≥80%, while persistence was assessed as no gap of ≥30, ≥60, or ≥90 days between days of supply. Outcomes were compared between FGA/SGA-LAI and OAP cohorts using chi-squared tests and adjusted odds ratios (OR). RESULTS: During follow-up, AP polypharmacy was more common in FGA-LAI patients (N=1,089; 36%; P=0.029) and less common in SGA-LAI patients (N=2,209; 27%; P<0.001) versus OAP patients (N=20,478; 33%). After adjustment, SGA-LAI patients had 24% higher odds of adherence at 12 months (OR: 1.24; P<0.001), in contrast to FGA-LAI patients who had 48% lower odds of adherence (OR: 0.52; P<0.001) relative to OAP patients. SGA-LAI patients were more likely to be persistent (no gap ≥60 days) at 12 months than OAP patients (37% vs 30%; P<0.001), but not FGA-LAI patients (31% vs 30%; P=0.776). In comparison to OAP patients, SGA-LAI patients had 46% higher adjusted odds of persistence (no gap ≥60 days; OR: 1.46; P<0.001), while FGA-LAI patients were not significantly different (OR: 0.95; P=0.501). CONCLUSION: Medicaid patients initiated on SGA-LAI demonstrated better treatment adherence and persistence compared to OAP patients, while those initiated on FGA-LAI did not show significant improvement in adherence or persistence and had more AP polypharmacy relative to OAP patients. These findings suggest the potential value of SGA-LAI in the treatment of schizophrenia.

N-(2,4)-dinitrophenyl-L-arginine Interacts with EphB4 and Functions as an EphB4 Kinase Modulator.

The erythropoietin-producing hepatocellular carcinoma receptor B4 is a receptor tyrosine kinase whose expression is preserved in various malignancies, including colon, gastric, and breast carcinoma. Hepatocellular carcinoma receptor B4 presence in tumor cells and involvement in cancer suppression makes it a potential therapeutic target for activating compounds. Moreover, modulators of its activity also have a strong potential to be used in diagnosis and therapy monitoring. We used virtual ligand screening to identify novel hepatocellular carcinoma receptor B4 kinase modulators for experimental testing. Three independent assay platforms confirmed that dinitrophenyl-L-arginine is likely to affect the kinase activity of hepatocellular carcinoma receptor B4. An enzyme-coupled spectrophotometric assay has been used to examine this possibility and may prove to be useful for assessing other novel kinase modulator candidates. Overall, our observations suggest that dinitrophenyl-L-arginine has an activating effect on hepatocellular carcinoma receptor B4 and, therefore, more efficient derivatives may have therapeutic effects in tumors where hepatocellular carcinoma receptor B4 exhibits antimalignant properties. The hepatocellular carcinoma receptor B4-activating effect is discussed with respect to previously described mechanisms, using predicted and experimental structures for docked ligands. As a novel kinase activity modulator, dinitrophenyl-L-arginine may provide new insights into molecular mechanisms by which kinases are activated or regulated, and may serve as a lead compound for the generation of novel hepatocellular carcinoma receptor B4-activating therapeutic compounds.

Identifying potential selective fluorescent probes for cancer-associated protein carbonic anhydrase IX using a computational approach.

Carbonic anhydrase IX (CAIX) is a biomarker for tumor hypoxia. Fluorescent inhibitors of CAIX have been used to study hypoxic tumor cell lines. However, these inhibitor-based fluorescent probes may have a therapeutic effect that is not appropriate for monitoring treatment efficacy. In the search for novel fluorescent probes that are not based on known inhibitors, a database of 20,860 fluorescent compounds was virtually screened against CAIX using hierarchical virtual ligand screening (HierVLS). The screening database contained 14,862 compounds tagged with the ATTO680 fluorophore plus an additional 5998 intrinsically fluorescent compounds. Overall ranking of compounds to identify hit molecular probe candidates utilized a principal component analysis (PCA) approach. Four potential binding sites, including the catalytic site, were identified within the structure of the protein and targeted for virtual screening. Available sequence information for 23 carbonic anhydrase isoforms was used to prioritize the four sites based on the estimated "uniqueness" of each site in CAIX relative to the other isoforms. A database of 32 known inhibitors and 478 decoy compounds was used to validate the methodology. A receiver-operating characteristic (ROC) analysis using the first principal component (PC1) as predictive score for the validation database yielded an area under the curve (AUC) of 0.92. AUC is interpreted as the probability that a binder will have a better score than a non-binder. The use of first component analysis of binding energies for multiple sites is a novel approach for hit selection. The very high prediction power for this approach increases confidence in the outcome from the fluorescent library screening. Ten of the top scoring candidates for isoform-selective putative binding sites are suggested for future testing as fluorescent molecular probe candidates.

Creating and virtually screening databases of fluorescently-labelled compounds for the discovery of target-specific molecular probes.

Our group has recently demonstrated that virtual screening is a useful technique for the identification of target-specific molecular probes. In this paper, we discuss some of our proof-of-concept results involving two biologically relevant target proteins, and report the development of a computational script to generate large databases of fluorescence-labelled compounds for computer-assisted molecular design. The virtual screening of a small library of 1,153 fluorescently-labelled compounds against two targets, and the experimental testing of selected hits reveal that this approach is efficient at identifying molecular probes, and that the screening of a labelled library is preferred over the screening of base compounds followed by conjugation of confirmed hits. The automated script for library generation explores the known reactivity of commercially available dyes, such as NHS-esters, to create large virtual databases of fluorescence-tagged small molecules that can be easily synthesized in a laboratory. A database of 14,862 compounds, each tagged with the ATTO680 fluorophore was generated with the automated script reported here. This library is available for downloading and it is suitable for virtual ligand screening aiming at the identification of target-specific fluorescent molecular probes.