Current prescribing practices for major depressive disorder (MDD) produce limited treatment success. Although pharmacogenomics may improve outcomes by identifying genetically inappropriate ...medications, studies to date were limited in scope. Outpatients (N = 1167) diagnosed with MDD and with a patient- or clinician-reported inadequate response to at least one antidepressant were enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial – a rater- and patient-blind randomized controlled trial. Patients were randomized to treatment as usual (TAU) or a pharmacogenomics-guided intervention arm in which clinicians had access to a pharmacogenomic test report to inform medication selections (guided-care). Medications were considered congruent (‘use as directed’ or ‘use with caution’ test categories) or incongruent (‘use with increased caution and with more frequent monitoring’ test category) with test results. Unblinding occurred after week 8. Primary outcome was symptom improvement change in 17-item Hamilton Depression Rating Scale (HAM-D17) at week 8; secondary outcomes were response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. At week 8, symptom improvement for guided-care was not significantly different than TAU (27.2% versus 24.4%, p = 0.107); however, improvements in response (26.0% versus 19.9%, p = 0.013) and remission (15.3% versus 10.1%, p = 0.007) were statistically significant. Patients taking incongruent medications prior to baseline who switched to congruent medications by week 8 experienced greater symptom improvement (33.5% versus 21.1%, p = 0.002), response (28.5% versus 16.7%, p = 0.036), and remission (21.5% versus 8.5%, p = 0.007) compared to those remaining incongruent. Pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for difficult-to-treat depression patients over standard of care (ClinicalTrials.gov NCT02109939).
Light suppresses melatonin in humans, with the strongest response occurring in the short-wavelength portion of the spectrum between 446 and 477 nm that appears blue. Blue monochromatic light has also ...been shown to be more effective than longer-wavelength light for enhancing alertness. Disturbed circadian rhythms and sleep loss have been described as risk factors for astronauts and NASA ground control workers, as well as civilians. Such disturbances can result in impaired alertness and diminished performance. Prior to exposing subjects to short-wavelength light from light-emitting diodes (LEDs) (peak λ = 469 nm; 1/2 peak bandwidth = 26 nm), the ocular safety exposure to the blue LED light was confirmed by an independent hazard analysis using the American Conference of Governmental Industrial Hygienists exposure limits. Subsequently, a fluence-response curve was developed for plasma melatonin suppression in healthy subjects (n = 8; mean age of 23.9 ± 0.5 years) exposed to a range of irradiances of blue LED light. Subjects with freely reactive pupils were exposed to light between 2:00 and 3:30 AM. Blood samples were collected before and after light exposures and quantified for melatonin. The results demonstrate that increasing irradiances of narrowband blue-appearing light can elicit increasing plasma melatonin suppression in healthy subjects (P < 0.0001). The data were fit to a sigmoidal fluence-response curve (R(2) = 0.99; ED(50) = 14.19 μW/cm(2)). A comparison of mean melatonin suppression with 40 μW/cm(2) from 4,000 K broadband white fluorescent light, currently used in most general lighting fixtures, suggests that narrow bandwidth blue LED light may be stronger than 4,000 K white fluorescent light for suppressing melatonin.
To perform a meta-analysis of prospective, two-arm studies examining the clinical utility of using the combinatorial pharmacogenomic test, GeneSight Psychotropic, to inform treatment decisions for ...patients with major depressive disorder (MDD).
The pooled mean effect of symptom improvement and pooled relative risk ratio (RR) of response and remission were calculated using a random effect model.
Overall, 1556 patients were included from four studies, with outcomes evaluated at week 8 or week 10. Patient outcomes were significantly improved for patients with MDD whose care was guided by the combinatorial pharmacogenomic test results compared with unguided care (symptom improvement Δ = 10.08%, 95% CI: 1.67-18.50; p = 0.019; response RR = 1.40, 95% CI: 1.17-1.67; p < 0.001; remission RR = 1.49, 95% CI: 1.17-1.89; p = 0.001).
GeneSight Psychotropic guided care improves outcomes among patients with MDD.
The objective of the Genomics Used to Improve DEpression Decisions (GUIDED) trial was to evaluate the utility of pharmacogenomic testing to improve outcomes among patients with major depressive ...disorder (MDD) who had not responded to at least 1 prior medication trial. The objective of the present analysis was to assess outcomes for the subset of patients expected to benefit from combinatorial pharmacogenomic testing because they were taking medications with predicted gene-drug interactions.
Participants (enrolled from April 14, 2014, to February 10, 2017) had an inadequate response to at least 1 psychotropic medication in the current episode of MDD. Patients were randomized to treatment as usual (TAU) or the guided-care arm, in which clinicians had access to a combinatorial pharmacogenomic test report to inform medication selection. Patients and raters were blinded to study arm through week 8. The following outcomes were assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17): symptom improvement (percent change in HDRS-17 score), response (≥ 50% decrease in HDRS-17 score), and remission (HDRS-17 score ≤ 7). In the GUIDED trial, the primary endpoint of symptom improvement did not reach significance in the intent-to-treat cohort (P = .069). Here, a post hoc analysis of patients who were taking medications subject to gene-drug interactions at baseline as predicted by combinatorial pharmacogenomic testing (N = 912) is presented.
Among participants taking medications subject to gene-drug interactions at baseline, outcomes at week 8 were significantly improved for those in the guided-care arm compared to TAU (symptom improvement: 27.1% versus 22.1%, P = .029; response: 27.0% versus 19.0%, P = .008; remission: 18.2% versus 10.7%, P = .003). When patients who switched medications were assessed, all outcomes were significantly improved in the guided-care arm compared to TAU (P = .011 for symptom improvement, P = .011 for response, P = .008 for remission).
By identifying and focusing on the patients with predicted gene-drug interactions, use of a combinatorial pharmacogenomic test significantly improved outcomes among patients with MDD who had at least 1 prior medication failure.
ClinicalTrials.gov identifier: NCT02109939.
Background
Cystoisospora felis is a common parasite of cats and is diagnosed by fecal flotation, but false‐negative results can be common.
Hypothesis/Objectives
To experimentally inoculate cats with ...C. felis oocysts, to compare fecal flotation and polymerase chain reaction (PCR) results, and to describe any clinical signs consistent with infection.
Animals
Six cats.
Methods
Cystoisospora felis oocysts were identified morphologically from feces of a naturally infected kitten with diarrhea, sporulated oocysts (5000) were inoculated to 6 cats that were negative for fecal parasites by fecal flotation and by a fluorescent antibody assay (FA) for Giardia spp. and Cryptosporidium spp. Cats were observed daily for the presence of clinical signs consistent with infection. Fecal samples were evaluated by fecal flotation and FA up to 3 times per week post inoculation (PI) to Day 27. Thirty‐six samples collected before inoculation and from Days 8, 10, 13, 15, and 20 PI were assayed using an internal transcribed spacer 1 (ITS1) PCR that amplifies DNA of C. felis.
Results
All cats were negative for C. felis by both assays before inoculation. All cats shed C. felis oocysts by Day 10 PI, oocysts were not detected by fecal flotation after Day 15 PI. Cystoisospora felis DNA was amplified from 24/36 (66.6%) fecal samples from 6/6 (100%) of the cats. Oocysts were not detected by fecal flotation in 4 of the samples that were positive for C. felis DNA by PCR. Clinical signs were not recognized in any of the study cats.
Conclusions and Clinical Importance
Fecal flotation is a convenient assay for detection of C. felis but could occasionally give false‐negative results when compared to this ITS1 PCR.
The efficacy of drugs targeting the CNS is influenced by their limited brain access, which can lead to complete pharmacoresistance. Recently a tissue‐specific and selective upregulation of the ...multidrug efflux transporter ABCB1 or P‐glycoprotein (P‐gp) in the spinal cord of both patients and the mutant SOD1‐G93A mouse model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that prevalently kills motor neurons has been reported. Here, we extended the analysis of P‐gp expression in the SOD1‐G93A ALS mouse model and found that P‐gp upregulation was restricted to endothelial cells of the capillaries, while P‐gp expression was not detected in other cells of the spinal cord parenchyma such as astrocytes, oligodendrocytes, and neurons. Using both in vitro human and mouse models of the blood–brain barrier (BBB), we found that mutant SOD1 astrocytes were driving P‐gp upregulation in endothelial cells. In addition, a significant increase in reactive oxygen species production, Nrf2 and NFκB activation in endothelial cells exposed to mutant SOD1 astrocytes in both human and murine BBB models were observed. Most interestingly, astrocytes expressing FUS‐H517Q, a different familial ALS‐linked mutated gene, also drove NFκB‐dependent upregulation of P‐gp. However, the pathway was not dependent on oxidative stress but rather involved TNF‐α release. Overall, these findings indicated that nuclear translocation of NFκB was a converging mechanism used by endothelial cells of the BBB to upregulate P‐gp expression in mutant SOD1‐linked ALS and possibly other forms of familial ALS. GLIA 2016 GLIA 2016;64:1298–1313
Main Points
ALS‐linked mutant SOD1 astrocytes increase endothelial P‐glycoprotein expression and activity via oxidative stress
Mutant FUS astrocytes upregulate endothelial P‐glycoprotein via TNF‐α release
Pathways of upregulation converge on NFκB activation in endothelial cells
Abstract ATP-binding cassette (ABC) drug efflux transporters in the CNS are predominantly localized to the luminal surface of endothelial cells in capillaries to impede CNS accumulation of ...xenobiotics. Inflammatory mediators and cellular stressors regulate their activity. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of upper and lower motor neurons characterized by extensive neuroinflammation. Here we tested the hypothesis that disease-driven changes in ABC transporter expression and function occur in ALS. Given the multitude of ABC transporters with their widespread substrate recognition, we began by examining expression levels of several ABC transporters. We found a selective increase in only two transporters: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) both at mRNA and protein levels, in the SOD1-G93A mouse model of ALS, specifically in disease-affected CNS regions. Detailed analysis revealed a similar disease-driven increase in P-gp and BCRP levels in spinal cord microvessels, indicating that their altered expression occurs at the blood spinal cord barrier. Transport activity of P-gp and BCRP increased with disease progression in spinal cord and cerebral cortex capillaries. Finally, P-gp and BCRP protein expression also increased in spinal cords of ALS patients. Preclinical drug trials in the mouse model of ALS have failed to decisively slow or arrest disease progression; pharmacoresistance imparted by ABC transporters is one possible explanation for these failures. Our observations have large implications for ALS therapeutics in humans and suggest that the obstacle provided by these transporters to drug treatments must be overcome to develop effective ALS pharmacotherapies.
Objective:
We compared economic outcomes when elderly patients with neuropsychiatric disorders received psychotropic medications guided by a combinatorial pharmacogenomic (PGx) test.
Methods:
This is ...a subanalysis of a 1-year prospective assessment of medication cost for patients with neuropsychiatric disorders receiving combinatorial PGx testing. Pharmacy claims were used to compare per member per year (PMPY) medication cost for patients ≥65 and <65 years old when medications were congruent or incongruent with the PGx test. Polypharmacy was also assessed.
Results:
Congruent prescribing was associated with savings of US$3497 PMPY (P < .001) for patients ≥65 years and US$2467 PMPY (P < .001) for patients <65, compared to incongruent prescribing. Congruent prescribing in patients ≥65 treated by primary care providers was associated with US$4113 PMPY (P = .026) in savings, while congruent prescribing by psychiatrists was associated with US$120 PMPY (P = .719). Congruent prescribing was also associated with one fewer neuropsychiatric medication for patients ≥65 (P = .070).
Conclusion:
Congruence with PGx testing was associated with medication cost savings in elderly patients.
This work addresses the questions: (i) Among all left-invariant Riemannian metrics on a given Lie group, is there any whose isometry group or isometry algebra contains that of all others? (ii) Do ...expanding left-invariant Ricci solitons exhibit such maximal symmetry? Question (i) is addressed both for semisimple and for solvable Lie groups. Building on previous work of the authors on Einstein metrics, a complete answer is given to (ii): expanding homogeneous Ricci solitons have maximal isometry algebras although not always maximal isometry groups. As a consequence of the tools developed to address these questions, partial results of Böhm, Lafuente, and Lauret are extended to show that left-invariant Ricci solitons on solvable Lie groups are unique up to scaling and isometry.
•Pharmacogenomics (PGx) can be used to identify gene-drug interactions (GDI)•PGx tests or single-gene guidelines are often used to guide prescribing based on GDI•Only the PGx test predicted variation ...in outcomes for patients with depression•Both single-gene guidelines and the PGx test predicted medication blood levels•The combinatorial PGx test was a better predictor than the single-gene guidelines
We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD).
This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and ≥1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to predict patient outcomes was validated against week 8 outcomes (17-item Hamilton Depression Rating Scale; symptom improvement, response, remission). Analyses were performed for patients taking any eligible medication (outcomes N=1,022, blood levels N=1,034) and the subset taking medications with single-gene guidelines (outcomes N=584, blood levels N=372). The combinatorial pharmacogenomic test was the only significant predictor of patient outcomes. Both the combinatorial pharmacogenomic test and single-gene guidelines were significant predictors of blood levels for all medications when evaluated separately; however, only the combinatorial pharmacogenomic test remained significant when both were included in the multivariate model. There were no substantial differences when all medications were evaluated or for the subset with single-gene guidelines. Overall, this evaluation of clinical validity demonstrates that the combinatorial pharmacogenomic test was a superior predictor of patient outcomes and medication blood levels when compared with guidelines based on individual genes.
PDF
