Combinatorial pharmacogenomic algorithm is predictive of sertraline metabolism in patients with major depressive disorder.

Pharmacogenomic testing can be used to guide medication selection in patients with major depressive disorder (MDD). Currently, there is no consensus on which gene or genes to consider in medication management. Here, we assessed the clinical validity of the combinatorial pharmacogenomic algorithm to predict sertraline blood levels in a subset of patients enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial. Patients who reported taking sertraline within ≤2 weeks of the screening blood draw were included. All patients received combinatorial pharmacogenomic testing, which included a weighted assessment of individual phenotypes for multiple pharmacokinetic genes relevant for sertraline (CYP2C19, CYP2B6, and CYP3A4). Sertraline blood levels were compared between phenotypes based on: 1) the pharmacokinetic portion of the combinatorial pharmacogenomic algorithm, and 2) individual genes. When evaluated separately, individual genes (for CYP2C19 and CYP2B6) and the combinatorial algorithm were significant predictors of sertraline blood levels. However, in multivariate analyses that included individual genes and the combinatorial pharmacogenomic algorithm, only the combinatorial pharmacogenomic algorithm remained a significant predictor of sertraline blood levels. These findings support the clinical validity of the combinatorial pharmacogenomic algorithm, in that it is a superior predictor of sertraline blood levels compared to individual genes.

Clinical validation of combinatorial pharmacogenomic testing and single-gene guidelines in predicting psychotropic medication blood levels and clinical outcomes in patients with depression.

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.

Combinatorial Pharmacogenomic Algorithm is Predictive of Citalopram and Escitalopram Metabolism in Patients with Major Depressive Disorder.

Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism. Here, we evaluated the ability of individual pharmacokinetic genes (CYP2C19, CYP2D6, CYP3A4) and a combinatorial pharmacogenomic test (GeneSight Psychotropic®; weighted assessment of all three genes) to predict citalopram/escitalopram blood levels in patients with MDD. Patients from the Genomics Used to Improve DEpression Decisions (GUIDED) trial who were taking citalopram/escitalopram at screening and had available blood level data were included (N=191). In multivariate analysis of the individual genes and combinatorial pharmacogenomic test separately (adjusted for age, smoking status), the F statistic for the combinatorial pharmacogenomic test was 1.7 to 2.9-times higher than the individual genes, showing that it explained more variance in citalopram/escitalopram blood levels. In multivariate analysis of the individual genes and combinatorial pharmacogenomic test together, only the combinatorial pharmacogenomic test remained significant. Overall, this demonstrates that the combinatorial pharmacogenomic test was a superior predictor of citalopram/escitalopram blood levels compared to individual genes.

The clinical utility of combinatorial pharmacogenomic testing for patients with depression: a meta-analysis.

Aim: 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). Patients & methods: The pooled mean effect of symptom improvement and pooled relative risk ratio (RR) of response and remission were calculated using a random effect model. Results: 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). Conclusion: GeneSight Psychotropic guided care improves outcomes among patients with MDD.

Economic Outcomes Following Combinatorial Pharmacogenomic Testing for Elderly Psychiatric Patients.

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.

Impact of Pharmacogenomics on Clinical Outcomes for Patients Taking Medications With Gene-Drug Interactions in a Randomized Controlled Trial.

OBJECTIVE: 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. METHODS: 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 Depre​ssion 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. RESULTS: 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). CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02109939​.

Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study.

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).

Analytical validation of a psychiatric pharmacogenomic test.

AIM: The aim of this study was to validate the analytical performance of a combinatorial pharmacogenomics test designed to aid in the appropriate medication selection for neuropsychiatric conditions. MATERIALS & METHODS: Genomic DNA was isolated from buccal swabs. Twelve genes (65 variants/alleles) associated with psychotropic medication metabolism, side effects, and mechanisms of actions were evaluated by bead array, MALDI-TOF mass spectrometry, and/or capillary electrophoresis methods (GeneSight Psychotropic, Assurex Health, Inc.). RESULTS: The combinatorial pharmacogenomics test has a dynamic range of 2.5-20 ng/µl of input genomic DNA, with comparable performance for all assays included in the test. Both the precision and accuracy of the test were >99.9%, with individual gene components between 99.4 and 100%. CONCLUSION: This study demonstrates that the combinatorial pharmacogenomics test is robust and reproducible, making it suitable for clinical use.

Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P-Glycoprotein) in endothelial cells of the blood-brain barrier in mutant superoxide dismutase 1-linked amyotrophic lateral sclerosis.

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.

Asymmetric Response of Ferroelastic Domain-Wall Motion under Applied Bias.

The switching of domains in ferroelectric and multiferroic materials plays a central role in their application to next-generation computer systems, sensing applications, and memory storage. A detailed understanding of the response to electric fields and the switching behavior in the presence of complex domain structures and extrinsic effects (e.g., defects and dislocations) is crucial for the design of improved ferroelectrics. In this work, in situ transmission electron microscopy is coupled with atomistic molecular dynamics simulations to explore the response of 71° ferroelastic domain walls in BiFeO3 with various orientations under applied electric-field excitation. We observe that 71° domain walls can have intrinsically asymmetric responses to opposing biases. In particular, when the electric field has a component normal to the domain wall, forward and backward domain-wall velocities can be dramatically different for equal and opposite fields. Additionally, the presence of defects and dislocations can strongly affect the local switching behaviors through pinning or nucleation of the domain walls. These results offer insight for controlled ferroelastic domain manipulation via electric-field engineering.

The influence of red light exposure at night on circadian metabolism and physiology in Sprague-Dawley rats.

Early studies on rodents showed that short-term exposure to high-intensity light (> 70 lx) above 600 nm (red-appearing) influences circadian neuroendocrine and metabolic physiology. Here we addressed the hypothesis that long-term, low-intensity red light exposure at night (rLEN) from a 'safelight' emitting no light below approximately 620 nm disrupts the nocturnal circadian melatonin signal as well as circadian rhythms in circulating metabolites, related regulatory hormones, and physi- ologic parameters. Male Sprague-Dawley rats (n = 12 per group) were maintained on control 12:12-h light:dark (300 lx; lights on, 0600) or experimental 12:12 rLEN (8.1 lx) lighting regimens. After 1 wk, rats underwent 6 low-volume blood draws via cardiocentesis (0400, 0800, 1200, 1600, 2000, and 2400) over a 4-wk period to assess arterial plasma melatonin, total fatty acid, glucose, lactic acid, pO2, pCO2, insulin, leptin and corticosterone concentrations. Results revealed plasma melatonin levels (mean ± 1 SD) were high in the dark phase (197.5 ± 4.6 pg/mL) and low in the light phase (2.6 ± 1.2 pg/mL) of control condi- tions and significantly lower than controls under experimental conditions throughout the 24-h period (P < 0.001). Prominent circadian rhythms of plasma levels of total fatty acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were significantly (P < 0.05) disrupted under experimental conditions as compared with the corresponding entrained rhythms under control conditions. Therefore, chronic use of low-intensity rLEN from a common safelight disrupts the circadian organization of neuroendocrine, metabolic, and physiologic parameters indicative of animal health and wellbeing.

The clinical validity and utility of combinatorial pharmacogenomics: Enhancing patient outcomes.

Prescribing safe and effective medications is a challenge in psychiatry. While clinical use of pharmacogenomic testing for individual genes has provided some clinical benefit, it has largely failed to show clinical utility. However, pharmacogenomic testing that integrates relevant genetic variation from multiple loci for each medication has shown clinical validity, utility and cost savings in multiple clinical trials. While some challenges remain, the evidence for the clinical utility of "combinatorial pharmacogenomics" is mounting. Expanding education of pharmacogenomic testing is vital to implementation efforts in psychiatric treatment settings with the overall goal of improving medication selection decisions.

ABC transporter-driven pharmacoresistance in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a slowly progressing neurodegenerative disease that affects motor neurons of the nervous system. Despite the identification of many potential therapeutics targeting pathogenic mechanisms in in vitro models, there has been limited progress in translating them into a successful pharmacotherapy in the animal model of ALS. Further, efforts to translate any promising results from preclinical trials to effective pharmacotherapies for patients have been unsuccessful, with the exception of riluzole, the only FDA-approved medication, which only modestly extends survival both in the animal model and in patients. Thus, it is essential to reconsider the strategies for developing ALS pharmacotherapies. Growing evidence suggests that problems identifying highly effective ALS treatments may result from an underestimated issue of drug bioavailability and disease-driven pharmacoresistance, mediated by the ATP-binding cassette (ABC) drug efflux transporters. ABC transporters are predominately localized to the lumen of endothelial cells of the blood-brain and blood-spinal cord barriers (BBB, BSCB) where they limit the entry into the central nervous system (CNS) of a wide range of neurotoxicants and xenobiotics, but also therapeutics. In ALS, expression and function of ABC transporters is increased at the BBB/BSCB and their expression has been detected on neurons and glia in the CNS parenchyma, which may further reduce therapeutic action in target cells. Understanding and accounting for the contribution of these transporters to ALS pharmacoresistance could both improve the modest effects of riluzole and set in motion a re-evaluation of previous ALS drug disappointments. In addition, identifying pathogenic mechanisms regulating ABC transporter expression and function in ALS may lead to the development of new therapeutic strategies. It is likely that novel pharmacological approaches require counteracting pharmacoresistance to improve therapeutic efficacy. This article is part of a Special Issue entitled ALS complex pathogenesis.

Observation of self-assembled core-shell structures in epitaxially embedded TbErAs nanoparticles.

Self-assembled core-shell structured rare-earth nanoparticles (TbErAs) are observed in a III-V semiconductor host matrix (In0.53Ga0.47As) nominally lattice-matched to InP, grown via molecular beam epitaxy. Atom probe tomography demonstrates that the TbErAs nanoparticles have a core-shell structure, as seen both in the tomographic atom-by-atom reconstruction and concentration profiles. A simple thermodynamic model is created to determine when it is energetically favorable to have core-shell structures; the results strongly agree with the observations.

Real-time observation of local strain effects on nonvolatile ferroelectric memory storage mechanisms.

We use in situ transmission electron microscopy to directly observe, at high temporal and spatial resolution, the interaction of ferroelectric domains and dislocation networks within BiFeO3 thin films. The experimental observations are compared with a phase field model constructed to simulate the dynamics of domains in the presence of dislocations and their resulting strain fields. We demonstrate that a global network of misfit dislocations at the film-substrate interface can act as nucleation sites and slow down domain propagation in the vicinity of the dislocations. Networks of individual threading dislocations emanating from the film-electrode interface play a more dramatic role in pinning domain motion. These dislocations may be responsible for the domain behavior in ferroelectric thin-film devices deviating from conventional Kolmogorov-Avrami-Ishibashi dynamics toward a Nucleation Limited Switching model.

Effect of different spectral transmittances through tinted animal cages on circadian metabolism and physiology in Sprague-Dawley rats.

The suprachiasmatic nucleus is synchronized by the light:dark cycle and is the master biologic clock that serves as a pacemaker to regulate circadian rhythms. We explored the hypothesis that spectral transmittance (tint) of light through caging alters circadian rhythms of endocrine and metabolic plasma constituents in nonpigmented Sprague-Dawley rats. Rats (Crl:SD; n = 12 per group) were housed in a 12:12-h light:dark environment (300 lx; 123.0 µ W/cm(2); lights on, 0600) in either clear-, amber-, blue-, or red-tinted rodent cages. Blood was collected at 0400, 0800, 1200, 1600, 2000, and 2400 and measured for melatonin, total fatty acids, pH, glucose, lactic acid, corticosterone, insulin, and leptin. As expected, plasma melatonin levels were low during the light phase but higher during the dark phase in all groups; however, when compared with the clear-cage group, rats in amber-, blue-, and red-tinted cages had 29%, 74%, and 48%, respectively, greater total daily melatonin levels due to an increased duration and, in some cases, amplitude of the nocturnal melatonin signal. No differences were found in dietary and water intake, body growth rates, total fatty acids, pH, or glucose among groups. Disruptions in circadian rhythms, manifesting as alterations in phase timing, amplitude, or duration, occurred in the melatonin, lactic acid, corticosterone, insulin, and leptin levels of rats in tinted compared with clear cages. Therefore, the use of variously tinted animal cages significantly alters circadian rhythms in plasma measures of metabolism and physiology in laboratory rats, thus potentially altering the outcomes of scientific investigations.

Inhibiting drug efflux transporters improves efficacy of ALS therapeutics.

OBJECTIVE: Research identified promising therapeutics in cell models of Amyotrophic Lateral Sclerosis (ALS), but there is limited progress translating effective treatments to animal models and patients, and ALS remains a disease with no effective treatment. One explanation stems from an acquired pharmacoresistance driven by the drug efflux transporters P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP), which we have shown are selectively upregulated at the blood-brain and spinal cord barrier (BBB/BSCB) in ALS mice and patients. Pharmacoresistance is well appreciated in other brain diseases, but overlooked in ALS despite many failures in clinical trials. METHODS: Here, we prove that a P-gp/BCRP-driven pharmacoresistance limits the bioavailability of ALS therapeutics using riluzole, the only FDA-approved drug for ALS and a substrate of P-gp and BCRP. ALS mice (SOD1-G93A) were treated with riluzole and elacridar, to block P-gp and BCRP, and monitored for survival as well as behavioral and physiological parameters. RESULTS: We show that riluzole, which normally is not effective when given at onset of symptoms, is now effective in the ALS mice when administered in combination with the P-gp/BCRP inhibitor elacridar. Chronic elacridar treatment increases riluzole Central nervous system (CNS) penetration, improves behavioral measures, including muscle function, slowing down disease progression, and significantly extending survival. INTERPRETATION: Our approach improves riluzole efficacy with treatment beginning at symptom onset. Riluzole will not provide a cure, but enhancing its efficacy postsymptoms by addressing pharmacoresistance demonstrates a proof-of-principle concept to consider when developing new ALS therapeutic strategies. We highlight a novel improved therapeutic approach for ALS and demonstrate that pharmacoresistance can no longer be ignored in ALS.

Effect of spectral transmittance through red-tinted rodent cages on circadian metabolism and physiology in nude rats.

Light entrains normal circadian rhythms of physiology and metabolism in all mammals. Previous studies from our laboratory demonstrated that spectral transmittance (color) of light passing through cages affects these responses in rats. Here, we addressed the hypothesis that red tint alters the circadian nocturnal melatonin signal and circadian oscillation of other metabolic and physiologic functions. Female nude rats (Hsd:RH-Foxn1(rnu); n = 12 per group) were maintained on a 12:12-h light (300 lx; 123.0 µW/cm(2); lights on 0600):dark regimen in standard polycarbonate translucent clear or red-tinted cages. After 1 wk, rats underwent 6 low-volume blood draws via cardiocentesis over a 4-wk period. Plasma melatonin levels were low during the light phase (1.0 ± 0.2 pg/mL) in rats in both types of cages but were significantly lower in red-tinted (105.0 ± 2.4 pg/mL) compared with clear (154.8 ± 3.8 pg/mL) cages during the dark. Normal circadian rhythm of plasma total fatty acid was identical between groups. Although phase relationships of circadian rhythms in glucose, lactic acid, pO2, and pCO2 were identical between groups, the levels of these analytes were lower in rats in red-tinted compared with clear cages. Circadian rhythms of plasma corticosterone, insulin, and leptin were altered in terms of phasing, amplitude, and duration in rats in red-tinted compared with clear cages. These findings indicate that spectral transmittance through red-colored cages significantly affects circadian regulation of neuroendocrine, metabolic, and physiologic parameters, potentially influencing both laboratory animal health and wellbeing and scientific outcomes.

Effects of spectral transmittance through standard laboratory cages on circadian metabolism and physiology in nude rats.

Light is potent in circadian, neuroendocrine, and neurobehavioral regulation, thereby having profound influence on the health and wellbeing of all mammals, including laboratory animals. We hypothesized that the spectral quality of light transmitted through colored compared with clear standard rodent cages alters circadian production of melatonin and temporal coordination of normal metabolic and physiologic activities. Female nude rats (Hsd:RH-Foxn1(rnu); n = 6 per group) were maintained on a 12:12-h light:dark regimen (300 lx; lights on, 0600) in standard translucent clear, amber, or blue rodent cages; intensity and duration of lighting were identical for all groups. Rats were assessed for arterial blood levels of pO(2) and pCO(2), melatonin, total fatty acid, glucose, lactic acid, insulin, leptin, and corticosterone concentrations at 6 circadian time points. Normal circadian rhythms of arterial blood pO(2) and pCO(2) were different in rats housed in cages that were blue compared with amber or clear. Plasma melatonin levels (mean ± 1 SD) were low (1.0 ± 0.2 pg/mL) during the light phase in all groups but higher at nighttime in rats in blue cages (928.2 ± 39.5 pg/mL) compared with amber (256.8 ± 6.6 pg/mL) and clear (154.8 ± 9.3 pg/mL) cages. Plasma daily rhythms of total fatty acid, glucose, lactic acid, leptin, insulin, and corticosterone were disrupted in rats housed in blue or amber compared with clear cages. Temporal coordination of circadian rhythms of physiology and metabolism can be altered markedly by changes in the spectral quality of light transmitted through colored standard rodent cages.