Falls, healthcare resources and costs in older adults with insomnia treated with zolpidem, trazodone, or benzodiazepines.

BACKGROUND: Falls are the leading cause of injury-related death among older Americans. While some research has found that insomnia heightens falls, health care resource utilization (HCRU) and costs, the impact of insomnia treatments on fall risk, mortality, HCRU and costs in the elderly population, which could be of substantial interest to payers, has not been fully elucidated. This study evaluated the risk of falls and related consequences among adults ≥ 65 years of age treated with common prescription medications for insomnia compared with non-sleep disordered controls. METHODS: This was a retrospective cohort analysis of deidentified Medicare claims from January 2011 through December 2017. Medicare beneficiaries treated for insomnia receiving zolpidem extended-release, zolpidem immediate-release, trazodone, or benzodiazepines were matched with non-sleep disordered controls. The main outcomes were falls, mortality, healthcare resource utilization (HCRU), and medical costs during the 12 months following the earliest fill date for the insomnia medication of interest. Generalized linear models controlled for several key covariates, including age, race, sex, geographic region and Charlson Comorbidity Index score. RESULTS: The study included 1,699,913 Medicare beneficiaries (59.9% female, mean age 75 years). Relative to controls, adjusted analyses showed that beneficiaries receiving insomnia medication experienced over twice as many falls (odds ratio [OR] = 2.34, 95% CI: 2.31-2.36). In adjusted analyses, patients receiving benzodiazepines or trazodone had the greatest risk. Crude all-cause mortality rates were 15-times as high for the insomnia-treated as controls. Compared with controls, beneficiaries receiving insomnia treatment demonstrated higher estimated adjusted mean number of inpatient, outpatient, and emergency department visits and longer length of inpatient stay. All-cause total adjusted mean costs were higher among insomnia treated patients ($967 vs $454). CONCLUSIONS: Individuals receiving insomnia treatment had an increased risk of falls and mortality and higher HCRU and costs compared with matched beneficiaries without sleep disorders. Trazodone and benzodiazepines were associated with the greatest risk of falls. This analysis suggests that significant risks are associated with common, older generation insomnia medication treatments in the elderly. Nonetheless, these results should be interpreted with caution as the use of these medications may be indicative of underlying morbidity with potential for residual confounding.

Establishing US norms for the Adult ADHD Self-Report Scale (ASRS-v1.1) and characterising symptom burden among adults with self-reported ADHD.

AIMS: To estimate Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist normative total scores among the US adult general population and to evaluate overall attention-deficit hyperactivity disorder (ADHD) symptom burden among US adults with ADHD. METHODS: Prior 2012 and 2013 US National Health and Wellness Survey respondents were re-contacted. Demographics, comorbidities, and ASRS-v1.1 data were collected. ASRS-v1.1 scores were compared by sex, age, ADHD diagnosis, and ADHD medication use. Group differences were evaluated using chi-square tests and independent samples t-tests for categorical and continuous variables, respectively. RESULTS: Of 22 397 respondents, 465 self-reported being diagnosed with ADHD by a physician; of these, 174 self-reported using ADHD medication. The mean ASRS-v1.1 total score was 2.0 (SD = 3.2); scores differed by age and sex (all, P < 0.001). ADHD (vs no ADHD) was associated with depression (58.1% vs 18.0%), anxiety (53.1% vs 16.0%), and sleep difficulties (37.0% vs 14.0%) (all, P < 0.001). ADHD medication use (vs no use) was associated with depression (68.4% vs 51.9%), anxiety (67.2% vs 44.7%), panic disorder (25.9% vs 17.2%), and insomnia (27.6% vs 19.6%) (all, P < 0.05). ADHD (vs no ADHD) respondents scored higher on all 18 ASRS-v1.1 items (all, P < 0.05). Medication users (vs non-users) scored higher on six items (all, P < 0.05). DISCUSSION: Adult ADHD may be undertreated or sub-optimally treated, despite a high symptom burden. Normative data will allow comparisons with individuals' scores to support the assessment of ADHD symptom burden among adults. CONCLUSION: Findings highlight the importance of assessing ADHD symptom burden, especially among adults presenting with comorbidities.

Comparing label-free quantitative peptidomics approaches to characterize diurnal variation of peptides in the rat suprachiasmatic nucleus.

Mammalian circadian rhythm is maintained by the suprachiasmatic nucleus (SCN) via an intricate set of neuropeptides and other signaling molecules. In this work, peptidomic analyses from two times of day were examined to characterize variation in SCN peptides using three different label-free quantitation approaches: spectral count, spectra index and SIEVE. Of the 448 identified peptides, 207 peptides were analyzed by two label-free methods, spectral count and spectral index. There were 24 peptides with significant (adjusted p-value < 0.01) differential peptide abundances between daytime and nighttime, including multiple peptides derived from secretogranin II, cocaine and amphetamine regulated transcript, and proprotein convertase subtilisin/kexin type 1 inhibitor. Interestingly, more peptides were analyzable and had significantly different abundances between the two time points using the spectral count and spectral index methods than with a prior analysis using the SIEVE method with the same data. The results of this study reveal the importance of using the appropriate data analysis approaches for label-free relative quantitation of peptides. The detection of significant changes in so rich a set of neuropeptides reflects the dynamic nature of the SCN and the number of influences such as feeding behavior on circadian rhythm. Using spectral count and spectral index, peptide level changes are correlated to time of day, suggesting their key role in circadian function.

Quantitative peptidomics for discovery of circadian-related peptides from the rat suprachiasmatic nucleus.

In mammals the suprachiasmatic nucleus (SCN), the master circadian clock, is sensitive to light input via the optic chiasm and synchronizes many daily biological rhythms. Here we explore variations in the expression levels of neuropeptides present in the SCN of rats using a label-free quantification approach that is based on integrating peak intensities between daytime, Zeitgeber time (ZT) 6, and nighttime, ZT 18. From nine analyses comparing the levels between these two time points, 10 endogenous peptides derived from eight prohormones exhibited significant differences in their expression levels (adjusted p-value <0.05). Of these, seven peptides derived from six prohormones, including GRP, PACAP, and CART, exhibited ≥ 30% increases at ZT 18, and the VGRPEWWMDYQ peptide derived from proenkephalin A showed a >50% increase at nighttime. Several endogenous peptides showing statistically significant changes in this study have not been previously reported to alter their levels as a function of time of day, nor have they been implicated in prior functional SCN studies. This information on peptide expression changes serves as a resource for discovering unknown peptide regulators that affect circadian rhythms in the SCN.

Direct cellular peptidomics of hypothalamic neurons.

The chemical complexity of cell-to-cell communication has emerged as a fundamental challenge to understanding brain systems. This is certainly true for the hypothalamus, where neuropeptide signals are heterogeneous, localized and dynamic. Thus far, most hypothalamic peptidomic studies have centered on the entire structure; however, recent advances in collection strategies and analytical technologies have enabled direct, high-resolution peptidomic profiles focused on two regions of interest, the suprachiasmatic and supraoptic nuclei, including their sub-regions and individual cells. Suites of peptides now can be identified and probed for function. High spatial and analytical sensitivities reveal that discrete hypothalamic nuclei have distinct peptidomic signatures. Peptidomic discovery not only reveals unanticipated complexity, but also peptides previously unknown that act as key circuit components. Analysis of tissue releasates identifies peptides secreted into the extracellular environment and available for transmitting intercellular signals. Direct sampling techniques define peptide-releasate profiles in spatial, temporal and event-dependent patterns. These approaches are providing remarkable new insights into the complexity of neuropeptidergic cell-to-cell signaling central to neuroendocrine physiology.

Endogenous peptide discovery of the rat circadian clock: a focused study of the suprachiasmatic nucleus by ultrahigh performance tandem mass spectrometry.

Understanding how a small brain region, the suprachiasmatic nucleus (SCN), can synchronize the body's circadian rhythms is an ongoing research area. This important time-keeping system requires a complex suite of peptide hormones and transmitters that remain incompletely characterized. Here, capillary liquid chromatography and FTMS have been coupled with tailored software for the analysis of endogenous peptides present in the SCN of the rat brain. After ex vivo processing of brain slices, peptide extraction, identification, and characterization from tandem FTMS data with <5-ppm mass accuracy produced a hyperconfident list of 102 endogenous peptides, including 33 previously unidentified peptides, and 12 peptides that were post-translationally modified with amidation, phosphorylation, pyroglutamylation, or acetylation. This characterization of endogenous peptides from the SCN will aid in understanding the molecular mechanisms that mediate rhythmic behaviors in mammals.

Improvement in fatigue and sleep measures with the dual orexin receptor antagonist lemborexant in adults with insomnia disorder.

OBJECTIVE: Fatigue is a common symptom in patients with insomnia. This analysis evaluated whether treatment of nighttime symptoms of insomnia with a dual orexin receptor antagonist, lemborexant, might also reduce fatigue. METHODS: Analyses were conducted of two phase 3 studies of subjects with insomnia disorder. Subjects received placebo, lemborexant 5 mg, or lemborexant 10 mg in the 12-month (6 months placebo-controlled) Study E2006-G000-303 (Study 303: SUNRISE-2) of adults (N = 949; full analysis set [FAS]), and the 1-month, placebo- and active-controlled Study E2006-G000-304 (Study 304; SUNRISE-1) of older adults (females ≥55 years, males ≥65 years) (N = 1006; FAS). Fatigue was assessed using the Fatigue Severity Scale (FSS). Patient-reported sleep onset and maintenance endpoints were analyzed using data from electronic sleep diaries. RESULTS: Lemborexant significantly reduced subject-reported fatigue versus placebo over a 6-month treatment period (FSS total score least-squares mean treatment difference of -2.50 for 5 mg and -2.56 for 10 mg of lemborexant; p < 0.05 for both). This reduction was sustained over 12 months of lemborexant in both the overall population and in subjects with clinically meaningful fatigue (FSS total score ≥36) at baseline. Improvements in fatigue over time positively correlated with improvements in sleep onset and maintenance parameters. Improvements in sleep quality were evident as early as 1 week after lemborexant treatment, whereas longer-term treatment (>1 month) may be needed for improvements in insomnia-related fatigue. CONCLUSIONS: In addition to improving sleep onset and sleep maintenance in subjects with insomnia disorder, lemborexant provides further benefit by reducing daytime fatigue. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02952820 and https://clinicaltrials.gov/ct2/show/NCT02783729. ABBREVIATIONS: DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; FSS = Fatigue Severity Scale; ICSD-3 = International Classification of Sleep Disorders, Third Edition; LSM = least squares mean; sSE = subjective sleep efficiency; sSOL = subjective sleep onset latency; sTST = subjective total sleep time; sWASO = subjective sleep after wake onset.

Impact of lemborexant treatment on insomnia severity: analyses from a 12-month study of adults with insomnia disorder.

OBJECTIVE/BACKGROUND: Evaluate changes in insomnia severity in subjects with moderate to severe insomnia (Insomnia Severity Index [ISI] score ≥15) treated for 12 months nightly with lemborexant. PATIENTS/METHODS: This phase 3 randomized study comprised two 6-month treatment periods. In Period 1, 949 subjects were randomized to placebo, lemborexant 5 mg (LEM5) or 10 mg (LEM10). In Period 2, placebo subjects were rerandomized to LEM5 or LEM10; subjects initially randomized to lemborexant continued their assigned treatment. Insomnia severity was assessed using baseline ISI and 1-, 3-, 6-, 9-, and 12-month post-treatment scores. RESULTS: Mean ISI scores improved significantly across treatment groups and disease severities, with greater decreases from baseline in the LEM5 and LEM10 versus placebo groups at months 1 (-7.1, -7.2, -5.2, respectively), 3 (-8.6, -8.9, -6.1, respectively), and 6 (-9.9, -9.8, -7.2 respectively); ISI score improvements were maintained with LEM5 and LEM10 at months 9 (-11.1 and -11.2, respectively) and 12 (-11.5 and -11.2, respectively). At months 1, 3, and 6, significantly more treatment responders (≥7-point ISI score decrease from baseline) were observed with LEM5 (44%-57%) and LEM10 (44%-52%) versus placebo (30%-41%). At months 1, 3, and 6, more remitters (ISI total score <10 and < 8) were observed with LEM5 (30%-44% and 22%-34%, respectively) and LEM10 (31%-41% and 22%-31%, respectively) versus placebo (18%-28% and 11%-21%, respectively). CONCLUSIONS: Lemborexant significantly reduced insomnia severity for 12 months and increased clinically meaningful response and remission rates versus placebo. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

Fall Risk, Healthcare Resource Use, and Costs Among Adult Patients in the United States Treated for Insomnia with Zolpidem, Trazodone, or Benzodiazepines: A Retrospective Cohort Study.

INTRODUCTION: Falls are a common cause for morbidity and mortality among patients taking prescription insomnia medication. The objective of this study is to compare the risk of falls, all-cause healthcare resource utilization (HCRU), and costs among patients treated with commonly used, older generation insomnia medications and non-sleep-disordered controls. METHODS: This retrospective cohort study used the IBM® MarketScan® Commercial and Medicare Supplemental Databases to identify patients aged at least 18 years treated with commonly prescribed medications for insomnia (zolpidem, trazodone, benzodiazepines) between 1 January 2012 and 30 September 2017. The insomnia-treated cohort were age- and sex-matched (1:1) to non-sleep-disordered controls. Odds ratios (ORs) compared risk of falls in each cohort, adjusting for covariates. Costs were adjusted to 2018 dollars, the most recent year for the study data. RESULTS: Relative to matched controls (n = 313,086), the insomnia-treated cohort had a higher rate of falls (3.34% vs. 1.33%), and higher risk of falls [OR = 2.36 (95% confidence interval 2.27-2.44)]. Relative to other index treatments, patients treated with trazodone had the greatest risk of falls. Compared with matched controls, the estimated mean number of inpatient visits, emergency department visits, outpatient visits, and mean length of inpatient stay were all significantly higher among patients treated for insomnia. Such patients incurred greater total costs per patient per month than matched controls ($2100 versus $888; estimated mean ratio, 2.36; 95% CI 2.35-2.38; p < 0.0001). CONCLUSIONS: Relative to matched controls, the insomnia-treated cohort showed higher risk of falls with greater HCRU and costs. Each outcome measured was highest among patients treated with trazodone, relative to other index treatments. Findings suggest the need for new treatment options to optimize quality of care for patients with insomnia.

Mass spectrometry-based discovery of circadian peptides.

A significant challenge to understanding dynamic and heterogeneous brain systems lies in the chemical complexity of secreted intercellular messengers that change rapidly with space and time. Two solid-phase extraction collection strategies are presented that relate time and location of peptide release with mass spectrometric characterization. Here, complex suites of peptide-based cell-to-cell signaling molecules are characterized from the mammalian suprachiasmatic nucleus (SCN), site of the master circadian clock. Observed SCN releasates are peptide rich and demonstrate the co-release of established circadian neuropeptides and peptides with unknown roles in circadian rhythms. Additionally, the content of SCN releasate is stimulation specific. Stimulation paradigms reported to alter clock timing, including electrical stimulation of the retinohypothalamic tract, produce releasate mass spectra that are notably different from the spectra of compounds secreted endogenously over the course of the 24-h cycle. In addition to established SCN peptides, we report the presence of proSAAS peptides in releasates. One of these peptides, little SAAS, exhibits robust retinohypothalamic tract-stimulated release from the SCN, and exogenous application of little SAAS induces a phase delay consistent with light-mediated cues regulating circadian timing. These mass spectrometry-based analyses provide a new perspective on peptidergic signaling within the SCN and demonstrate that the integration of secreted compounds with information relating time and location of release generates new insights into intercellular signaling in the brain.

Lemborexant for the Treatment of Insomnia: Direct and Indirect Comparisons With Other Hypnotics Using Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed.

Objective: To describe lemborexant for the treatment of insomnia (DSM-5) in adults using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).Methods: Lemborexant data were obtained from two Phase 3 trials conducted 2016-2018. Efficacy was assessed using different categorical definitions for response, and tolerability was assessed by evaluating rates of adverse events (AEs). Direct comparisons were made with zolpidem extended release (ER), and indirect comparisons were made with other hypnotic agents, including suvorexant, doxepin, ramelteon, zolpidem immediate release, eszopiclone, zaleplon, and selected benzodiazepines, using data from published reports and regulatory documents.Results: Lemborexant had a clinically relevant magnitude of therapeutic effect, as evidenced by NNT values versus placebo as robust as 3 (95% CI, 2-3). In general, NNH values for lemborexant versus placebo were ≥ 10, suggesting that lemborexant is relatively tolerable. Somnolence was the most common AE, with NNH estimates of 28 (95% CI, 18-61) and 15 (95% CI, 11-22) for lemborexant 5 mg and 10 mg, respectively. Rates of discontinuation of lemborexant because of an AE were low, and for lemborexant 5 mg the rate was lower than that for placebo. LHH contrasting the statistically significant endpoint efficacy measures versus discontinuation because of an AE ranged from 13 to 54. NNT values for lemborexant were generally more robust than for zolpidem ER for the polysomnography and sleep diary outcomes. In indirect comparisons, NNT data for the other hypnotics demonstrated effect sizes that were generally similar to those for lemborexant.Conclusions: In Phase 3 trials, the benefit-risk ratio for lemborexant is favorable as measured by NNT, NNH, and LHH.Trial Registration: ClinicalTrials.gov identifiers: NCT02783729, NCT02952820.

The Patient Perspective: Unmet Treatment Needs in Adults With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: To characterize impairments in daily life experienced by pharmacologically treated adults with attention-deficit/hyperactivity disorder (ADHD) versus adults without ADHD and to identify unmet needs in ADHD treatment from the perspective of adults with ADHD. METHODS: Adults with ADHD taking prescription medication for ≥ 6 months and adults without ADHD agreed to participate in a cross-sectional online survey during December 2016. Participants with ADHD were stratified by their current ADHD medication: long-acting (LA) once daily, short-acting (SA) ≤ 2 times/d, and augmenters (AU; LA > 1 time/d, SA > 2 times/d, or LA plus SA). RESULTS: A total of 616 adults with ADHD (SA: n = 166, LA: n = 201, AU: n = 249) and 200 adults without ADHD completed the survey. Even with treatment, adults with ADHD reported substantial impairments in their everyday life, particularly at home, at school/work, and in their social life and relationships. Participants with ADHD experienced impairments throughout the day, especially in the afternoon and evening. Signs or symptoms were reported when the ADHD medication was wearing off, resulting in negative effects (including school work, homework, work responsibilities, household responsibilities, emotional responses, mood, and relationships) on the daily life of adults with ADHD. CONCLUSIONS: Adults with ADHD, despite receiving medication, experienced impairments and challenges in many aspects of their daily life. Adults with ADHD described various unmet needs, especially those relating to the duration of treatment effect. When optimizing treatment for adults with ADHD, it is important that the treatment regimen is sufficient to meet the needs of the patient throughout the day.

Functional Peptidomics: Stimulus- and Time-of-Day-Specific Peptide Release in the Mammalian Circadian Clock.

Daily oscillations of brain and body states are under complex temporal modulation by environmental light and the hypothalamic suprachiasmatic nucleus (SCN), the master circadian clock. To better understand mediators of differential temporal modulation, we characterize neuropeptide releasate profiles by nonselective capture of secreted neuropeptides in an optic nerve horizontal SCN brain slice model. Releasates are collected following electrophysiological stimulation of the optic nerve/retinohypothalamic tract under conditions that alter the phase of the SCN activity state. Secreted neuropeptides are identified by intact mass via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). We found time-of-day-specific suites of peptides released downstream of optic nerve stimulation. Peptide release was modified differentially with respect to time-of-day by stimulus parameters and by inhibitors of glutamatergic or PACAPergic neurotransmission. The results suggest that SCN physiology is modulated by differential peptide release of both known and unexpected peptides that communicate time-of-day-specific photic signals via previously unreported neuropeptide signatures.

The patient experience with DSM-5-defined binge eating disorder: characteristics, barriers to treatment, and implications for primary care physicians.

BACKGROUND: Binge eating disorder (BED) is now a formal diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). However, post-DSM-5 patient profiles and viewpoints on BED diagnosis and treatment remain unclear. This study used a focus group methodology to examine demographic and clinical characteristics, as well as perceptions of diagnosis and treatment from patients with BED symptoms who were either formally diagnosed with BED or undiagnosed. METHODS: Binge eating disorder-diagnosed individuals (n = 11) or those meeting the DSM-5 BED diagnostic criteria but were undiagnosed (n = 14) participated in 6 semistructured focus groups conducted by trained staff at 3 geographic locations in the United States. Patients completed a series of demographic and clinical measures and then engaged in a moderated discussion focused on identifying factors associated with their experiences with BED. RESULTS: Sixty percent of the patients were female, 48% were white and 40% were black, and 76% were employed. The diagnosed group had a slightly higher socioeconomic status; undiagnosed patients had a higher average body mass index. In the overall sample, comorbid anxiety (40%) and depression (40%) were the most common psychiatric comorbidities. Even in the diagnosed group, only half of the patients (54.5%) became aware of BED through their health care provider (HCP; n = 6). Patients perceived that HCPs were focused more on physical ailments, were judgmental about weight, and were unable to distinguish BED from obesity. They also expressed a desire for safe, nonjudgmental interactions with HCPs. CONCLUSIONS: Education and income may be factors affecting access to care and BED diagnosis. Both patient groups reported considerable psychopathology and medical comorbidities. Moreover, the patient groups perceived HCPs as both having inadequate understanding of BED and providing insensitive and ineffective communication regarding eating behaviors. The study findings in diagnosed and undiagnosed patient groups underscore the need for greater BED disease state awareness and patient sensitivity among HCPs.

Non-laser capture microscopy approach for the microdissection of discrete mouse brain regions for total RNA isolation and downstream next-generation sequencing and gene expression profiling.

As technological platforms, approaches such as next-generation sequencing, microarray, and qRT-PCR have great promise for expanding our understanding of the breadth of molecular regulation. Newer approaches such as high-resolution RNA sequencing (RNA-Seq)(1) provides new and expansive information about tissue- or state-specific expression such as relative transcript levels, alternative splicing, and micro RNAs(2-4). Prospects for employing the RNA-Seq method in comparative whole transcriptome profiling(5) within discrete tissues or between phenotypically distinct groups of individuals affords new avenues for elucidating molecular mechanisms involved in both normal and abnormal physiological states. Recently, whole transcriptome profiling has been performed on human brain tissue, identifying gene expression differences associated with disease progression(6). However, the use of next-generation sequencing has yet to be more widely integrated into mammalian studies. Gene expression studies in mouse models have reported distinct profiles within various brain nuclei using laser capture microscopy (LCM) for sample excision(7,8). While LCM affords sample collection with single-cell and discrete brain region precision, the relatively low total RNA yields from the LCM approach can be prohibitive to RNA-Seq and other profiling approaches in mouse brain tissues and may require sub-optimal sample amplification steps. Here, a protocol is presented for microdissection and total RNA extraction from discrete mouse brain regions. Set-diameter tissue corers are used to isolate 13 tissues from 750-µm serial coronal sections of an individual mouse brain. Tissue micropunch samples are immediately frozen and archived. Total RNA is obtained from the samples using magnetic bead-enabled total RNA isolation technology. Resulting RNA samples have adequate yield and quality for use in downstream expression profiling. This microdissection strategy provides a viable option to existing sample collection strategies for obtaining total RNA from discrete brain regions, opening possibilities for new gene expression discoveries.

Circadian integration of glutamatergic signals by little SAAS in novel suprachiasmatic circuits.

BACKGROUND: Neuropeptides are critical integrative elements within the central circadian clock in the suprachiasmatic nucleus (SCN), where they mediate both cell-to-cell synchronization and phase adjustments that cause light entrainment. Forward peptidomics identified little SAAS, derived from the proSAAS prohormone, among novel SCN peptides, but its role in the SCN is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Little SAAS localization and co-expression with established SCN neuropeptides were evaluated by immunohistochemistry using highly specific antisera and stereological analysis. Functional context was assessed relative to c-FOS induction in light-stimulated animals and on neuronal circadian rhythms in glutamate-stimulated brain slices. We found that little SAAS-expressing neurons comprise the third most abundant neuropeptidergic class (16.4%) with unusual functional circuit contexts. Little SAAS is localized within the densely retinorecipient central SCN of both rat and mouse, but not the retinohypothalamic tract (RHT). Some little SAAS colocalizes with vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP), known mediators of light signals, but not arginine vasopressin (AVP). Nearly 50% of little SAAS neurons express c-FOS in response to light exposure in early night. Blockade of signals that relay light information, via NMDA receptors or VIP- and GRP-cognate receptors, has no effect on phase delays of circadian rhythms induced by little SAAS. CONCLUSIONS/SIGNIFICANCE: Little SAAS relays signals downstream of light/glutamatergic signaling from eye to SCN, and independent of VIP and GRP action. These findings suggest that little SAAS forms a third SCN neuropeptidergic system, processing light information and activating phase-shifts within novel circuits of the central circadian clock.