The warming climate has lengthened the growing season across mid-latitude regions, driven largely by an earlier onset of the frost-free period in spring. Earlier spring warming can advance plant phenological development but may also increase exposure to subsequent frost or freeze events that damage vulnerable new vegetative growth, commonly referred to as a 'false spring'. We examine long-term trends in growing degree day (GDD) accumulation prior to the last frost (0 degrees C) and last hard freeze (-2.2 degrees C) in spring across the continental United States. Using daily temperature data from 186 stations over the period 1952-2021, we calculate GDD totals and rates on the date of last frost and freeze for each year and assess long-term trends using least-squares linear regression. We find an earlier spring onset at 54 stations based on the freeze threshold and at 56 using our frost criterion. Increasing GDD trends are evident at 22 locations for frost and 18 for freeze, mostly in the northeastern and north-central United States. At most of these locations, the date of the last frost or freeze has not advanced significantly. However, after accounting for spatial autocorrelation using a false discovery rate adjustment, most GDD and GDD-rate trends are no longer statistically significant at the continental scale. These results indicate that, despite widespread earlier spring onset, there is limited evidence for a coherent, large-scale increase in false spring risk across the United States over the past seven decades. Localised increases in early-season heat accumulation may nonetheless have important ecological and agricultural implications, underscoring the need to consider both phenological responses and atmospheric circulation variability when assessing frost and freeze risk in a warming climate.

The relationship between diurnal temperature range (DTR) and daily mortality from 2005 to 2020 is examined for seven large metropolitan areas in Virginia using distributed lag non-linear models that control for temperature and humidity. The relative risk of mortality increases for very high DTR, and there is a short lag effect of several days. High risk DTR days are rare, typically occurring less than 1% of the time at most locations. These days primarily occur in spring and are characterized by high pressure and low humidity that allow overnight temperatures to drop substantially. High DTR days are often associated with elevated respiratory and cardiovascular mortality and tend to impact the elderly. The similarity between the mortality response to high DTR and that of high temperatures alone, coupled with the lack of clear physiological underpinnings, challenges the notion that these responses are independent. The prevalent spring peak in dangerous DTR days suggests that lack of acclimatization to hot and humid conditions may impose strain on the cardiovascular and respiratory systems.

This Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of lumateperone to treat bipolar depression. Patients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode were randomized 1:1:1 to 6-week lumateperone 28 mg ( n = 183), lumateperone 42 mg ( n = 185), or placebo ( n = 186). Primary and key secondary endpoints were change from baseline to Day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total score and time to first sustained response (≥50% reduction from baseline in MADRS Total score), respectively. Safety assessments included adverse events, extrapyramidal symptoms (EPS), laboratory evaluations, and vital signs. Neither dose of lumateperone achieved significant improvement vs. placebo ( P > 0.05) in the primary endpoint (MADRS Total score, least squares mean difference vs. placebo: 28 mg, 0.9; 42 mg, −1.0) or in the key secondary endpoint (MADRS Total time to first sustained response hazard ratio vs. placebo: 28 mg, 1.00; 42 mg, 0.93), likely due to a high placebo response. Both lumateperone doses were well tolerated, with low EPS risk and minimal changes in weight, prolactin, and cardiometabolic or endocrine parameters. While study efficacy objectives were not met, both doses of lumateperone were generally safe and well tolerated in patients with bipolar depression.

Background: College students face challenging environments in which risky coping mechanisms, such as non-suicidal self-injury (NSSI) and substance use may be used to mitigate psychological strain. The purpose of this research was to examine relationships between substance use, psychological distress, and various aspects of NSSI. Methods: Cross-sectional survey data were collected from students recruited from a large university in the southern United States (n = 502). Instrumentation included validated and reliable scales on substance use, psychological conditions, NSSI behaviors, demographics, and suicidality measures. Results: In all, 21% reported engagement in some form of NSSI within the past year. A lower GPA, identifying as a sexual minority, engaging in marijuana and other drug use, screening positive for depression, anxiety, suicidality significantly increased the likelihood NSSI. Suicidal ideation and living on campus increased the likelihood of engaging in multiple forms of NSSI. Identifying as female, age at alcohol onset, presence of depression, and all forms of suicidality predicted more frequent NSSI. Following covariate adjustment NSSI outcomes were prominently associated with psychological dysregulation. Conclusions: Identification of evidence suggestive of NSSI behaviors may be an important indicator of underlying psychological distress and substance related issues. Thereby, providing opportunities for early intervention that precedes suicide attempts.

This 6-month open-label extension (OLE) period of a Phase 3 placebo-controlled study (NCT02600494) examined the safety of lumateperone in patients with bipolar I or bipolar II depression. Eligible patients completing the placebo-controlled period received lumateperone 42 mg once daily up to 175 days. The primary endpoint was safety and tolerability, assessed by adverse events (AEs) and clinical laboratory evaluations analyzed by imputing missing data using a last observation carried forward approach. The secondary endpoint was efficacy measured by Montgomery-Åsberg Depression Rating Scale (MADRS) total and Clinical Global Impression Scale-Bipolar Version-Severity (CGI-BP-S) scores. Of 127 patients in the OLE, 58.3% completed treatment, and 42.5% experienced a drug-related treatment-emergent AE (TEAE); the most common TEAEs were headache (20.5%), dry mouth (11.8%), dizziness (10.2%), and nausea (10.2%). The majority (92%) of TEAEs were of mild or moderate severity. There were no notable changes in extrapyramidal symptom scores, cardiometabolic parameters, or body morphology. MADRS total score (mean change, −8.9, nominal P < 0.0001), CGI-BP-S total score (−2.3, nominal P < 0.0001), and CGI-BP-S depression subscore (−1.3, nominal P < 0.0001) improved over time, from baseline to Day 175. Overall, 6-month lumateperone 42 mg was generally well tolerated, and depressive symptoms based on MADRS total score and CGI-BP-S improved over time.

Development of more efficacious medications with improved safety profiles to manage and treat multiple forms of pain is a critical element of healthcare. To this end, we have designed and synthesized a novel class of tetracyclic pyridopyrroloquinoxalinone derivatives with analgesic properties. The receptor binding profiles and analgesic properties of these tetracyclic compounds were studied. Systematic optimizations of this novel scaffold culminated in the discovery of the clinical candidate, (6bR,10aS)-8-[3-(4-fluorophenoxy)propyl]-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3 ',4 ':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (compound 5, ITI-333), which exhibited potent binding affinity to serotonin 5-HT2A (K-i = 8.3 nM) and mu-opioid receptors (MOR, K-i = 11 nM) and moderate affinity to adrenergic alpha(1A) (K-i = 28 nM) and dopamine D-1 (K-i = 50 nM) receptors. ITI-333 acts as a 5-HT2A receptor antagonist, a MOR partial agonist, and an adrenergic alpha(1A) receptor antagonist. ITI-333 exhibited dose-dependent analgesic effects in rodent models of acute pain. Currently, this investigational new drug is in phase I clinical development.

Abstract Introduction Lumateperone (LUMA) is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. An open-label study (Study 303) evaluated the safety and tolerability of LUMA in outpatients with stable schizophrenia who switched from previous antipsychotic (AP) treatment. This post hoc analysis of Study 303 investigated the safety and tolerability of LUMA stratified by previous AP in patients who switched to LUMA treatment for 6 weeks. Methods Adult outpatients (≥18 years) with stable schizophrenia were switched from previous AP to LUMA 42 mg once daily for 6 weeks followed by switching to another approved AP for 2 weeks follow-up. Post hoc analyses were stratified by most common previous AP: risperidone or paliperidone (RIS/PAL); quetiapine (QET); aripiprazole or brexpiprazole (ARI/BRE); olanzapine (OLA). Safety analyses included adverse events (AE), vital signs, and laboratory tests. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions-Severity (CGI-S) scale. Results The safety population comprised 301 patients, of which 235 (78.1%) were previously treated with RIS/PAL (n=95), QET (n=60), ARI/BRE (n=43), or OLA (n=37). Rates of treatment-emergent AEs (TEAEs) while on LUMA were similar between previous AP groups (44.2%-55.8%). TEAEs with incidences of ≥5% in any AP group were dry mouth, somnolence, sedation, headache, diarrhea, cough, and insomnia. Most TEAEs were mild or moderate in severity for all groups. Rates of serious TEAEs were low and similar between groups (0%–7.0%). Statistically significant (P<.05) decreases from baseline were observed in the OLA group that switched to LUMA in total cholesterol and low-density lipoprotein cholesterol with significant decreases thereafter on LUMA. Statistically significant decreases in prolactin levels were observed in both the RIS/PAL (P<.0001) and OLA (P<.05) groups. Patients switched from RIS/PAL to LUMA showed significant (P<.05) decreases for body mass index, waist circumference, and weight. At follow-up, 2 weeks after patients switched back from LUMA to another AP, none of the decreases in laboratory parameters or body morphology observed while on LUMA maintained significance. Those switching from QET had significant improvements from baseline at Day 42 in PANSS Total score (mean change from baseline −3.47; 95% confidence interval [CI] −5.27, −1.68; P<.001) and CGI-S Total score (mean change from baseline −0.24; 95% CI, −0.38, −0.10; P<.01). Conclusion In outpatients with stable schizophrenia, LUMA 42 mg treatment was well tolerated in patients switching from a variety of previous APs. Patients switching from RIS/PAL or OLA to LUMA had significant improvements in cardiometabolic and prolactin parameters. These data further support the favorable safety, tolerability, and efficacy of LUMA in patients with schizophrenia. Funding Intra-Cellular Therapies, Inc.

Using an extensive database of every resident death in Virginia from 2005 to 2020, climate-mortality relationships are examined for 12 climatically homogeneous regions within the Commonwealth. Each region is represented by a first-order weather station from which archived temperature and humidity data are used to generate a variety of biometeorologically relevant indices. Using these indices and other variables (such as air quality and heat and cold waves), daily mortality and climate relationships are modeled for each region over a 21-day lag period utilizing generalized additive models and distributed lag non-linear models. Optimal models are identified for each region, and a consensus model was also run based on maximum temperature to facilitate inter-regional comparisons. The relative risk of mortality varies markedly as a function of climate between regions, with U-shaped, J-shaped, and inverse linear relationships evident. Cold mortality exceeds heat mortality across most of Virginia (typical relative risks are 1.10 for cold and 1.03 for heat), with cold risks strongest at lags 3 to 10. Low temperatures (or low humidity) are protective at lags 0-2 days except in the colder, western parts of state. Heat mortality occurs at short lags (0-2 days) for three-fourths of the stations, but the spatial pattern is random. Mortality displacement is evident for most regions for several days following the heat-related spike. Although the use of region-specific models is justified, the simple consensus model based on a consistent set of predictors provides similar results.

Diseases of the kidney and urinary tract impose a significant portion of the total disease burden, and linkages to high temperature exposure suggest that this burden may increase in the near future. We examined the association between climate and daily emergency department (ED) visits for kidney and urinary disease at the University of Virginia main hospital in Charlottesville, Virginia from 2005 to 2020. Generalized additive models and distributed lag nonlinear models were used to examine these associations over a 21-day lag period. After testing a variety of weather variables from observations taken at the Charlottesville, Albemarle County Airport weather station, 1 p.m. temperature was found to have the strongest association with ED visits for renal and urinary visits while controlling for seasonal and trend factors, air quality, day of the week, and wintry weather. The relative risk of ED visits exhibited a stronger association with high temperatures compared to low temperatures. The heat response was pronounced at short lags (0-1 days) with the relative risk (RR) increasing when 1 p.m. temperatures exceeded 20°C and peaking at 29°C (RR = 1.28). By comparison, low temperatures (≤0°C) exhibited a negative association (RR = 0.80 at -10°C) at short lags (0-1 day), with evidence of a weak RR increase at lags of 2-3 and 9-14 days. These results for ED visitation are consistent with other studies linking high temperatures to acute kidney injury, chronic kidney disease, the development of kidney stones, and other associated illnesses. A better understanding of the impact of temperature extremes in generating or exacerbating existing conditions could assist medical health professionals in the prevention and management of these diseases during extreme weather events.

Snow cover mapping algorithms utilizing multispectral satellite data at various spatial resolutions are available, each treating subpixel variation differently. Past evaluations of snow mapping accuracy typically relied on satellite data collected at a higher spatial resolution than the data in question. However, these optical data cannot characterize snow cover mapping performance under forest canopies or at the meter scale. Here, we use 3 m spatial resolution snow depth maps collected on 116 d by an aerial laser scanner to validate band ratio and spectral-mixture snow cover mapping algorithms. Such a comprehensive evaluation of sub-canopy snow mapping performance has not been undertaken previously. The following standard (produced operationally by an agency) products are evaluated: NASA gap-filled Moderate Resolution Imaging Spectroradiometer (MODIS) MOD10A1F, NASA gap-filled Visible Infrared Imaging Radiometer Suite (VIIRS) VNP10A1F, and United States Geological Survey (USGS) Landsat 8 Level-3 Fractional Snow Covered Area. Two spectral-unmixing approaches are also evaluated: Snow-Covered Area and Grain Size (SCAG) and Snow Property Inversion from Remote Sensing (SPIReS), both of which are gap-filled MODIS products and are also run on Landsat 8. We assess subpixel snow mapping performance while considering the fractional snow-covered area (fSCA), canopy cover, sensor zenith angle, and other variables within six global seasonal snow classes. Metrics are calculated at the pixel and basin scales, including the root-mean-square error (RMSE), bias, and F statistic (a detection measure). The newer MOD10A1F Version 61 and VNP10A1F Version 1 product biases (− 7.1 %, −9.5 %) improve significantly when linear equations developed for older products are applied (2.8 %, −2.7 %) to convert band ratios to fSCA. The F statistics are unchanged (94.4 %, 93.1 %) and the VNP10A1F RMSE improves (18.6 % to 15.7 %), while the MOD10A1F RMSE worsens (12.7 % to 13.7 %). Consistent with previous studies, spectral-unmixing approaches (SCAG, SPIReS) show lower biases (−0.1 %, −0.1 %) and RMSE (12.1 %, 12.0 %), with higher F statistics (95.6 %, 96.1 %) relative to the band ratio approaches for MODIS. Landsat 8 products are all spectral-mixture methods with low biases (−0.4 % to 0.3 %), low RMSE (11.4 % to 15.8 %), and high F statistics (97.3 % to 99.1 %). Spectral-unmixing methods can improve snow cover mapping at the global scale.

Background: Students’ yearly visits to university counseling centers have increased, concurrent with an increase in diagnosed anxiety and depression. Physical activity (PA) has positive effects on mental health. PA referral may be an option to utilize PA in university mental healthcare. However, clinicians’ perceptions and capacity of PA referral need to be established before implementation. Methods: Using a qualitative descriptive design, 14 licensed mental health professionals across seven southern universities participated in semi-structured virtual interviews to explore perceptions of prescribing PA to patients and referring patients to a PA specialist. Results: Thematic analysis revealed professionals perceived PA to be important for mental health, support prescribing PA to patients, face barriers to prescribing PA, professionals support referring patients to a PA specialist, and professionals face barriers referring to a PA specialist. Conclusions: Professionals agreed that PA was important for mental health and referring to a PA specialist would be the most feasible strategy to incorporate PA in their therapeutic work for patients struggling with physical inactivity and mental health. Future studies should investigate a PA referral system's implementation within university counseling centers and how this system can affect the mental health and PA of college students seeking mental health treatment.

AbstractBackgroundLumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder as monotherapy and as adjunctive therapy with lithium or valproate. This post hoc analysis investigated the efficacy and tolerability of lumateperone in patients with schizophrenia via number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).MethodsData were pooled from three late-phase 4–6 week placebo-controlled studies of lumateperone 42 mg/day in adults with schizophrenia and an acute exacerbation of psychosis (Study 005 [NCT01499563], Study 301 [NCT02282761], Study 302 [NCT02469155]). NNT and NNH were calculated vs placebo for several different Positive and Negative Syndrome Scale [PANSS] Total score response cutoffs (percent reduction from baseline) and for adverse events (AEs), respectively.ResultsIn the two informative studies (placebo, n=221; lumateperone, n=224), the NNT vs placebo for lumateperone was statistically significant for PANSS Total score reductions from baseline to 4 weeks/endpoint of ≥20% (NNT=9, 95% confidence interval [CI] 5–36) and ≥30% (NNT=8; 95%CI 5–21). In all studies pooled (placebo, n=412; lumateperone, n=406), study discontinuations due to AEs were uncommon and the NNH (389) was not statistically significant from placebo. The only AE with NNH vs placebo <10 was somnolence/sedation (NNH=8; 95%CI 6–12). With lumateperone treatment, weight gain ≥7% from baseline was similar to placebo (NNH=112) and fewer patients experienced akathisia than placebo. Lumateperone LHH ratios were >>1 for all AEs (range 13.6–48.6) except somnolence/sedation (LHH~1).ConclusionLumateperone’s benefit-risk profile was favorable in late-phase schizophrenia trials.FundingIntra-Cellular Therapies, Inc.

A recent Phase 3, randomized, double-blind, placebo-controlled study established that lumate-perone 42-mg monotherapy significantly improved symptoms of depression in patients with bipolar depression. This manuscript reports prespecified secondary and post hoc efficacy anal-yses. Patients with bipolar I or bipolar II disorder experiencing a major depressive episode were randomized 1:1 to lumateperone 42 mg or placebo, administered orally once daily for 6 weeks. Prespecified analyses evaluated change from baseline to Day 43 in individual Montgomery -Asberg Depression Rating Scale (MADRS) item scores in the modified intent-to-treat population (mITT) and bipolar I and bipolar II disorder subgroups. Post hoc analyses investigated the MADRS anhedonia factor and categorical shifts in MADRS item scores. In the mITT, there was significant improvement from baseline to Day 43 with lumateperone 42 mg compared with placebo for all 10 MADRS items; most MADRS items significantly improved in subgroups with bipolar I (9 items) and bipolar II disorder (8 items). A significantly higher proportion of patients receiving lumate-perone compared with placebo shifted from baseline MADRS item score >= 4 to <= 2 at end of treatment in Reported Sadness, Reduced Sleep, Concentration Difficulties, Lassitude, Inability to Feel, and Pessimistic Thoughts. Lumateperone significantly improved the MADRS anhedo-nia factor from baseline to Day 43 compared with placebo in the mITT (effect size, -0.47) and subgroups with bipolar I ( -0.36) and bipolar II disorder (-0.90). Lumateperone 42 mg treatment significantly improved depression symptoms compared with placebo, with consistent efficacy across a broad range of symptoms in people with bipolar I and bipolar II disorder.(c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

AbstractBackgroundAnhedonia – a diminished interest or pleasure in activities – is a core self-reported symptom of depression which is poorly understood and often resistant to conventional antidepressants. This symptom may occur due to dysfunction in one or more sub-components of reward processing: motivation, consummatory experience and/or learning. However, the precise impairments remain elusive. Dissociating these components (ideally, using cross-species measures) and relating them to the subjective experience of anhedonia is critical as it may benefit fundamental biology research and novel drug development.MethodsUsing a battery of behavioural tasks based on rodent assays, we examined reward motivation (Joystick-Operated Runway Task, JORT; and Effort-Expenditure for Rewards Task, EEfRT) and reward sensitivity (Sweet Taste Test) in a non-clinical population who scored high (N = 32) or low (N = 34) on an anhedonia questionnaire (Snaith–Hamilton Pleasure Scale).ResultsCompared to the low anhedonia group, the high anhedonia group displayed marginal impairments in effort-based decision-making (EEfRT) and reduced reward sensitivity (Sweet Taste Test). However, we found no evidence of a difference between groups in physical effort exerted for reward (JORT). Interestingly, whilst the EEfRT and Sweet Taste Test correlated with anhedonia measures, they did not correlate with each other. This poses the question of whether there are subgroups within anhedonia; however, further work is required to directly test this hypothesis.ConclusionsOur findings suggest that anhedonia is a heterogeneous symptom associated with impairments in reward sensitivity and effort-based decision-making.

Lumateperone is indicated for the treatment of schizophrenia in adults and for depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate (Calabrese et al., 2021). It is currently under evaluation for the treatment of major depressive disorder ( www.ClinicalTrials.gov ). Lumateperone acts by selectively modulating serotonin, dopamine, and glutamate neurotransmission in the brain. However, other mechanisms could be involved in the actions of lumateperone, and because of the connection between the immune system and psychiatric health, we hypothesized that lumateperone might improve symptoms of depression, at least in part, by normalizing pathologic inflammation. Here, we show that in male and female C57BL/6 mice subjected to an acute immune challenge, lumateperone reduced aberrantly elevated levels of key proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) in both brain and serum; lumateperone also reduced proinflammatory cytokines in male mice under acute behavioral stress. Further, we demonstrate that lumateperone altered key genes/pathways involved in maintaining tissue integrity and supporting blood–brain barrier function, such as claudin-5 and intercellular adhesion molecule 1. In addition, in acutely stressed male Sprague Dawley rats, lumateperone conferred anxiolytic- and antianhedonic-like properties while enhancing activity in the mammalian target of rapamycin complex 1 pathway in the PFC. Together, our preclinical findings indicate that lumateperone, in addition to its ability to modulate multiple neurotransmitter systems, could also act by reducing the impact of acute inflammatory challenges. SIGNIFICANCE STATEMENT Lumateperone is indicated in adults to treat schizophrenia and depressive episodes associated with bipolar I or II disorder, as monotherapy and adjunctive therapy with lithium or valproate. Because aberrant immune system activity is associated with increased depressive symptoms, the relationship between lumateperone and immune function was studied. Here, lumateperone reduced the levels of proinflammatory cytokines that were increased following an immune challenge or stress in mice. Additionally, lumateperone altered genes and pathways that maintain blood–brain barrier integrity, restored an index of blood–brain barrier function, reduced anxiety-like behavior in rodents, and enhanced mammalian target of rapamycin complex 1 pathway signaling in the PFC. These results highlight the anti-inflammatory actions of lumateperone and describe how lumateperone may reduce immune pathophysiology, which is associated with depressive symptoms.