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Majid Moshirfar,1– 3 Michael S Herron,4 David S Cha,5 Jordan M Santos,6 Levi T Miller,7 Phillip C Hoopes Sr1 1Hoopes Vision Research Center, Hoopes Vision, Draper, UT, 84020, USA; 2John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA; 3Utah Lions Eye Bank, Murray, UT, USA; 4University of Nevada, Reno School of Medicine, Reno, NV, USA; 5Saint Louis University School of Medicine, St. Louis, MO, USA; 6University of Arizona, Phoenix School of Medicine, Phoenix, AZ, USA; 7Utah State University, Department of Electrical and Computer Engineering, Logan, UT, USACorrespondence: Majid Moshirfar, Hoopes Vision Research Center, 11820 S. State St. &num;200, Draper, UT, 84020, USA, Tel\Fax +1 801-568-0200, Email cornea2020@me.comPurpose: We assess the relationship between preoperative myopic sphere, astigmatism, and spherical equivalent and effective optical zone (EOZ) size, shape, and decentration within individual populations of post-LASIK, PRK, and SMILE patients.Patients and Methods: A retrospective chart review was conducted with 118 LASIK, 144 PRK, and 41 SMILE eyes from 179 total patients that underwent compound myopic ablation. One-year postoperative Pentacam tangential difference maps were used for EOZ data measurements. Correlational analysis between compound myopic measures [sphere, cylinder, manifest refractive spherical equivalent (MRSE)] and EOZ parameters was performed, and differences between groups of myopic sphere and cylinder within each surgery type were assessed.Results: An increase in absolute myopic sphere (and subsequent MRSE) is associated with a smaller EOZ area in SMILE (r=0.454, p=0.003) and a more circular EOZ shape in LASIK (r=0.396, p< 0.001) and PRK (r=0.563, p< 0.001). An increase in absolute myopic cylinder is associated with an increased EOZ area in all three surgery types [LASIK (r=− 0.459, p< 0.001), PRK (r=− 0.716, p< 0.001), SMILE (r=− 0.429, p=0.005)] and a more elliptical EOZ in LASIK (r=− 0.491, p< 0.001) and PRK (r=− 0.538, p< 0.001).Conclusion: While astigmatism may be correlated to EOZ size within all three refractive surgery types, myopic sphere alone is insufficient to estimate EOZ size differences for procedures with a large blend zone of ablation like LASIK or PRK. Shape is just as important a factor as size to consider when examining corneal EOZ differences; reported correlative findings likely result from inherent differences in surgical technique and abruptness of planned surgical ablation borders.Keywords: EOZ, OZ, Pentacam, tangential difference map

Majid Moshirfar,1– 3 Jordan M Santos,4 David S Cha,5 Michael Herron,6 Isabella M Stoakes,1,7 Phillip C Hoopes1 1Hoopes Vision Research Center, Hoopes Vision, Draper, UT, USA; 2John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA; 3Utah Lions Eye Bank, Murray, UT, USA; 4University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA; 5Saint Louis University School of Medicine, St Louis, MO, USA; 6University of Nevada, Reno School of Medicine, Reno, NV, USA; 7Pacific Northwest University of Health Sciences, Yakima, WA, USACorrespondence: Majid Moshirfar, Hoopes Vision Research Center, Hoopes Vision, 11820 S. State St. &num;200, Draper, UT, 84020, USA, Tel +1 801-568-0200, Fax +1 801-563-0200, Email cornea2020@me.comPurpose: To provide a comprehensive guide of all implantable collamer lens (ICL) sizing nomograms and the respective preoperative diagnostic devices that are required. This guide would help clinicians in choosing the appropriate ICL size for myopic patients to optimize postoperative vault height.Methods: A literature search of peer-reviewed journals describing methods and postoperative outcomes of ICL sizing was conducted. Research articles containing ICL nomograms or formulas were identified from this search. Preoperative variables necessary for these nomograms and the required diagnostic devices to measure these parameters such as topography, biometry, or ultrasound biomicroscopy (UBM) were noted. An additional search was conducted to identify artificial intelligence (AI) or machine learning (ML)-derived nomograms.Results: Eighteen ICL sizing nomograms were identified through literature search. Five of these nomograms are available for use and require topography or biometry devices. Of these, four include the manufacturer’s, optimized white-to-white (WTW), Kang, Kim, and Rocamora Nomograms. Eight of the 18 nomograms available for use require UBM. Eight of these include the Kojima, Nakamura, KS, ZZ, Dougherty, Parkhurst, Russo, and Reinstein Nomograms. Four of the 18 nomograms are ML-derived including Shen, Rocamora, Russo, and Kang Nomograms.Conclusion: ICL nomograms are a vital tool in helping clinicians select the right ICL size for myopic patients to optimize postoperative vault reducing risk of postoperative complications. Based on available diagnostic devices such as topography, biometry, or UBM clinicians can integrate specific nomograms into practice.Keywords: phakic intraocular lens, pIOL, myopia, implantable contact lens, EVO, Visian ICL, artificial intelligence, machine learning model, ICL sizing, ICL formula

Majid Moshirfar,1– 3 Joshua S Theis,4 David S Cha,5 Kaiden B Porter,4 Carter J Payne,1,6 Phillip C Hoopes1 1Hoopes Vision Research Center, Hoopes Vision, Draper, UT, USA; 2John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA; 3Utah Lions Eye Bank, Murray, UT, USA; 4University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA; 5Saint Louis University School of Medicine, Saint Louis, MO, USA; 6Department of Ophthalmology, George Washington University School of Medicine and Health Sciences, Washington, DC, USACorrespondence: Majid Moshirfar, Hoopes Vision Research Center, 11820 S. State St. &num;200, Draper, UT, 84020, USA, Tel +1 801 568 – 0200, Fax +1 415-476-0336, Email cornea2020@me.comPurpose: To compare 3 of the most common corneal refractive procedures; PRK, LASIK, and SMILE assessing ΔK/ΔSEQ ratio and its correlation with preoperative demographics including age, keratometry, pachymetry, cylinder value, and attempted myopic correction. The goal was to analyze the relative strength of each preoperative parameter in accounting for changes in ∆K/∆SEQ.Patients and Methods: A total of 370 eyes from 102 male and 97 female patients (173 eyes PRK, 153 LASIK, and 44 SMILE) with ages ranging from 20 to 51 underwent refractive surgery for myopia between − 0.25 and − 7.71 D manifest refraction spherical equivalent (MRSE). All surgeries were performed at a single surgery center in Draper, Utah. The Pentacam was used for all optical measurements and data were gathered pre-operatively and then again 1-year post-operatively. Only patients who achieved emmetropia at a visual acuity of 20/25 or better were included.Results: The mean ΔK/ΔSEQ ratio for LASIK (0.839 ± 0.020) was significantly greater than that of PRK (0.775 ± 0.022) and SMILE (0.709 ± 0.046). Age was found to negatively correlate with ΔK/ΔSEQ for both LASIK (r = − 0.177) and SMILE (r = − 0.451) procedures. Pre-op keratometry was found to negatively correlate with ΔK/ΔSEQ for LASIK (r = − 0.202) but not for PRK or SMILE. Pre-op pachymetry was not correlated with ΔK/ΔSEQ for any of the procedures. Attempted myopic spherical equivalent (SEQ) correction was positively correlated with ΔK/ΔSEQ for LASIK (r = 0.236), PRK (r = 0.459), and SMILE (r = 0.304). Lastly, pre-op cylinder value was found to be correlated to ΔK/ΔSEQ in SMILE (r = − 0.367), but not in LASIK or PRK.Conclusion: The ΔK/ΔSEQ ratio not only differs depending on the procedure being done but also by pre-operative factors such as age, keratometry, attempted correction, and cylinder value. Multiple linear regression analysis revealed that the attempted correction had the greatest effect on ∆K/∆SEQ out of all parameters in LASIK and PRK. For SMILE, age had the greatest predictive value of the change in ∆K/∆SEQ. While the exact effect of these parameters will vary by surgeon, all of these should be factored into a refractive surgeon’s nomograms in order to achieve optimal visual outcomes for their patients.Keywords: cornea, refractive surgery, spherical equivalent, nomogram, keratometry, pachymetry, age, cylinder

Majid Moshirfar,1–3 Joshua S Theis,4 David S Cha,5 Kaiden B Porter,4 Carter J Payne,1,6 Phillip C Hoopes1 1Hoopes Vision Research Center, Hoopes Vision, Draper, UT, USA; 2John A. Moran Eye Center, University of Utah, School of Medicine, Salt Lake City, UT, USA; 3Utah Lions Eye Bank, Murray, UT, USA; 4University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA; 5Saint Louis University, School of Medicine, Saint Louis, MO, USA; 6Department of Ophthalmology, George Washington University School of Medicine and Health Sciences, Washington, DC, USACorrespondence: Majid Moshirfar, Hoopes Vision Research Center, 11820 S. State St. &num;200, Draper, UT, 84020, USA, Tel +1 801 568 – 0200, Fax +1 415-476-0336, Email cornea2020@me.com

Vincent Chin-Hung Chen,1,2 Yi-Chun Liu,3 Seh-Huang Chao,4 Roger S McIntyre,5–7 Danielle S Cha,5,8 Yena Lee,5,6 Jun-Cheng Weng2,9 1School of Medicine, Chang Gung University, Taoyuan, Taiwan; 2Department of Psychiatry, Chang Gung Memorial Hospital, Chiayi, Taiwan; 3Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan; 4Center of Metabolic and Bariatric Surgery, Jen-Ai Hospital, Taichung, Taiwan; 5Mood Disorder Psychopharmacology Unit, University Health Network, Department of Psychiatry, University of Toronto, ON, Canada; 6Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 7Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, ON, Canada; 8School of Medicine, University of Queensland, Queensland, Brisbane, Australia; 9Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan Purpose: Obesity is a complex and multifactorial disease identified as a global epidemic. Convergent evidence indicates that obesity differentially influences patients with neuropsychiatric disorders providing a basis for hypothesizing that obesity alters brain structure and function associated with the brain’s propensity toward disturbances in mood and cognition. Herein, we characterize alterations in brain structures and networks among obese subjects (ie, body mass index [BMI] ≥30 kg/m2) when compared with non-obese controls.Patients and methods: We obtained noninvasive diffusion tensor imaging and generalized q-sampling imaging scans of 20 obese subjects (BMI=37.9±5.2 SD) and 30 non-obese controls (BMI=22.6±3.4 SD). Graph theoretical analysis and network-based statistical analysis were performed to assess structural and functional differences between groups. We additionally assessed for correlations between diffusion indices, BMI, and anxiety and depressive symptom severity (ie, Hospital Anxiety and Depression Scale total score).Results: The diffusion indices of the posterior limb of the internal capsule, corona radiata, and superior longitudinal fasciculus were significantly lower among obese subjects when compared with controls. Moreover, obese subjects were more likely to report anxiety and depressive symptoms. There were fewer structural network connections observed in obese subjects compared with non-obese controls. Topological measures of clustering coefficient (C), local efficiency (Elocal), global efficiency (Eglobal), and transitivity were significantly lower among obese subjects. Similarly, three sub-networks were identified to have decreased structural connectivity among frontal–temporal regions in obese subjects compared with non-obese controls.Conclusion: We extend knowledge further by delineating structural interconnectivity alterations within and across brain regions that are adversely affected in individuals who are obese. Keywords: obesity, diffusion tensor imaging, DTI, generalized q-sampling imaging, GQI, graph theoretical analysis, GTA, network-based statistical analysis, NBS

To investigate the efficacy and the mechanism of the anti-inflammatory effect of Taraxacum officinale leaves (TOLs), the effect of a methanol extract and its fractions recovered from TOLs on lipopolysaccharide (LPS)-induced responses was studied in the mouse macrophage cell line, RAW 264.7. Cells were pretreated with various concentrations of the methanol extract and its fractions and subsequently incubated with LPS (1 microg/mL). The levels of nitric oxide (NO), prostaglandin (PG) E(2), and pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were determined using enzyme-linked immunosorbent assays. Expressions of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 and activation of mitogen-activated protein (MAP) kinases were analyzed using western blotting. The methanol extract and its fractions inhibited LPS-induced production of NO, pro-inflammatory cytokines, and PGE(2) in a dose-dependent manner. The chloroform fraction significantly suppressed production of NO, PGE(2), and two pro-inflammatory cytokines (TNF-alpha and IL-1beta) in a dose-dependent manner with 50% inhibitory concentration values of 66.51, 90.96, 114.76, and 171.06 microg/mL, respectively. The ethyl acetate fraction also inhibited production of the inflammatory molecules. The chloroform and ethyl acetate fractions reduced LPS-induced expressions of iNOS and COX-2 and activation of MAP kinases in a dose-dependent manner. Among the fractions of the methanol extract, the chloroform and ethyl acetate fractions exhibited the most effective anti-inflammatory activities. These results show that the anti-inflammatory effects of TOLs are probably due to down-regulation of NO, PGE(2), and pro-inflammatory cytokines and reduced expressions of iNOS and COX-2 via inactivation of the MAP kinase signal pathway. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) is the most common substance use disorder and poses a significant global health challenge. Despite pharmacological advances, no single drug effectively treats all AUD patients. This study explores the protective potential of hispidol, a 6,4'-dihydroxyaurone, for AUD using the Caenorhabditis elegans model system. Our findings demonstrate that hispidol-fed worms exhibited more pronounced impairments in thrashes, locomotory speed, and bending amplitude, indicating that hispidol exacerbated the detrimental effects of acute ethanol exposure. However, hispidol significantly improved ethanol withdrawal behaviors, such as locomotory speed and chemotaxis performance. These beneficial effects were absent in slo-1 worms (the ortholog of mammalian α-subunit of BK channel) but were restored with the slo-1 (+) or hslo (+) transgene, suggesting the involvement of BK channel activity. Additionally, hispidol increased fluorescence intensity and puncta in the motor neurons of slo-1::mCherry-tagged worms, indicating enhanced BK channel expression and clustering. Notably, hispidol did not alter internal ethanol concentrations, suggesting that its action is independent of ethanol metabolism. In the mouse models, hispidol treatment also demonstrated anxiolytic activity against ethanol withdrawal. Overall, these findings suggest hispidol as a promising candidate for targeting the BK channel in AUD treatment.

Purpose: The purpose of this study was to compare changes in the posterior curvature and the posterior-anterior radii ratio of the cornea, 1 year postoperatively in laser in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), and small incision lenticule extraction (SMILE)., Methods: This retrospective study was performed at a single surgical center. 199 eyes were included in the study from 119 patients with manifest refraction spherical equivalents from -7.61 to -2.54 D. 67 eyes underwent LASIK, 89 underwent PRK, and 43 underwent SMILE. Both preoperative and 1-year postoperative front and back sagittal keratometry were measured at 4- to 6-mm zones around the corneal vertex. Corneal asphericity (Q-value) was measured at an 8-mm zone around the corneal vertex., Results: The average change in the posterior-anterior radii ratio after LASIK, PRK, and SMILE did not differ between surgery groups at 4 mm (LASIK: -0.075, PRK: -0.073, SMILE: -0.072, P = 0.720), 5 mm (LASIK: -0.072, PRK: -0.068, SMILE: -0.068, P = 0.531), or 6 mm (LASIK: -0.075, PRK: -0.071, SMILE: -0.072, P = 0.456) zones. Anterior Q-value significantly positively increased after all 3 surgeries ( P < 0.001). The posterior Q-value also significantly positively increased after LASIK ( P < 0.001) and SMILE ( P < 0.001), but not after PRK ( P = 0.227). Both anterior and posterior keratometric power decreased significantly after LASIK, PRK, and SMILE for all diameters., Conclusions: The change in the posterior-anterior radii ratio was not influenced by the type of refractive surgery performed, as indicated by statistically identical preoperative, postoperative, and delta values. In addition, the posterior cornea exhibited paracentral flattening after LASIK, SMILE, and PRK and increased oblateness after LASIK and SMILE., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The gut microbiome influences drug metabolism and therapeutic efficacy. Still, the lack of a general label-free approach for monitoring bacterial or host metabolic contribution hampers deeper insights. Here, a 2D nuclear magnetic resonance (NMR) approach is introduced that enables real-time monitoring of the metabolism of Levodopa (L-dopa), an anti-Parkinson drug, in both live bacteria and bacteria-host (Caenorhabditis elegans) symbiotic systems. The quantitative method reveals that discrete Enterococcus faecalis substrains produce different amounts of dopamine in live hosts, even though they are a single species and all have the Tyrosine decarboxylase (TyrDC) gene involved in L-dopa metabolism. The differential bacterial metabolic activity correlates with differing Parkinson's molecular pathology concerning alpha-synuclein aggregation as well as behavioral phenotypes. The gene's existence or expression is not an indicator of metabolic activity is also shown, underscoring the significance of quantitative metabolic estimation in vivo. This simple approach is widely adaptable to any chemical drug to elucidate pharmacomicrobiomic relationships and may help rapidly screen bacterial metabolic effects in drug development., (© 2024 The Author(s). Small Methods published by Wiley‐VCH GmbH.)

Herein, we describe the synthesis of the proposed structure of the caffeamide alkaloid bassiamide A. The amide moiety of bassiamide A was readily formed via an amide coupling reaction between caffeic acid and the known N-(3-aminopropyl)-3-methylbutanamide. However, the spectral data of the synthesized bassiamide A did not agree with that of a previous study. The structure of the synthesized bassiamide A was confirmed using combined two-dimensional NMR analysis. Extended analyses of the bioactivity of the synthesized bassiamide A revealed its efficacy in protecting dopaminergic neurons from MPP + -induced neurotoxicity in Caenorhabditis elegans. Additionally, treatment with bassiamide A notably ameliorated the impaired food-sensing ability and locomotion of Caenorhabditis elegans, suggesting a protective effect on the functionality of dopaminergic neurons., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Introduction: Major depressive disorder (MDD) is a common and debilitating mental illness. Postpartum depression (PPD) impacts women globally and is one of the most common complications of childbirth that is underdiagnosed and undertreated, adversely impacting the mental health of women, children, and partners.Available antidepressant medications require weeks to months before showing effect. In this setting, zuranolone, an oral neuroactive steroid and a positive allosteric modulator of GABA A receptors, is an attractive alternative as a rapid-acting antidepressant treatment., Areas Covered: This article reviews zuranolone (SAGE217), focusing on available clinical studies in individuals with PPD and MDD. This paper adds to the extant literature by presenting the efficacy data as Number Needed to Treat (NNT) to facilitate indirect comparisons with other antidepressants., Expert Opinion: Zuranolone is a novel rapid-acting (i.e. two week course) oral antidepressant for the treatment of adults with PPD with ongoing clinical trials evaluating its efficacy in adults with MDD. Zuranolone is well tolerated with no significant safety concerns in any clinical trials completed to date. Zuranolone will be scheduled by the Drug Enforcement Agency (DEA).

Purpose: To explore size, decentration, and eccentricity of effective optical zones (EOZs) in laser in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), and small incision lenticule extraction (SMILE) and correlate them to higher order aberrations (HOAs)., Methods: This was a retrospective chart review of 188 eyes that underwent refractive surgery for compound myopia (61 LASIK, 84 PRK, 43 SMILE). EOZ measurements were determined using 1-year postoperative Pentacam (Oculus Optikgeräte GmbH) tangential difference maps. HOA data were measured using Pentacam wavefront aberration Zernike polynomials. Correlations between EOZs and HOAs were analyzed., Results: The EOZs of LASIK and PRK are smaller than SMILE at 19.54 ± 1.44, 19.39 ± 1.66, and 22.18 ± 2.61 mm 2 , respectively ( P < .001). No difference existed in absolute decentration from corneal vertex ( P = .078) or pupil center ( P = .131), but horizontal and vertical components differed significantly ( P < .001). Smaller EOZ areas were correlated with greater spherical aberration induction (rLASIK = -0.378, rPRK = -0.555, rSMILE = -0.501) and total HOA induction in all groups. Absolute decentration from corneal vertex positively correlated with total HOA (rLASIK = 0.396, rPRK = 0.463, rSMILE = 0.399) and directional vertical coma induction negatively correlated with vertical decentration from the corneal vertex (rLASIK = -0.776, rPRK = -0.665, rSMILE = -0.576) in all groups., Conclusions: SMILE results in a larger EOZ than LASIK and PRK, and absolute decentration remains comparable regardless of surgical reference center, despite horizontal/vertical differences. Surgical planning to ensure adequate EOZ size and centration may reduce induction of HOAs, including spherical aberrations and vertical coma. [ J Refract Surg . 2023;39(11):741-750.] .

The ratio of posterior-to-anterior curvature radii of the cornea (P/A ratio) is an important element in determining corneal refractive power. P/A ratio has been well studied in patients prior to undergoing refractive surgery, but its postoperative value remains less so. We aimed to examine the value of preoperative characteristics of refractive surgery patients in predicting the 1-year postoperative P/A ratio in LASIK, PRK, and SMILE using both linear and multivariate regression analyses. This was a retrospective study that included patients with manifest refraction spherical equivalents (MRSE) from -7.71D to -0.25D. In total, 164 eyes underwent LASIK, 183 underwent PRK, and 46 underwent SMILE. All patients had preoperative and 1-year postoperative front sagittal and back sagittal keratometry measurements at 4, 5, and 6 mm around the corneal vertex. Postoperative P/A after LASIK, PRK, and SMILE was found to be significantly correlated with MRSE and preoperative P/A. Stepwise variable selection in multivariate regression revealed that spherical equivalent was the most significant predictor of postoperative P/A. When coupled with other preoperative characteristics, including P/A, age, asphericity, and keratometry, the multivariate regressions were able to produce models with high predictive value in LASIK (adjusted R 2 : 0.957), PRK (adjusted R 2 : 0.934), and SMILE (adjusted R 2 : 0.894).

2-(Quinoline-8-carboxamido)benzoic acid (2-QBA; 1 ) is a natural quinoline alkaloid isolated from the deep-sea-derived fungus Aspergillus sp. SCSIO06786. Alkaloid 1 was synthesized by an amidation reaction of 8-quinolinecaroxylic acid with methyl anthranilate, followed by hydrolysis. The neuroprotective properties of 1 were evaluated using a Caenorhabditis elegans Parkinson's disease model, which revealed that 1 significantly ameliorated 1-methyl-4-phenylpyridinium (MPP + )-induced dopaminergic neurodegeneration in a dose-dependent manner. MPP + -induced behavioral defects in worms, including impaired locomotion and basal slowing ability, were restored by treatment with 1 . We further demonstrated that treatment with 1 modulates the formation of neurotoxic α-synuclein oligomers by suppressing α-synuclein expressions and enhancing proteasome activity. These results suggest that 1 is a promising therapeutic candidate for the treatment of Parkinson's disease.

Converging evidence has suggested that disturbances in monetary reward processing may subserve the shared biosignature between major depressive disorder (MDD) and obesity. However, there remains a paucity of studies that have evaluated the deficits in specific subcomponents of reward functioning in populations with MDD and obesity comorbidity. We evaluated the association between effort-expenditure for monetary reward and neural activation in regions associated with reward-based decision making (i.e., the caudate nucleus, anterior cingulate cortex (ACC) and hippocampus) in people with MDD and obesity comorbidity. We acquired structural and functional magnetic resonance imaging (fMRI) in 12 participants and performed a spherical region-of-interest analysis (ROI) using previously defined peak MNI coordinates. A one-sample t-test was employed to compare ROI-specific blood-oxygen-level-dependent (BOLD) signal change during the task choice selection window (i.e., high-effort vs. low-effort task) of the effort-expenditure for reward task (EEfRT). We observed no change in activation of the caudate nucleus, ACC or hippocampus in participants with increased BMI when contrasting the high effort > low effort reward magnitude condition for the EEfRT. The findings from our exploratory study evaluated the disturbances in fundamental reward processes, including cost-benefit decision making, in people MDD and obesity. Future studies should further investigate this relationship with a larger sample size., Competing Interests: Declaration of Competing Interest Dr. Roger McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Funding for the study was provided by Bausch Health. Dr. Joshua D Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Labatt Family Innovation Fund, Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from Janssen, Allergan, Lundbeck, Sunovion and COMPASS. He is the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of Braxia Health (Canadian Rapid Treatment Centre of Excellence). Dr. Rodrigo B. Mansur has received research funding from the Canadian Institutes of Health Research, Physician Services Incorporated foundation, the Baszucki Brain Research Fund, and an Academic Scholar Award from the University of Toronto, Department of Psychiatry. All other authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier B.V.)

The use of psilocybin as treatment for major depressive disorder (MDD) has been examined as a promising alternative to traditional first-line options. We reviewed existing literature to provide a synthesis of the extant neuroimaging observations with psilocybin, and to identify putative therapeutic targets for target engagement studies with psilocybin, and potentially other psychedelics. We assessed neuroimaging observations with psilocybin among participants with MDD and healthy populations. A systematic search was conducted on PubMed, Google Scholar and PsycINFO from database inception to November 17th, 2021. The study quality (i.e., risk of bias) was assessed using the revised Cochrane risk-of-bias tool for randomized trials. A total of ten studies evaluated psilocybin in healthy populations and three studies assessed psilocybin in MDD participants using neuroimaging techniques. Following psilocybin administration, a decrease in amygdala activity and a reduction in depressive symptoms was observed in two studies. Changes in functional connectivity and activation of prefrontal limbic structures, specifically the ventral medial prefrontal cortex and amygdala, was seen in healthy populations. There was high heterogeneity in methodology (e.g., dosing schedule and imaging methods) amongst included studies. Longitudinal studies are needed to further elucidate psilocybin treatment for MDD, its long-term effects and the possibility of sustained therapeutic effects., (Copyright © 2022. Published by Elsevier B.V.)

Background: Patients unsuccessfully treated by neurostimulation may represent a highly intractable subgroup of depression. While the efficacy of intravenous (IV) ketamine has been established in patients with treatment-resistant depression (TRD), there is an interest to evaluate its effectiveness in a subpopulation with a history of neurostimulation., Methods: This retrospective, posthoc analysis compared the effects of four infusions of IV ketamine in 135 (x̄ = 44 ± 15.4 years of age) neurostimulation-naïve patients to 103 (x̄ = 47 ± 13.9 years of age) patients with a history of neurostimulation. The primary outcome evaluated changes in depression severity, measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR16). Secondary outcomes evaluated suicidal ideation (SI), anxiety severity, measured by the Generalized Anxiety Disorder 7-Item (GAD-7), and consummatory anhedonia, measured by the Snaith-Hamilton Pleasure Scale (SHAPS)., Results: Following four infusions, both cohorts reported a significant reduction in QIDS-SR16 Total Score (F (4, 648) = 73.4, P < .001), SI (F (4, 642) = 28.6, P < .001), GAD-7 (F (2, 265) = 53.8, P < .001), and SHAPS (F (2, 302) = 45.9, P < .001). No between-group differences emerged. Overall, the neurostimulation-naïve group had a mean reduction in QIDS-SR16 Total Score of 6.4 (standard deviation [SD] = 5.3), whereas the history of neurostimulation patients reported a 4.3 (SD = 5.3) point reduction., Conclusion: IV ketamine was effective in reducing symptoms of depression, SI, anxiety, and anhedonia in both cohorts in this large, well-characterized community-based sample of adults with TRD.

Evodileptin B (1) is a natural anthranilate derivative isolated from the ethanol extract of the aerial parts of Evodia lepta (Spreng.) Merr., a traditional medicinal plant of the family Rutaceae. We readily synthesized 1 via the amidation of phloretic with methyl anthranilate and evaluate its neuroprotective activity using a C. elegans Parkinson's disease (PD) model. The results showed that evodilpetin B ameliorated MPP + -induced dopaminergic (DA) neurodegeneration in a dose-dependent manner. Evodileptin B treatment also significantly improved the DA neurotransmission-related behavioral defects such as reduced locomotory and food-sensing ability of worms under MPP + exposure conditions, suggesting its potential application for the functional restoration of DA neurons. In addition, we found that 1 has an ability to regulate aggregation of α-synuclein by increasing proteasome activity in the human α-synuclein-expressing mutant worms. These results demonstrate that evodileptin B has strong neuroprotective properties and may be useful in the treatment of PD., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Background Extant literature has identified Major Depressive Disorder (MDD) as a comorbid disorder in individuals with seropositive human immunodeficiency disorder (HIV), and this may affect HIV-treatment efficacy. However, there is a paucity of literature evaluating the effects of antidepressant use on antiretroviral therapies (ART) in HIV-positive individuals. Herein, the following review assesses the effects of antidepressant medications on ART adherence in HIV-positive individuals with diagnosed MDD. Methods A systematic search on PubMed, Scopus, Web of Science, and Google Scholar search engines were conducted between database inception to June 12th, 2020 using the search and MeSH terms: (HIV) AND (antiretroviral or treatment) AND (depress*) AND (antidepressants) AND (adherence). Results We identified nine articles that evaluated ART adherence in HIV-positive individuals using antidepressants. Of the nine included articles, eight articles evaluated participants undergoing ART, and one article evaluated participants undergoing highly active antiretroviral therapy (HAART). Our primary findings suggest that patients who took antidepressant treatment for depression demonstrated greater adherence to HIV treatments and a reduction in missed HIV medication dosage. Limitations The heterogeneity of study design between the included studies was high. Conclusion The current review suggests that response to antidepressant medication may improve adherence to HIV treatments in HIV-positive individuals with comorbid depression. Further studies should expand the findings to explore the effects of disparate psychotropic agents on adherence behaviors among patients with HIV to identify the benefits of these agents on long-term health outcomes in this vulnerable clinical population., (Copyright © 2021. Published by Elsevier B.V.)

Sleep disturbances are commonly reported in patients with treatment-resistant depression (TRD). Available data have shown that intravenous (IV) ketamine is an effective treatment for patients with TRD and growing data suggest ketamine may improve overall sleep architecture. In the present study, we evaluated whether changes in sleep symptoms mediated the anti-depressive and/or anti-suicidal effects of IV ketamine and whether improvement in sleep correlated with a higher likelihood of achieving response or remission. Adults with TRD received four infusions of IV ketamine at a community-based clinic. Total depressive symptom severity was measured with the Quick Inventory Depressive Symptoms Self-Report 16-Item (QIDS-SR 16 ) at baseline and was repeated across four infusions. Suicidal ideation (SI) and four sleep symptoms were measured using the SI item and the five sleep items on the QIDS-SR 16 . A total of 323 patients with TRD received IV ketamine. Self-reported improvements in insomnia, night-time restlessness, hypersomnia, early morning waking, and total sleep were significant partial mediators to the improvements observed in depression severity. Similarly, insomnia, night-time restlessness, early morning waking and total sleep improvements mediated the reduction of IV ketamine on SI. All sleep items, except for hypersomnia, were associated with an increased likelihood of achieving response or remission. Notably, each point improvement in total sleep score was significantly associated with achieving responder/remitter status (odds ratio 3.29, 95% confidence interval 2.00-5.41). Insomnia, sleep restlessness, early morning waking and total sleep improvements were significant mediators of antidepressant and anti-suicidal improvements in patients with TRD receiving IV ketamine., (© 2021 European Sleep Research Society.)

The COVID-19 pandemic has resulted in a predominantly global quarantine response that has been associated with social isolation, loneliness, and anxiety. The foregoing experiences have been amply documented to have profound impacts on health, morbidity, and mortality. This narrative review uses the extant neurobiological and theoretical literature to explore the association between social isolation, loneliness, and anxiety in the context of quarantine during the COVID-19 pandemic. Emerging evidence suggests that distinct health issues (e.g., a sedentary lifestyle, a diminished overall sense of well-being) are associated with social isolation and loneliness. The health implications of social isolation and loneliness during quarantine have a heterogenous and comorbid nature and, as a result, form a link to anxiety. The limbic system plays a role in fear and anxiety response; the bed nucleus of the stria terminalis, amygdala, HPA axis, hippocampus, prefrontal cortex, insula, and locus coeruleus have an impact in a prolonged anxious state. In the conclusion, possible solutions are considered and remarks are made on future areas of exploration.

Approximately 0.35-1% of the general population is afflicted with psychotic depression at some time in their life. Psychotic depression is a subtype of major depressive disorder characterized by mood congruent hallucinations and/or delusions. Patients with psychotic depression often represent the most severe cases, with high relapse and mortality rate. Although treatment guidelines recommend a combination of antidepressants and antipsychotics or electroconvulsive therapy, most patients subsequently relapse due to treatment resistance. Furthermore, with the concern of antipsychotic drug's side effects (e.g., tardive dyskinesia), there is a need for an alternative pharmacotherapy for psychotic depression. Recently, several case studies demonstrated that treatment with ketamine not only ameliorated mood, but also improved psychotic symptoms in patients with treatment-resistant depression and psychotic features. However, the safety of ketamine in these patients is controversial since ketamine is known to induce psychotomimetic and dissociative effects. Additionally, the efficacy and safety of ketamine in patients with psychotic depression has not been established as most clinical trials have excluded these persons due to the theorized risk of aggravating psychotic symptoms. Notwithstanding, it is not established empirically that ketamine treatment in psychotic depression would predictably amplify psychotic symptoms and/or overall illness presentation. Future trials evaluating ketamine in depression should include patients with psychotic features to inform whether ketamine is safe and effective in this subpopulation., (Copyright © 2021. Published by Elsevier B.V.)

A concise and efficient synthesis of the proposed structure of aaptoline A, a 7,8-dihydroxyquinoline derived from a marine sponge, was accomplished in seven steps with a 52% overall yield. A key feature of the synthesis is the high-yielding Ag(I)-catalyzed cycloisomerization of the N -propargylaniline precursor to afford the quinoline carboxylate skeleton from acid-labile methyl aminobenzoate. However, the spectral data of the synthesized aaptoline A were not consistent with those of previous studies. The structure of the synthesized aaptoline A was confirmed by combined 2D NMR analysis. Additional studies on the bioactivity of the synthesized aaptoline A revealed that it has the ability to protect dopaminergic neurons against MPP + -induced neurotoxicity in C. elegans . In addition, impaired food-sensing ability and travel distance capability in C. elegans were significantly ameliorated by aaptoline A treatment, suggesting that aaptoline A can protect dopaminergic neurons both morphologically and functionally.

Background: In recent years, ketamine and esketamine treatment have demonstrated rapid antidepressant effects in adults with treatment-resistant depression (TRD). Hitherto, relatively few studies have reported the effect of ketamine/esketamine treatment on functional outcomes (e.g., psychosocial functioning, workplace functioning). Herein, we review and synthesize extant literature reporting functional outcomes with ketamine/esketamine treatment in adults with TRD., Methods: A systematic review of clinical studies reporting subjective or objective ratings of general functioning as primary or secondary outcomes was performed., Results: Four randomized-controlled trials, one open-label clinical study and one case series reported on the efficacy of ketamine/esketamine on subjective measures of general functioning. Overall, mixed results were reported with respect to the effect across disparate functional measures (e.g., Sheehan Disability Scale [SDS]) using ketamine/esketamine. A single study demonstrated a significant decrease (i.e., improvement) in SDS total scores in TRD with esketamine treatment; most studies, however, did not report on functional outcomes and have functional outcomes as a (co)-primary outcome measure., Limitations: Clinical studies that were included evaluated work- or social-related disability as a secondary outcome using subjective rating scales., Conclusion: Functional outcomes in adults with TRD receiving ketamine/esketamine was insufficiently characterized. Available evidence indicates that improvements in general psychosocial functioning is apparent. The association, if any, between symptomatic improvement and functional improvement in TRD, as well as the temporality to improve functioning, are future research vistas., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To evaluate the safety, tolerability, and effectiveness of repeated doses of intravenous (IV) ketamine in older adults (i.e., ≥60 years of age) with treatment-resistant depression., Method: In this case series, fifty-three older adults (M age  = 67, SD = 6; 57% female [n = 30]) received 4 IV ketamine infusions, administered over 1-2 weeks. Effectiveness of IV ketamine was measured using the Quick Inventory for Depressive Symptomatology-Self Report 16 (QIDS-SR16) approximately 2 days after infusions 1-3, and 1-2 weeks after infusion 4. Safety was measured as hemodynamic changes before, during, immediately after, and 20 minutes after each infusion. Tolerability was assessed via systematic reporting of treatment-emergent adverse events during and after each infusion, in addition to symptoms of dissociation measured using the Clinician Administered Dissociative States Scale. Partial response (25%-50% symptomatic improvement from baseline), response (≥50% symptomatic improvement from baseline), clinically significant improvements (≥25% symptomatic improvement from baseline), and remission rates (QIDS-SR16 ≤5) were also calculated., Results: Participants reported significant decreases in depressive symptoms (i.e., as measured by the QIDS-SR16) with repeated ketamine infusions (F(4, 92) = 7.412, p <0.001). The mean QIDS-SR16 score was 17.12 (SD = 5.33) at baseline and decreased to 12.52 (SD = 5.79) following 4 infusions. After 4 infusions, 31% (n = 8) of participants partially responded to IV ketamine, 27% (n = 7) responded, 58% (n = 15) experienced clinically significant improvements, and 10% (n = 3) met remission criteria. Thirty-six participants (69%) experienced treatment-emergent hypertension during at least 1 infusion, and 10 (19%) required intervention with an antihypertensive. Drowsiness was the most commonly reported adverse event (50% of infusions; n = 73)., Conclusion: Ketamine was associated with transient treatment-emergent hypertension. Response and remission rates were comparable to those reported in general adult samples. Findings are limited by the open-label, chart review nature of this study., (Copyright © 2021 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The efficacy of monoamine-based antidepressants in adults with major depressive disorder (MDD) is attenuated in persons with greater pre-treatment functional impairment. Herein, we investigated whether pre-treatment functioning in outpatients with treatment-resistant depression (TRD) moderates response to intravenous (IV) ketamine., Methods: Adults (N= 326; M age  = 45) with DSM-5-defined MDD or bipolar disorder and TRD received repeat-dose IV ketamine at a community-based clinic. Function was evaluated with the Sheehan Disability Scale (SDS), using total scores as well as scores on the subdomains of workplace/school, social life, and family life/home responsibilities. The primary dependent measure was change in depressive symptoms from pre-treatment to post-infusion 4, as measured by the Quick Inventory for Depressive Symptomatology-Self Report-16., Results: Total functional disability, as well as the subdomains of social life and family life/home responsibilities, significantly moderated response to IV ketamine (p = .003; p = .008; p = .008). Follow-up simple slopes analyses indicated a significant improvement in depressive symptoms across the functional domain spectrum (ps < .001). Above average functional disability (i.e., 1 SD > mean functional impairment within the sample) was associated with a greater change in depressive symptoms. Workplace function did not significantly moderate response to IV ketamine (p = .307), suggesting that individuals with significantly impaired workplace functioning may expect a similar response to ketamine as those with less workplace impairment., Conclusions: Symptomatic benefit with IV ketamine was observed in patients with TRD and significant pre-treatment functional impairment. The foregoing result has implications for mechanism of action, cost-effectiveness, and patient selection in adults with TRD receiving IV ketamine., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Depression severity and efficacy measurement scales employed for rapid-acting treatments (e.g., ketamine) were initially validated in adults receiving conventional monoamine-based antidepressants. The emergence of rapid-acting antidepressants in psychiatry provides the impetus for outcome measures that have been validated as sensitive to change with rapid-acting treatments. Herein, we provide results validating the McIntyre and Rosenblat Rapid Response Scale (MARRRS)., Methods: Adults with treatment-resistant depression (TRD) receiving intravenous (IV) ketamine had depressive symptoms measured with the 16-Item Quick Inventory Depressive Symptoms Self-Report (QIDS-SR-16) and MARRRS at baseline and as a repeated measure across an acute course of four infusions. The MARRRS is a self-report measure assessing depressive symptoms during the past 72 hours., Results: Sixty-four patients (M age  = 45.4 ± 13.5) were included. The MARRRS had a high internal consistency across acute infusions as determined by Cronbach's alpha (0.84 to 0.94). There was significant convergent validity between the QIDS-SR-16 and MARRRS total scores across infusions (rs(292) = .87, p < .001); the MARRRS was also sensitive to change (rs(49) = .70, p < .001). Exploratory factor analysis revealed that MARRRS items loaded onto two factors (i.e., dysphoria and psychic anxiety) accounting for 63.4% of the total variance., Limitations: Heterogenous sample of adults with TRD receiving open-label treatment without placebo comparison., Conclusion: The MARRRS is a brief validated self-report metric of depression symptom severity that is sensitive to change with the rapid-acting antidepressant ketamine. Measuring outcomes with the MARRRS informs treatment progress and facilitates treatment decisions in persons receiving the rapid-acting antidepressant ketamine. Studies of other rapid-acting antidepressants should incorporate outcome measures that are validated as sensitive to change with rapid-acting antidepressants., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Ketamine treatment is capable of significant and rapid symptom improvement in adults with treatment-resistant depression (TRD). A limitation of ketamine treatment in TRD is the relatively short duration of time to relapse (e.g., median 2-4 weeks). The objective of the systematic review herein is to identify strategies capable of prolonging the acute efficacy of ketamine in adults with TRD., Methods: PubMed/MEDLINE databases were searched from inception to December 2020 for clinical studies written in English using the following key terms: ketamine, prolong, and depression. A total of 454 articles were identified from the literature search which included all clinical studies regarding prolonging the antidepressant effects of ketamine. Twenty-two articles were included: ten randomized controlled trials (RCTs), eight prospective open-label trials, one retrospective chart review, and three case reports. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for data extraction. The primary outcome was prolonged effect, defined as statistically significant antidepressant effects following acute ketamine treatment., Results: A total of 454 articles were identified, and 22 articles were included. Different treatment modalites including pharmacological interventions, manualized-based psychotherapies, electroconvulsive therapy, transcranial magnetic stimulation, and intravenous monotherapy were examined to determine their impact on the prolongation of antidepressant effects following acute ketamine treatment. No treatment modality, other than repeat-dose IV ketamine, has demonstrated ability to significantly prolong the acute efficacy of IV ketamine in TRD., Conclusion: Hitherto, available open-label data and controlled trial data support repeat administration of IV ketamine as an effective strategy to prolong the efficacy of ketamine's antidepressant effects (although not the focus of the study herein, maintenance repeat-dose esketamine treatment is proven effective in esketamine responders). There is a need to identify multimodality strategies that are safe and capable of prolonging the efficacy of ketamine in adults with TRD.

Objective: Converging evidence suggests abnormalities in monetary reward processing may underlie the shared pathophysiology between major depressive disorder and obesity. As such, there is a need to parse deficits in specific subcomponents of monetary reward functioning (i.e., valuation, learning and anticipation)., Methods: PsycINFO, Google Scholar and PubMed databases were searched for English-language articles published between database inception to June 6th, 2020. Studies were identified using the following medical search heading (MeSH) terms and search strings: (reward (valuation OR motivation OR anticipation OR learning OR functioning OR decision-making OR reinforcement)) AND ((obesity OR overweight OR obese)., Results: Findings were reviewed from 11 studies evaluating the association between obesity and monetary reward processing. Four studies found significant differences in reward learning in individuals with obesity compared to normal-weight participants. Five studies found body mass index (BMI) to be predictive of willingness to expend effort (i.e., valuation) for a monetary reward. Three studies found changes in neural activations in the ventral striatum during anticipatory phases preceding receipt of a monetary reward in participants with obesity., Conclusions: Participants with obesity demonstrated significantly poorer performance in task-based measures of reward learning, valuation, and anticipation, resulting in lower monetary reward outcomes across all studies compared to healthy controls. Notably, participants with obesity and comorbid depression performed worse than participants with no comorbid depression., Limitations: There persists heterogeneity between studies with regards to inclusion of mood disorder populations and exclusion of psychiatric comorbidities in groups with obesity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Women are disproportionately represented amongst samples of adults with treatment-resistant depression (TRD). Ketamine has demonstrated rapid and robust efficacy in adults with TRD. Herein, we sought to determine whether the effectiveness of intravenous (IV) ketamine was influenced by menopausal status in women with TRD. We defined premenopausal women as those under the age of 45 (n = 52), while postmenopausal women (n = 54) were those over the age of 51. Participants received four IV ketamine infusions over one-to-two weeks at a community-based center for adults with TRD. The primary outcome of interest was the change in depressive symptom severity as measured by the Quick Inventory of Depressive Symptomatology Self-Report 16 (QIDS-SR 16 ) following four infusions, compared to pretreatment. The secondary outcomes were improvements in suicidal ideation (SI; i.e., QIDS-SR 16 SI item), anxiety (i.e., Generalized Anxiety Disorder-7 scale), anhedonic severity (i.e., Snaith-Hamilton Pleasure Scale), and workplace and psychosocial function (i.e., Sheehan Disability Scale). Menopausal status did not influence overall treatment response, F (4, 280) = 1.83, p = .123, η p 2  = 0.025. Both premenopausal and postmenopausal participants demonstrated similar response rates (30% and 26%, respectively) and remission rates (both 13%) to IV ketamine treatment following four infusions. Premenopausal women experienced improvements in social function more rapidly than postmenopausal women, F (2, 174) = 1.65, p = .047, η p 2  = 0.019. Postmenopausal women experienced reduction in SI more rapidly than premenopausal women, F (4, 280) = 2.72, p = .030, η p 2  = 0.037. These preliminary post-hoc findings provide the impetus for future studies to investigate the moderational role of menopausal status, as defined by hormone levels, on response to IV ketamine for TRD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Intravenous (IV) ketamine has been shown to have rapid and robust antidepressant effects in adults with treatment-resistant depression (TRD). Urological toxicity has been observed in chronic ketamine abusers as evidenced by dysuria, urgency, and hematuria. The foregoing observation provides the basis for evaluating whether ketamine-induced urological toxicity (KIUT) is associated with sub-anesthetic doses of ketamine (0.5-1.0 mg/kg) in adults with mood disorders. The overarching objective of this article is to identify potential mechanisms of KIUT which appears to be dose and frequency dependent. Available research indicates that high-frequency ketamine is associated with disruption of the urothelial barrier as well as direct ketamine toxicity (i.e., decreased expression of junction proteins) in KIUT of the bladder. Chronic and high-frequency ketamine use is also associated with bladder inflammation mediated via neurogenic and IgE inflammation. Other non-mutually exclusive causes are nerve hyperplasia, hypersensitivity, cell apoptosis, microvascular damage, and overexpression of carcinogenic genes. Notwithstanding the evidence of KIUT in ketamine abusers, there is no evidence that ketamine and/or esketamine treatment in adults with mood disorders is associated with KIUT. However, all patients receiving ketamine/esketamine for mood disorder treatment should be queried about genitourinary symptoms during acute and, where applicable, maintenance dosing.

In this study, we evaluated the protective effects of damaurone D (DaD), a dihydropyranoaurone compound, on dopaminergic (DA) neurodegeneration in Caenorhabditis elegans. The results showed that DaD treatment could successfully increase the survival rate of the worms under MPP + exposure. Additionally, DaD protected against the MPP + -induced neurodegeneration in all eight DA neurons of the worms. Similarly, diminished DA neuronal damage was observed in the DaD-fed transgenic mutant overexpressing tyrosine hydroxylase. In addition, the corresponding behavioral impairment induced by MPP + was strongly improved in the DaD treated worms, implying DaD has protective properties for DA neuronal function. Then, we further investigated the effect of DaD on α-synuclein aggregation, a key pathogenesis of Parkinson's disease (PD). In this study, DaD reduced the fluorescence signals of transgenic mutants that carried YFP-fused α-synuclein. A similar reduction in expressions of α-synuclein was observed by Western blot. Interestingly, our result from the dot-blot assay demonstrated that the formation of oligomers was significantly attenuated by the DaD treatment. Furthermore, DaD improved the abnormal fat storage and shortened lifespan of the animals with the same genetic background which supports the beneficial action of DaD on the α-synuclein-induced DA neurodegeneration. These results demonstrate that DaD could protect against both chemical- and genetic-induced DA neurodegeneration possibly through the modulation of oxidative stress, DA metabolism, and α-synuclein toxicity. Based on our present findings, we suggest that DaD might have a potential therapeutic role in Parkinson's disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Early symptomatic improvement with monoamine-based antidepressants is predictive of treatment response. The objective of this study was to determine if early symptomatic improvements with intravenous (IV) ketamine predicted treatment response to an acute course of four infusions., Method: 134 adults with treatment resistant depression (TRD) received four ketamine infusions over one to two weeks. Depressive symptoms were measured using the Quick Inventory for Depressive Symptomatology Self-Report 16 (QIDS-SR 16 ) at baseline and post-infusions 1, 2, 3, and 4. Early improvement was defined as ≥20% reduction in QIDS-SR 16 scores after the first or second infusion. Linear models were used to determine whether early improvement was associated with post-infusion 4 QIDS-SR 16 scores after controlling for baseline characteristics., Results: Early improvement post-infusion 1 (β = -3.52, 95% BCa CI [-5.40, -1.78]) and 2 (β = -3.16, 95% BCa CI [-5.75, -1.59]) both significantly predicted QIDS-SR 16 scores post-infusion 4. Early improvers had significantly lower QIDS-SR 16 scores at post-infusion 4 (post-infusion 1 improvers: M = 9.8, SD = 4.5; post-infusion 2 improvers: M = 10.6, SD = 5.7) compared to non-early improvers (post-infusion 1 non-improvers: M = 13.7, SD = 5.8; post-infusion 2 non-improvers: M = 14.1, SD = 5.3) when controlling for baseline characteristics. The majority (58%) of individuals who did not improve post-infusions 1 or 2 still experienced an antidepressant response or partial response (≥20% reduction in QIDS-SR 16 ) post-infusion 4., Limitations: This is a post-hoc analysis of an open-label study., Conclusion: Early improvement was associated with greater antidepressant effects following a course of four ketamine infusions. However, individuals who did not show early improvements still had a high likelihood of experiencing clinically significant symptom reduction after the fourth infusion, suggesting that completing four infusions, regardless of early symptom changes, is appropriate and merited., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Dissociation is a treatment-emergent adverse event commonly associated with IV ketamine, often measured using the 23-item Clinician-Administered Dissociative States Scale (CADSS). The objective of this study was to develop a short form version of the CADSS for easier clinical use., Methods: Retrospective data of 260 patients with treatment-resistant depression (TRD) receiving IV ketamine were randomly divided into two datasets. The first dataset (n = 130) was leveraged to develop a brief 6-item version of the CADSS (CADSS-6) based on items most sensitive to ketamine-induced dissociation. The CADSS-6 questions were then applied to the second dataset (n = 130) and the Spearman's correlation between the full-length CADSS and the CADSS-6 were assessed., Results: The CADSS-6 was developed from questions 1, 2, 6, 7, 15, and 22 from the full length CADSS. There was a strong significant correlation between the CADSS-6 total score and the CADSS total score at infusions 1 (rs(106) = 0.92, p < 0.001), 2 (rs(100) = 0.91, p < 0.001), 3(rs(99) = 0.95, p < 0.001) and 4 (rs(102) = 0.94, p < 0.001)., Limitations: The CADSS-6 was developed using a retrospective data; therefore, the scale remains unvalidated in this population., Conclusions: The CADSS-6 presented herein was sensitive to dissociation experienced by patients receiving IV ketamine. Overall, the CADSS-6 was strongly correlated at each infusion with the full-length CADSS. While future studies should look to validate the CADSS-6 in a TRD sample, this scale offers clinicians a brief assessment that can be used to characterize symptoms of dissociation., (Copyright © 2020. Published by Elsevier B.V.)

Cognitive impairment is common in bipolar disorder and is emerging as a therapeutic target to enhance quality of life and function. A systematic search was conducted on PubMed, PsycInfo, Cochrane, clinicaltrials.gov, and Embase databases for blinded or open-label randomized controlled trials evaluating the pro-cognitive effects of pharmacological, neurostimulation, or psychological interventions for bipolar disorder. Twenty-two trials were identified, evaluating a total of 16 different pro-cognitive interventions. The methodological quality of the identified trials were assessed using the Cochrane Risk of Bias tool. Currently, no intervention (i.e., pharmacologic, neurostimulation, cognitive remediation) has demonstrated robust and independent pro-cognitive effects in adults with bipolar disorder. Findings are preliminary and methodological limitations limit the interpretation of results. Methodological considerations including, but not limited to, the enrichment with populations with pre-treatment cognitive impairment, as well as the inclusion of individuals who are in remission are encouraged. Future trials may also consider targeting interventions to specific cognitive subgroups and the use of biomarkers of cognitive function.

Objective: To determine the effectiveness of intravenous (IV) ketamine on anxiety, irritability, agitation, and suicidality, in adults with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD)., Method: Adults (N = 201) with treatment-resistant MDD or BD received repeat-dose IV ketamine treatment at a community-based clinic. Mixed features were measured using symptoms of anxiety, irritability, and agitation (AIA), as measured by the Generalized Anxiety Disorder-7 (GAD-7) scale. The Quick Inventory for Depressive Symptomatology Self-Report-16 (QIDS-SR 16 ) was used to measure overall treatment response, and the QIDS-SR 16 suicidal ideation (SI) item was used to measure change in SI symptoms with ketamine treatment. The anxiety, irritability, and agitation items on the GAD-7 were used to assess effectiveness of IV ketamine in treating symptoms of mixed features., Results: In this retrospective analysis, 113 participants met AIA criteria. Participants with AIA experienced a significantly greater reduction in overall depressive symptoms (F(1, 558) = 9.49, P = .002), SI (F(1, 558) = 3.103, P = .079), anxiety (F(1, 198) = 5.52, P = .007), irritability (F(1, 198) = 28.35, P < .001), and agitation as measured by "trouble relaxing" (F(1, 198) = 6.70, P = .010) from baseline compared to the non-AIA group, regardless of number of treatments received., Conclusions: Our preliminary results suggest that IV ketamine is effective in rapidly treating AIA and SI in adults with treatment-resistant mood disorders. This observation suggests that IV ketamine could be considered a treatment alternative for adults with MDD or BD presenting with mixed features., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Mental illness has a chronic course of illness with a number of clinical manifestations. Affected individuals experience significant functional, emotional, cognitive, and/or behavioral impairments. The growing prevalence of mental illness has been associated with significant social and economic costs. Indeed, the economic burden of mental illness is estimated to exceed $1.8 trillion USD over the next 30 years. A significant number of individuals affected by mental illness fail to respond to first-line treatment options. Therefore, there remains an unmet need for rapidly attenuating therapeutic options for mental health disorders with minimal social and economic burden., Areas Covered: The paucity of novel treatment options warrants a renewed investigation of psychedelic-based psychotherapy. Herein, the authors will evaluate the therapeutic potential of traditional psychedelics, psilocybin, and MDMA, in the treatment of mental illness with a narrative review of available literature., Expert Opinion: Psychedelics, such as psilocybin and MDMA, offer an alternative avenue of therapy for many mental health disorders. Available evidence indicates that psychedelics may offer a single-dose, rapid effect model that have robust effects with treatment-resistant mental disorders and a unique advantage as a possible monotherapy for mental illness. Novel clinical trials that evaluate the safety, tolerability, and efficacy in clinically representative populations are warranted.

In this study, we investigated the longevity effects of hispidol, a 6,4'-dihydroxyaurone, using the Caenorhabditis elegans model system. Our lifespan assay data revealed that hispidol could prolong the lifespan of wild-type worms under normal culture condition. Moreover, hispidol increased the survival rate of the worms against a heat stress condition through up-regulated expressions of HSP-16.2. Similarly, hispidol protected worms from paraquat-induced oxidative stress. We also found that the hispidol elevated the activities of antioxidant enzymes, thereby attenuating the generation of intracellular reactive oxygen species. These results suggest that the enhancement of lifespan and stress resistance by the hispidol treatment might be attributed to its strong in vivo antioxidant capacity and regulation of stress proteins. Further tests on the aging-related factors revealed that hispidol could regulate the speed of pharyngeal pumping, indicating the association of dietary restriction with the hispidol-mediated longevity. However, there were no significant alterations in the body length of the worms between the groups. We then investigated the effects of hispidol on body movement and lipofuscin accumulation in aged worms. Interestingly, these healthspan parameters were strongly improved by the hispidol treatment. Our genetic studies showed no significant change in the lifespan of the daf-16 null mutants by hispidol supplementation. In addition, enhanced nuclear translocation of DAF-16 was observed in the hispidol-fed DAF-16::GFP fused transgenic mutants, suggesting the requirement of DAF-16/FOXO activation for the longevity effect of hispidol., (© 2020 International Union of Biochemistry and Molecular Biology.)

Background: Anhedonia is a trans-diagnostic, multidimensional phenotype that mediates patient outcomes and suicidality. Convergent evidence suggests that ketamine may be effective in targeting measures of anhedonia in adults with treatment resistant depression (TRD)., Methods: This retrospective, post-hoc analysis included 203 (x̄ = 45 ± 14.6 years of age) patients receiving four infusions of intravenous (IV) ketamine at a community-based clinic. The primary outcome measure was change in anhedonia severity, as measured by the Snaith-Hamilton Pleasure Scale (SHAPS). Secondary measures sought to determine if improvement on the SHAPS mediated the effect of repeated IV ketamine infusions on symptoms of depression and suicidal ideations, as measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR 16 ) and anxiety, as measured using the Generalized Anxiety Disorder-7 (GAD-7)., Results: After adjusting for age, sex, primary diagnosis, concomitant medication, body mass index, and baseline depression severity, there was a statistically significant reduction in symptoms of anhedonia with IV ketamine treatment (F (2, 235.6) = 31.6, p < 0.001). Improvements in depressive symptoms, suicidal ideation, and anxiety symptoms with repeated-dose IV ketamine were significantly partially mediated by reduction in anhedonic severity. Moreover, the combination of number of infusions received and change in anhedonic severity accounted for 26% of the variance in depressive score improvements., Limitations: This is a post-hoc analysis of retrospective data and lacks a control group., Conclusion: Ketamine was effective in improving measures of anhedonia in this large, well-characterized community-based sample of adults with TRD. Improvements in anhedonia also partially mediated the significant improvement in depressive symptoms, suicidality, and anxiety., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Rigorous clinical trials suggest ketamine is safe and well-tolerated in patients with treatment-resistant depression (TRD). There is a paucity of data on the safety and tolerability of ketamine in community-based clinics treating patients with TRD., Methods: Retrospective data was analyzed from 203 patients with TRD who received repeat-dose IV ketamine. Safety was operationalized as hemodynamic changes. Tolerability was evaluated through the reporting of adverse events and dissociation symptom severity, as measured by the Clinician-Administered Dissociative States Scale., Results: Ketamine was well-tolerated, with less than 5% of patients withdrawing due to tolerability concerns. Blood pressure significantly increased during infusion, with 44.3% meeting criteria for treatment-emergent hypertension (i.e., blood pressure ≥ 165/100 mmHg). 12% of patients exhibiting hypertension required pharmacological intervention. The most frequently reported adverse events included drowsiness (56.4%), dizziness (45.2%), dissociation (35.6%), and nausea (13.3%). Dissociation severity significantly attenuated after the first infusion, but plateaued for subsequent infusions., Conclusion: Intravenous ketamine was safe and well-tolerated. Hypertension was commonly observed and was often transient. Dissociation was most frequently reported after the first infusion but remained a consistent but not treatment-limiting adverse event thereafter. No patients exhibited psychosis, mania, or new onset suicidality with IV ketamine.

Objectives: Metabolically based distinctions for disturbances in glucose and insulin may provide meaningful insights both clinically and mechanistically., Methods: Data were derived from 352 subjects of previously completed clinical studies with a mood disorder (MD) (bipolar disorder: n = 179, major depressive disorder: n = 173) and 218 healthy controls from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy. We conducted a factor analysis to replicate a priori dissociable factors informed by glucose and insulin levels and indices of insulin resistance and beta-cell function: elevated insulin and insulin resistance ("insulin-IR"), and increased fasting glucose and reduced insulin secretion ("glucotoxicity"). Cluster analyses were conducted, separately in men and women, to evaluate the clinical relevance of subtyping individuals with MDs using insulin-IR and glucotoxicity (GT) factor scores., Results: Factors insulin-IR and GT explained 92.64% and 92.09% of the variance in men and women respectively. Three clusters were replicated in men and women separately: metabolically healthy (MH), high GT, and insulin-resistant (IR). After adjusting for age, gender, study cohort, MD diagnosis, and antipsychotics use, body mass index (BMI) and mean arterial pressure were higher in IR- vs GT- or MH-clustered individuals; GT-clustered individuals had more metabolic syndrome components and higher C-reactive protein. Glucotoxic-clustered subjects reported greater impairments in cognitive function and global functioning when compared to MH- or IR-clustered subjects., Conclusions: Using simple, cost-effective, and accessible measures, we identified stable, gender-convergent, subgroups of individuals that significantly diverged on measures of cognitive dysfunction, self-reported anhedonia, functional disability, BMI, and blood pressure., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction : Approximately 50% of adults with major depressive disorder (MDD) who receive a first-line antidepressant treatment, at an appropriate dose, do not achieve an adequate response. Brexpiprazole is a novel serotonin-dopamine activity modulator in the second generation/atypical antipsychotic class that was approved by the United States Food & Drug Administration in 2015 for use as an adjunctive agent in the treatment of MDD inadequately responsive to antidepressant treatment. In general, second generation/atypical antipsychotics are widely used in the treatment of treatment resistant depression with brexpiprazole providing preliminary evidence for broad-spectrum efficacy across multiple domains affected by MDD, providing a basis for further elucidating its mechanistic effects to inform novel drug discovery. Areas covered : The review herein presents the evidence base for the use of brexpiprazole as an augmentation agent to antidepressants in individuals with treatment resistant MDD, including its efficacy, safety, and tolerability profile. Expert opinion : Brexpiprazole has been demonstrated to be effective and safe to use as an augmentation agent to antidepressant treatment among individuals with treatment resistant MDD due to its considerably improved tolerability profile when compared to other second generation/atypical antipsychotics; however, it is important to exercise clinical judgment when selecting disparate augmentation agents on a case-by-case basis weighing individual risks versus benefits.

Introduction: Machine learning capability holds promise to inform disease models, the discovery and development of novel disease modifying therapeutics and prevention strategies in psychiatry. Herein, we provide an introduction on how machine learning/Artificial Intelligence (AI) may instantiate such capabilities, as well as provide rationale for its application to psychiatry in both research and clinical ecosystems., Methods: Databases PubMed and PsycINFO were searched from 1966 to June 2016 for keywords:Big Data, Machine Learning, Precision Medicine, Artificial Intelligence, Mental Health, Mental Disease, Psychiatry, Data Mining, RDoC, and Research Domain Criteria. Articles selected for review were those that were determined to be aligned with the objective of this particular paper., Results: Results indicate that AI is a viable option to build useful predictors of outcome while offering objective and comparable accuracy metrics, a unique opportunity, particularly in mental health research. The approach has also consistently brought notable insight into disease models through processing the vast amount of already available multi-domain, semi-structured medical data. The opportunity for AI in psychiatry, in addition to disease-model refinement, is in characterizing those at risk, and it is likely also relevant to personalizing and discovering therapeutics., Conclusions: Machine learning currently provides an opportunity to parse disease models in complex, multi-factorial disease states (e.g. mental disorders) and could possibly inform treatment selection with existing therapies and provide bases for domain-based therapeutic discovery., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Animal models of central nervous system (CNS) demyelination, including toxin-induced focal demyelination and immune-mediated demyelination through experimental autoimmune encephalomyelitis (EAE), have provided valuable insights into the mechanisms of neuroinflammation and CNS remyelination. However, the ability to track changes in transcripts, proteins, and metabolites, as well as cellular populations during the evolution of a focal lesion, has remained challenging. Here, we developed a method to label CNS demyelinating lesions by the intraperitoneal injection of a vital dye, neutral red (NR), into mice before killing. We demonstrate that NR-labeled lesions can be easily identified on the intact spinal cord in both lysolecithin- and EAE-mediated demyelination models. Using fluorescence microscopy, we detected NR in activated macrophages/microglia and astrocytes, but not in oligodendrocytes present in lesions. Importantly, we successfully performed RT-qPCR, Western blot, flow cytometry, and mass spectrometry analysis of precisely dissected NR-labeled lesions at 5, 10, and 20 d postlesion (dpl) and found differential changes in transcripts, proteins, cell populations, and metabolites in lesions over the course of remyelination. Therefore, NR administration is a simple and powerful method to track and analyze the detailed molecular, cellular, and metabolic changes that occur within the lesion microenvironment over time following CNS injury. Furthermore, this method can be used to identify molecular and metabolic pathways that regulate neuroinflammation and remyelination and facilitate the development of therapies to promote repair in demyelinating disorders such as multiple sclerosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: The aim of this study was to examine the role of perceived sleep quality in predicting subjective as well as objective cognitive function in adults with major depressive disorder (MDD)., Methods: Adults with recurrent MDD (n = 100) experiencing a major depressive episode of at least moderate severity and age-, sex-, and education-matched healthy controls (HC) (n = 100) were recruited to participate in a clinical trial validating the THINC-integrated tool (THINC-it; NCT02508493) for cognitive function. The THINC-it includes subjective and objective measures of cognitive function. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI)., Results: Compared with HC, individuals with MDD reported significantly poorer sleep quality, as assessed by domain and global PSQI scores (all P values <.05). Both perceived sleep quality ( P < .001) and depression severity (P = .002) were found to independently predict impairments in subjective cognitive performance. Only perceived sleep quality predicted objective cognitive impairments (P = .017). Exploratory mediation analysis revealed depression severity to be a partial mediator of the relationship between perceived sleep quality and subjective cognitive performance (95% confidence interval [CI]: -0.56, -0.33)., Conclusions: The results indicate that the subjective and objective cognitive impairments are differentially related to perceived sleep quality and depression severity and emphasize the importance of treating sleep disturbances in MDD.