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Journal of Affective Disorders Sep 2024The absence of clinically-validated biomarkers or objective protocols hinders effective major depressive disorder (MDD) diagnosis. Compared to healthy control (HC), MDD...
BACKGROUND
The absence of clinically-validated biomarkers or objective protocols hinders effective major depressive disorder (MDD) diagnosis. Compared to healthy control (HC), MDD exhibits anomalies in plasma protein levels and neuroimaging presentations. Despite extensive machine learning studies in psychiatric diagnosis, a reliable tool integrating multi-modality data is still lacking.
METHODS
In this study, blood samples from 100 MDD and 100 HC were analyzed, along with MRI images from 46 MDD and 49 HC. Here, we devised a novel algorithm, integrating graph neural networks and attention modules, for MDD diagnosis based on inflammatory cytokines, neurotrophic factors, and Orexin A levels in the blood samples. Model performance was assessed via accuracy and F1 value in 3-fold cross-validation, comparing with 9 traditional algorithms. We then applied our algorithm to a dataset containing both the aforementioned protein quantifications and neuroimages, evaluating if integrating neuroimages into the model improves performance.
RESULTS
Compared to HC, MDD showed significant alterations in plasma protein levels and gray matter volume revealed by MRI. Our new algorithm exhibited superior performance, achieving an F1 value and accuracy of 0.9436 and 94.08 %, respectively. Integration of neuroimaging data enhanced our novel algorithm's performance, resulting in an improved F1 value and accuracy, reaching 0.9543 and 95.06 %.
LIMITATIONS
This single-center study with a small sample size requires future evaluations on a larger test set for improved reliability.
CONCLUSIONS
In comparison to traditional machine learning models, our newly developed MDD diagnostic model exhibited superior performance and showed promising potential for inclusion in routine clinical diagnosis for MDD.
Topics: Humans; Depressive Disorder, Major; Biomarkers; Magnetic Resonance Imaging; Adult; Female; Male; Neuroimaging; Neural Networks, Computer; Middle Aged; Algorithms; Orexins; Gray Matter; Cytokines; Machine Learning; Attention; Case-Control Studies
PubMed: 38824965
DOI: 10.1016/j.jad.2024.05.136 -
Journal of Ethnopharmacology Oct 2024Compound Zaoren Granules (CZG), an optimized herbal formulation based on the traditional Chinese medicine prescription Suanzaoren decoction, are designed specifically...
ETHNOPHARMACOLOGICAL RELEVANCE
Compound Zaoren Granules (CZG), an optimized herbal formulation based on the traditional Chinese medicine prescription Suanzaoren decoction, are designed specifically for insomnia treatment. However, the mechanisms underlying its efficacy in treating insomnia are not yet fully understood.
AIM OF THE STUDY
The research investigated the mechanisms of CZG's improvement in insomnia by regulating cAMP/CREB signaling pathway and metabolic profiles.
METHODS
The main components of CZG were characterized by liquid chromatography-mass spectrometry (LC-MS). Subsequently, these validated components were applied to network pharmacological analysis to predict signaling pathways associated with insomnia. We evaluated the effect of CZG on BV-2 cells in vitro. We also evaluated the behavioral indexes of CUMS combined with PCPA induced insomnia in rats. HE staining and Nissl staining were used to observe the pathological damage of hippocampus. ELISA was used to detect the levels of various neurotransmitters, orexins, HPA axis, and inflammatory factors in insomnia rats. Then we detected the expression of cAMP/CREB signaling pathway through ELISA, WB, and IHC. Finally, the metabolomics was further analyzed by using UHPLC-QTOF-MS/MS to investigate the changes in the hippocampus of insomnia rats and the possible metabolic pathways were also speculated.
RESULTS
The results of CZG in vitro experiments showed that CZG has protective and anti-inflammatory effects on LPS induced BV-2 cells. A total of 161 chemical components were identified in CZG. After conducting network pharmacology analysis through these confirmed components, we select the cAMP/CREB signaling pathway for further investigate. The behavioral research results on insomnia rats showed that CZG significantly prolonged sleep time, mitigated brain tissue pathological damage, and exhibited liver protective properties. CZG treats insomnia by regulating the content of various neurotransmitters, reducing levels of orexin, HPA axis, and inflammatory factors. It can also treat insomnia by upregulating the expression of the cAMP/CREB signaling pathway. Hippocampus metabolomics analysis identified 69 differential metabolites associated with insomnia. The metabolic pathways related to these differential metabolites have also been predicted.
CONCLUSION
These results indicate that CZG can significantly prolong sleep time. CZG is used to treat insomnia by regulating various neurotransmitters, HPA axis, inflammatory factors, cAMP/CREB signaling pathways, and metabolic disorders.
Topics: Animals; Signal Transduction; Drugs, Chinese Herbal; Male; Sleep Initiation and Maintenance Disorders; Cyclic AMP Response Element-Binding Protein; Rats; Cyclic AMP; Rats, Sprague-Dawley; Hippocampus; Metabolic Diseases; Mice; Cell Line; Network Pharmacology
PubMed: 38815875
DOI: 10.1016/j.jep.2024.118401 -
Postgraduate Medicine May 2024Appraise the evidence for daridorexant 50 mg and 25 mg versus placebo when treating chronic insomnia disorder in terms of number needed to treat (NNT), number needed... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Appraise the evidence for daridorexant 50 mg and 25 mg versus placebo when treating chronic insomnia disorder in terms of number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).
METHODS
NNT, NNH, and LHH were calculated from a 3-month pivotal Phase 3 study ( = 930; randomized 1:1:1 to daridorexant 50 mg, daridorexant 25 mg, or placebo once nightly). Wakefulness after sleep onset, latency to persistent sleep, self-reported total sleep time, Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), and Insomnia Severity Index were used for the NNT efficacy analysis. NNH safety analysis was performed using rates of adverse events (AEs) occurring in >1% of the participants in any arm. LHH was assessed for all NNT estimates, contrasting them with NNH estimates for somnolence, headache, and fatigue AEs.
RESULTS
NNT estimates for daridorexant 50 mg versus placebo were <10 for clinically meaningful thresholds across all outcomes. NNT estimates for daridorexant 25 mg versus placebo were not as robust as those observed for daridorexant 50 mg, with many values exceeding 10. NNH estimates for daridorexant 50 mg and 25 mg versus placebo did not show a statistically significant treatment difference except for falls, where NNH was negative for the daridorexant 50 mg group (-44 [95% CI -328; -21]; rate of falls was greater with placebo than for daridorexant 50 mg). All LHH ratios at Months 1 and 3 were >1 (except for daridorexant 25 mg for the IDSIQ alert/cognition domain), indicating that patients were more likely to respond to daridorexant 50 mg and 25 mg than to experience an AE of somnolence, headache, or fatigue.
CONCLUSION
Daridorexant 50 mg and 25 mg have a favorable benefit-risk ratio over 3 months. Daridorexant 50 mg demonstrated more robust (lower) NNT estimates versus placebo than daridorexant 25 mg.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Male; Female; Middle Aged; Adult; Numbers Needed To Treat; Double-Blind Method; Aged; Young Adult; Imidazoles; Pyrrolidines
PubMed: 38814132
DOI: 10.1080/00325481.2024.2359891 -
F1000Research 2024Insomnia is difficulty initiating or maintaining sleep for at least three nights a week or more and lasting for at least 3 months. One of the molecules that play a role...
Insomnia is difficulty initiating or maintaining sleep for at least three nights a week or more and lasting for at least 3 months. One of the molecules that play a role in the circadian rhythm of arousal system is Orexin activates the p38-MAPK signaling pathway and increases phosphorylated ERK1/2 levels. (CA) has a role in the signal work of the MAPK/ERK, Akt, and p38 path in many various diseases. The research method used is true laboratory experimental. The research approach used was randomized control group post-test only. Zebrafish embryos aged 0-7 dpf were used in this study. The treatment group consisted of 5 groups: normal, insomnia, insomnia + 2.5 μg/mL CA, insomnia + 5 μg/mL CA, and insomnia + 10 μg/mL CA. The locomotor motion of zebrafish larvae was observed using Basler cameras on days five-, six- and seven-day post fertilization (dpf), then analyzed by using Western Blot method. The results proved that exposure to CA extract was able to reduce the expression of orexin (91963 ± 9129) and p38 (117425 ± 6398) as an arousal trigger in the sleep-wake cycle, with the most optimal concentration of CA 5 μg/mL. Exposure to CA extract was also able to reduce the expression of ERK (94795 ± 30830) and Akt (60113.5 ± 27833.5) with an optimum concentration of CA 2.5 μg/mL. Exposure to CA extract was able to improve the sleep activity of zebrafish larvae insomnia model by extending the total inactivity time ( ) and shortening the duration of first sleep ( ) in light and dark phases through inhibition of orexin, ERK, p38, and Akt.
Topics: Animals; Zebrafish; Orexins; Sleep Initiation and Maintenance Disorders; Larva; Proto-Oncogene Proteins c-akt; Plant Extracts; p38 Mitogen-Activated Protein Kinases; Triterpenes; Centella; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Ethanol; MAP Kinase Signaling System
PubMed: 38812527
DOI: 10.12688/f1000research.141064.1 -
Molecular and Cellular Biochemistry May 2024Renin angiotensin system (RAS) alters various mechanisms related to muscle wasting. The RAS system consists of classical and non-classical pathways, which mostly... (Review)
Review
Renin angiotensin system (RAS) alters various mechanisms related to muscle wasting. The RAS system consists of classical and non-classical pathways, which mostly function differently. Classical RAS pathway, operates through angiotensin II (AngII) and angiotensin type 1 receptors, is associated with muscle wasting and sarcopenia. On the other hand, the non-classical RAS pathway, which operates through angiotensin 1-7 and Mas receptor, is protective against sarcopenia. The classical RAS pathway might induce muscle wasting by variety of mechanisms. AngII reduces body weight, via reduction in food intake, possibly by decreasing hypothalamic expression of orexin and neuropeptide Y, insulin like growth factor-1 (IGF-1) and mammalian target of rapamycin (mTOR), signaling, AngII increases skeletal muscle proteolysis by forkhead box transcription factors (FOXO), caspase activation and muscle RING-finger protein-1 transcription. Furthermore, AngII infusion in skeletal muscle reduces phospho-Bad (Ser136) expression and induces apoptosis through increased cytochrome c release and DNA fragmentation. Additionally, Renin angiotensin system activation through AT1R and AngII stimulates tumor necrosis factor-α, and interleukin-6 which induces muscle wasting, Last but not least classical RAS pathway, induce oxidative stress, disturb mitochondrial energy metabolism, and muscle satellite cells which all lead to muscle wasting and decrease muscle regeneration. On the contrary, the non-classical RAS pathway functions oppositely to mitigate these mechanisms and protects against muscle wasting. In this review, we summarize the mechanisms of RAS-induced muscle wasting and putative implications for clinical practice. We also emphasize the areas of uncertainties and suggest potential research areas.
PubMed: 38811433
DOI: 10.1007/s11010-024-05043-8 -
BMC Psychiatry May 2024To examine whether the "Effectiveness of Guideline for Dissemination and Education in psychiatric treatment (EGIUDE)" project affects the rate of prescriptions of...
The effect of education regarding treatment guidelines for schizophrenia and major depressive disorders on psychiatrists' hypnotic medication prescribing behavior: a multicenter study.
BACKGROUND
To examine whether the "Effectiveness of Guideline for Dissemination and Education in psychiatric treatment (EGIUDE)" project affects the rate of prescriptions of hypnotic medication and the type of hypnotic medications prescribed among psychiatrists, for schizophrenia and major depressive disorder in Japan.
METHODS
The EGUIDE project is a nationwide prospective study of evidence-based clinical guidelines for schizophrenia and major depressive disorder in Japan. From 2016 to 2021, clinical and prescribing data from patients discharged from hospitals participating in the EGUIDE project were used to examine hypnotic medication prescriptions The prescribing rate of hypnotics and the prescribing rate of each type of hypnotic (benzodiazepine receptor agonist, nonbenzodiazepine receptor agonist, melatonin receptor agonist, and orexin receptor antagonist) were compared among patients who had been prescribed medication by psychiatrists participating in the EGUIDE project and patients who had been prescribed medication by nonparticipating psychiatrists. Multivariate logistic regression analysis was performed to examine the effect of the EGUIDE project on the prescription of hypnotic medications.
RESULTS
A total of 12,161 patients with schizophrenia and 6,167 patients with major depressive disorder were included. Psychiatrists participating in the EGUIDE project significantly reduced the rate of prescribing hypnotic medication and benzodiazepine receptor agonists for both schizophrenia (P < 0.001) and major depressive disorder (P < 0.001) patients.
CONCLUSION
This is the first study to investigate the educational effects of guidelines for the treatment of psychiatric disorders on psychiatrists in terms of prescribing hypnotic medications to patients. The EGUIDE project may play an important role in reducing hypnotic medication prescription rates, particularly with respect to benzodiazepine receptor agonists. The results suggest that the EGUIDE project may result in improved therapeutic behavior.
Topics: Humans; Depressive Disorder, Major; Schizophrenia; Male; Female; Hypnotics and Sedatives; Middle Aged; Practice Patterns, Physicians'; Japan; Adult; Practice Guidelines as Topic; Psychiatry; Prospective Studies; Drug Prescriptions; Psychiatrists
PubMed: 38807065
DOI: 10.1186/s12888-024-05816-x -
Expert Opinion on Drug Safety Jun 2024Package inserts for the FDA-approved dual orexin receptor antagonists (DORAs) suvorexant, lemborexant and daridorexant state that suicide risk should be monitored. It...
Association between dual orexin receptor antagonists (DORAs) and suicidality: reports to the United States Food and Drug Administration Adverse Event Reporting System (FAERS).
BACKGROUND
Package inserts for the FDA-approved dual orexin receptor antagonists (DORAs) suvorexant, lemborexant and daridorexant state that suicide risk should be monitored. It remains unknown whether suicidality is attributed to DORAs. We aim to evaluate suicidality associated with DORAs reported to the FDA Adverse Event Reporting System (FAERS).
METHODS
The reporting odds ratio (ROR) was determined with trazodone as the control. Significant disproportionate reporting was determined when 95% confidence intervals (CIs) did not encompass 1.0. We used information components (ICs) to calculate the lower limit of the 95% CI (IC). IC was significantly increased when the IC ≥0.
RESULTS
Suvorexant (0.025 ROR), lemborexant (0.019 ROR) and daridorexant (0.002 ROR) were significantly associated with lower odds of reported completed suicides compared to trazodone ( < 0.05). There was no significantly increased RORs for the DORAs regarding suicidal ideation, depression suicidal, suicidal behavior and suicide attempts. Nonsignificant associations between all parameters of suicidality were observed for each DORA using IC.
CONCLUSION
We did not find a significant association between any parameter of suicidality captured in the FAERS for each DORA. All persons treated for insomnia pharmacologically/non-pharmacologically should be evaluated for emergence/worsening of any suicidality aspect.
PubMed: 38804896
DOI: 10.1080/14740338.2024.2361300 -
Clinical Case Reports Jun 2024[This corrects the article DOI: 10.1002/ccr3.8740.].
[This corrects the article DOI: 10.1002/ccr3.8740.].
PubMed: 38799523
DOI: 10.1002/ccr3.8961 -
BioRxiv : the Preprint Server For... May 2024Glucose-inhibited (GI) neurons of the ventromedial hypothalamus (VMH) depend on neuronal nitric oxide synthase (nNOS) and AMP-activated protein kinase (AMPK) for...
Reducing neuronal nitric oxide synthase (nNOS) expression in the ventromedial hypothalamus (VMH) increases body weight and blood glucose levels while decreasing physical activity in female mice.
Glucose-inhibited (GI) neurons of the ventromedial hypothalamus (VMH) depend on neuronal nitric oxide synthase (nNOS) and AMP-activated protein kinase (AMPK) for activation in low glucose. The Lopez laboratory has shown that the effects of estrogen on brown fat thermogenesis and white fat browning require inhibition of VMH AMPK. This effect of estrogen was mediated by downstream lateral hypothalamus (LH) orexin neurons . We previously showed that estrogen inhibits activation of GI neurons in low glucose by inhibiting AMPK . Thus, we hypothesized that VMH AMPK- and nNOS-dependent GI neurons project to and inhibit orexin neurons. Estrogen inhibition of AMPK in GI neurons would then disinhibit orexin neurons and stimulate brown fat thermogenesis and white fat browning, leading to decreased body weight. To test this hypothesis, we reduced VMH nNOS expression using nNOS shRNA in female mice and measured body weight, adiposity, body temperature, white and brown fat uncoupling protein (UCP1; an index of thermogenesis and browning), locomotor activity, and blood glucose levels. Surprisingly, we saw no effect of reduced VMH nNOS expression on body temperature or UCP1. Instead, body weight and adiposity increased by 30% over 2 weeks post injection of nNOS shRNA. This was associated with increased blood glucose levels and decreased locomotor activity. We also found that VMH nNOS-GI neurons project to the LH. However, stimulation of VMH-LH projections increased excitatory glutamate input onto orexin neurons. Thus, our data do not support our original hypothesis. Excitation of orexin neurons has previously been shown to increase physical activity, leading to decreased blood glucose and body weight . We now hypothesize that VMH nNOS-GI neurons play a role in this latter function of orexin neurons.
PubMed: 38798316
DOI: 10.1101/2024.05.15.594324 -
Experimental Eye Research Jul 2024Orexin A and B (OXA and OXB) and their receptors are expressed in the majority of retinal neurons in humans, rats, and mice. Orexins modulate signal transmission between...
Orexin A and B (OXA and OXB) and their receptors are expressed in the majority of retinal neurons in humans, rats, and mice. Orexins modulate signal transmission between the different layers of the retina. The suprachiasmatic nucleus (SCN) and the retina are central and peripheral components of the body's biological clocks; respectively. The SCN receives photic information from the retina through the retinohypothalamic tract (RHT) to synchronize bodily functions with environmental changes. In present study, we aimed to investigate the impact of inhibiting retinal orexin receptors on the expression of retinal Bmal1 and c-fos, as well as hypothalamic c-fos, Bmal1, Vip, and PACAP at four different time-points (Zeitgeber time; ZT 3, 6, 11, and ZT-0). The intravitreal injection (IVI) of OX1R antagonist (SB-334867) and OX2R antagonist (JNJ-10397049) significantly up-regulated c-fos expression in the retina. Additionally, compared to the control group, the combined injection of SB-334867 and JNJ-10397049 showed a greater increase in retinal expression of this gene. Moreover, the expression of hypothalamic Vip and PACAP was significantly up-regulated in both the SB-334867 and JNJ-10397049 groups. In contrast, the expression of Bmal1 was down-regulated. Furthermore, the expression of hypothalamic c-fos was down-regulated in all groups treated with SB-334867 and JNJ-10397049. Additionally, the study demonstrated that blocking these receptors in the retina resulted in alterations in circadian rhythm parameters such as mesor, amplitude, and acrophase. Finally, it affected the phase of gene expression rhythms in both the retina and hypothalamus, as identified through cosinor analysis and the zero-amplitude test. This study represents the initial exploration of how retinal orexin receptors influence expression of rhythmic genes in the retina and hypothalamus. These findings could provide new insights into how the retina regulates the circadian rhythm in both regions and illuminate the role of the orexinergic system expression within the retina.
Topics: Animals; Male; Rats; Proto-Oncogene Proteins c-fos; Hypothalamus; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats, Wistar; Orexin Receptors; Retina; Vasoactive Intestinal Peptide; Naphthyridines; ARNTL Transcription Factors; Gene Expression Regulation; Orexin Receptor Antagonists; Benzoxazoles; Urea; Circadian Rhythm; Suprachiasmatic Nucleus; Dioxanes; Isoquinolines; Phenylurea Compounds; Pyridines
PubMed: 38797259
DOI: 10.1016/j.exer.2024.109943