-
Progress in Molecular Biology and... 2024Researchers are interested in drug repurposing or drug repositioning of existing pharmaceuticals because of rising costs and slower rates of new medication development.... (Review)
Review
Researchers are interested in drug repurposing or drug repositioning of existing pharmaceuticals because of rising costs and slower rates of new medication development. Other investigations that authorized these treatments used data from experimental research and off-label drug use. More research into the causes of depression could lead to more effective pharmaceutical repurposing efforts. In addition to the loss of neurotransmitters like serotonin and adrenaline, inflammation, inadequate blood flow, and neurotoxins are now thought to be plausible mechanisms. Because of these other mechanisms, repurposing drugs has resulted for treatment-resistant depression. This chapter focuses on therapeutic alternatives and their effectiveness in drug repositioning. Atypical antipsychotics, central nervous system stimulants, and neurotransmitter antagonists have investigated for possible repurposing. Nonetheless, extensive research is required to ensure their formulation, effectiveness, and regulatory compliance.
Topics: Drug Repositioning; Humans; Depression; Antidepressive Agents; Animals
PubMed: 38942546
DOI: 10.1016/bs.pmbts.2024.03.037 -
Environmental Pollution (Barking, Essex... Jun 2024Emerging pollutants, such as pharmaceuticals and microplastics have become a pressing concern due to their widespread presence and potential impacts on ecological...
Emerging pollutants, such as pharmaceuticals and microplastics have become a pressing concern due to their widespread presence and potential impacts on ecological systems. To assess the ecosystem-level effects of these pollutants within a multi-stressor context, we simulated real-world conditions by exposing a near-natural multi-trophic aquatic food web to a gradient of environmentally relevant concentrations of fluoxetine and microplastics in large mesocosms over a period of more than three months. We measured the biomass and abundance of different trophic groups, as well as ecological functions such as nutrient availability and decomposition rate. To explore the mechanisms underlying potential community and ecosystem-level effects, we also performed behavioral assays focusing on locomotion parameters as a response variable in three species: Daphnia magna (zooplankton prey), Chaoborus flavicans larvae (invertebrate pelagic predator of zooplankton) and Asellus aquaticus (benthic macroinvertebrate), using water from the mesocosms. Our mesocosm results demonstrate that presence of microplastics governs the response in phytoplankton biomass, with a weak non-monotonic dose-response relationship due to the interaction between microplastics and fluoxetine. However, exposure to fluoxetine evoked a strong non-monotonic dose-response in zooplankton abundance and microbial decomposition rate of plant material. In the behavioral assays, the locomotion of zooplankton prey D. magna showed a similar non-monotonic response primarily induced by fluoxetine. Its predator C. flavicans, however, showed a significant non-monotonic response governed by both microplastics and fluoxetine. The behavior of the decomposer A. aquaticus significantly decreased at higher fluoxetine concentrations, potentially leading to reduced decomposition rates near the sediment. Our study demonstrates that effects observed upon short-term exposure result in more pronounced ecosystem-level effects following chronic exposure.
PubMed: 38942279
DOI: 10.1016/j.envpol.2024.124439 -
Journal of Affective Disorders Jun 2024Early symptomatic improvement may predict treatment response in bipolar I disorder. Cariprazine has demonstrated early treatment effects in bipolar I depression and...
Early improvement with cariprazine as a predictor of antidepressant, anxiolytic, and antimanic response in bipolar I mania and depression: A pooled post hoc analysis of randomized cariprazine trials.
BACKGROUND
Early symptomatic improvement may predict treatment response in bipolar I disorder. Cariprazine has demonstrated early treatment effects in bipolar I depression and mania studies; therefore, we assessed whether early improvement with cariprazine predicts eventual treatment response.
METHODS
Post hoc analyses used pooled data from randomized, double-blind, placebo-controlled bipolar I depression (NCT02670538, NCT02670551) and mania (NCT00488618, NCT01058096, NCT01058668) trials. In depression studies (cariprazine 1.5 mg/d, 3 mg/d, or placebo), early improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A) total scores (≥25 % improvement at day 15) and subsequent depressive/anxiety symptom response status (≥50 % improvement at week 6) were assessed. In mania studies (cariprazine 3-12 mg/d or placebo), early improvement in Young Mania Rating Scale (YMRS) total scores (≥25 % improvement at day 7) and manic symptom response status (≥50 % improvement at week 3) were assessed.
RESULTS
Patients with bipolar I depression and early MADRS improvement were approximately 4- to 6-times as likely to achieve MADRS or HAM-A response than those without early improvement; patients with early HAM-A improvement were approximately 3- to 4-times as likely to achieve MADRS or HAM-A response. A subset of patients without early improvement with cariprazine 1.5 mg/d (20-31 %) subsequently responded following up-titration. Patients with mania and early YMRS improvement were approximately 5 times more likely to have manic symptom response than those without early improvement.
LIMITATIONS
Post hoc analysis; relatively short study durations; flexible-dosing (mania studies).
CONCLUSIONS
Early symptom improvement with cariprazine may inform therapeutic decisions for patients with bipolar I disorder.
PubMed: 38942209
DOI: 10.1016/j.jad.2024.06.100 -
Ageing Research Reviews Jun 2024Lithium therapy received approval during the 1970s, and it has been used for its antidepressant, antimanic, and anti-suicidal effects for acute and long-term prophylaxis... (Review)
Review
Lithium therapy received approval during the 1970s, and it has been used for its antidepressant, antimanic, and anti-suicidal effects for acute and long-term prophylaxis and treatment of bipolar disorder (BPD). These properties have been well established; however, the molecular and cellular mechanisms remain controversial. In the past few years, many studies demonstrated that at the cellular level, lithium acts as a regulator of neurogenesis, aging, and Ca homeostasis. At the molecular level, lithium modulates aging by inhibiting glycogen synthase kinase-3β (GSK-3β), and the phosphatidylinositol (PI) cycle; latter, lithium specifically inhibits inositol production, acting as a non-competitive inhibitor of inositol monophosphatase (IMPase). Mitochondria and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) have been related to lithium activity, and its regulation is mediated by GSK-3β degradation and inhibition. Lithium also impacts Ca homeostasis in the mitochondria modulating the function of the lithium-permeable mitochondrial Na-Caexchanger (NCLX), affecting Ca efflux from the mitochondrial matrix to the endoplasmic reticulum (ER). A close relationship between the protease Omi, GSK-3β, and PGC-1α has also been established. The purpose of this review is to summarize some of the intracellular mechanisms related to lithium activity and how, through them, neuronal aging could be controlled.
PubMed: 38942199
DOI: 10.1016/j.arr.2024.102396 -
Regulatory Toxicology and Pharmacology... Jun 2024Depressive disorders are one of the most common mental disorders globally and progress in treating these disorders has been hampered, in part, by a lack of suitable... (Review)
Review
Depressive disorders are one of the most common mental disorders globally and progress in treating these disorders has been hampered, in part, by a lack of suitable nonclinical efficacy tests. Two common tests used in nonclinical efficacy studies of antidepressants-the forced swim test (FST) and tail suspension test (TST)-have come under criticism in recent years for their inconsistency and lack of validity, yet they continue to be used in the pharmaceutical industry. In this review, we provide a rationale for why international pharmaceutical regulatory and guidance agencies should begin issuing direction on methods for non-clinical efficacy testing that traditionally use the FST and TST, particularly considering that some regulators, such as those in the U.S. and E.U., allow the authorization of clinical trials to proceed without requiring tests in animals. The area of antidepressant drug discovery represents an important opportunity for reducing the attrition of psychiatric drugs, harmonizing regulatory requirements, and reducing animal use. Specific recommendations for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) have been provided.
PubMed: 38942190
DOI: 10.1016/j.yrtph.2024.105666 -
Biochemical Pharmacology Jun 2024GPR56, also known as GPR56/ADGRG1, is a member of the ADGRG subgroup belonging to adhesion G protein-coupled receptors (aGPCRs). aGPCRs are the second largest subfamily... (Review)
Review
GPR56, also known as GPR56/ADGRG1, is a member of the ADGRG subgroup belonging to adhesion G protein-coupled receptors (aGPCRs). aGPCRs are the second largest subfamily of the GPCR superfamily, which is the largest family of membrane protein receptors in the human genome. Studies in recent years have demonstrated that GPR56 is integral to the normal development of the brain and functions as an important player in cortical development, suggesting that GPR56 is involved in many physiological processes. Indeed, aberrant expression of GPR56 has been implicated in multiple neurological and psychiatric disorders, including bilateral frontoparietal polymicrogyria (BFPP), depression and epilepsy. In a recent study, it was found that upregulated expression of GPR56 reduced depressive-like behaviours in an animal model of depression, indicating that GPR56 plays an important role in the antidepressant response. Given the link of GPR56 with the antidepressant response, the function of GPR56 has become a focus of research. Although GPR56 may be a potential target for the development of antidepressants, the underlying molecular mechanisms remain largely unknown. Therefore in this review, we will summarize the latest findings of GPR56 function in neurological and psychiatric disorders (depression, epilepsy, autism, and BFPP) and emphasize the mechanisms of GPR56 in activation and signalling in those conditions. After reviewing several studies, attributing to its significant biological functions and exceptionally long extracellular N-terminus that interacts with multiple ligands, we draw a conclusion that GPR56 may serve as an important drug target for neuropsychological diseases.
PubMed: 38942087
DOI: 10.1016/j.bcp.2024.116395 -
Molecular Genetics and Metabolism Jun 2024Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary...
Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis.
PubMed: 38941880
DOI: 10.1016/j.ymgme.2024.108516 -
Phytomedicine : International Journal... Jun 2024Since the pathogenesis of depression is complex, antidepressant therapy remains unsatisfactory. Recent evidence suggests a link between depression and lipid metabolism....
BACKGROUND
Since the pathogenesis of depression is complex, antidepressant therapy remains unsatisfactory. Recent evidence suggests a link between depression and lipid metabolism. Saikosaponin (SS) exhibits antidepression and lipid-regulating effects in modern pharmacology. However, it is unknown whether lipid regulation is the key mechanism of the SS antidepressant effect and how it works.
PURPOSE
In this study, we investigated the relationship between the antidepressant activity of SS and the regulation of lipid metabolism and explored potential mechanisms.
METHODS
APOE mice, in combination with the chronic unpredictable mild stress (CUMS) model, were used to study the relationship between SS antidepressant activity and lipid metabolism through behavioral, electrophysiological techniques, and non-targeted lipidomics. Western blot, primary cell culture technology, and laser speckle cerebral blood flow imaging were employed to elucidate potential mechanisms. GraphPad Prism was used for statistical analysis, and p < 0.05 was considered statistically significant.
RESULTS
APOE mice exhibit more severe depressive-like behavior and dysregulation of sphingolipid metabolism in CUMS. SS alleviates depressive behavior and cortical sphingolipid metabolism disorder caused by CUMS, but has no effect on APOE mice. SS alleviates the imbalance between ceramide (Cer) and sphingomyelin (SM) through acidic sphingomyelinase (AMSase). In addition, SS regulates neuronal glutamate release via sphingolipid metabolism, thereby alleviating the CUMS-induced inhibition of neurovascular coupling (regulates metabotropic glutamate receptor and IP3 receptor), which ameliorates the reduction of cerebral blood flow in depressed mice.
CONCLUSION
Our study highlights the role of lipid metabolism in the antidepressant activity of SS and explores its underlying mechanisms. This study provided new insights into the better understanding of the antidepressant mechanisms of phytomedicine while increasing the possibility of lipid metabolism as a therapeutic strategy for depression.
PubMed: 38941813
DOI: 10.1016/j.phymed.2024.155829 -
General Hospital Psychiatry Jun 2024Several medications are associated with delirium; however, studies with adequate statistical power are limited, and it is difficult to determine the effects of the...
OBJECTIVE
Several medications are associated with delirium; however, studies with adequate statistical power are limited, and it is difficult to determine the effects of the various concomitant medications used in clinical practice. Therefore, in this study, we aimed to comprehensively evaluate the safety signals of delirium-associated drugs using a spontaneous adverse event reporting system.
METHOD
The JAPIC AERS (Food and Drug Administration Adverse Event Reporting System pre-processed by the Japan Pharmaceutical Information Center) was used for the analysis in this pharmacovigilance study. The reporting odds ratio (ROR) for delirium was adjusted for using multivariate logistic regression analysis with sex, age, indication, and melatonin receptor agonist use, and 22 drug categories were targeted as covariates.
RESULTS
After excluding patients with missing information, 7,527,568 patients were included in the study. Delirium signals were detected even after adjusting for covariates in 17 drug categories, including benzodiazepines (adjusted ROR, 1.76; 95% confidence interval [CI], 1.64-1.89), opioids (adjusted ROR, 4.42; 95% CI, 4.21-4.64), and tricyclic antidepressants (adjusted ROR, 2.44; 95% CI, 2.20-2.71).
CONCLUSIONS
These findings suggest that many drug classes, such as benzodiazepines, are independent risk factors for delirium and strengthen the evidence of an association between delirium and medications.
PubMed: 38941744
DOI: 10.1016/j.genhosppsych.2024.06.012 -
Journal of AOAC International Jun 2024Reboxetine (RBX) is the first FDA-approved antidepressant drug of the selective noradrenaline reuptake inhibitors class. There is a serious need for a convenient...
Development of Two Green and High Throughput Microwell Spectrometric Platforms for Determination of Reboxetine, the First FDA-Approved Selective Noradrenaline Reuptake Inhibitor Antidepressant Drug.
BACKGROUND
Reboxetine (RBX) is the first FDA-approved antidepressant drug of the selective noradrenaline reuptake inhibitors class. There is a serious need for a convenient analytical tool for the quantitation of RBX in its dosage form.
OBJECTIVE
This study aims to the development and validation of two green and high throughput microwell spectrometric platforms for the pharmaceutical analysis of RBX.
METHODS
The two platforms, abbreviated as MW-AB and MW-FL, involved microwell-based analysis assisted with a multifunction microplate plate reader for measuring absorbance and fluorescence signals, respectively. The MW-AB and MW-FL platforms involved the formation of colored and fluorescent derivatives upon the reaction of RBX with oxidized pyrocatechol reagent (OPC) and tetracyanoquinodimethane (TCNQ), respectively. The absorbance of colored RBX-OPC derivative at 520 nm, and the fluorescence of RBX-TCNQ charge transfer complex at 283 nm and 484 nm for excitation and emission, respectively. The optimum conditions of both reactions were established, their molar ratios were determined, and reaction mechanisms were postulated.
RESULTS
Both platforms were optimized and validated according to the guidelines of the International Council on Harmonization. The limits of quantitation were 19.6 µg/mL and 27 ng/mL for MW-AB and MW-FL, respectively. Both platforms were applied with excellent reliability to the quantitation of RBX content in Edranox® tablets and their drug uniformity. The greenness levels of both platforms were assessed by two comprehensive tools, and the results confirmed the high level of greenness for both platforms.
CONCLUSIONS
Both platforms involved one-step reactions, adapted microwell analysis, and simultaneous handling of large number of samples. Therefore, they have the advantages of greenness and high throughput analysis.
HIGHLIGHTS
The proposed two platforms are valuable tools for the rapid quantitation of RBX.
PubMed: 38941495
DOI: 10.1093/jaoacint/qsae051