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The high comorbidity and mutually reinforcing relation between depression and cardiovascular disease have raised concerns about the cardiovascular risk of antidepressants. To gain a better understanding of this correlation, we performed a comprehensive evaluation regarding the types and degrees of cardiovascular adverse events (AEs) associated with 37 commonly prescribed antidepressants. AE reports from January 2004 to December 2023 were retrieved from the FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis was performed to identify antidepressant-related cardiovascular signals using the reporting odds ratio, proportional reporting ratio, and information component. Influencing factors of cardiovascular death, including age, sex, antidepressant choice, and concomitant medication, were explored. The underlying mechanisms of antidepressant-associated cardiovascular risk related to neurotransmitter transporters/receptors were further explored. The use of antidepressants was associated with eight categories of Standardized MedDRA Queries of cardiovascular events. Different antidepressants exerted varying types and degrees of cardiovascular risks along with contributions to death in reports with cardiovascular AEs. Among them, monoamine oxidase inhibitors had the highest risk of developing six cardiovascular event categories: torsades de pointes (TdP)/QT prolongation, hypertension, cardiac arrhythmias, cardiomyopathy, pulmonary hypertension, and ischaemic heart disease. Age, male and the use of 24 types of antidepressants and concomitant medications were positively correlated with death in cardiovascular AEs. The highest risk associated with antidepressants was found in amoxapine (OR = 5.00 [2.13, 11.75], P < 0.001), followed by moclobemide (OR = 3.66 [1.85, 7.24], P < 0.001). Correlation analysis indicated the occurrence of antidepressant-related TdP/QT prolongation, hypertension and cardiomyopathy was associated with the binding and uptake inhibition of dopamine and norepinephrine transporters as well as their selectivity over serotonin transporters. The retrospective analysis revealed that cardiovascular AEs were connected with antidepressant use, and the binding/uptake inhibitory potency and selectivity of neurotransmitters of antidepressants played an important role, providing a preliminary basis for further in-depth study of antidepressant-related cardiovascular toxicity. However, as an exploratory study, prospective studies are needed to validate our findings in the future. • Antidepressants induced cardiovascular adverse events, with varying types and degrees of risks and contributions to death. • Monoamine oxidase inhibitors had the highest risk of developing most cardiovascular events. • Cardiovascular risk of antidepressants was related to the binding/uptake potency of neurotransmitter transporters. [ABSTRACT FROM AUTHOR]

Background: Monoamine oxidase inhibitors (MAOIs) are considered third‐line treatments for treatment resistant depression; however, they are underused in clinical practice. Aims: This study aimed to assess the efficacy, tolerability, and acceptability of MAOIs for the treatment of depression in comparison with other antidepressant treatments. Methods: A systematic review and network meta‐analysis of randomised clinical trials was performed to compare the efficacy, tolerability and acceptability between MAOIs and other antidepressant treatments for the treatment of depressive episodes. Results: A total of 83 double‐blinded, randomised controlled trials were included in the analysis, with 7765 participants assigned to an active treatment and 1844 assigned to placebo. Several MAOIs, including isocarboxazid, phenelzine, tranylcypromine and moclobemide, showed significantly higher efficacy compared with placebo. The tolerability and acceptability of MAOIs was comparable to other antidepressants. Limitations: A disproportionate number of studies investigating the most commonly used MAOIs, such as moclobemide and phenelzine, and a lack of specific studies focusing on treatment‐resistant and atypical depression. Conclusions: MAOIs are similar in efficacy to other antidepressants for the treatment of depression. However, more studies are needed comparing MAOI treatment in people with treatment‐resistant, atypical and bipolar depression. [ABSTRACT FROM AUTHOR]

We read with great interest the report on the new anti-obesity potential in mice models of reversible monoamine oxidase B inhibitors by Moonsun et al., as opposed to the lack of such effects observed with irreversible MAO-B inhibitors (iMAO-Bi). Our research aimed to explore the potential anti-obesity effects of iMAO-Bi in patients with Parkinson's disease (PD). This retrospective study included 37 PD in-patients from 2018 to 2023. Patients who took iMAO-Bi were assigned to the iMAO-Bi group, and those who never took iMAO-Bi were assigned to the control. The major outcomes were changes in body weight and body mass index (BMI) during follow-up. A subgroup analysis was conducted to compare the anti-obesity effect between the short-term and long-term administrations of the iMAO-Bi group. The results showed a slight yet insignificant trend of bodyweight loss among the iMAO-Bi group of PD patients. Subgroup analysis showed that short-term treatment of iMAO-Bi (less than six months) led to reductions in BMI and body weight, while the long-term treatment of iMAO-Bi displayed a slight increase in BMI and body weight. The results suggested that short-term administration of iMAO-Bi may have potential weight-loss effects. Further studies with larger sample sizes are needed to evaluate the weight-loss effect of iMAO-Bi. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer’s disease (AD) is the leading cause of dementia, and currently, no effective treatments are available to reverse or halt its progression in clinical practice. Although a plethora of studies have highlighted the benefits of physical exercise in combating AD, elder individuals often have limited exercise capacity. Therefore, mild physical exercise and nutritional interventions represent potential strategies for preventing and mitigating neurodegenerative diseases. Our research, along with other studies, have demonstrated that platycodin D (PD) or its metabolite, platycodigenin, derived from the medicinal plant Platycodon grandiflorus, exerts neuroprotective effects against amyloid β (Aβ)-induced neuroinflammation. However, the combined effects of PD and physical exercise on alleviating AD have yet to be explored. The current study aimed to investigate whether combined therapy could synergistically ameliorate memory deficits and AD pathology in 5 × FAD mice. Methods: Five-month-old 5 × FAD mice were randomly assigned to four groups, and received either PD (5 mg/kg/day, p.o.), voluntary running, or a combination of both for 47 days. Nest building test, locomotion test, and Morris water maze test were used to evaluate the cognitive function. Immunohistochemical and ELISA analysis was performed to determine Aβ build-up, microglia and astrocytes hyperactivation, and survival neurons in the hippocampus and perirhinal cortex. Real-time quantitative PCR analysis was used to assess the polarization of microglia and astrocytes. HPLC analysis was performed to measure monoamine neurotransmitters in the hippocampus. Results and discussion: The combination of PD and voluntary running synergistically restored nest-building behavior, alleviated recognition and spatial memory deficits, and showed superior effects compared to monotherapy. In addition, the PD and voluntary running combination reduced Aβ build-up, decreased hyperactivation of microglia and astrocytes in the hippocampus and perirhinal cortex, promoted the polarization of inflammatory M1 microglia and reactive astrocytes toward beneficial phenotypes, and lowered systemic circulating pro-inflammatory cytokines while increasing anti-inflammatory cytokines in 5 × FAD mice. Furthermore, combined therapy effectively protected neurons and increased levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) in the hippocampus of 5 × FAD mice. In conclusion, the combination of PD and voluntary running holds great potential as a treatment for AD, offering promise for delaying onset or progression of AD. [ABSTRACT FROM AUTHOR]

In this work we introduce Target Fisher, a consensus structure‐based target prediction tool that integrates molecular docking and machine learning with the aim to aid in the identification of potential biological targets and the optimization of the use of bioassays. Target Fisher uses per‐residue energy decomposition profiles extracted from docking poses as fingerprints to train target‐specific machine learning models. It provides predictions for a curated set of 37 protein targets, covering a diverse range of biological entities, and offers a user‐friendly interface accessible via a web server (https://gqc.quimica.unlp.edu.ar/targetfisher/). In this sense, Target Fisher is a valuable tool to aid organic and medicinal chemistry groups in target identification, drug discovery and drug repurposing. As a case study, we demonstrate the efficacy of Target Fisher by screening a small library of assorted natural products for targets relevant to neurodegenerative diseases, which resulted in the identification and experimental validation of selective inhibitors of monoamine oxidase B (MAO−B). [ABSTRACT FROM AUTHOR]

Depression and Parkinson's disease (PD) are devastating psychiatric and neurological disorders that require the development of novel therapeutic interventions. Drug repurposing targeting predefined pharmacological targets is a widely use approach in modern drug discovery. Monoamine oxidase B (MAOB) is a critical protein implicated in Depression and PD. In this study, we undertook a systematic exploration of repurposed drugs as potential inhibitors of MAO-B. Exploring a library of 3,648 commercially available drug molecules, we conducted virtual screening using a molecular docking approach to target the MAO-B binding pocket. Two promising drug molecules, Brexpiprazole and Trifluperidol, were identified based on their exceptional binding potential and drug profiling. Subsequently, all-atom molecular dynamics (MD) simulations were performed on the MAO-B-ligand complexes for a trajectory of 300 nanoseconds (ns). Simulation results demonstrated that the binding of Brexpiprazole and Trifluperidol induced only minor structural alterations in MAO-B and showed significant stabilization throughout the simulation trajectory. Overall, the finding suggests that Brexpiprazole and Trifluperidol exhibit strong potential as repurposed inhibitors of MAO-B that might be explored further in experimental investigations for the development of targeted therapies for depression and PD. [ABSTRACT FROM AUTHOR]

Children with high Callous-Unemotional (CU) traits show deficits in recognizing and processing facial expressions. Alterations in emotion recognition have been linked to a higher synaptic concentration of monoaminergic neurotransmitters. The current study investigated the relationship between the MAOA-Low-activity alleles and the ability to recognize and process facial expressions in 97 male children (8–12 years old) diagnosed with disruptive behavior disorder. Participants completed a computerized emotion-recognition task while an eye-tracking system recorded the number (Fixation Count, FC) and length (Fixation Duration, FD) of fixations to the eye region of the emotional stimuli. Children with high CU traits exhibited lower scores in recognition of sadness and anger, and lower FC and FD for sadness and fear than children with low CU traits. Children carrying the MAOA-Low-activity alleles displayed lower FD for sadness, and FD and FC for fear than those carrying the MAOA-High-activity alleles. These genetic effects appeared even stronger in children with CU traits. Moderation analysis revealed that CU traits were associated with lower FC and FD for fear, and lower FD for sadness, probably due to the MAOA-Low-activity alleles. Our findings, although to be replicated, suggest MAOA-Low-activity alleles as potential genetic biomarkers to identify CU children in need of training focused on emotion processing. [ABSTRACT FROM AUTHOR]

As the most common psychiatric symptom, depression represents a subject of high interest for the medical community. Background/Objectives: International guidelines consider selective serotonin reuptake inhibitors (SSRIs) the first-line treatment of depression. Although having better efficacy and tolerability in comparison to tricyclic antidepressants or monoamine oxidase inhibitors, the diversity and potential severity of adverse effects and interactions manifested by SSRIs, combined with the frequency of prescriptions, lead to the necessity of evaluating real-world data. The aim of this study was to identify and evaluate the drug interactions reported in EudraVigilance (EV) for the six SSRIs representatives that are authorized in Europe: fluoxetine (FXT), fluvoxamine (FVM), citalopram (CIT), escitalopram (ESC), paroxetine (PAR) and sertraline (SER). The entire class of SSRIs was examined as a comparator to identify whether one of the representatives was more prone to reporting. Methods: Descriptive analysis and disproportionality analysis were conducted on data extracted from the EV database. Results: A total of 326,450 adverse reactions (ADRs) were reported for the SSRIs group. Approximately a quarter of these (n = 83,201; 25.46%) were reported for SER and 22.37% (n = 73,131) for PAR. Of the total ADRs reported, 2.12% (n = 6925) represent preferred terms related to drug-drug interactions (DDIs): SER (n = 1474; 22.37%), CIT (n = 1272, 19.86), and FXT (n = 1309, 19.83%). Specific ADRs related to inhibitory activity represent 0.98%, and for potentiating activity, 1.89%. Conclusions: Although representing a small value of the total ADRs, DDIs may be related to severe outcomes. Awareness should be raised for this category of ADRs that can be reduced by the joined efforts of physicians and pharmacists. [ABSTRACT FROM AUTHOR]

A patient-tailored therapy of the heterogeneous, neuropsychiatric disorder of Parkinson's disease (PD) aims to improve dopamine sensitive motor symptoms and associated non-motor features. A repeated, individual adaptation of dopamine substituting compounds is required throughout the disease course due to the progress of neurodegeneration. Therapeutic drug monitoring of dopamine substituting drugs may be an essential tool to optimize drug applications. We suggest plasma determination of levodopa as an initial step. The complex pharmacology of levodopa is influenced by its short elimination half-life and the gastric emptying velocity. Both considerably contribute to the observed variability of plasma concentrations of levodopa and its metabolite 3-O-methyldopa. These amino acids compete with other aromatic amino acids as well as branched chain amino acids on the limited transport capacity in the gastrointestinal tract and the blood brain barrier. However, not much is known about plasma concentrations of levodopa and other drugs/drug combinations in PD. Some examples may illustrate this lack of knowledge: Levodopa measurements may allow further insights in the phenomenon of inappropriate levodopa response. They may result from missing compliance, interactions e.g. with treatments for other mainly age-related disorders, like hypertension, diabetes, hyperlipidaemia, rheumatism or by patients themselves independently taken herbal medicines. Indeed, uncontrolled combination of compounds for accompanying disorders as given above with PD drugs might increase the risk of side effects. Determination of other drugs used to treat PD in plasma such as dopamine receptor agonists, amantadine and inhibitors of catechol-O-methyltransferase or monoamine oxidase B may refine and improve the value of calculations of levodopa equivalents. How COMT-Is change levodopa plasma concentrations? How other dopaminergic and non-dopaminergic drugs influence levodopa levels? Also, delivery of drugs as well as single and repeated dosing and continuous levodopa administrations with a possible accumulation of levodopa, pharmacokinetic behaviour of generic and branded compounds appear to have a marked influence on efficacy of drug treatment and side effect profile. Their increase over time may reflect progression of PD to a certain degree. Therapeutic drug monitoring in PD is considered to improve the therapeutic efficacy in the course of this devastating neurologic disorder and therefore is able to contribute to the patients' precision medicine. State-of-the-art clinical studies are urgently needed to demonstrate the usefulness of TDM for optimizing the treatment of PD. [ABSTRACT FROM AUTHOR]

Background: In recent years, both meditation and psychedelics have attracted rapidly increasing scientific interest. While the current state of evidence suggests the promising potential of psychedelics, such as psilocybin, to enhance meditative training, it remains equivocal whether these effects are specifically bound to psilocybin or if other classical psychedelics might show synergistic effects with meditation practice. One particularly promising candidate is N,N -dimethyltryptamine (DMT), an active ingredient of ayahuasca. Aim: This study aims to investigate the effect of the psychedelic substance DMT, combined with the monoamine oxidase inhibitor harmine (DMT-harmine), on meditative states, compared to meditation with a placebo. Method: Forty experienced meditators (18 females and 22 males) participated in a double-blind, placebo-controlled study over a 3-day meditation retreat, receiving either placebo or DMT-harmine. Participants' levels of mindfulness, compassion, insight, and transcendence were assessed before, during, and after the meditation group retreat, using psychometric questionnaires. Results: Compared to meditation with a placebo, meditators who received DMT and harmine self-attributed greater levels of mystical-type experiences, non-dual awareness, and emotional breakthrough during the acute substance effects and, when corrected for baseline differences, greater psychological insight 1 day later. Mindfulness and compassion were not significantly different in the DMT-harmine group compared to placebo. At 1-month follow-up, the meditators who received DMT and harmine rated their experience as significantly more personally meaningful, spiritually significant, and well-being-enhancing than the meditators who received placebo. Conclusion: Investigating the impact of DMT-harmine on meditators in a naturalistic mindfulness group retreat, this placebo-controlled study highlights the specific effects of psychedelics during meditation. Trial registration: ClinicalTrials.gov identifier NCT05780216. [ABSTRACT FROM AUTHOR]

Nowadays, an efficient and robust virtual screening procedure is crucial in the drug discovery process, especially when performed on large and chemically diverse databases. Virtual screening methods, like molecular docking and classic QSAR models, are limited in their ability to handle vast numbers of compounds and to learn from scarce data, respectively. In this study, we introduce a universal methodology that uses a machine learning-based approach to predict docking scores without the need for time-consuming molecular docking procedures. The developed protocol yielded 1000 times faster binding energy predictions than classical docking-based screening. The proposed predictive model learns from docking results, allowing users to choose their preferred docking software without relying on insufficient and incoherent experimental activity data. The methodology described employs multiple types of molecular fingerprints and descriptors to construct an ensemble model that further reduces prediction errors and is capable of delivering highly precise docking score values for monoamine oxidase ligands, enabling faster identification of promising compounds. An extensive pharmacophore-constrained screening of the ZINC database resulted in a selection of 24 compounds that were synthesized and evaluated for their biological activity. A preliminary screen discovered weak inhibitors of MAO-A with a percentage efficiency index close to a known drug at the lowest tested concentration. The approach presented here can be successfully applied to other biological targets as target-specific knowledge is not incorporated at the screening phase. [ABSTRACT FROM AUTHOR]

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Background: Women with gynecologic disorders requiring a hysterectomy often have co-existing psychiatric diagnoses. A change in the dispensing pattern of antidepressant (AD) and antianxiety (AA) medications around the time of hysterectomy may be due to improvement in gynecologic symptoms, such as pelvic pain and abnormal bleeding, or the emotional impact of the hysterectomy. Unfortunately, these dispensing patterns before and after hysterectomy are currently undescribed. Objectives: To model the dispensing patterns of AD and AA medications over time among women with psychiatric disorders before and after benign hysterectomy for endometriosis and uterine fibroids; and to characterize clusters of patients with various dispensing behaviors based on these patterns. Design: Retrospective cohort study. Methods: This is a study of women who underwent a benign hysterectomy using data from the Merative MarkertScan® Research Databases (Ann Arbor, MI, USA). Inclusion criteria were reproductive-aged women (18–50 years), diagnosis of at least one mood or anxiety disorder, and at least one dispensing of AD or AA medications. We measured monthly adherence and persistence of AD/AA medication use over 12 months after hysterectomy. Group-based-trajectory modeling (GBTM) was used to identify trajectory groups of monthly AD/AA medication dispensing over the study period. Multinomial logistic regression was used to identify factors independently associated with individual dispensing trajectory patterns. Results: For a total of 11,607 patients, 6 dispensing trajectory groups were identified during the study period: continuously high (27.0%), continuously moderate (21.9%), continuously low (17.9%), low-to-high (10.0%), moderate-to-low (9.8%), and low-to-moderate (13.4%). Compared with the continuously high group, younger age, no history of a mood disorder, and uterine fibroids were clinical predictors of low dispensing. The discontinuation rate at 3 months after hysterectomy was higher at 88.6% in the continuously low group and at 66.5% in the continuously low-to-moderate group. Conclusions: This study demonstrates that GBTM identified six distinct trajectories of AD/AA medication dispensing in the perioperative period. Trajectory models could be used to identify specific dispensing patterns for targeting interventions. Plain language summary: Dispensing patterns of antidepressant and antianxiety medications for psychiatric disorders after benign hysterectomy in reproductive-aged women: Results from the group-based trajectory modeling Women with gynecologic disorders often have coexisting psychiatric diagnoses. A change in the dispensing pattern of antidepressant and antianxiety medications may be due to improvement in gynecologic symptoms or the emotional impact of the hysterectomy. However, static measures, such as the proportion of days covered or medication possession ratio, may not adequately predict meaningful dispensing patterns. Using the group-based trajectory modeling, 6 distinct patterns of medication dispensing over the perioperative periods of women with benign hysterectomy are identified and therefore used to assess how certain clinical characteristics influence these dispensing patterns. This study concludes that trajectory modeling may be a more appropriate approach to investigating dispensing patterns among women with preexisting psychiatric conditions. [ABSTRACT FROM AUTHOR]

Background/Objectives: Several psychological conditions, including stress and depression, can adversely affect oral health; in fact, antidepressants, commonly used to treat depressive disorders, may have conflicting effects on the periodontal status of individuals. The aim of this review was to determine the effects of antidepressants on the periodontium. Methods: A literature search was conducted using electronic databases, Pubmed/MEDLINE, Cochrane Library, focusing on the use of antidepressants and their effects on periodontal health in animals or humans. Results: Seventeen articles have been included with the use of amitriptyline (two studies), desipramine (one study), imipramine (two studies), desvenlafaxine (one study), fluoxetine (six studies), venlafaxine (three studies) and tianeptine (two studies). One study evaluated several categories of antidepressants, such as selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic, atypical and monoamine oxidase inhibitors (MAO). Most trials showed improvements in periodontal health, especially with fluoxetine, but also with imipramine, desipramine, desvenlafaxine and tianeptine; on the contrary, worsening of clinical periodontal indices and increased loss of alveolar bone were reported with venlafaxine. Conclusions: This review suggests that in the presence of comorbidity between periodontitis and depression, pharmacological treatment with SNRIs, SSRIs and mixed antidepressants is associated with improvement in periodontal parameters, except for venlafaxine. Healthcare professionals (especially oral and mental health professionals) should investigate proper adherence to medication therapy in patients with a history of periodontitis and depression. Further clinical trials are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Background Trichotillomania (TTM) is a psychiatric disorder with dermatological consequences, characterized by recurrent hair pulling. It affects 1–3% of the population, and often coexists with other psychiatric disorders, leading to emotional distress. Effective management of TTM can be challenging because of underdiagnosis, symptom heterogeneity and stigma. Pharmacological interventions, including selective serotonin reuptake inhibitors and N -acetyl cysteine (NAC) are commonly used. Objectives To assess the existing literature on pharmacotherapy for TTM and identify potential avenues for future research and treatment advancements. Methods A systematic review of the literature was performed using PubMed and Scopus databases within the past 10 years (PROSPERO: CRD42023454009). Included studies assessed pharmacotherapy for TTM and provided insights into current evidence and potential directions for future research and treatment advancements. Results In total, 23 articles were identified that met inclusion criteria. The most successful interventions were NAC, aripiprazole and monoamine oxidase inhibitors. NAC was identified as the most impressive adjunctive therapy to selective serotonin reuptake inhibitors and behavioural therapies in treatment through its mechanism of decreased glutamate-induced excitatory neuronal damage, with adjunctive antioxidant properties. Most of the other therapeutics that were identified require further research and controlled trials to validate their findings. Conclusions Even if successful therapeutic outcomes are achieved, it is important to consider the patient's comorbidities and to combine pharmacological interventions with behavioural therapy interventions to comprehensively manage TTM. [ABSTRACT FROM AUTHOR]

Ten isatin-based hydrazone derivatives were synthesized using two subseries, IA (isatin + acetophenone) and IB (isatin + benzaldehyde), and evaluated for their monoamine oxidases (MAOs) inhibitory activity. All the compounds showed stronger MAO-A inhibition than MAO-B, and the IB series showed more effective MAO-A inhibitory activity than IA series. Compound IB4 most potently inhibited MAO-A (half maximal inhibitory concentration IC50 = 0.015 µM), followed by IB3 (IC50 = 0.019 µM). On the contrary, compound IB3 showed the highest MAO-B inhibition (IC50 = 0.068 µM), followed by IB4 (IC50 = 1.87 µM). Compound IB3 and IB4 had low selectivity indices of 3.68 and 8.50, respectively. Structurally, the methyl group of IA series decreased the inhibition of both MAO-A and MAO-B. Among them, IB3 and IB4 (4-Cl and 4-Br in B-ring, respectively) showed higher MAO-A and MAO-B inhibition than the other substitutions. Inhibition constant Ki values of IB3 and IB4 for MAO-A were 0.0088 and 0.0063 µM, respectively, and those for MAO-B were 0.048 and 0.060 µM, respectively. IB3 and IB4 were competitive, reversible inhibitors of MAO-A and MAO-B. Molecular docking analysis predicted that IB3 and IB4 formed stable hydrogen bonds between Asn181 and the NH atom of isatin in the ligand-protein complex. Dynamic analysis revealed that IB3 and IB4 are stable with both MAO isoforms. These observations suggest IB3 and IB4 are potent and reversible MAO-A and MAO-B inhibitors and both compounds can be used as therapeutic agents for neurological disorders. [ABSTRACT FROM AUTHOR]

Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson's disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC50 value of 0.203 μM, followed by S16 (IC50 = 0.979 μM). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC50 value of 3.691 μM, followed by S5 (IC50 = 3.857 μM). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH3 > -F > -CN > -CH3 > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the Ki values of S5 and S16 for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 μM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood-brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi-pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders. [ABSTRACT FROM AUTHOR]

The article discusses the underutilization of monoamine oxidase inhibitors (MAOIs) in the treatment of major depression. MAOIs were the first licensed antidepressants, but their use has declined due to concerns about safety and drug interactions. However, recent studies suggest that MAOIs, especially tranylcypromine and phenelzine, may be effective in treating bipolar depression and treatment-resistant depression. The authors emphasize the importance of educating psychiatrists about the potential benefits of MAOIs in certain subtypes of major depression. [Extracted from the article]

Abstract Nowadays, an efficient and robust virtual screening procedure is crucial in the drug discovery process, especially when performed on large and chemically diverse databases. Virtual screening methods, like molecular docking and classic QSAR models, are limited in their ability to handle vast numbers of compounds and to learn from scarce data, respectively. In this study, we introduce a universal methodology that uses a machine learning-based approach to predict docking scores without the need for time-consuming molecular docking procedures. The developed protocol yielded 1000 times faster binding energy predictions than classical docking-based screening. The proposed predictive model learns from docking results, allowing users to choose their preferred docking software without relying on insufficient and incoherent experimental activity data. The methodology described employs multiple types of molecular fingerprints and descriptors to construct an ensemble model that further reduces prediction errors and is capable of delivering highly precise docking score values for monoamine oxidase ligands, enabling faster identification of promising compounds. An extensive pharmacophore-constrained screening of the ZINC database resulted in a selection of 24 compounds that were synthesized and evaluated for their biological activity. A preliminary screen discovered weak inhibitors of MAO-A with a percentage efficiency index close to a known drug at the lowest tested concentration. The approach presented here can be successfully applied to other biological targets as target-specific knowledge is not incorporated at the screening phase.

Data on medication interactions with psychedelics are limited. Here we present what may be the first published report of a hypertensive emergency following the combination of psilocybin mushrooms with a monoamine oxidase inhibitor (MAOI). A 42-year-old man with treatment-resistant major depressive disorder took 1 g of Psilocybe cubensis mushrooms, while prescribed tranylcypromine, extended-release dextroamphetamine-amphetamine, and other medications. Approximately half an hour later, he developed severe hypertension with chest pain, palpitations, and headache. Upon hospital presentation, the electrocardiogram demonstrated ST-elevation. The patient was diagnosed with a myocardial infarction and treated with lorazepam, nitroglycerin, and aspirin. He subsequently underwent emergency cardiac catheterization, which revealed no significant cardiac abnormalities. Following overnight hospitalization, he was discharged home with no lasting physical sequelae. Though data are few, past studies suggest that classic serotonergic psychedelics (5HT-2A receptor agonists) such as dimethyltryptamine (DMT), lysergic acid (LSD), and synthetic psilocybin should not produce hypertensive emergency when combined with MAOIs. We suspect phenylethylamine, found in Psilocybe cubensis and other species of psilocybin mushrooms, interacted with tranylcypromine and dextroamphetamine-amphetamine to produce this hypertensive emergency. Patients prescribed MAOIs should be warned of the potential for hypertensive emergency when consuming psilocybin mushrooms, particularly when also prescribed norepinephrine releasers such as dextroamphetamine-amphetamine. [ABSTRACT FROM AUTHOR]

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin–sulfonamide–nitroindazolyl–triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a–c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases. [ABSTRACT FROM AUTHOR]

Chalcones (trans-1,3-diphenyl-2-propen-1-ones) form simple chemical structures that act as precursors for the biogenesis of flavonoids. These are distributed in plants and have two aromatic or heteroaromatic rings connected by a three-carbon α, β-unsaturated carbonyl group. Considering the importance of chalcones as monoamine oxidase and acetylcholinesterase inhibitors, the study was designed as a comprehensive and systematic analysis to evaluate the pharmacological activities leading to the formation of drug molecules against Alzheimer's disease (AD). Based on our previous research, 11 indolyl chalcones (IC1–IC11) were synthesised and investigated for MAO-B inhibitory activity. The inhibitory potential was evaluated based on binding and reversibility studies using purified enzymes. The active and most promising molecule, (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one (IC9), also found predominant acetylcholinesterase inhibition and hence it was found dual acting in vitro. Based on this, the molecule IC9 was further subjected to cell line studies to further explore its role as a neuroprotective agent against neuronal degeneration, one of the main contributing parameters related to AD. [ABSTRACT FROM AUTHOR]

Purpose of Review: On 1 July 2023, the Therapeutic Goods Administration approved 3,4‐methylenedioxymethamphetamine (MDMA)‐assisted psychotherapy for the treatment of post‐traumatic stress disorder (PTSD). Accordingly, the purpose of this review is to provide an overview of MDMA and what pharmacists should know as this treatment emerges. Sources of Information: EMBASE, MEDLINE, and CINAHL databases were searched to provide an overview narrative synthesis of the literature on MDMA, relevant to pharmacists. Key Findings: Cytochrome P450 2D6 is involved in the metabolic pathway of MDMA, an enzyme inhibited by a number of drugs used in the pharmacological management of PTSD (e.g. selective serotonin reuptake inhibitors). Co‐administration of these drugs with MDMA can lead to increases in plasma MDMA concentrations. Additionally, inhibition of the serotonin transporter can inhibit the uptake of MDMA into the presynaptic terminal, dampening the effects of MDMA and potentially, limiting the effectiveness of MDMA‐assisted psychotherapy. Accordingly, these drugs are typically withdrawn prior to treatment with MDMA. While selective serotonin reuptake inhibitor/serotonin noradrenaline reuptake inhibitor drugs with MDMA are unlikely to cause serotonin toxicity, monoamine oxidase inhibitors can. Other drugs, such as caffeine, alcohol, over‐the‐counter medicines, and complimentary/alternative medicines, can also interact with MDMA. Conclusion: With a detailed knowledge of the pharmacology of MDMA, pharmacists may play a role in MDMA‐assisted psychotherapy by collecting a detailed medication history and assisting clinicians in the withdrawal of interacting medicines. [ABSTRACT FROM AUTHOR]

Monoamine oxidases (MAOs) are mitochondrial enzymes that catalyse the oxidative deamination of monoamine neurotransmitters and various xenobiotic amines in the central nervous system and peripheral tissues. They are of two types, MAO-A and MAO-B, which are different in terms of their substrates and tissue distributions. MAO-A oxidizes epinephrine, serotonin and norepinephrine, while MAO-B catalyzes the deamination of phenylethylamine and benzylamine. MAO-A inhibitors are used in the treatment of depression, while MAO-B inhibitors are used in the treatment of neurodegenerative diseases such as Parkinson's and Alzheimer diseases. MAO inhibitors are listed as the second choice in the treatment of major depression after selective serotonin reuptake inhibitors (SSRI) or tricyclic antidepressants. Various heterocyclic compounds with two or four nitrogen atoms have been used in the synthesis of selective and reversible MAO inhibitors for many years. In this study, the inhibitory effects of 2-(3-(4-methoxyphenyl)-5-aryl-4,5-dihydropyrazol-1-yl)benzo[d]thiazole compounds, having a 2-pyrazoline skeleton, on the MAO isoenzymes were investigated. Among the tested derivatives, compound 12 achieved IC50 values of 0.041 ± 0.001 mM. The nature of inhibition was also determined to be non-competitive based on the Lineweaver–Burk plot. Molecular docking studies were also performed for compound 12, which is the most potent agent in the MAO-Aand MAO-B catalytic sites. The evaluation and explanation of the biological results at the atomic level with the positive compounds selected for each target are provided. Studies can be developed based on compound 12 as a candidate lead compound for further research as a non-competitive MAO-A and MAO-B inhibitor. [ABSTRACT FROM AUTHOR]

Purpose: The principal objective of this project was to review and thoroughly examine the chemical characteristics, pharmacological activity, and quantification methods associated with contezolid. Methods: The article was based on published and ongoing preclinical and clinical studies on the application of contezolid. These studies included experiments on the physicochemical properties of contezolid, in vitro antimicrobial research, in vivo antimicrobial research, and clinical trials in various phases. There were no date restrictions on these studies. Results: In June 2021, contezolid was approved for treating complicated skin and soft tissue infections. The structural modification of contezolid has resulted in better efficacy compared to linezolid. It inhibits bacterial growth by preventing the production of the functional 70S initiation complex required to translate bacterial proteins. The current evidence has indicated a substantial decline in myelosuppression and monoamine oxidase inhibition without impairing its antibacterial properties. Contezolid was found to have a more significant safety profile and to be metabolised by flavin monooxygenase 5, reducing the risk of harmful effects due to drug–drug interactions. Adjusting doses is unnecessary for patients with mild to moderate renal or hepatic insufficiency. Conclusion: As an oral oxazolidinone antimicrobial agent, contezolid is effective against multi-drug resistant Gram-positive bacteria. The introduction of contezolid provided a new clinical option. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the neuroprotective effect of caffeic acid (CAF) against cadmium chloride (CdCl2) in rats via its effect on memory index as well as on altered enzymatic activity in the brain of CdCl2-induced neurotoxicity. The experimental rats were divided into seven groups (n=6 rats per group) of healthy rats (group 1), CdCl2 -induced (CD) (3 mg/kg BW) rats (group 2), CD rats + Vitamin C (group 3), CD rats + CAF (10 and 20 mg/kg BW respectively) (group 4 & 5), and healthy rat + CAF (10 and 20 mg/kg BW respectively) (group 6 & 7). Thereafter, CdCl2 and CAF were administered orally to the experimental rats in group 2 to group 5 on daily basis for 14 days. Then, the Y-maze test was performed on the experimental rats to ascertain their memory index. CdCl2 administration significantly altered cognitive function, the activity of cholinesterase, monoamine oxidase, arginase, purinergic enzymes, nitric oxide (NOx), and antioxidant status of Cd rats (untreated) when compared with healthy rats. Thereafter, CD rats treated with vitamin C and CAF (10 and 20 mg/kg BW) respectively exhibited an improved cognitive function, and the observed altered activity of cholinesterase, monoamine oxidase, arginase, purinergic were restored when compared with untreated CD rats. Also, the level of brain NOx and antioxidant status were significantly (p<0.05) enhanced when compared with untreated CD rats. In the same vein, CAF administration offers neuro-protective effect in healthy rats vis-à-vis improved cognitive function, reduction in the activity of some enzymes linked to the progression of cognitive dysfunction, and improved antioxidant status when compared to healthy rats devoid of CAF. This study demonstrated the neuroprotective effect of CAF against CdCl2 exposure and in healthy rats. [ABSTRACT FROM AUTHOR]

De novo molecular design is the process of searching chemical space for drug-like molecules with desired properties, and deep learning has been recognized as a promising solution. In this study, I developed an effective computational method called Scoring-Assisted Generative Exploration (SAGE) to enhance chemical diversity and property optimization through virtual synthesis simulation, the generation of bridged bicyclic rings, and multiple scoring models for drug-likeness. In six protein targets, SAGE generated molecules with high scores within reasonable numbers of steps by optimizing target specificity without a constraint and even with multiple constraints such as synthetic accessibility, solubility, and metabolic stability. Furthermore, I suggested a top-ranked molecule with SAGE as dual inhibitors of acetylcholinesterase and monoamine oxidase B through multiple desired property optimization. Therefore, SAGE can generate molecules with desired properties by optimizing multiple properties simultaneously, indicating the importance of de novo design strategies in the future of drug discovery and development. Scientific contribution: The scientific contribution of this study lies in the development of the Scoring-Assisted Generative Exploration (SAGE) method, a novel computational approach that significantly enhances de novo molecular design. SAGE uniquely integrates virtual synthesis simulation, the generation of complex bridged bicyclic rings, and multiple scoring models to optimize drug-like properties comprehensively. By efficiently generating molecules that meet a broad spectrum of pharmacological criteria—including target specificity, synthetic accessibility, solubility, and metabolic stability—within a reasonable number of steps, SAGE represents a substantial advancement over traditional methods. Additionally, the application of SAGE to discover dual inhibitors for acetylcholinesterase and monoamine oxidase B not only demonstrates its potential to streamline and enhance the drug development process but also highlights its capacity to create more effective and precisely targeted therapies. This study emphasizes the critical and evolving role of de novo design strategies in reshaping the future of drug discovery and development, providing promising avenues for innovative therapeutic discoveries. [ABSTRACT FROM AUTHOR]

Detailed data on post-stroke depression (PSD) in older adults are limited in spite of the high vulnerability of this population to stroke. In fact, PSD prevalence in older adults ranges from 16.0 to 43.9%; however, timing and instruments of evaluation often differ significantly across all available studies. The etiology, genetic and inflammatory factors, as well as structural brain alterations, are claimed as part of a multifaceted mechanism of action in PSD onset. Thus, the aim of this narrative review was to further elaborate on the prevalence, etiology, diagnosis, consequences and treatment of PSD in older adults. The consequences of PSD in older adults may be devastating, including a poor functional outcome after rehabilitation and lower medication adherence. In addition, lower quality of life and reduced social participation, higher risk of new stroke, rehospitalization, and mortality have been reported. In this scenario, treating PSD represents a crucial step to prevent these complications. Both pharmacological and non-pharmacological therapies are currently available. The pharmacological treatment utilizes antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TAs) and new multimodal antidepressants (NMAs). Non-pharmacological therapies include psychological interventions and non-invasive brain stimulation techniques, while excluding drug administration. In the general population experiencing PSD, SSRIs (sertraline in particular) are the most prescribed, whereas the combination of antidepressants and psychotherapy is underused. Furthermore, about one-third of patients do not receive treatment for PSD. In regard to older adults with PSD, the possibility of more adverse effects or contraindications to antidepressant prescription due to comorbidities may limit the therapeutic window. Although drugs such as citalopram, escitalopram, sertraline, venlafaxine, and vortioxetine are usually well tolerated by older patients with PSD, the few randomized controlled trials (RCTs) specifically considering older adults with PSD have been conducted with fluoxetine, fluvoxamine, reboxetine, citalopram and nortriptyline, often with very small patient samples. Furthermore, data regarding the results of non-pharmacological therapies are scarce. High-quality RCTs recruiting large samples of older adults are needed in order to better manage PSD in this population. In addition, adequate screening and diagnosis instruments, with reliable timing of evaluation, should be applied. [ABSTRACT FROM AUTHOR]

Around 10 million people worldwide have Parkinson's and in the UK the estimated figure is 153 000. The condition is characterised by motor symptoms including tremors, stiffness, slowness, balance problems and/or gait disorders, but people can develop a wide range of associated psychological and physical problems. Treatment for Parkinson's includes a combination of multidisciplinary input from specialists such as physiotherapy, speech and language therapy and occupational therapy, alongside the use of recognised medication regimens. Most first-line medication requires titration and is started at a low dose and increased gradually, to reduce the risk of side effects and to monitor response to treatment. Medications for Parkinson's are complex to manage, and many have side effects that could affect patient concordance. Any prescribing decisions should be discussed with the person with Parkinson's and their family members. There are a variety of medications available to manage motor and non-motor symptoms in Parkinson's, but this article will focus on levodopa, dopamine agonists, MAO-B inhibitors and catechol-O-methyltransferase inhibitors. [ABSTRACT FROM AUTHOR]

4-(2-Methyloxazol-4-yl)benzenesulfonamide was synthesized by the reaction of 4-(2-bromoacetyl)benzenesulfonamide with an excess of acetamide. The compound was evaluated as a potential inhibitor of human monoamine oxidase (MAO) A and B and was found to inhibit these enzymes with IC50 values of 43.3 and 3.47 μM, respectively. The potential binding orientation and interactions of the inhibitor with MAO-B were examined by molecular docking, and it was found that the sulfonamide group binds and interacts with residues of the substrate cavity. 4-(2-Methyloxazol-4-yl)benzenesulfonamide showed no cytotoxic effect against human stromal bone cell line (HS-5) in the concentration range of 1–100 µmol. Thus, the new selective MAO-B inhibitor was identified, which may be used as the lead compound for the development of antiparkinsonian agents. [ABSTRACT FROM AUTHOR]

Around 10 million people worldwide have Parkinson's disease and in the UK the estimated figure is 153000. The condition is characterised by motor symptoms including tremors, stiffness, slowness, balance problems and/or gait disorders, but sufferers can develop a wide range of associated psychological and physical problems. Treatment includes a combination of pharmacological and supportive physical therapies, supplied by a multidisciplinary team. As the condition progresses, medication regimens expand to include a combination of drug therapies. For those who do not benefit from pharmacological therapy deep brain stimulation surgery can be considered. Some people find that alternative therapies such as homeopathy, music and massage are useful additions to standard medical treatments. This article will give an overview of Parkinson's disease, including symptoms and diagnosis, and explore issues for consideration when prescribing common first-line Parkinson's medications. [ABSTRACT FROM AUTHOR]

Six compounds were isolated from Penicillium sp. SG-W3, a marine-derived fungus, and their inhibitory activities against target enzymes relating to neurological diseases were evaluated. Compound 1 (pannorin) was a potent and selective monoamine oxidase (MAO)-A inhibitor with a 50% inhibitory concentration (IC50) of 1.734 μM and a selectivity index (SI) of > 23.07 versus MAO-B, and it showed an efficient antioxidant activity. All compounds showed weak inhibitory activities against acetylcholinesterase, butyrylcholinesterase, and β-secretase. The inhibition constant (Ki) of 1 for MAO-A was 1.049 ± 0.030 μM with competitive inhibition. Molecular docking simulation predicted that compound 1 forms hydrogen bonds with MAO-A, and binds more tightly to MAO-A than to MAO-B (− 25.02 and − 24.06 kcal/mol, respectively). These results suggest that compound 1 is a selective, reversible, and competitive MAO-A inhibitor that can be a therapeutic candidate for treating neurological diseases. [ABSTRACT FROM AUTHOR]

Monoamine oxidases (MAOs), specifically MAO-A and MAO-B, play important roles in the breakdown of monoamine neurotransmitters. Therefore, MAO inhibitors are crucial for treating various neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, we developed a novel cheminformatics pipeline by generating three diverse molecular feature-based machine learning-assisted quantitative structural activity relationship (ML-QSAR) models concerning MAO-B inhibition. PubChem fingerprints, substructure fingerprints, and one-dimensional (1D) and two-dimensional (2D) molecular descriptors were implemented to unravel the structural insights responsible for decoding the origin of MAO-B inhibition in 249 non-reductant molecules. Based on a random forest ML algorithm, the final PubChem fingerprint, substructure fingerprint, and 1D and 2D molecular descriptor prediction models demonstrated significant robustness, with correlation coefficients of 0.9863, 0.9796, and 0.9852, respectively. The significant features of each predictive model responsible for MAO-B inhibition were extracted using a comprehensive variance importance plot (VIP) and correlation matrix analysis. The final predictive models were further developed as a web application, MAO-B-pred (https://mao-b-pred.streamlit.app/), to allow users to predict the bioactivity of molecules against MAO-B. Molecular docking and dynamics studies were conducted to gain insight into the atomic-level molecular interactions between the ligand-receptor complexes. These findings were compared with the structural features obtained from the ML-QSAR models, which supported the mechanistic understanding of the binding phenomena. The presented models have the potential to serve as tools for identifying crucial molecular characteristics for the rational design of MAO-B target inhibitors, which may be used to develop effective drugs for neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Background: Safinamide (SAF), an α-aminoamide derivative and a selective, reversible monoamine oxidase (MAO)-B inhibitor, has both dopaminergic and nondopaminergic (glutamatergic) properties. Several studies have explored the potential of SAF against various neurological disorders; however, to what extent SAF modulates the magnitude, gating, and voltage-dependent hysteresis [Hys(V)] of ionic currents remains unknown. Methods: With the aid of patch-clamp technology, we investigated the effects of SAF on voltage-gated sodium ion (NaV) channels in pituitary GH3 cells. Results: SAF concentration-dependently stimulated the transient (peak) and late (sustained) components of voltage-gated sodium ion current (INa) in pituitary GH3 cells. The conductance–voltage relationship of transient INa [INa(T)] was shifted to more negative potentials with the SAF presence; however, the steady-state inactivation curve of INa(T) was shifted in a rightward direction in its existence. SAF increased the decaying time constant of INa(T) induced by a train of depolarizing stimuli. Notably, subsequent addition of ranolazine or mirogabalin reversed the SAF-induced increase in the decaying time constant. SAF also increased the magnitude of window INa induced by an ascending ramp voltage Vramp. Furthermore, SAF enhanced the Hys(V) behavior of persistent INa induced by an upright isosceles-triangular Vramp. Single-channel cell-attached recordings indicated SAF effectively increased the open-state probability of NaV channels. Molecular docking revealed SAF interacts with both MAO and NaV channels. Conclusion: SAF may interact directly with NaV channels in pituitary neuroendocrine cells, modulating membrane excitability. [ABSTRACT FROM AUTHOR]

Depression, a global cause of disability and premature death, is often treated by traditional healers in Africa using medicinal herbs such as Ximenia americana (L.). With recent pharmacological studies showing the potential antidepressant properties of X. americana extract, this study aimed to evaluate the antidepressant-like effects of the compound(s) isolated from X. americana extract using the forced swim test (FST) and tail suspension test (TST) models predictive of depression. The extracts, administered orally within a dose range of 100–400 mg/kg, notably decreased the immobility time in both the FST and the TST. The most significant reduction occurred at the highest dose of 400 mg/kg, with a decrease of 117.66 s in FST and 53.5 s in TST. However, this reduction in immobility was not linked to changes in movements, as observed in an open-field test (OFT), suggesting that the effect of the extracts was not due to activation of locomotion. Subsequently, a sesquiterpene lactone, dehydrocostus lactone (1) was isolated through solubility-based fractionation and column chromatography of the active root bark extract of X. americana. Dehydrocostus lactone (400 mg/kg) demonstrated a 46.50 s reduction in immobility time in the FST, which was comparable to the positive control, imipramine (30 mg/kg). With a highly favorable docking score of −8.365 kcal/mol on an antidepressant target, monoamine oxidase A (MAO-A; pdb ID: 2BXS), dehydrocostus lactone (1) potentially outperforms the standard MAO-A inhibitor drug, isocarboxazid (−5.847 kcal/mol). Dehydrocostus lactone (1) displayed strong interactions involving hydrogen bond and hydrophobic and electrostatic interactions with specific MAO-A binding site residues. These findings highlight that the antidepressant-like activity of X. americana is partly attributed to the presence of dehydrocostus lactone. Additionally, it also supports the traditional medicinal use of the plant for treating depression. [ABSTRACT FROM AUTHOR]

Background: Serotonin syndrome is a rare and potentially fatal adverse drug reaction caused by serotonergic drugs and is due to an increase in serotonin concentration or activation of the 5-HT receptor in the central nervous system. We analysed adverse events in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data set to investigate the main drug classes related to reports of serotonin syndrome and the reporting risk in relation to age and sex. Methods: We analysed data from the FAERS database to evaluate the main drug classes related to reports of the serotonin syndrome, and the reporting risk in relation to age and sex. Results: We found 8,997 cases of serotonin syndrome; selective serotonin reuptake inhibitors (SSRIs) was the class of drugs with most reports, followed by opioids and other antidepressants. The highest Reporting Odds Ratios (ROR) for drug classes was for monoamine oxidase (MAO) inhibitors (45.99, 95% confidence interval (CI): 41.21–51.33) and SSRIs (32.66, 95% CI: 31.33–34.04), while the ten active substances with the highest ROR were moclobemide, isocarboxazid, oxitriptane, tranylcypromine, melitracen, phenelzine, linezolid, amoxapine, reboxetine and tryptophan; with values of ROR ranging from 44.19 (95% CI: 25.38–76.94) of tryptophan to 388.36 (95% CI: 314.58-479.46) of moclobemide. The ROR for the most commonly involved drugs was higher in the group of older adults (65 > years old), and higher in males. Conclusion: Prescribers need to be vigilant about drugs that can raise serotonin concentration or influence serotonergic neurotransmission, also when using drugs with less well-known risk for serotonin syndrome, like linezolid and triptans. [ABSTRACT FROM AUTHOR]

Objective. Calcium pyrophosphate (CPP) crystal deposition in the joints is associated with a heterogeneous set of debilitating syndromes characterized by inflammation and pain, for which no effective therapies are currently available. Because we found that the mitochondrial enzyme monoamine oxidase B (MAO-B) plays a fundamental role in promoting inflammatory pathways, this study aims at assessing the efficacy of two clinical-grade inhibitors (iMAO-Bs) in pre)clinical models of this disease to pave the way for a novel treatment. Methods. We tested our hypothesis in two murine models of CPP-induced arthritis, by measuring cytokine and chemokine levels, along with immune cell recruitment. iMAO-Bs (rasagiline and safinamide) were administered either before or after crystal injection. To elucidate the molecular mechanism, we challenged in vitro primed macrophages with CPP crystals and assessed the impact of iMAO-Bs in dampening proinflammatory cytokines and in preserving mitochondrial function. Results. Both in preventive and therapeutic in vivo protocols, iMAO-Bs blunted the release of proinflammatory cytokines (interleukin [IL]-6 and IL1-β) and chemokines (CXCL10, CXCL1, CCL2 and CCL5) (n > 6 mice/group). Importantly, they also significantly reduced ankle swelling (50.3% vs 17.1%; P < 0.001 and 23.1%; P = 0.005 for rasagiline and safinamide, respectively). Mechanistically, iMAO-Bs dampened the burst of reactive oxygen species and the mitochondrial dysfunction triggered by CPP crystals in isolated macrophages. Moreover, iMAO-Bs blunted cytokine secretion and NLRP3 inflammasome activation through inhibition of the NF-κB and STAT3 pathways. Conclusion. iMAO-Bs dampen inflammation in murine models of crystal-induced arthropathy, thereby uncovering MAO-B as a promising target to treat these diseases. [ABSTRACT FROM AUTHOR]

Background: There is concern internationally about increasing antidepressant use. Most antidepressants are prescribed in general practice. The aim of this study was to compare trends in antidepressant dispensing in Australia and the Netherlands over the 9 years from 2013 to 2021, and to explore reasons for differences. Methods: A convergent mixed methods study including analysis of publicly available antidepressant dispensing data obtained from Australia's Pharmaceutical Benefits Scheme and Repatriation Pharmaceutical Benefits Scheme and the Dutch Foundation for Pharmaceutical Statistics and a search of relevant literature to compare contextual factors influencing prescribing were undertaken. Results: In 2013, antidepressant dispensing rates in Australia were nearly twice as high as those in the Netherlands (82.5 versus 44.3 DDD/1000/day) and increased to be more than twice as high by 2021 (115.6 versus 48.8 DDD/1000/day). Antidepressant dispensing increased by 40% in Australia over the nine study years, but by only 10% in the Netherlands. Our scan of the literature confirms that while population factors, health system structure, and clinical guideline recommendations are largely consistent across the two countries, a multifaceted approach in the Netherlands involving improved access to non-pharmacological alternatives, initiatives targeting safer antidepressant prescribing, and tight regulation of pharmaceutical industry influence on prescribers, has successfully curtailed increasing antidepressant use. Conclusions: Australia may learn from the Netherlands' approach to redress increasing antidepressant use. The rate of antidepressant use in Australia is among the highest in the world (one in seven adults) and increasing, while the rate in the Netherlands is about half that of Australia and remained steady over 2013–2021. The Netherlands achieved this through a multifaceted approach including improved access to non-pharmacological alternatives, initiatives targeting safer antidepressant prescribing and deprescribing, and tight regulation of pharmaceutical company influence on prescribers. Australia may learn from the Netherlands' approach to redress increasing antidepressant use. [ABSTRACT FROM AUTHOR]

Molecular docking is a promising and reliable technology for the purpose of discovering lead compounds via virtual screening. In addition to allowing for the testing of a large number of compounds, it also allows for the determination of how the selected compounds inhibit the targeted protein/receptor based on the scoring function and ranking. Because selective cholinesterase and monoamine oxidase inhibitors play a critical role in the treatment of Alzheimer disease, this research focuses on elucidating the mechanism of binding interactions of a few quinolone derivatives within the active sites of cholinesterase (acetyl-cholinesterase (AChE) and butyrylcholinesterase (BChE) and monoamine oxidase (MAO, monoamine oxidase A & B). As a result of these discoveries, it is possible that the newly identified inhibitors will be used as lead compounds in the development of novel enzyme inhibitors for the treatment of specific diseases, hence enabling the development of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: There is growing scientific evidence for the therapeutic benefits of the Amazonian plant-based psychedelic "ayahuasca" for neuropsychiatric disorders such as depression and anxiety. However, there are certain challenges when incorporating botanical ayahuasca into biomedical research and clinical therapy environments. Formulations inspired by ayahuasca, which contain specific and standardized active components, are a potential remedy. Methods: We investigated subjective acute and persisting effects of a novel formulation containing the reversible monoamine oxidase inhibitor harmine (orodispersible tablet containing 100 mg MAO-I) and N,N-dimethyltryptamine (incremental intranasal dosing of up to 100 mg DMT), compared with two other conditions, namely harmine alone and placebo, in a crossover RCT in 31 healthy male subjects. Results: DMT + harmine, but not harmine alone, induced a psychedelic experience assessed with the 5D-ASC rating scale [global score: F(2,60) = 80.21, p < 0.001] and acute experience sampling items over time, characterized by psychological insights [PIQ, F(2,58.5) = 28.514, p < 0.001], emotional breakthroughs [EBI, F(2,60) = 26.509, p < 0.001], and low scores on the challenging experience questionnaire [CEQ, F(2,60) = 12.84, p < 0.001]. Participants attributed personal and spiritual significance to the experience (GSR) with mainly positive persisting effects (PEQ) at 1- and 4-months follow-up. Acute drug effects correlated positively with persisting effects. We found no changes in trait measures of personality, psychological flexibility, or general well-being, and no increases in psychopathology (SCL-90-R) were reported. Discussion and Conclusion: Our results suggest that the experience induced by the standardized DMT + harmine formulation induces a phenomenologically rich psychedelic experience, demonstrates good psychological safety and tolerability, is well tolerated, and induces beneficial psychological processes that could possibly support psychotherapy. Further studies are required to investigate the psychotherapeutic potential in patients. [ABSTRACT FROM AUTHOR]

Background. Rasagiline or pramipexole monotherapy has been suggested for the management of early Parkinson's disease (PD). The aim of this research was to systematically review the clinical efficacy and safety of rasagiline or pramipexole in early PD (defined as disease duration ≤5 years and Hoehn and Yahr stage of ≤3). Methods. Randomized controlled trials (RCTs) of rasagiline or pramipexole for early PD published up to September 2021 were retrieved. Outcomes of interest included changes in the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III and the incidence of adverse events. Standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (CI) were calculated, and heterogeneity was measured with the I2 test. Results. Nine rasagiline and eleven pramipexole RCTs were included. One post hoc analysis of one rasagiline study was included. Five studies for each drug were included in meta-analyses of the UPDRS scores. The rasagiline meta-analysis focused on patients receiving 1 mg/day. Rasagiline and pramipexole significantly improved UPDRS Part II and III scores when compared to placebo. Significant heterogeneity among the studies was present (I2 > 70%). Neither rasagiline nor pramipexole increased the relative risk for any adverse events, serious adverse events, or adverse events leading to withdrawal when compared with placebo. Conclusion. Applying a Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to summarize the evidence, we found moderate confidence in the body of evidence for the efficacy of rasagiline or pramipexole in early PD, suggesting further well-designed, multicenter comparative RCTs remain needed. [ABSTRACT FROM AUTHOR]

Sixteen isatin-based hydrazone derivatives (IS1–IS16) were synthesized and assessed for their ability to inhibit monoamine oxidases (MAOs). All the molecules showed improved inhibitory MAO-B activity compared to MAO-A. Compound IS7 most potently inhibited MAO-B with an IC50 value of 0.082 μM, followed by IS13 and IS6 (IC50 = 0.104 and 0.124 μM, respectively). Compound IS15 most potently inhibited MAO-A with an IC50 value of 1.852 μM, followed by IS3 (IC50 = 2.385 μM). Compound IS6 had the highest selectivity index (SI) value of 263.80, followed by IS7 and IS13 (233.85 and 212.57, respectively). In the kinetic study, the Ki values of IS6, IS7, and IS13 for MAO-B were 0.068 ± 0.022, 0.044 ± 0.002, and 0.061 ± 0.001 μM, respectively, and that of IS15 for MAO-A was 1.004 ± 0.171 μM, and the compounds were reversible-type inhibitors. The lead compounds were central nervous system (CNS) permeable, as per parallel artificial membrane permeability assay (PAMPA) test results. The lead compounds were examined for their cytotoxicity and potential neuroprotective benefits in hazardous lipopolysaccharide (LPS)-exposed SH-SY5Y neuroblastoma cells. Pre-treatment with lead compounds enhanced anti-oxidant levels (SOD, CAT, GSH, and GPx) and decreased ROS and pro-inflammatory cytokine (IL-6, TNF-alpha, and NF-kB) production in LPS-intoxicated SH-SY5Y cells. To confirm the promising effects of the compound, molecular docking, dynamics, and MM-GBSA binding energy were used to examine the molecular basis of the IS7-MAO-B interaction. Our findings indicate that lead compounds are potential therapeutic agents to treat neurological illnesses, such as Parkinson's disease. [ABSTRACT FROM AUTHOR]

Antipsychotics, tricyclic and 5-hydroxytryptamine reuptake inhibitors (SSRI) and 5-hydroxytryptamine and norepinephrine reuptake inhibitor (SNRI) antidepressants, and monoamine oxidase inhibitors can produce dream-rendering behaviors and/or dystonic deregulation during REM sleep. Acute episodes are also seen with withdrawal from alcohol or sedative-hypnotics, and the use of tricyclic and SSRI antidepressants. In this article, we present a case of olanzapine treatment of a patient with cerebrovascular disease with psychobehavioural symptoms. The patient was an elderly patient who developed psychobehavioural symptoms after a sudden cerebral infarction. Initially, his symptoms improved when he took olanzapine (5"mg orally once/night). However, the patient subsequently developed symptoms of hypersomnia when he continued to take olanzapine, and the symptoms of hypersomnia gradually worsened as the dose of olanzapine was gradually increased. Benzodiazepines are often used to treat anomalous sleep, and clonazepam is one of the commonly prescribed drugs. In this case, the patient's abnormal sleep behavior was alleviated after treatment with clonazepam. As an atypical antipsychotic drug, olanzapine has been reported to cause abnormal sleep behavior during clinical use, and only one case has been reported in China. Clinicians should be aware that heteromorphic sleep can occur in patients treated with olanzapine. [ABSTRACT FROM AUTHOR]

Optimum serotonin level in the serotonergic synapses of the central nervous system (CNS) is related to mood, behavior, and sleep. Serotonin syndrome (SS) is a rare yet very dangerous adverse effect resulting from increased serotonin in CNS. The diagnosis of SS is based on the presence of clinical symptoms, which can include agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, tremors, sweating, and diarrhea. SS is invariably caused by inadvertent use of serotonergic medicines. There is an ever-growing list of medicines that are associated with the risk of SS. Some of the common classes of drugs that can contribute to the development of SS include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, stimulants (e.g., amphetamines and cocaine), lithium, opioids, drugs used for recreational purposes like ecstasy Methylenedioxymethamphetamine (MDMA), and some herbal supplements (e.g., St. John's Wort). SS can occur when these medications are taken alone or in combination, especially when a new medication is added, or the dose of an existing medication is changed. The management of SS typically involves discontinuing the use of the substance that caused the excess serotonin levels and providing supportive care, such as intravenous fluids and electrolytes. In severe cases, benzodiazepines may be used to control agitation and muscle rigidity, while serotonin antagonists, such as cyproheptadine, may be used to reduce serotonin levels. The literature review points to a general unawareness among physicians about the condition or drugs associated with it. Consequently, this potentially fatal condition is overlooked. There is a need for regular information updates and reminders to all those who prescribe medications to the patients. [ABSTRACT FROM AUTHOR]

Objective: Parkinson's disease (PD) presents as a chronic condition with symptoms that worsen over time. Many PD patients experience pain at some point during their illness. This complaint is often overlooked because PD is primarily a motor disorder. The main objective is to assess the prevalence and the most frequent type of pain in this population, as well as its relation to common neuropsychiatric factors. Methods: A cross-sectional study was conducted including 196 patients diagnosed with PD. The variables analyzed included age, gender, smoking, alcohol consumption, anxiety, depression, antiparkinsonian treatment (levodopa, dopaminergic agonists, monoamine oxidase inhibitors, and amantadine), intake of antidepressants or antipsychotics, age of symptom onset, age of diagnosis, years of progression, total MDS-UPDRS 3.3 score, total MDS-UPDRS score, MDS-non-motor symptom scores, Hamilton depression and anxiety scales, and montreal Cognitive Assessment. Results: Our patient cohort consisted of 115 males (58.7%) and 81 females (41.3%), with a mean age of 63.56 ± 11.88. The mean disease duration was 7.18 ± 4.9 years. The most common type of pain was musculoskeletal pain, present in 66.7%, followed by radicular pain (24.2%), pain related to fluctuations (22.7%), chronic pain (20.7%), nocturnal pain (17.2%), discoloration, edema, or swollen pain (14.6%), and orofacial pain (5.6%). Conclusions: From the study carried out, it can be observed that the most common type of pain was musculoskeletal pain, followed by radicular pain. Pain patients had a significant association with depression and anxiety due to the intensity of pain. [ABSTRACT FROM AUTHOR]

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In the current work, new and diverse hydrazone derivatives were designed and synthesized through a facile and multistep synthetic approach. The chemical structures were elucidated by various spectroscopic techniques. In vitro bioactivity analysis demonstrated selective and potent inhibitory potential of hydrazone derivatives against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. (E)‐3‐chloro‐N′‐(1‐phenylethylidene) benzohydrazide remarkably emerged as a lead candidate exhibiting potent and selective inhibition of AChE with an IC50 value of 0.63±0.01 μM whereas (E)‐3‐chloro‐N′‐(1‐(thiophen‐2‐yl)ethylidene)benzohydrazide delivered the strong potency and selective inhibition towards monoamine oxidase A with an IC50 value of 0.89±0.04 μM. Moreover, (E)‐3‐chloro‐N′‐(1‐(4‐methylthiophen‐2‐yl)ethylidene)benzohydrazide (IC50=2.06±0.01 μM) and (E)‐3‐chloro‐N′‐(1‐(5‐chlorothiophen‐2‐yl)ethylidene)benzohydrazide (IC50=2.06±0.05 μM) were identified as lead inhibitors of monoamine oxidase B. Molecular docking studies of potent and selective inhibitors exhibited various important interactions with amino acid residues in the active pocket of both enzymes, thus strengthening our in vitro results. The kinetics analysis of the most potent compound against AChE revealed non‐competitive mode of inhibition, whereas against monoamine oxidase (A & B), the corresponding lead inhibitors exhibited mixed type of inhibition. Molecular dynamics simulations were also performed to investigate the energetically stable complex formation ability of potent compounds with the target protein. Finally, the results of in silico pharmacokinetic properties showed that the potent compounds have promising pharmacological effects that follow all the parameters of drug‐likeness and could serve as effective drug candidates for future investigations. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive brain disease characterised by progressive memory loss and cognition impairment, ultimately leading to death. There are three FDA-approved acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine, AChEIs) for the symptomatic treatment of AD. Monoamine oxidase B (MAO-B) has been considered to contribute to pathologies of AD. Therefore, we reviewed the dual inhibitors of acetylcholinesterase (AChE) and MAO-B developed in the last five years. In this review, these dual-target inhibitors were classified into six groups according to the basic parent structure, including chalcone, coumarin, chromone, benzo-fused five-membered ring, imine and hydrazine, and other scaffolds. Their design strategies, structure-activity relationships (SARs), and molecular docking studies with AChE and MAO-B were analysed and discussed, giving valuable insights for the subsequent development of AChE and MAO-B dual inhibitors. Challenges in the development of balanced and potent AChE and MAO-B dual inhibitors were noted, and corresponding solutions were provided. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases such as Alzheimer's disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional "one-target, one-molecule" approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H3 receptor ligands (H3R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a Ki value of 0.012 μM. The multitargeting potential of these H3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a Ki value of 0.036 μM at H3R and IC50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents. [ABSTRACT FROM AUTHOR]