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Neurochemistry International May 2021Monoamine oxidase (MAO) enzymes, type A and B metabolise the amine neurotransmitters of the body. Selective inhibition of either enzyme is an approach for treating...
Monoamine oxidase (MAO) enzymes, type A and B metabolise the amine neurotransmitters of the body. Selective inhibition of either enzyme is an approach for treating neurodegenerative and stress-induced disorders, and inhibition of an enzyme is proportional to the binding of the MAO inhibitor. Conventionally, the binding of test compounds to enzymes is assessed by radiolabelled ligands in ex vivo and in vivo occupancy assays. Regulatory restrictions and turnaround time are the limitations of the methods that use radiolabelled ligands. But the use of non-radiolabelled tracers and sensitive mass spectrometry (LC-MS/MS) based assays accelerated the determination of target occupancy in pre-clinical species. A report on use of non-radiolabelled ligand in in vivo MAO occupancy assay is not available. The objectives of the present study were to optimise non-radiolabelled harmine and deprenyl as selective tracers in MAO-A and MAO-B occupancy assays and evaluate MAO occupancy of test compounds in rat brain. Tracer optimisation resulted in a detectable, stable, and low ratio (<3.0) of tracer concentrations between any two brain tissues. In occupancy assay, tracer was intravenously administered (10 μg/kg, harmine or 60 μg/kg, L-deprenyl) after the treatment with test compound (clorgyline or tranylcypromine or pargyline or phenelzine or thioperamide). Specific brain tissues were isolated at a defined interval and tracer concentrations were quantified using LC-MS/MS method. Pre-treatment with MAO inhibitors resulted in a decrease (maximum, 80-85%) in harmine or an increase (maximum, 85-300%) in L-deprenyl concentrations. But we considered the change in tracer concentration, relative to the vehicle and positive control groups to calculate MAO occupancy. The observed selectivity and ratio of occupancies (ED) of test compound towards MAO-A and MAO-B are comparable with the results from in vitro radiolabelled ligand-based inhibition assay. The results demonstrated the application of these non-radiolabelled tracers as suitable pre-clinical tools to determine MAO occupancy.
Topics: Administration, Intravenous; Animals; Brain; Dose-Response Relationship, Drug; Harmine; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Protein Binding; Rats; Rats, Sprague-Dawley; Selegiline
PubMed: 33636211
DOI: 10.1016/j.neuint.2021.105006 -
Journal of Affective Disorders Mar 2021Monoamine oxidase inhibitors (MAOIs) were the first class of modern antidepressants; however, they are under-utilized as compared to the newer antidepressants. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Monoamine oxidase inhibitors (MAOIs) were the first class of modern antidepressants; however, they are under-utilized as compared to the newer antidepressants.
METHODS
In this systematic review, network meta-analysis was used to investigate the comparative efficacy and acceptability of MAOIs for depressive disorders. Overall, the network meta-analysis included 52 double-blind, randomized controlled trials (RCTs) that compared 14 antidepressants or placebo. Across studies, the mean arm size was n = 58 participants from a total N = 6462 (5309 active drug; 1153 placebo).
RESULTS
Except fluvoxamine, all antidepressants demonstrated superior efficacy to placebo, and none demonstrated substantially better or worse all-cause dropout rates. Phenelzine demonstrated superior evidence for efficacy compared to all other treatments, and clomipramine demonstrated superior evidence for acceptability compared to all other treatments.
LIMITATIONS
The study is primarily limited by low estimate precision due to a relative paucity of studies for some of the included treatment conditions. Further evidence is required to study the relative efficacy of MAOIs against newer antidepressants.
CONCLUSIONS
The results of this analysis largely support the re-evaluation of the use of MAOIs as antidepressant agents in the treatment algorithm of depression.
Topics: Antidepressive Agents; Depressive Disorder; Humans; Monoamine Oxidase Inhibitors; Network Meta-Analysis; Randomized Controlled Trials as Topic
PubMed: 33601690
DOI: 10.1016/j.jad.2021.01.021 -
Translational Research : the Journal of... May 2021Oligodendrocyte progenitor cells (OPCs) in the infant brain give rise to mature oligodendrocytes that myelinate CNS axons. OPCs are particularly vulnerable to oxidative...
Oligodendrocyte progenitor cells (OPCs) in the infant brain give rise to mature oligodendrocytes that myelinate CNS axons. OPCs are particularly vulnerable to oxidative stress that occurs in many forms of brain injury. One common cause of infant brain injury is neonatal intraventricular hemorrhage (IVH), which releases blood into the CSF and brain parenchyma of preterm infants. Although blood contains the powerful oxidant hemoglobin, the direct effects of hemoglobin on OPCs have not been studied. We utilized a cell culture system to test if hemoglobin induced free radical production and mitochondrial dysfunction in OPCs. We also tested if phenelzine (PLZ), an FDA-approved antioxidant drug, could protect OPCs from hemoglobin-induced oxidative stress. OPCs were isolated from Sprague Dawley rat pups and exposed to hemoglobin with and without PLZ. Outcomes assessed included intracellular reactive oxygen species levels using 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent dye, oxygen consumption using the XFe96 Seahorse assay, and proliferation measured by BrdU incorporation assay. Hemoglobin induced oxidative stress and impaired mitochondrial function in OPCs. PLZ treatment reduced hemoglobin-induced oxidative stress and improved OPC mitochondrial bioenergetics. The effects of hemoglobin and PLZ on OPC proliferation were not statistically significant, but showed trends towards hemoglobin reducing OPC proliferation and PLZ increasing OPC proliferation (P=0.06 for both effects). Collectively, our results indicate that hemoglobin induces mitochondrial dysfunction in OPCs and that antioxidant therapy reduces these effects. Therefore, antioxidant therapy may hold promise for white matter diseases in which hemoglobin plays a role, such as neonatal IVH.
Topics: Animals; Animals, Newborn; Cell Proliferation; Female; Gene Expression Regulation; Hemoglobins; L-Lactate Dehydrogenase; Mitochondria; Oligodendroglia; Oxidative Stress; Oxygen Consumption; Phenelzine; Pregnancy; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Stem Cells
PubMed: 33460824
DOI: 10.1016/j.trsl.2021.01.005 -
ACS Pharmacology & Translational Science Dec 2020The purpose of this analysis was to assess, from the patients' perspective, the effectiveness and relative safety of tramadol as an off-label antidepressant and to...
The purpose of this analysis was to assess, from the patients' perspective, the effectiveness and relative safety of tramadol as an off-label antidepressant and to determine if patients' views and experiences are consistent with the biomedical literature. A data mining approach was used to analyze databases available at drugs.com. Tramadol was reported to be an effective or very effective antidepressant by 94.6% of patients (123/130) who provided ratings submitted to (https://www.drugs.com/comments/tramadol/for-depression.html). When compared to 34 other antidepressants in the database titled (https://www.drugs.com/condition/depression.html), for which there were ≥100 individual reviews for each drug, tramadol was rated as being the most effective (effectiveness rating = 9.1/10). Phenelzine (effectiveness rating = 8.7/10) was the only other antidepressant having ≥100 individual reviews coupled with a very high (8.0-10.0) effectiveness rating. Eleven patients reported significant symptoms of withdrawal upon cessation of tramadol, and five patients reported loss or reduction of libido as a side effect. Most (57/72, 79.2%) patients who reported a dose consumed experienced relief from depression at low therapeutic doses (25-150 mg/day). Fourteen patients reported taking this antidepressant for 5-10 years, and four patients reported taking tramadol for 10 or more years. Results demonstrated that most patients' comments and beliefs are consistent with the biomedical literature. Patients' reviews coupled with a survey of the biomedical literature indicate that at low therapeutic doses in the absence of interactions with other drugs, adult patients found tramadol to be a generally safe, effective, and fast-acting medication for relief from depression.
PubMed: 33344902
DOI: 10.1021/acsptsci.0c00132 -
Journal of Pharmacy Practice Oct 2021The objectives of this manuscript are to describe a case report of a patient whose phenelzine maintenance therapy was discontinued due to concern for a... (Review)
Review
The objectives of this manuscript are to describe a case report of a patient whose phenelzine maintenance therapy was discontinued due to concern for a phenelzine-morphine drug interaction, to review the available literature regarding the potential for this drug-drug interaction, and provide recommendations for this clinical scenario. A PubMed/MEDLINE literature search was conducted and all publications determined to be relevant to this case report were included. Literature describing data, case reports/human studies, and review articles concerning the interaction between morphine and monoamine oxidase inhibitors (MAOIs) were included. A total of 14 publications pertinent to the potential phenelzine-morphine interaction were included in this review including 5 studies, 4 human studies, and 6 review articles detailing the drug interaction profile between opioids and antidepressants. Of these publications, only a single case report of a potential drug interaction between morphine and phenelzine was identified. The literature suggesting a drug interaction between morphine and phenelzine is limited. The combination of phenelzine and morphine, with close monitoring for signs and symptoms of serotonin syndrome, is reasonable for patients with appropriate indications for both agents.
Topics: Analgesics, Opioid; Drug Interactions; Humans; Monoamine Oxidase Inhibitors; Morphine; Pharmaceutical Preparations; Phenelzine
PubMed: 33267714
DOI: 10.1177/0897190020970752 -
Scientific Reports Oct 2020Over the past decade, there has been increasing evidence highlighting the implication of the gut microbiota in a variety of brain disorders such as depression, anxiety,...
Over the past decade, there has been increasing evidence highlighting the implication of the gut microbiota in a variety of brain disorders such as depression, anxiety, and schizophrenia. Studies have shown that depression affects the stability of gut microbiota, but the impact of antidepressant treatments on microbiota structure and metabolism remains underexplored. In this study, we investigated the in vitro antimicrobial activity of antidepressants from different therapeutic classes against representative strains of human gut microbiota. Six different antidepressants: phenelzine, venlafaxine, desipramine, bupropion, aripiprazole and (S)-citalopram have been tested for their antimicrobial activity against 12 commensal bacterial strains using agar well diffusion, microbroth dilution method, and colony counting. The data revealed an important antimicrobial activity (bacteriostatic or bactericidal) of different antidepressants against the tested strains, with desipramine and aripiprazole being the most inhibitory. Strains affiliating to most dominant phyla of human microbiota such as Akkermansia muciniphila, Bifidobacterium animalis and Bacteroides fragilis were significantly altered, with minimum inhibitory concentrations (MICs) ranged from 75 to 800 μg/mL. A significant reduction in bacterial viability was observed, reaching 5 logs cycle reductions with tested MICs ranged from 400 to 600 μg/mL. Our findings demonstrate that gut microbiota could be altered in response to antidepressant drugs.
Topics: Akkermansia; Antidepressive Agents; Bacteroides fragilis; Bifidobacterium animalis; Depression; Desipramine; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Gastrointestinal Microbiome; Humans; Microbial Sensitivity Tests; Phenelzine; Venlafaxine Hydrochloride
PubMed: 33087796
DOI: 10.1038/s41598-020-74934-9 -
The Australian and New Zealand Journal... Aug 2021
Topics: Humans; Phenelzine
PubMed: 33040569
DOI: 10.1177/0004867420965700 -
Pharmaceuticals (Basel, Switzerland) Sep 2020Buch.-Ham. is commonly used in folk medicine against various disorders. The present study investigated the antidepressant and cytotoxicity activity of methanol extract...
Buch.-Ham. is commonly used in folk medicine against various disorders. The present study investigated the antidepressant and cytotoxicity activity of methanol extract of (MECP) along with quantitative phytochemical analysis by GC-MS method. Here, the GC-MS study of MECP presented 41 compounds, among which most were fatty acids, esters, terpenoids and oximes. The antidepressant activity was assessed by the forced swimming test (FST) and tail suspension test (TST) models. In contrast, MECP (200 and 400 mg/kg) exhibited a significant and dose-dependent manner reduction in immobility comparable with fluoxetine (10 mg/kg) and phenelzine (20 mg/kg). MECP showed a weak toxicity level in the brine shrimp lethality bioassay (ED: 358.65 µg/mL) comparable to the standard drug vincristine sulfate (ED: 2.39 µg/mL). Three compounds from the GC-MS study were subjected to density functional theory (DFT) calculations, where only cyclopentadecanone oxime showed positive and negative active binding sites. Cyclopentadecanone oxime also showed a good binding interaction in suppressing depression disorders by blocking monoamine oxidase and serotonin receptors with better pharmacokinetic and toxicological properties. Overall, the MECP exhibited a significant antidepressant activity with moderate toxicity, which required further advance studies to identify the mechanism.
PubMed: 32899148
DOI: 10.3390/ph13090232 -
Journal of Psychiatric Research Nov 2020The purpose of this study was to compare efficacy and acceptability among drug treatments for adults with post-traumatic stress disorder (PTSD) through a systematic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The purpose of this study was to compare efficacy and acceptability among drug treatments for adults with post-traumatic stress disorder (PTSD) through a systematic review, random-effects pairwise and network meta-analyses.
METHODS
Double-blind randomized controlled trials comparing pharmacological interventions for adults with PTSD were searched from database inception through Aug. 28, 2018, on Cochrane (Central), Embase, LILACS, PILOTS, PsycINFO, PubMed, and Web of Science. Clinical trial registries and the websites of pharmaceutical companies were also searched. The GRADE system was used to assess the quality of the evidence.
RESULTS
The systematic review included 58 studies comprising 6766 patients randomized to 26 different interventions. Regarding efficacy, topiramate (SMD = -0.57; 95%CrI: -1.07,-0.10), risperidone (SMD = -0.53; 95%CrI: -0.93,-0.15), quetiapine (SMD = -0.59; 95%CrI: -1.06,-0.11), paroxetine (SMD = -0.35; 95%CrI: -0.48,-0.21), venlafaxine (SMD = -0.25; 95%CrI: -0.44,-0.05), fluoxetine (SMD = -0.28; 95%CrI: -0.46,-0.08), and sertraline (SMD = -0.21; 95%CrI: -0.33,-0.09) outperformed placebo. Moreover, phenelzine (RR = 3.39; 95%CrI: 1.43,11.09), lamotrigine (RR = 4.39; 95%CrI: 1.18,26.38), and fluoxetine (RR = 1.28%CrI: 1.01,1.59) outperformed placebo in terms of acceptability.
CONCLUSIONS
The NMA supports topiramate, risperidone, quetiapine, paroxetine, venlafaxine, fluoxetine and sertraline as effective pharmacological choices for the treatment of PTSD. Quetiapine and topiramate have the shortcoming of relying on a few small studies, but the clinically meaningful change in symptoms is noteworthy and merits further investigation. Among the pharmacological treatments with evidence of efficacy compared to placebo, fluoxetine achieved a relatively high rank regarding acceptability. To the best of our knowledge, this is the largest contemporary NMA on the subject and the addition of new medications is an important extension of previous meta-analyses, enabling a larger number of drug comparisons.
Topics: Adult; Humans; Network Meta-Analysis; Paroxetine; Randomized Controlled Trials as Topic; Sertraline; Stress Disorders, Post-Traumatic; Venlafaxine Hydrochloride
PubMed: 32891916
DOI: 10.1016/j.jpsychires.2020.07.046