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The Journal of Neuroscience : the... May 2020Emerging evidence suggests that there is a reduction in overall cortical excitatory to inhibitory balance in major depressive disorder (MDD), which afflicts ∼14%-20%...
Emerging evidence suggests that there is a reduction in overall cortical excitatory to inhibitory balance in major depressive disorder (MDD), which afflicts ∼14%-20% of individuals. Reduced pyramidal cell arborization occurs with stress and MDD, and may diminish excitatory neurotransmission. Enhanced deposition of perineuronal net (PNN) components also occurs with stress. Since parvalbumin-expressing interneurons are the predominant cell population that is enveloped by PNNs, which enhance their ability to release GABA, excess PNN deposition likely increases pyramidal cell inhibition. In the present study, we investigate the potential for matrix metalloprotease-9 (MMP-9), an endopeptidase secreted in response to neuronal activity, to contribute to the antidepressant efficacy of the serotonin/norepinephrine reuptake inhibitor venlafaxine in male mice. Chronic venlafaxine increases MMP-9 levels in murine cortex, and increases both pyramidal cell arborization and PSD-95 expression in the cortex of WT but not MMP-9-null mice. We have previously shown that venlafaxine reduces PNN deposition and increases the power of γ oscillations in conventionally housed mice. γ power is increased with pyramidal cell disinhibition and with remission from MDD. Herein we observe that PNN expression is increased in a corticosterone-induced stress model of disease and reduced by venlafaxine. Compared with mice that receive concurrent venlafaxine, corticosterone-treated mice also display reduced γ power and impaired working memory. Autopsy-derived PFC samples show elevated MMP-9 levels in antidepressant-treated MDD patients compared with controls. These preclinical and postmortem findings highlight a link between extracellular matrix regulation and MDD. Reduced excitatory neurotransmission occurs with major depressive disorder, and may be normalized by antidepressant treatment. Underlying molecular mechanisms are, however, not well understood. Herein we investigate a potential role for an extracellular protease, released from neurons and known to play a role in learning and memory, in antidepressant-associated increases in excitatory transmission. Our data suggest that this protease, matrix metalloprotease-9, increases branching of excitatory neurons and concomitantly attenuates the perineuronal net to potentially reduce inhibitory input to these neurons. Matrix metalloprotease-9 may thus enhance overall excitatory/inhibitory balance and neuronal population dynamics, which are important to mood and memory.
Topics: Adult; Aged; Animals; Cells, Cultured; Cerebral Cortex; Depressive Disorder, Major; Female; Gamma Rhythm; Humans; Male; Matrix Metalloproteinase 9; Memory, Short-Term; Mice; Mice, Inbred C57BL; Middle Aged; Neural Inhibition; Pyramidal Cells; Serotonin and Noradrenaline Reuptake Inhibitors; Stress, Psychological; Venlafaxine Hydrochloride
PubMed: 32269106
DOI: 10.1523/JNEUROSCI.2387-19.2020 -
BMJ Open Dec 2023Investigate risk for falls, fractures and syncope in older adult patients treated with nortriptyline compared with paroxetine and alternative medications.
Adverse drug events associated with nortriptyline compared with paroxetine and alternative medications in an older adult population: a retrospective cohort study in Southern California.
OBJECTIVE
Investigate risk for falls, fractures and syncope in older adult patients treated with nortriptyline compared with paroxetine and alternative medications.
DESIGN
Retrospective cohort study.
SETTING
The electronic medical record and prescription drug database of a large integrated healthcare system in Southern California.
PARTICIPANTS
Ambulatory patients, age ≥65 years diagnosed with depression, anxiety disorder or peripheral neuropathy, dispensed one or more of ten study medications between 1 January 2008 and 31 December 2018.
MAIN OUTCOME MEASURES
HR for falls, fractures and syncope with exposure to study medications adjusted for patient demographic variables and comorbidities.
RESULTS
Among 195 207 subjects, 19 305 falls, 15 088 fractures and 11 313 episodes of syncope were observed during the study period. Compared with the reference medication, nortriptyline, the adjusted HRs (aHRs) for falls were statistically significantly greater for: paroxetine (aHR 1.48, 95% CI 1.39 to 1.57), amitriptyline (1.20, 95% CI 1.08 to 1.33), venlafaxine (1.44, 95% CI 1.34 to 1.56), duloxetine (1.25, 95% CI 1.12 to 1.40), fluoxetine (1.51, 95% CI 1.44 to 1.59), sertraline (1.53, 95% CI 1.44 to 1.62), citalopram (1.61, 95% CI 1.52 to 1.71) and escitalopram (1.37, 95% CI 1.21 to 1.54), but not gabapentin (0.95, 95% CI 0.89 to 1.02). For fractures, compared with nortriptyline, aHRs were significantly greater for: paroxetine, venlafaxine, duloxetine, fluoxetine, sertraline, citalopram, escitalopram and gabapentin, with aHRs ranging from 1.30 for gabapentin to 1.82 for escitalopram; risk was statistically similar for amitriptyline. For syncope, the aHRs were significantly greater for: paroxetine, venlafaxine, fluoxetine, sertraline and citalopram, with aHRs ranging from 1.19 for fluoxetine and paroxetine up to 1.30 for citalopram and sertraline; risk was similar for amitriptyline, duloxetine, escitalopram and gabapentin.
CONCLUSIONS
Compared with therapeutic alternatives, nortriptyline was found to represent a lower risk for falls, fractures and syncope, versus comparator medications, except for a few instances that had equivalent risk. The risk for these adverse events from paroxetine was comparable to the alternative medications.
Topics: Humans; Aged; Paroxetine; Nortriptyline; Citalopram; Fluoxetine; Sertraline; Venlafaxine Hydrochloride; Amitriptyline; Duloxetine Hydrochloride; Retrospective Studies; Escitalopram; Gabapentin; Drug-Related Side Effects and Adverse Reactions; Syncope
PubMed: 38154883
DOI: 10.1136/bmjopen-2023-076028 -
The Journal of Steroid Biochemistry and... Dec 2019Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via...
Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells. Based on molecular simulations, the present study illustrates that the SRIs fluoxetine, norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition. Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas, we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine, paroxetine and sertraline decrease aromatase activity in primary villous trophoblast. The effects of paroxetine and sertraline in primary villous trophoblasts were observed at the lower doses tested. We also showed that 5-HT and the 5-HT receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation of CYP19 was also associated with DOI treatment. Our results contribute to better understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production. Moreover, this study suggests that alteration of placental 5-HT levels due to depression and/or SRI treatment during pregnancy may be associated with disruption of placental estrogen production.
Topics: Aromatase; Cells, Cultured; Citalopram; Female; Fluoxetine; Humans; Molecular Docking Simulation; Paroxetine; Placenta; Pregnancy; Serotonin; Selective Serotonin Reuptake Inhibitors; Sertraline; Trophoblasts; Venlafaxine Hydrochloride
PubMed: 31509772
DOI: 10.1016/j.jsbmb.2019.105470 -
International Journal of Molecular... Sep 2022Drug metabolizing enzyme activity is affected by various factors such as drug-drug interactions, and a method to quantify drug metabolizing enzyme activity in real time...
Drug metabolizing enzyme activity is affected by various factors such as drug-drug interactions, and a method to quantify drug metabolizing enzyme activity in real time is needed. In this study, we developed a novel radiopharmaceutical for quantitative imaging to estimate hepatic CYP3A4 and CYP2D6 activity. Iodine-123- and 125-labeled -desmethylvenlafaxine (I-ODV) was obtained with high labeling and purity, and its metabolism was found to strongly involve CYP3A4 and CYP2D6. SPECT imaging in normal mice showed that the administered I-ODV accumulated early in the liver and was excreted into the gallbladder, as evaluated by time activity curves. In its biological distribution, I-ODV administered to mice accumulated early in the liver, and only the metabolite of I-ODV was quickly excreted into the bile. In CYP3A4- and CYP2D6-inhibited model mice, the accumulation in bile decreased more than in normal mice, indicating inhibition of metabolite production. These results indicated that imaging and quantifying the accumulation of radioactive metabolites in excretory organs will aid in determining the dosages of various drugs metabolized by CYP3A4 and CYP2D6 for individualized medicine. Thus, I-ODV has the potential to direct, comprehensive detection and measurement of hepatic CYP3A4 and CYP2D6 activity by a simple and less invasive approach.
Topics: Animals; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Desvenlafaxine Succinate; Iodine Radioisotopes; Liver; Mice; Radiopharmaceuticals; Venlafaxine Hydrochloride
PubMed: 36232758
DOI: 10.3390/ijms231911458 -
Marine Pollution Bulletin Jul 2023The assessment of exposure to the antidepressant venlafaxine and its major metabolite o-desmethylvenlafaxine in Holothuria tubulosa, Anemonia sulcata and Actinia equina...
Accumulation and metabolization of the antidepressant venlafaxine and its main metabolite o-desmethylvenlafaxine in non-target marine organisms Holothuria tubulosa, Anemonia sulcata and Actinia equina.
The assessment of exposure to the antidepressant venlafaxine and its major metabolite o-desmethylvenlafaxine in Holothuria tubulosa, Anemonia sulcata and Actinia equina is proposed. A 28-day exposure experiment (10 μg/L day) followed by a 52-day depuration period was conducted. The accumulation shows a first-order kinetic process reaching an average concentration of 49,125/54342 ng/g dw in H. tubulosa and 64,810/93007 ng/g dw in A. sulcata. Venlafaxine is considered cumulative (BCF > 2000 L/kg dw) in H. tubulosa, A. sulcata and A. equina respectively; and o-desmethylvenlafaxine in A. sulcata. Organism-specific BCF generally followed the order A. sulcata > A. equina > H. tubulosa. The study revealed differences between tissues in metabolizing abilities in H. tubulosa this effect increases significantly with time in the digestive tract while it was negligible in the body wall. The results provide a description of venlafaxine and o-desmethylvenlafaxine accumulation in common and non-target organisms in the marine environment.
Topics: Animals; Venlafaxine Hydrochloride; Desvenlafaxine Succinate; Holothuria; Aquatic Organisms; Antidepressive Agents; Sea Anemones
PubMed: 37207394
DOI: 10.1016/j.marpolbul.2023.115055 -
Current Therapeutic Research, Clinical... 2023Intranasal administration is among the most effective alternatives to deliver drugs directly to the brain and prevent first-pass metabolism. Venlafaxine-loaded liposomes...
BACKGROUND
Intranasal administration is among the most effective alternatives to deliver drugs directly to the brain and prevent first-pass metabolism. Venlafaxine-loaded liposomes are biocompatible carriers that enhance transport qualities over the nasal mucosa.
OBJECTIVE
This research aimed to develop, formulate, characterize, and observe the prepared formulation.
METHODS
The formulation was developed using the thin-film hydration technique. The response surface plot interrelationship between three independent variables are lipid, cholesterol and polymer and four dependent variables such as particle size, percentage entrapment efficiency, and percentage drug release were ascertained using the Box-Behnken design.
RESULTS
The drug-release chitosan-coated liposomes were reported to have a particle size distribution, entanglement efficiency, and 84%, respectively, of 191 ± 34.71 nm, 94 ± 2.71% and 94 ± 2.71%. According to investigations, liposomes as a delivery system for the nasal route provided a more sustained drug release than the oral dosing form.
CONCLUSIONS
The intranasal administration of venlafaxine liposomal vesicles effectively enhanced the absolute bioavailability, retention time, and brain delivery of venlafaxine.
PubMed: 37727460
DOI: 10.1016/j.curtheres.2023.100714 -
The Science of the Total Environment Sep 2022The COVID-19 pandemic has been a major challenge worldwide, forcing countries to take restrictive measures beyond conventional methods in their fight against the spread...
The COVID-19 pandemic has been a major challenge worldwide, forcing countries to take restrictive measures beyond conventional methods in their fight against the spread of the disease. Followingly, many studies have been conducted on the effects of these measures on mental health. Wastewater-based epidemiology (WBE) was used in this study to monitor and estimate changes in antidepressant use under normal conditions (2019) and COVID-19 pandemic conditions (2020). Likewise, this study utilized wastewater-based epidemiology (WBE) to monitor and assess changing trends from the pre-pandemic period (2019) to COVID-19 pandemic conditions in antidepressant use (2020). Wastewater samples were collected from 11 cities in Turkey throughout six sampling periods covering the pre-pandemic and during-pandemic periods (June 2019-December 2020). Then, samples were analyzed via LC-MS/MS method. As a result, we observed that venlafaxine was the drug with the highest concentration (mean ± SD: 103.6 ± 112.1 mg/1000p/day). Moreover, city number 6 presented the highest venlafaxine use and the most dramatic increase during the pandemic period. Finally, this study revealed the potential of WBE to estimate the changing trends in mental health during the ongoing pandemic.
Topics: Antidepressive Agents; COVID-19; Chromatography, Liquid; Humans; Pandemics; Tandem Mass Spectrometry; Turkey; Venlafaxine Hydrochloride; Wastewater
PubMed: 35568186
DOI: 10.1016/j.scitotenv.2022.155916 -
Environmental Science and Pollution... Feb 2023Psychiatric drugs released by humans in wastewater have received more attention because of their potential risks for aquatic organisms. In this study, the occurrence of...
Psychiatric drugs released by humans in wastewater have received more attention because of their potential risks for aquatic organisms. In this study, the occurrence of the two most common groups of psychiatric drugs (sedatives-hypnotics-anxiolytics and antidepressants) were evaluated in the Tehran South Municipal Wastewater Treatment Plant. All the target sedatives-hypnotics-anxiolytics (alprazolam, phenobarbital, and thioridazine) and antidepressants (fluoxetine, citalopram, sertraline, and venlafaxine) were observed in influent and secondary clarification (SC) effluent. Thioridazine (164.25 ± 218.74 ng/L) and citalopram (672.53 ± 938.56 ng/L) had the highest mean concentrations in the influent, while alprazolam (5.09 ± 2.33 ng/L) and citalopram (776.97 ± 1088.01 ng/L) had the highest concentrations in the SC effluent. The higher concentrations of the psychiatric drugs, except thioridazine, were detected in the SC effluent compared to the concentrations in the influent. The increased drugs concentrations, with negative removal efficiencies, were more distinctive in the cold season samples. Psychiatric drugs processed in the chlorination unit followed a completely different pattern compared to the drugs in the biological treatment unit. All the drugs' concentrations, except thioridazine, decreased in the chlorination unit, ranging between 27 ± 14% for alprazolam and 75 ± 10% for citalopram. However, the mean concentrations of the detected drugs were as follows: sertraline (11.96 ± 11.62 ng/L) and venlafaxine (184.94 ± 219.74 ng/L) which could cause environmental and ecological concerns.
Topics: Humans; Water Pollutants, Chemical; Citalopram; Sertraline; Venlafaxine Hydrochloride; Thioridazine; Anti-Anxiety Agents; Alprazolam; Iran; Antidepressive Agents; Pharmaceutical Preparations; Water Purification; Hypnotics and Sedatives; Environmental Monitoring; Waste Disposal, Fluid
PubMed: 36374381
DOI: 10.1007/s11356-022-23667-5 -
CNS Neuroscience & Therapeutics Mar 2024To explore the pharmacological treatment of vascular depression (VaDep) and whether the blood levels of neurotransmitters can reflect the VaDep severity. (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of venlafaxine hydrochloride combined with tandospirone citrate for patients with vascular depression accompanied by somatic symptoms: An open-labeled randomized control trial.
AIMS
To explore the pharmacological treatment of vascular depression (VaDep) and whether the blood levels of neurotransmitters can reflect the VaDep severity.
METHODS
VaDep patients with somatic symptoms were enrolled and randomly received venlafaxine + tandospirone (Combined Group) or venlafaxine (Monotherapy Group). The treatment efficacy was assessed by Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Patient Health Questionnaire-15 (PHQ-15). The levels of blood monoamine neurotransmitters were measured by enzyme-linked immunosorbent assay.
RESULTS
Both groups reported a progressive decrease in HAMD, HAMA, and PHQ-15 scores to below the baseline after the respective treatment. Compared with the Monotherapy Group, the Combined Group reported a significant decrease in HAMD score at week 2 and markedly lower HAMA and PHQ-15 scores at weeks 1, 2, 4, and 8. Both groups showed a decrease in the levels of blood monoamine neurotransmitters at weeks 4 and 8 when compared with the baseline. A strong positive association was evident between the plasma 5-HT levels and the HAMD score.
CONCLUSION
The combined therapy rapidly acts on VaDep comorbid with anxiety and somatic symptoms and significantly alleviates the anxiety and somatic symptoms. The plasma levels of 5-HT may serve as potential objective candidates in evaluating VaDep severity and the efficacy of the undertaken treatment regimen.
Topics: Humans; Anti-Anxiety Agents; Citrates; Depression; Isoindoles; Medically Unexplained Symptoms; Piperazines; Pyrimidines; Selective Serotonin Reuptake Inhibitors; Serotonin; Treatment Outcome; Vascular Depression; Venlafaxine Hydrochloride; Drug Therapy, Combination
PubMed: 38514905
DOI: 10.1111/cns.14650 -
Journal of Psychiatry & Neuroscience :... Jan 2021Late-life depression is often associated with non-response or relapse following conventional antidepressant treatment. The pathophysiology of late-life depression likely... (Clinical Trial)
Clinical Trial
BACKGROUND
Late-life depression is often associated with non-response or relapse following conventional antidepressant treatment. The pathophysiology of late-life depression likely involves a complex interplay between aging and depression, and may include abnormalities in cortical inhibition and plasticity. However, the extent to which these cortical processes are modifiable by antidepressant pharmacotherapy is unknown.
METHODS
Sixty-eight patients with late-life depression received 12 weeks of treatment with open-label venlafaxine, a serotonin-norepinephrine reuptake inhibitor (≤ 300 mg/d). We combined transcranial magnetic stimulation of the left motor cortex with electromyography recordings from the right hand to measure cortical inhibition using contralateral cortical silent period and paired-pulse short-interval intracortical inhibition paradigms; cortical facilitation using a paired-pulse intracortical facilitation paradigm; and short-term cortical plasticity using a paired associative stimulation paradigm. All measures were collected at baseline, 1 week into treatment ( = 23) and after approximately 12 weeks of treatment.
RESULTS
Venlafaxine did not significantly alter cortical inhibition, facilitation or plasticity after 1 or 12 weeks of treatment. Improvements in depressive symptoms during treatment were not associated with changes in cortical physiology.
LIMITATIONS
The results presented here are specific to the motor cortex. Future work should investigate whether these findings extend to cortical areas more closely associated with depression, such as the dorsolateral prefrontal cortex.
CONCLUSION
These findings suggest that antidepressant treatment with venlafaxine does not exert meaningful changes in motor cortical inhibition or plasticity in late-life depression. The absence of changes in motor cortical physiology, alongside improvements in depressive symptoms, suggests that age-related changes may play a role in previously identified abnormalities in motor cortical processes in latelife depression, and that venlafaxine treatment does not target these abnormalities.
Topics: Aged; Aged, 80 and over; Depressive Disorder, Major; Electric Stimulation; Electromyography; Evoked Potentials, Motor; Female; Humans; Male; Middle Aged; Motor Cortex; Neural Inhibition; Neuronal Plasticity; Outcome Assessment, Health Care; Serotonin and Noradrenaline Reuptake Inhibitors; Transcranial Magnetic Stimulation; Venlafaxine Hydrochloride
PubMed: 33119493
DOI: 10.1503/jpn.200001