-
Journal of Integrative Neuroscience Jul 2023Stress can lead to emotional and mental symptoms such as anxiety, sadness, panic attacks, and depression. Malic acid was chosen due to malic acid has the ability to...
BACKGROUND
Stress can lead to emotional and mental symptoms such as anxiety, sadness, panic attacks, and depression. Malic acid was chosen due to malic acid has the ability to improve antioxidant activity and improves liver damage. This study evaluates malic acid anti-depressant activity in the hypothalamus of stressed rats.
METHODS
Thirty-six male albino rats were divided into 2 equal groups; Normal and chronic mild stress (CMS) rats. Normal rats were divided into 3 equal groups; control, malic acid, and venlafaxine drug groups: normal rats were administered orally with 1 mL of saline solution, 250 mg/kg of malic acid, and 20 mg/kg of venlafaxine drug, respectively. CMS rats were divided into 3 equal groups; CMS, CMS + malic acid, and CMS + venlafaxine drug: CMS rats were administered orally with 1 mL of saline solution, 250 mg/kg of malic acid, and 20 mg/kg of venlafaxine drug, respectively. All the above-mentioned treatments were administered once a day by oral gavage for 6 weeks.
RESULTS
The obtained results revealed that the animal behavioral tests such as forced swimming test, tail suspension test, sucrose preference test, and open-field test (center square entries test, center square duration test, and distance travelled test), norepinephrine, dopamine, serotonin, γ-aminobutyric acid, nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity, oxidative index, conjugated dienes, catalase, glutathione peroxidase, superoxide dismutase, malondialdehyde, interleukin-6, tumor necrosis factor-α, interleukin-10, interleukin-1β, sodium/potassium-ATPase activity, and histamine-N-methyl transferase () and tyrosine hydroxylase () enzymes in the hypothalamus of stressed rats, were returned to approaching the normal state in the stressed group after treating with malic acid for 6 weeks.
CONCLUSIONS
Malic acid ameliorated stressed-related symptoms and it inhibited superoxide anion and neuro-inflammation in the hypothalamus of stressed rats.
Topics: Rats; Male; Animals; Venlafaxine Hydrochloride; Saline Solution; Depression; Hypothalamus; Stress, Psychological; Oxidative Stress
PubMed: 37519180
DOI: 10.31083/j.jin2204098 -
Comparative Biochemistry and... Jul 2023Venlafaxine (VFX), a commonly prescribed antidepressant often detected in wastewater effluent, and acute temperature elevations from climate change and increased...
Venlafaxine (VFX), a commonly prescribed antidepressant often detected in wastewater effluent, and acute temperature elevations from climate change and increased urbanization, are two environmental stressors currently placing freshwater ecosystems at risk. This study focused on understanding if exposure to VFX impacts the agitation temperature (T) and critical thermal maximum (CT) of zebrafish (Danio rerio). Additionally, we examined the interactive effects of VFX and acute thermal stress on zebrafish heat shock and inflammatory immune responses. A 96 h 1.0 μg/L VFX exposure experiment was conducted, followed by assessment of thermal tolerance via CT challenge. Heat shock proteins and pro-inflammatory immune cytokines were quantified through gene expression analysis by quantitative PCR (qPCR) on hsp 70, hsp 90, hsp 47, il-8, tnfα, and il-1β within gill and liver tissue. No significant changes in agitation temperature between control and exposed fish were observed, nor were there any differences in CT based on treatment. Unsurprisingly, hsp 47, 70, and 90 were all upregulated in groups exposed solely to CT, while only hsp 47 within gill tissue showed signs of interactive effects, which was significantly decreased in fish exposed to both VFX and CT. No induction of an inflammatory response occurred. This study demonstrated that environmentally relevant concentrations of VFX have no impact on thermal tolerance performance in zebrafish. However, VFX can cause diminished function of protective heat shock mechanisms, which could be detrimental to freshwater fish populations and aquatic ecosystems as temperature spikes become more frequent from climate change and urbanization near watersheds.
Topics: Animals; Zebrafish; Venlafaxine Hydrochloride; Ecosystem; Heat-Shock Response; Antidepressive Agents
PubMed: 37004898
DOI: 10.1016/j.cbpc.2023.109620 -
Journal of Affective Disorders Dec 2022The prevalence of major depressive disorder in patients with schizophrenia (SZ-MDD) has been reported to be about 32.6 %, but it varies considerably depending on the...
Electrical stimulus combined with venlafaxine and mirtazapine improves brain Ca activity, pre-pulse inhibition, and immobility time in a model of major depressive disorder in schizophrenia.
BACKGROUND
The prevalence of major depressive disorder in patients with schizophrenia (SZ-MDD) has been reported to be about 32.6 %, but it varies considerably depending on the stage (early or chronic) and state (acute or post-psychotic) of schizophrenia. The exploration of ideal strategies for the treatment of major depressive disorder in the context of schizophrenia is urgently needed. Thus, the present study was conducted to investigate the treatment effects of clozapine, electrical stimulation (ECS; the mouse model equivalent of electroconvulsive therapy for humans), venlafaxine, and mirtazapine for SZ-MDD.
METHODS
A mouse model of SZ-MDD was established with MK801 administration and chronic unpredictable mild stress exposure. Clozapine and ECS, alone and with mirtazapine and/or venlafaxine, were used as treatment strategies. In-vivo two-photon imaging was performed to visualize Ca neural activity in the prefrontal cortex (PFC). Mouse performance on behavioral assays was taken to reflect acute treatment effects.
RESULTS
ECS + venlafaxine + mirtazapine performed significantly better than other treatments in alleviating major depressive disorder, as reflected by PFC Ca activity and behavioral assay performance. Clozapine + venlafaxine + mirtazapine did not have an ideal treatment effect. Brain Ca activity alterations did not correlate with behavioral expression in any treatment group.
CONCLUSIONS
In this mouse model of SZ-MDD, ECS + venlafaxine + mirtazapine improved brain Ca2+ activity, pre-pulse inhibition, and immobility time. These findings provide useful information for the further exploration of treatment methods for patients with SZ-MDD, although the mechanisms underlying this comorbidity needed to be investigated further.
Topics: Humans; Animals; Mice; Venlafaxine Hydrochloride; Mirtazapine; Depressive Disorder, Major; Schizophrenia; Clozapine; Prefrontal Cortex
PubMed: 36162671
DOI: 10.1016/j.jad.2022.09.037 -
Neurochemistry International Oct 2023Antidepressants are used to treat depression and some anxiety disorders, including use in pregnant patients. The pharmacological actions of these drugs generally...
Antidepressants are used to treat depression and some anxiety disorders, including use in pregnant patients. The pharmacological actions of these drugs generally determine the uptake and metabolism of a series of neurotransmitters, such as serotonin, norepinephrine, or dopamine, along with an increase in BDNF expression. However, many aspects of antidepressant action remain unknown, particularly whether antidepressants interfere with normal neurodevelopment when taken by pregnant women. In order to reveal cellular and molecular implications crucial to the functioning of pathways related to antidepressant effects, we performed an investigation on neuronally differentiating human SH-SY5Y cells. To our knowledge, this is the first time human SH-SY5Y cells in cultures of purely neuronal cells induced by controlled differentiation with retinoic acid are followed by short-term 48-h exposure to 0.1-10 μM escitalopram or venlafaxine. Treatment with antidepressants (1 μM) did not affect the electrophysiological properties of SH-SY5Y cells. However, the percentage of mature neurons exhibiting voltage-gated sodium currents was substantially higher in cultures pre-treated with either antidepressant. After exposure to escitalopram or venlafaxine, we observed a concentration-dependent increase in activity-dependent BDNF promoter IV activation. The assessment of neurite metrics showed significant down-regulation of neurite outgrowth upon exposure to venlafaxine. Identified changes may represent links to molecular processes of importance to depression and be involved in neurodevelopmental alterations observed in postpartum children exposed to antidepressants antenatally.
Topics: Child; Female; Humans; Pregnancy; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Cell Differentiation; Cell Line, Tumor; Escitalopram; Neuroblastoma; Neuronal Outgrowth; Neurons; Venlafaxine Hydrochloride
PubMed: 37451345
DOI: 10.1016/j.neuint.2023.105571 -
Life Sciences Jan 2022Venlafaxine, a norepinephrine and serotonin reuptake inhibitor, impairs rat sperm parameters, spermatogenesis and causes high intratesticular estrogen and testosterone...
Venlafaxine, a norepinephrine and serotonin reuptake inhibitor, impairs rat sperm parameters, spermatogenesis and causes high intratesticular estrogen and testosterone levels, indicating that Leydig cells (LCs) may be a venlafaxine target. We evaluated the effect of venlafaxine treatment on rat LCs, focusing on adrenergic signaling, EGF immunoexpression and steroidogenesis. Germ cells mitotic/meiotic activity and UCHL1 levels were also evaluated in the seminiferous epithelium. Eighteen adult male rats received 30 mg/kg of venlafaxine (n = 9) or distilled water (n = 9). The seminiferous tubules, epithelium and LCs nuclear areas were measured, and the immunoexpression of Ki-67, UCHL1, StAR, EGF, c-Kit and 17β-HSD was evaluated. UCHL1, StAR and EGF protein levels and Adra1a, Nur77 and Ndrg2 expression were analyzed. Malondialdehyde (MDA) and nitrite testicular levels, and serum estrogen and testosterone levels were measured. Venlafaxine induced LCs hypertrophy and Ndrg2 upregulation in parallel to increased number of Ki-67, c-Kit- and 17β-HSD-positive interstitial cells, indicating that this antidepressant stimulates LCs lineage proliferation and differentiation. Upregulation of Adra1a and Nur77 could explain the high levels of StAR and testosterone levels, as well as aromatization. Enhanced EGF immunoexpression in LCs suggests that this growth fact is involved in adrenergically-induced steroidogenesis, likely via upregulation of Nur77. Slight tubular atrophy and weak Ki-67 immunoexpression in germ cells, in association with high UCHL1 levels, indicate that spermatogenesis is likely impaired by this enzyme under supraphysiological estrogen levels. These data corroborate the unchanged MDA and nitrite levels. Therefore, venlafaxine stimulates LCs steroidogenesis via adrenergic signaling, and EGF may be involved in this process.
Topics: Animals; Epidermal Growth Factor; Gene Expression Regulation; Leydig Cells; Male; Nuclear Receptor Subfamily 4, Group A, Member 1; Rats; Venlafaxine Hydrochloride
PubMed: 34688693
DOI: 10.1016/j.lfs.2021.120069 -
Journal of Hazardous Materials Dec 2020Antidepressant metabolites are found in natural and waste waters. However, investigation of their toxic effects on aquatic animals, single or in mixture with other...
Antidepressant metabolites are found in natural and waste waters. However, investigation of their toxic effects on aquatic animals, single or in mixture with other occurring psychoactive drugs, has been neglected. Here, effects of 80hpf exposure to norfluoxetine (0.64-400 ng/L), venlafaxine (16-10000 ng/L) or their combination (3.2 ng/L +2000 ng/L, respectively) were investigated in embryos and zebrafish larvae. Mortality, embryonic malformations, sensorymotor reflexes and the expression of 34 genes involved in the toxicants mode-of-action (MoA) and metabolism were evaluated (i.e. monoamine receptors and transporters, nuclear receptors, and detoxification transporters and enzymes). Compared to controls, norfluoxetine treatments only caused depigmentation of embryos and larvae. Venlafaxine-exposed larvae exhibited depigmentation and spinal deformities, impaired sensorymotor reflexes, alterations in the expression of genes belonging to the serotonergic, noradrenergic and dopaminergic pathways, as well as nuclear receptors related to lipid and drug metabolism. The mixture elicited distinct interaction effects, depending on the level of biological organisation analysed and the neurotransmitter pathways affected; synergism (lethality), no interaction (sensorymotor reflexes), antagonism and inverse agonism (gene expression). The results call for investigation of the toxicity of pharmaceutical metabolites single and in mixture, as well as their risk assessment in approaches accounting for possible interactions with other endocrine-disrupting compounds.
Topics: Animals; Embryo, Nonmammalian; Fluoxetine; Larva; Pharmaceutical Preparations; Risk Assessment; Venlafaxine Hydrochloride; Water Pollutants, Chemical; Zebrafish
PubMed: 32593945
DOI: 10.1016/j.jhazmat.2020.123171 -
Genes Apr 2021Preclinical studies conducted to date suggest that depression could be elicited by the elevated expression of proinflammatory molecules: these play a key role in the...
Chronic Mild Stress and Venlafaxine Treatment Were Associated with Altered Expression Level and Methylation Status of New Candidate Inflammatory Genes in PBMCs and Brain Structures of Wistar Rats.
Preclinical studies conducted to date suggest that depression could be elicited by the elevated expression of proinflammatory molecules: these play a key role in the mediation of neurochemical, neuroendocrine and behavioral changes. Thus, this study investigates the effect of chronic mild stress (CMS) and administration of venlafaxine (SSRI) on the expression and methylation status of new target inflammatory genes: TGFA, TGFB, IRF1, PTGS2 and IKBKB, in peripheral blood mononuclear cells (PMBCs) and in selected brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or venlafaxine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our results indicate that both CMS and chronic treatment with venlafaxine were associated with changes in expression of the studied genes and their promoter methylation status in PMBCs and the brain. Moreover, the effect of antidepressant administration clearly differed between brain structures. Summarizing, our results confirm at least a partial association between TGFA, TGFB, IRF1, PTGS2 and IKBKB and depressive disorders.
Topics: Animals; Brain; Cyclooxygenase 2; DNA Methylation; I-kappa B Kinase; Interferon Regulatory Factor-1; Leukocytes, Mononuclear; Male; Rats; Rats, Wistar; Serotonin and Noradrenaline Reuptake Inhibitors; Stress, Psychological; Transcriptome; Transforming Growth Factor beta; Venlafaxine Hydrochloride
PubMed: 33946816
DOI: 10.3390/genes12050667 -
International Clinical... Nov 2018We assessed the effect of body weight and BMI on plasma concentrations of venlafaxine (VEN), O-desmethylvenlafaxine (ODVEN), active moiety (AM=VEN+ODVEN), and...
We assessed the effect of body weight and BMI on plasma concentrations of venlafaxine (VEN), O-desmethylvenlafaxine (ODVEN), active moiety (AM=VEN+ODVEN), and dose-corrected plasma concentrations (C/D). A database containing concentrations of VEN and ODVEN including 737 of 1594 eligible patients was analyzed. Analyses included sex, body weight, and BMI as well as concentrations of VEN, ODVEN, AM, and C/D. A positive correlation was detected between body weight and daily dosage (rs=0.168, P<0.001). A negative correlation was found between body weight and AM (rs=-0.124, P=0.001) and ODVEN (rs=-0.137, P<0.001). Negative correlations were also found between body weight and C/D ratios (C/D VEN: rs=-0.134, P<0.001, C/D ODVEN: rs=-0.239, P<0.001, C/D AM: rs=-0.256, P<0.001). No correlations were detected between BMI and concentrations for VEN, ODVEN, and AM. Comparing low-BMI (<20 kg/m²), medium-BMI (20-29.9 kg/m²), and high-BMI (≥30 kg/m²) groups, higher values of some pharmacokinetic variables in the lower BMI group did not remain significant after controlling for sex. Women had higher VEN, ODVEN, AM, and C/D values for AM, VEN, and ODVEN than men (P<0.001 for all comparisons). Our results highlight the role of different pharmacokinetically relevant parameters and foremost of sex as mediators for the effect of BMI on VEN metabolism.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Body Mass Index; Body Weight; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Sex Characteristics; Venlafaxine Hydrochloride; Young Adult
PubMed: 30028351
DOI: 10.1097/YIC.0000000000000234 -
Psychopharmacology Feb 2024The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet.
OBJECTIVES
We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression.
METHODS
Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal.
RESULTS
High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75-225 mg/day). The population-based concentration ranges (25-75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225-450 ng/ml for the AM and (ii) 144-302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140-600 ng/ml.
CONCLUSION
VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.
Topics: Humans; Antidepressive Agents; Depression; Desvenlafaxine Succinate; Norepinephrine; Reference Values; Serotonin; Venlafaxine Hydrochloride
PubMed: 37857898
DOI: 10.1007/s00213-023-06484-7 -
The World Journal of Biological... Mar 2022Therapeutic Drug Monitoring (TDM) represents one of the most promising tools in clinical practice to optimise antidepressant treatment. Nevertheless, little is still...
BACKGROUND
Therapeutic Drug Monitoring (TDM) represents one of the most promising tools in clinical practice to optimise antidepressant treatment. Nevertheless, little is still known regarding the relationship between clinical efficacy and serum concentration of venlafaxine (VEN). The aim of our study was to investigate the association between serum concentration of venlafaxine + O-desmethylvenlafaxine (SCVO) and antidepressant response (AR).
METHODS
52 depressed outpatients treated with VEN were recruited and followed in a naturalistic setting for three months. Hamilton Depression Rating Scale-21 was administered at baseline, at month 1 and at month 3 to assess AR. SCVO was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCVO and AR.
RESULTS
Our results showed an association between AR and SCVO that follows a bell-shaped quadratic function with a progressive increase of AR within the therapeutic reference range of SCVO (i.e. 100-400 ng/mL) and a subsequent decrease of AR at higher serum levels.
DISCUSSION
This study strongly suggests that TDM could represent a more appropriate tool than the oral dosage to optimise the treatment with VEN. Specifically, highest efficacy might be achieved by titrating patients at SCVO levels around 400 ng/mL.
Topics: Humans; Aged; Desvenlafaxine Succinate; Venlafaxine Hydrochloride; Outpatients; Antidepressive Agents; Drug Monitoring; Cyclohexanols; Antidepressive Agents, Second-Generation
PubMed: 34096828
DOI: 10.1080/15622975.2021.1938668