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Journal of Affective Disorders Nov 2020Recent studies have suggested the role of mammalian target of rapamycin complex 1 (mTORC1) in the pathophysiology of depression. Although venlafaxine was thought to be a...
BACKGROUND
Recent studies have suggested the role of mammalian target of rapamycin complex 1 (mTORC1) in the pathophysiology of depression. Although venlafaxine was thought to be a serotonin and norepinephrine reuptake inhibitor (SNRI), its pharmacological mechanism remain elusive. In this study, the effects of venlafaxine on the mTORC1 system were studied in both chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS) models.
METHOD
First, we examined whether repeated venlafaxine treatment reversed the effects of CUMS and CSDS on the mTORC1 signaling cascade in both the hippocampus and medial prefrontal cortex (mPFC). Second, several selective pharmacological inhibitors of the mTORC1 system, including rapamycin, LY294002 and U0126, were used together to determine whether the protective effects of venlafaxine against the CUMS and CSDS models were prevented by mTORC1 system blockade. Finally, genetic knockdown of mTORC1 by mTORC1-shRNA was further adopted to test whether mTORC1 was necessary for the anti-stress effects of venlafaxine in mice.
RESULT
Our results showed that the decreasing effects of CUMS and CSDS on the mTORC1 signaling cascade in the hippocampus and mPFC were restored by venlafaxine, and the use of rapamycin, LY294002, U0126 and mTORC1-shRNA fully abolished the anti-stress actions of venlafaxine in mice.
CONCLUSION
The mTORC1 system is involved in the pharmacological mechanism of venlafaxine.
Topics: Animals; Antidepressive Agents; Depression; Disease Models, Animal; Hippocampus; Mice; Mice, Inbred C57BL; Signal Transduction; Stress, Psychological; Venlafaxine Hydrochloride
PubMed: 32871684
DOI: 10.1016/j.jad.2020.07.096 -
Environmental Science and Pollution... Apr 2023Bays are transition zones connecting freshwater ecosystems and marine ecosystems, and they are strongly influenced by intensive human activities. Pharmaceuticals are of...
Bays are transition zones connecting freshwater ecosystems and marine ecosystems, and they are strongly influenced by intensive human activities. Pharmaceuticals are of concern in bay aquatic environments because of their potential threat to marine food web. We studied the occurrence, spatial distribution, and ecological risks of 34 pharmaceutical active compounds (PhACs) in Xiangshan Bay, a heavily industrialized and urbanized area in Zhejiang Province, Eastern China. PhACs were ubiquitously detected in the coastal waters of the study area. A total of twenty-nine compounds were detected in at least one sample. Carbamazepine, lincomycin, diltiazem, propranolol, venlafaxine, anhydro erythromycin, and ofloxacin had the highest detection rate (≥ 93%). These compounds were detected with maximum concentrations of 31, 127, 0.52, 1.96, 2.98, 75, and 98 ng/L, respectively. Human pollution activities included marine aquacultural discharge and effluents from the local sewage treatment plants. These activities were the most influential sources in this study area based on principal component analysis. Lincomycin was an indicator of veterinary pollution of coastal aquatic environment, and the concentrations of lincomycin were positively related to the total phosphorus in this area (r = 0.28, p < 0.05). Typical PhACs such as venlafaxine, ofloxacin, norfloxacin, roxithromycin, and clarithromycin were significantly and positively correlated with nitrate and total nitrogen (r > 0.26, p < 0.05) based on Pearson's correlation analysis. Carbamazepine was negatively correlated with salinity (r < - 0.30, p < 0.01). Land use pattern was also correlated with the occurrence and distribution of PhACs in the Xiangshan Bay. Some PhACs, i.e., ofloxacin, ciprofloxacin, carbamazepine, and amitriptyline posed medium to high ecological risks to this coastal environment. The results of this study could be helpful to understand the levels of pharmaceuticals, potential sources, and ecological risks in marine aquacultural environment.
Topics: Humans; Bays; Ecosystem; Water Pollutants, Chemical; Venlafaxine Hydrochloride; Environmental Monitoring; Ofloxacin; Lincomycin; Pharmaceutical Preparations; Carbamazepine; China
PubMed: 36811780
DOI: 10.1007/s11356-023-26019-z -
Journal of Clinical Psychopharmacology 2020The antidepressant venlafaxine is largely O-desmethylated by CYP2D6, whereas CYP2C19 mediates an alternative metabolic route of venlafaxine through N-desmethylation. The...
PURPOSE
The antidepressant venlafaxine is largely O-desmethylated by CYP2D6, whereas CYP2C19 mediates an alternative metabolic route of venlafaxine through N-desmethylation. The aim of this study was to investigate the combined effect of genotype-predicted CYP2D6 and CYP2C19 phenotypes on serum concentrations of venlafaxine and metabolites in a large patient population.
METHODS
Patients were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital in Oslo (Norway) between January 01, 2007, and December 31, 2017. The study population was divided into different phenotype subgroups according to the combinations of CYP2D6/CYP2C19 phenotypes; intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers, and compared using combined normal metabolizers (NMs) as reference.
FINDINGS
The dose-adjusted serum concentration of venlafaxine was 4- and 13-fold increased in combined CYP2D6 IM/CYP2C19 PMs and combined PMs, respectively, compared with combined NMs (P < 0.001). The sum concentration of venlafaxine + ODV (pharmacological active moiety) was increased 1.9 and 3.6-fold, respectively, in the same phenotype groups. Furthermore, the dose-adjusted active moiety exposure was similar in combined IMs as combined CYP2D6 PM/CYP2C19 NMs. CYP2D6 and CYP2C19 phenotypes explained 46% of the interindividual variability in dose-adjusted venlafaxine serum concentrations, whereas CYP2D6 alone explained 24%.
CONCLUSIONS
The combined CYP2D6/CYP2C19 phenotype has a significant impact on serum concentrations of venlafaxine and also on the active moiety of venlafaxine + ODV, than CYP2D6 alone. In clinical practice, it is therefore important to take into account phenotype variabilities of both enzymes when assessing the risk of dose-dependent adverse effects during venlafaxine treatment.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Desvenlafaxine Succinate; Female; Genotype; Humans; Male; Middle Aged; Venlafaxine Hydrochloride; Young Adult
PubMed: 32134850
DOI: 10.1097/JCP.0000000000001174 -
Psychopharmacology Bulletin May 2022Bipolar II disorder (BD-II) has limited evidence-based treatment guidelines. The aim of this systematic review and meta-analysis was to estimate the efficacy and safety... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Bipolar II disorder (BD-II) has limited evidence-based treatment guidelines. The aim of this systematic review and meta-analysis was to estimate the efficacy and safety of second-generation antidepressant (SGAD) monotherapy in acute BD-II depression.
METHODS
A literature search was conducted from the database inception through March 2021. Only randomized controlled trials (RCTs) were included. Outcome measures included: response rates, treatment-emergent affective switch (TEAS) rates, discontinuation due to side-effects, and all-cause discontinuation. Risk ratio (RR) was calculated using the Mantel-Haenszel random effects model.
RESULTS
3301 studies were screened, and 15 articles were selected for full-text review. Five studies met the inclusion criteria: Four double-blind RCTs (n = 533) and one open-label RCT (n = 83) were included. Two double-blind RCTs [n = 223, SGAD = 110 (venlafaxine = 65, sertraline = 45), lithium/control = 113] were included for meta-analysis. The response rate for SGAD monotherapy compared to lithium monotherapy were similar (RR = 1.44, 95% CI 0.78, 2.66). The TEAS rate for SGAD monotherapy was not significantly different from lithium monotherapy (p = 0.76). The discontinuation rate due to side-effects for SGAD monotherapy was significantly lower than lithium monotherapy with a RR = 0.32, 95% CI 0.11, 0.96, p = 0.04 but all-cause discontinuation rates were similar in both groups.
CONCLUSIONS
Limited data suggests short-term efficacy of venlafaxine and sertraline monotherapy in patients with acute BD-II depression with good side effect tolerability and without significantly increased switch rate. There is an urgent need for RCTs investigating the role of SGAD monotherapy in short and long-term among patients with BD-II.
Topics: Antidepressive Agents, Second-Generation; Bipolar Disorder; Depression; Humans; Lithium; Randomized Controlled Trials as Topic; Sertraline; Venlafaxine Hydrochloride
PubMed: 35721812
DOI: No ID Found -
Depression and Anxiety Sep 2016Current clinical practice guidelines (CPGs) for posttraumatic stress disorder (PTSD) offer contradictory recommendations regarding use of medications or psychotherapy as... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
Current clinical practice guidelines (CPGs) for posttraumatic stress disorder (PTSD) offer contradictory recommendations regarding use of medications or psychotherapy as first-line treatment. Direct head-to-head comparisons are lacking.
METHODS
Systemic review of Medline, EMBASE, PILOTS, Cochrane Central Register of Controlled Trials, PsycINFO, and Global Health Library was conducted without language restrictions. Randomized clinical trials ≥8 weeks in duration using structured clinical interview-based outcome measures, active-control conditions (e.g. supportive psychotherapy), and intent-to-treat analysis were selected for analyses. Independent review, data abstraction, and bias assessment were performed using standardized processes. Study outcomes were grouped around conventional follow-up time periods (3, 6, and 9 months). Combined effect sizes were computed using meta-analyses for medication versus control, medication pre-/posttreatment, psychotherapy versus control, and psychotherapy pre-/posttreatment.
RESULTS
Effect sizes for trauma-focused psychotherapies (TFPs) versus active control conditions were greater than medications versus placebo and other psychotherapies versus active controls. TFPs resulted in greater sustained benefit over time than medications. Sertraline, venlafaxine, and nefazodone outperformed other medications, although potential for methodological biases were high. Improvement following paroxetine and fluoxetine treatment was small. Venlafaxine and stress inoculation training (SIT) demonstrated large initial effects that decreased over time. Bupropion, citalopram, divalproex, mirtazapine, tiagabine, and topiramate failed to differentiate from placebo. Aripiprazole, divalproex, guanfacine, and olanzapine failed to differentiate from placebo when combined with an antidepressant.
CONCLUSIONS
Study findings support use of TFPs over nontrauma-focused psychotherapy or medication as first-line interventions. Second-line interventions include SIT, and potentially sertraline or venlafaxine, rather than entire classes of medication, such as SSRIs. Future revisions of CPGs should prioritize studies that utilize active controls over waitlist or treatment-as-usual conditions. Direct head-to-head trials of TFPs versus sertraline or venlafaxine are needed.
Topics: Antidepressive Agents; Combined Modality Therapy; Humans; Piperazines; Psychotherapy; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Sertraline; Stress Disorders, Post-Traumatic; Treatment Outcome; Triazoles; Venlafaxine Hydrochloride
PubMed: 27126398
DOI: 10.1002/da.22511 -
Pharmacopsychiatry May 2021The aim of this study was to compare the outcomes of monotherapy in individuals with bipolar disorder who are prescribed lithium, valproate, quetiapine, olanzapine,...
INTRODUCTION
The aim of this study was to compare the outcomes of monotherapy in individuals with bipolar disorder who are prescribed lithium, valproate, quetiapine, olanzapine, venlafaxine, or citalopram in private psychiatric practices in Germany.
METHODS
This retrospective study included bipolar disorder patients who had initially started on a monotherapy with lithium, valproate, quetiapine, olanzapine, venlafaxine, or citalopram in 93 private neuropsychiatric practices in Germany between January 2006 and December 2017. Treatment failure was defined as time to discontinuation of medication or addition of another mood stabilizer, antipsychotic, antidepressant, or benzodiazepine.
RESULTS
A total of 4990 bipolar patients was examined for the period between 2006 and 2019. Initially, monotherapy with lithium (n=1.098), valproate (n=502), quetiapine (n=927), olanzapine (n=927), venlafaxine (n=574), or citalopram (n=962) was prescribed. Within 24 months, treatment failure had occurred in 76.3% (lithium), 85.1% (valproate), 84.6% (quetiapine), 85.2% (venlafaxine), 92.1% (olanzapine), and 86.6% (citalopram) of patients, respectively. The hazard ratio for treatment failure compared to lithium as reference was highest for olanzapine at 1.66 (1.46-1.88), followed by citalopram 1.27 (1.15-1.39), quetiapine 1.18 (1.07-1.29), valproate 1.18 (1.06-1.33), and venlafaxine 1.14 (1.02-1.27).
CONCLUSIONS
Our results underline the importance of lithium in the maintenance treatment of bipolar disorders.
Topics: Antipsychotic Agents; Bipolar Disorder; Citalopram; Humans; Lithium; Olanzapine; Quetiapine Fumarate; Retrospective Studies; Valproic Acid; Venlafaxine Hydrochloride
PubMed: 33494115
DOI: 10.1055/a-1348-1523 -
Environmental Pollution (Barking, Essex... Apr 2021Ubiquitous use of antidepressants has resulted in increased concentrations of these pharmaceuticals in waterways receiving municipal wastewater effluent. Amongst these,...
Ubiquitous use of antidepressants has resulted in increased concentrations of these pharmaceuticals in waterways receiving municipal wastewater effluent. Amongst these, venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is commonly found at concentrations surpassing 1 ppb in surface waters. We recently showed that the deposition of venlafaxine in zebrafish (Danio rerio) embryos impacts neural development in the hypothalamus, suggesting the possibility of neuroendocrine disruptions due to this antidepressant. Here, we tested the hypothesis that early developmental exposure to venlafaxine disrupts the long-term functioning of the hypothalamus-pituitary-interrenal (HPI) axis in zebrafish. Embryos (1-4 cell stage) were injected with either 0, 1, or 10 ng venlafaxine, and the ontogeny of cortisol content, as well as changes in cortisol levels following a stressor in larvae and adults were assessed across 3 generations. Zygotic venlafaxine exposure did not affect the ontogeny of cortisol production, but there was a disruption in the cortisol response to stressor exposure, which was also evident in multiple generations. In the F generation, venlafaxine exposure did not affect cortisol levels in response to stressor exposure in larvae, but adult females, and not males, showed an attenuated cortisol response compared to control fish. This reduction in cortisol levels in the females was rescued by stimulation with adrenocorticotropic hormone, suggesting that the disruption was at the level of the hypothalamus-pituitary axis. Venlafaxine-mediated disruption in HPI axis functioning was also evident in the F and F generations, including impaired cortisol responses to a stressor in adult female and larval fish, respectively. Taken together, our results suggest that venlafaxine is an endocrine disruptor, and early developmental exposure to this antidepressant may have long-term and generational consequences on cortisol stress axis activity in zebrafish.
Topics: Animals; Female; Hydrocortisone; Larva; Stress, Physiological; Venlafaxine Hydrochloride; Zebrafish
PubMed: 33524651
DOI: 10.1016/j.envpol.2021.116535 -
Journal of Chromatography. A Oct 2023In this work, carboxymethylated maltodextrin (Cm-MD) was successfully synthesized as an efficient anionic chiral selector and applied for the enantiomer separation of...
In this work, carboxymethylated maltodextrin (Cm-MD) was successfully synthesized as an efficient anionic chiral selector and applied for the enantiomer separation of some basic drugs including tramadol, venlafaxine, verapamil, hydroxyzine, citalopram, fluoxetine, and amlodipine by capillary electrophoresis (CE). The synthesized chiral selector was characterized by the nuclear magnetic resonance and Fourier transform infrared spectrophotometry. Under the optimized Cm-MD modified CE conditions (background electrolyte: phosphate buffer (pH 5.0, 50 mM) containing 5% (w/v) Cm-MD; applied voltage: 20 kV; and capillary column temperature: 25 °C), successful enantiomer separation of all studied chiral drugs were observed. By comparison of Cm-MD and MD for enantiomer separation of the model drugs, it was revealed that Cm-MD exhibits a higher resolution in comparison to the MD modified CE. This enhanced resolution could be attributed to the electrostatic interactions between the cationic drugs and anionic Cm-MD and opposite direction mobility of the host-guest complex relative to the chiral analyte. The optimized Cm-MD modified CE method was successfully used for the assay of the enantiomers of citalopram and venlafaxine in commercial tablets. The proposed method showed the linear range of 5.0-150.0 mg/L and 10.0-150.0 mg/L for both enantiomers of citalopram and venlafaxine, respectively. The limits of quantification were 5.0 and 10.0 mg/L for the enantiomers of citalopram and venlafaxine, respectively. The limit of detection for all enantiomers was found to be < 3.0 mg/L. Intra- and inter-day RSDs (n = 4) were less than 9.7%. The relative errors were less than 9.4% for all enantiomers. The obtained results in this research show that Cm-MD as a new, efficient and inexpensive chiral selector can be used for enantiomer separation of basic drugs using the CE technique.
Topics: Citalopram; Venlafaxine Hydrochloride; Electrophoresis, Capillary; Amlodipine
PubMed: 37696127
DOI: 10.1016/j.chroma.2023.464335 -
Life Sciences Feb 2023Depressive disorders (DD) have affected millions of people worldwide. Venlafaxine, antidepressant of the class of serotonin and norepinephrine reuptake inhibitors, has...
Venlafaxine increases aromatization, reduces apical V-ATPase in clear cells and induces increased number of mast cells and smooth muscle cells death in rat cauda epididymis.
Depressive disorders (DD) have affected millions of people worldwide. Venlafaxine, antidepressant of the class of serotonin and norepinephrine reuptake inhibitors, has been prescribed for the treatment of DD. In rat testes, venlafaxine induces testosterone (T) aromatization and increases estrogen levels. Aromatase is a key enzyme for the formation of estrogen in the epididymis, an essential organ for male fertility. We investigated the impact of serotonergic/noradrenergic venlafaxine effect on the epididymal cauda region, focusing on aromatase, V-ATPase and EGF epithelial immunoexpression, smooth muscle (SM) integrity and mast cells number (MCN). Male rats were distributed into control (CG; n = 10) and venlafaxine (VFG, n = 10) groups. VFG received 30 mg/kg b.w. of venlafaxine for 35 days. The epididymal cauda was processed for light and transmission electron microscopy (TEM). The expression of connexin 43 (Cx43) and estrogen alpha (Esr1), adrenergic (Adra1a) and serotonergic (Htr1b) receptors were analyzed. Clear cells (CCs) area, SM thickness, viable spermatozoa (VS) and MCN were evaluated. Apoptosis was confirmed by TUNEL and TEM. The following immunoreactions were performed: T, aromatase, T/aromatase co-localization, V-ATPase, EGF, Cx43 and PCNA. The increased Adra1a and reduced Htr1b expressions confirmed the noradrenergic and serotonergic venlafaxine effects, respectively, corroborating the increased MCN, apoptosis and atrophy of SM. In VFG, the epithelial EGF increased, explaining Cx43 overexpression and basal cells mitotic activity. T aromatization and Esr1 downregulation indicate high estrogen levels, explaining CCs hypertrophy and changes in the V-ATPase localization, corroborating VS reduction. Thus, in addition to serotonergic/noradrenergic effects, T/estrogen imbalance, induced by venlafaxine, impairs epididymal structure and function.
Topics: Rats; Male; Animals; Epididymis; Venlafaxine Hydrochloride; Aromatase; Connexin 43; Mast Cells; Epidermal Growth Factor; Vacuolar Proton-Translocating ATPases; Estrogens; Myocytes, Smooth Muscle
PubMed: 36584913
DOI: 10.1016/j.lfs.2022.121329 -
Metabolic Brain Disease Feb 2020Opioid-induced neuroinflammation plays a role in the development of opioid physical dependence. Moreover, nitric oxide (NO) has been implicated in several oxidative and...
Opioid-induced neuroinflammation plays a role in the development of opioid physical dependence. Moreover, nitric oxide (NO) has been implicated in several oxidative and inflammatory pathologies. Here, we sought to determine whether treatment with venlafaxine during the development of morphine dependence could inhibit naloxone-precipitated withdrawal symptoms. The involvement of neuro-inflammation related cytokines, oxidative stress, and L-arginine (L-arg)-NO pathway in these effects were also investigated. Mice received morphine (50 mg/kg/daily; s.c.), plus venlafaxine (5 and 40 mg/kg, i.p.) once a day for 3 consecutive days. In order to evaluate the possible role of L-arg-NO on the effects caused by venlafaxine, animals received L-arg, L-NAME or aminoguanidine with venlafaxine (40 mg/kg, i.p.) 30 min before each morphine injection for 3 consecutive days. On 4 day of experiment, behavioral signs of morphine-induced physical dependence were evaluated after i.p. naloxone injection. Then, brain levels of tissue necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), brain-derived neurotrophic factor (BDNF), NO and oxidative stress factors including; total thiol, malondialdehyde (MDA) contents and glutathione peroxidase (GPx) activity were determined. Co-administration of venlafaxine (40 mg/kg) with morphine not only inhibited the naloxone-precipitated withdrawal signs including jumping and weight loss, but also reduced the up-regulation of TNF-α, IL-1β, IL-6, NO and MDA contents in mice brain tissue. However, repeated administration of venlafaxine inhibited the decrease in the brain levels of BDNF, total thiol and GPx. Pre-administration of L-NAME and aminoguanidine improved, while L-arg antagonized the venlafaxine-induced effects. These results provide evidences that venlafaxine could be used as a candidate drug to inhibit morphine withdrawal through the involvement of inflammatory cytokines and l-arginine-NO in mice.
Topics: Animals; Cytokines; Male; Mice; Morphine; Morphine Dependence; Naloxone; Nitric Oxide; Serotonin and Noradrenaline Reuptake Inhibitors; Substance Withdrawal Syndrome; Venlafaxine Hydrochloride
PubMed: 31630319
DOI: 10.1007/s11011-019-00491-4