-
The International Journal of... Apr 2022Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter...
BACKGROUND
Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT).
METHODS
This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine.
RESULTS
All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout.
CONCLUSION
These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.
Topics: Antidepressive Agents, Second-Generation; Atomoxetine Hydrochloride; Cyclohexanols; Depressive Disorder, Major; Humans; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Paroxetine; Serotonin; Selective Serotonin Reuptake Inhibitors; Tyramine; Venlafaxine Hydrochloride
PubMed: 34958348
DOI: 10.1093/ijnp/pyab086 -
Frontiers in Immunology 2023Up to 40 per cent of people with active inflammatory bowel disease (IBD) also suffer from mood disorders such as anxiety and depression. Notwithstanding, the fundamental...
BACKGROUND
Up to 40 per cent of people with active inflammatory bowel disease (IBD) also suffer from mood disorders such as anxiety and depression. Notwithstanding, the fundamental biological pathways driving depression in IBD remain unknown.
METHODS
We identified 33 core genes that drive depression in IBD patients and performed consensus molecular subtyping with the NMF algorithm in IBD. The CIBERSORT were employed to quantify the immune cells. Metabolic signature was characterized using the "IOBR" R package. The scoring system (D. score) based on PCA. Pre-clinical models are constructed using DSS.
RESULTS
Using transcriptome data from the GEO database of 630 IBD patients, we performed a thorough analysis of the correlation between IBD and depression in this research. Firstly, the samples were separated into two different molecular subtypes (D. cluster1 and D. cluster2) based on their biological signatures. Moreover, the immunological and metabolic differences between them were evaluated, and we discovered that D. cluster2 most closely resembled IBD patients concomitant with depression. We also developed a scoring system to assess the IBD-related depression and predict clinical response to anti-TNF- therapy, with a higher D. score suggesting more inflammation and worse reaction to biological therapies. Ultimately, we also identified through animal experiments an antidepressant, paroxetine, has the added benefit of lowering intestinal inflammation by controlling microorganisms in the digestive tract.
CONCLUSIONS
This study highlights that IBD patients with or without depression show significant variations and antidepressant paroxetine may help reduce intestinal inflammation.
Topics: Humans; Paroxetine; Depression; Tumor Necrosis Factor Inhibitors; Inflammatory Bowel Diseases; Anti-Inflammatory Agents; Antidepressive Agents; Inflammation
PubMed: 36923403
DOI: 10.3389/fimmu.2023.1145070 -
Journal of the American Heart... Jan 2021Background ADRB1 (adrenergic receptor beta 1) responds to neuroendocrine stimulations, which have great implications in hypertension. GRK2 (G protein-coupled receptor...
Background ADRB1 (adrenergic receptor beta 1) responds to neuroendocrine stimulations, which have great implications in hypertension. GRK2 (G protein-coupled receptor kinase 2) is an essential regulator for many G protein-coupled receptors and subsequent cell signaling cascades, but its role as a regulator of ADRB1 and associated cardiac hypertrophy in hypertension remains to be elucidated. Methods and Results In this study, we found the expressions of GRK2 and ADRB1 in peripheral blood mononuclear cells were positively associated with blood pressure levels in hypertensive patients and with their expression in heart. In vitro evidence showed a direct interaction in ADRB1 and GRK2 and genetic depletion of GRK2 blocks epinephrine-induced upregulation of hypertrophic and fibrotic genes in cardiomyocytes. Meanwhile, we discovered a selective serotonin reuptake inhibitor paroxetine specifically blockades GRK2 and ADRB1 interaction. In vivo, paroxetine treatment ameliorates hypertension-induced cardiac hypertrophy, dysfunction, and fibrosis in animal models. We found that paroxetine suppressed sympathetic overdrive and increased the adrenergic receptor sensitivity to catecholamines. Paroxetine treatment also blocks epinephrine-induced upregulation of hypertrophic and fibrotic genes as well as ADRB1 internalization in cardiomyocytes. Coadministration of paroxetine further potentiates metoprolol-induced reductions in blood pressure and heart rate, further attenuating cardiac hypertrophy in spontaneously hypertensive rats. Furthermore, in patients with hypertension accompanied with depression, we observed that cardiac remodeling was less severe in those with paroxetine treatment compared with those with other types of anti-depressive agents. Conclusions Paroxetine promotes ADRB1 sensitivity and attenuates cardiac hypertrophy partially via blocking GRK2-mediated ADRB1 activation and internalization in the context of hypertension.
Topics: Animals; Cardiomegaly; Cardiotonic Agents; Catecholamines; Cytochrome P-450 CYP2D6 Inhibitors; Disease Models, Animal; G-Protein-Coupled Receptor Kinase 2; Gene Knockout Techniques; Hypertension; Paroxetine; Rats; Receptors, Adrenergic, beta-1; Signal Transduction
PubMed: 33372534
DOI: 10.1161/JAHA.120.016364 -
Medicine Aug 2023Paroxetine therapy has been used for treatment of patients with depression and Parkinson's disease (dPD) in many clinical studies, but, the effects of paroxetine in dPD... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Paroxetine therapy has been used for treatment of patients with depression and Parkinson's disease (dPD) in many clinical studies, but, the effects of paroxetine in dPD patients are not completely understood. The aim of this study was to systematically evaluate the effects of paroxetine therapy on depressive symptom and motor function in the treatment of dPD, in order to confer a reference for clinical practice.
METHODS
Randomized controlled trials (RCTs) of paroxetine for dPD published up to October, 2022 were retrieved. Standardised mean difference (SMD), odds ratio (OR), and 95% confidence interval (CI) were calculated and heterogeneity was measured with the I2 test. The outcomes of interest were as follows: the efficacy, Hamilton depression rating scale score, unified Parkinson's disease rating scale score, Hamilton anxiety rating scale score or adverse events.
RESULTS
Thirty-four RCTs with 2819 participants were included. Compared with control group, the pooled effects of paroxetine therapy on depression were (22 trials; OR 3.62, 95% CI 2.63 to 4.98, P < .00001) for antidepressant response (25 trials; SMD -2.14, 95% CI -2.73 to -1.56, P < .00001) for Hamilton depression rating scale score, the pooled effects of paroxetine therapy on motor function were (10 trials; OR 4.63, 95% CI 3.15 to 6.79, P < .00001) for anti-PD efficacy (18 trials; SMD -2.02, 95% CI -2.48 to -1.55, P < .00001) for total unified Parkinson's disease rating scale score. The Hamilton anxiety rating scale score showed significant decrease in the paroxetine treatment group compared to control group (10 trials; SMD -1.93, 95% CI -2.65 to -1.22, P < .00001). In addition, paroxetine therapy reduced the number of any adverse events obviously in dPD patients (twenty trials; OR 0.42, 95% CI 0.31 to 0.57, P < .00001).
CONCLUSIONS
Paroxetine therapy has clinical benefits for improvement of depressive symptom and motor function in dPD patients, moreover, it is of high drug safety. Further well-designed, multi-center RCTs needed to identify these findings.
Topics: Humans; Paroxetine; Parkinson Disease; Depression; Control Groups; Mental Status and Dementia Tests
PubMed: 37653795
DOI: 10.1097/MD.0000000000034687 -
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 -
Mikrochimica Acta Oct 2021Multiplex detection of emerging pollutants is essential to improve quality control of water treatment plants, which requires portable systems capable of real-time...
Multiplex detection of emerging pollutants is essential to improve quality control of water treatment plants, which requires portable systems capable of real-time monitoring. In this paper we describe a flexible, dual electrochemical sensing device that detects nonylphenol and paroxetine in tap water samples. The platform contains two voltammetric sensors, with different working electrodes that were either pretreated or functionalized. Each working electrode was judiciously tailored to cover the concentration range of interest for nonylphenol and paroxetine, and square wave voltammetry was used for detection. An electrochemical pretreatment with sulfuric acid on the printed electrode enabled a selective detection of nonylphenol in 1.0-10 × 10 mol L range with a limit of detection of 8.0 × 10 mol L. Paroxetine was detected in the same range with a limit of detection of 6.7 × 10 mol L using the printed electrode coated with a layer of carbon spherical shells. Simultaneous detection of the two analytes was achieved in tap water samples within 1 min, with no fouling and no interference effects. The long-term monitoring capability of the dual sensor was demonstrated in phosphate buffer for 45 days. This performance is statistically equivalent to that of high-performance liquid chromatography (HPLC) for water analysis. The dual-sensor platform is generic and may be extended to other water pollutants and clinical biomarkers in real-time monitoring of the environment and health conditions. Silver pseudo-reference electrodes for paroxetine (REP) and nonylphenol (REN), working electrodes for paroxetine (WP) and nonylphenol (WN), and auxiliary electrode (AE). USP refers to the University of Sao Paulo. "Red" is reduced form and "Oxi" is oxidized form of analytes.
PubMed: 34599426
DOI: 10.1007/s00604-021-05024-4 -
PloS One 2022Depression in mammals is known to be associated with poor reproductive capacity. In males, it has been associated with decreased efficiency of spermatogenesis as well as...
Depression in mammals is known to be associated with poor reproductive capacity. In males, it has been associated with decreased efficiency of spermatogenesis as well as the production of spermatozoa of reduced structural and functional integrity. Although antidepressants are effective in correcting depressive states, there is controversy regarding their effectiveness in restoring male reproductive function. Here, using an animal model of depression induced by a forced swim test, we confirmed that depression is accompanied by impaired male reproductive function. We further show that administration of a conventional antidepressant of the serotonin reuptake inhibitor class (paroxetine) impairs male reproductive performance in terms of sperm production and quality when administered to healthy animals. Intriguingly, when paroxetine is administered to "depressed" animals, it resulted in a complete restoration of the animal's ability to produce sperm that appears to be as capable of meeting the parameters evaluated here as those of control animals. The one-carbon cycle (1CC) is one of the most important metabolic cycles that include the methionine and folate cycles and plays a major role in DNA synthesis, amino acids, and also the production of antioxidants. Our results show that depression affects the main components of this cycle and paroxetine on healthy mice increases homocysteine levels, decreases glycine and vitamin B12, while in depressed mice, it increases folate levels and decreases vitamin B12. Thus, paroxetine exerts negative impacts on male reproductive function when administered to healthy animals and it well correlate with the altered sperm parameters and functions of depressed animals, and its mechanism remains to be explored.
Topics: Male; Mice; Animals; Paroxetine; Semen; Models, Animal; Spermatozoa; Vitamin B 12; Folic Acid; Mammals
PubMed: 36480503
DOI: 10.1371/journal.pone.0271217 -
Translational Psychiatry Feb 2020Antidepressants exhibit similar efficacy, but varying tolerability, in randomized controlled trials. Predicting tolerability in real-world clinical populations may...
Antidepressants exhibit similar efficacy, but varying tolerability, in randomized controlled trials. Predicting tolerability in real-world clinical populations may facilitate personalization of treatment and maximize adherence. This retrospective longitudinal cohort study aimed to determine the extent to which incorporating patient history from electronic health records improved prediction of unplanned treatment discontinuation at index antidepressant prescription. Clinical data were analyzed from individuals from health networks affiliated with two large academic medical centers between March 1, 2008 and December 31, 2014. In total, the study cohorts included 51,683 patients with at least one International Classification of Diseases diagnostic code for major depressive disorder or depressive disorder not otherwise specified who initiated antidepressant treatment. Among 70,121 total medication changes, 16,665 (23.77%) of them were followed by failure to return; maximum risk was observed with paroxetine (27.71% discontinuation), and minimum with venlafaxine (20.78% discontinuation); Mantel-Haenzel χ (8 df) = 126.44, p = 1.54e-23 <1e-6. Models incorporating diagnostic and procedure codes and medication prescriptions improved per-medication Areas Under the Curve (AUCs) to a mean of 0.69 [0.64-0.73] (ranging from 0.62 for paroxetine to 0.80 for escitalopram), with similar performance in the second, replication health system. Machine learning applied to coded electronic health records facilitates identification of individuals at high-risk for treatment dropout following change in antidepressant medication. Such methods may assist primary care physicians and psychiatrists in the clinic to personalize antidepressant treatment on the basis not solely of efficacy, but of tolerability.
Topics: Antidepressive Agents; Depressive Disorder, Major; Humans; Longitudinal Studies; Paroxetine; Retrospective Studies
PubMed: 32066733
DOI: 10.1038/s41398-020-0716-y -
Psychoneuroendocrinology Oct 2021Selective serotonin reuptake inhibitors (SSRI) show high efficacy in treating depression, however during treatment side effects, like for instance sexual dysfunction,...
Selective serotonin reuptake inhibitors (SSRI) show high efficacy in treating depression, however during treatment side effects, like for instance sexual dysfunction, may appear, decreasing compliance. In some cases, this condition will last after drug discontinuation, leading to the so-called post-SSRI sexual dysfunction (PSSD). The etiology of PSSD is still unknown, however a role for neuroactive steroids may be hypothesized. Indeed, these molecules are key physiological regulators of the nervous system, and their alteration has been associated with several neuropathological conditions, including depression. Additionally, neuroactive steroids are also involved in the control of sexual function. Interestingly, sexual dysfunction induced by SSRI treatment has been also observed in animal models. On this basis, we have here evaluated whether a subchronic treatment with paroxetine for two weeks and/or its withdrawal (i.e., a month) may affect the levels of neuroactive steroids in brain areas (i.e., hippocampus, hypothalamus, and cerebral cortex) and/or in plasma and cerebrospinal fluid of male rats. Data obtained indicate that the SSRI treatment alters neuroactive steroid levels and the expression of key enzymes of the steroidogenesis in a brain tissue- and time-dependent manner. Indeed, these observations with the finding that plasma levels of neuroactive steroids are not affected suggest that the effect of paroxetine treatment is directly on neurosteroidogenesis. In particular, a negative impact on the expression of steroidogenic enzymes was observed at the withdrawal. Therefore, it is possible to hypothesize that altered neurosteroidogenesis may also occur in PSSD and consequently it may represent a possible pharmacological target for this disorder.
Topics: Animals; Hippocampus; Male; Neurosteroids; Paroxetine; Rats; Selective Serotonin Reuptake Inhibitors; Sexual Dysfunction, Physiological
PubMed: 34325207
DOI: 10.1016/j.psyneuen.2021.105364 -
Frontiers in Pharmacology 2022Post-stroke depression (PSD) is a common mental health problem after cerebrovascular accidents. There are several treatments that have been shown to be effective in...
Post-stroke depression (PSD) is a common mental health problem after cerebrovascular accidents. There are several treatments that have been shown to be effective in treating post-stroke depression. However, it is not clear which treatment is more effective. In this meta-analysis, an appropriate search strategy was used to search eligible randomized controlled trials (RCTs) on different treatments to treat patients with Post-stroke depression published up to December 2021 from the CNKI, PubMed, and Cochrane Library. We assessed the mean difference or odds ratio between each treatment and placebo and summarized them as the average and 95% confidence interval (CI) by conducting Bayesian network meta-analyses. By constructing a Bayesian network meta-analysis, we found that acupuncture combined with fluoxetine (vs placebo MD, -8.9; 95% CI, [-15, -2.9]) or paroxetine (vs placebo MD,-8.5; 95% CI, [-15, -2.5]) was the most effective for change in Hamilton depression scale (HAMD) at the end of the 4th week. For change in Hamilton depression scale at the end of the 8th week, rTMS combined with paroxetine (vs placebo MD, -13; 95% CI, [-17, -7.9]) had the greatest amount of change. The efficacy of medication combined with adjuvant therapy was also superior for the percentage of patients with Hamilton depression scale change over 50%. The combination of antidepressants with adjuvant therapy may enhance the efficacy of antidepressants and achieve better results than antidepressant monotherapy in both Hamilton depression scale changes at the end of week 4 or 8 and 50% Hamilton depression scale improvement rate. Acupuncture combined with fluoxetine treatment was more effective in the treatment of post-stroke depression at week 4, while rTMS combined with paroxetine was more effective at week 8. Further research is needed to determine whether acupuncture combined with fluoxetine is better than rTMS combined with paroxetine for post-stroke depression at week 8.
PubMed: 36601053
DOI: 10.3389/fphar.2022.1035895