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Purinergic Signalling Dec 2015P2X7 receptor (P2X7) activity may link inflammation to depressive disorders. Genetic variants of human P2X7 have been linked with major depression and bipolar disorders,...
P2X7 receptor (P2X7) activity may link inflammation to depressive disorders. Genetic variants of human P2X7 have been linked with major depression and bipolar disorders, and the P2X7 knockout mouse has been shown to exhibit anti-depressive-like behaviour. P2X7 is an ATP-gated ion channel and is a major regulator of the pro-inflammatory cytokine interleukin 1β (IL-1β) secretion from monocytes and microglia. We hypothesised that antidepressants may elicit their mood enhancing effects in part via modulating P2X7 activity and reducing inflammatory responses. In this study, we determined whether common psychoactive drugs could affect recombinant and native human P2X7 responses in vitro. Common antidepressants demonstrated opposing effects on human P2X7-mediated responses; paroxetine inhibited while fluoxetine and clomipramine mildly potentiated ATP-induced dye uptake in HEK-293 cells stably expressing recombinant human P2X7. Paroxetine inhibited dye uptake mediated by human P2X7 in a concentration-dependent manner with an IC(50) of 24 μM and significantly reduces ATP-induced inward currents. We confirmed that trifluoperazine hydrochloride suppressed human P2X7 responses (IC(50) of 6.4 μM). Both paroxetine and trifluoperazine did not inhibit rodent P2X7 responses, and mutation of a known residue (F 95L) did not alter the effect of either drug, suggesting neither drug binds at this site. Finally, we demonstrate that P2X7-induced IL-1β secretion from lipopolysaccharide (LPS)-primed human CD14(+) monocytes was suppressed with trifluoperazine and paroxetine.
Topics: Animals; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Clomipramine; Dose-Response Relationship, Drug; Fluoxetine; Humans; Interleukin-1beta; Lipopolysaccharide Receptors; Mice; Monocytes; Paroxetine; Purinergic P2X Receptor Agonists; Purinergic P2X Receptor Antagonists; Rats; Receptors, Purinergic P2X7; Recombinant Proteins; Trifluoperazine
PubMed: 26341077
DOI: 10.1007/s11302-015-9467-2 -
Journal of Substance Use 2018When smokers relapse, many cite stressful circumstances as the cause. Most smoking cessation medications do not prevent stress induced increases in craving and...
BACKGROUND
When smokers relapse, many cite stressful circumstances as the cause. Most smoking cessation medications do not prevent stress induced increases in craving and withdrawal symptom severity; however the effect of smoking prior to stress exposure on symptom severity is unclear.
METHODS
We examined how smoking a cigarette immediately prior to a stressful task affects craving and withdrawal symptom severity by analyzing data from a double-blind, crossover study assessing paroxetine's effects on the physiological response to the combination of stress and smoking. Measures were obtained prior to and following smoking / stress exposure and following a subsequent 30 minute period at two laboratory sessions (i.e., after one month each of paroxetine and placebo).
RESULTS
Among study completers (n=63), severity of craving decreased from the beginning of the session to immediately following the smoking / stress exposure (p<0.01) and severity of smoking urges decreased from the beginning to the end of the laboratory session (p<0.001). Withdrawal symptoms were less severe while taking paroxetine vs. placebo (p<0.05) but no treatment x time effects were observed.
CONCLUSIONS
Additional research is needed to identify interventions that could similarly decrease stress induced craving in order to determine if smoking cessation rates can be increased.
PubMed: 31768127
DOI: 10.1080/14659891.2018.1489008 -
Journal of Psychopharmacology (Oxford,... Apr 2023Dyslipidaemia is an important cardiovascular risk factor for people with severe mental illness, contributing to premature mortality. The link between antipsychotics and...
BACKGROUND
Dyslipidaemia is an important cardiovascular risk factor for people with severe mental illness, contributing to premature mortality. The link between antipsychotics and dyslipidaemia is well established, while evidence on antidepressants is mixed.
AIMS
To investigate if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants and if and genetic variation plays a role.
METHODS
Review of self-reported prescription medications identified participants taking antidepressants/antipsychotics. Total, low-, and high-density lipoprotein cholesterol (L/HDL-C) and triglycerides derived from blood samples. and metabolic phenotypes were assigned from genetic data. Linear regression investigated aims, adjusted for key covariates.
RESULTS
Of 469,739 participants, 36,043 took antidepressants (53% female, median age 58, 17% taking cholesterol-lowering medications) and 3255 took antipsychotics (58% female, median age 57, 27% taking cholesterol-lowering medications). Significant associations were found between use of each amitriptyline, fluoxetine, citalopram/escitalopram, sertraline, paroxetine and venlafaxine with higher total cholesterol, LDL-C, and triglycerides and lower HDL-C, compared to participants not taking each medication. Venlafaxine was associated with the worst lipid profile (total cholesterol, adjusted mean difference: 0.21 mmol/L, 95% confidence interval (CI): 0.17 to 0.26, < 0.001). Antipsychotic use was significantly associated with lower HDL-C and higher triglycerides. In participants taking sertraline, intermediate metabolisers had higher HDL-C (0.05 mmol/L, 95% CI: 0.01 to 0.09, = 0.007) and lower triglycerides (-0.17 mmol/L, 95% CI: -0.29 to -0.05, = 0.007), compared to normal metabolisers.
CONCLUSIONS
Antidepressants were significantly associated with adverse lipid profiles, potentially warranting baseline and regular monitoring. Further research should investigate the mechanistic pathways underlying the protective effects of the intermediate metaboliser phenotype on HDL-C and triglycerides in people taking sertraline.
Topics: Female; Male; Animals; Cytochrome P-450 CYP2D6; Sertraline; Antipsychotic Agents; Venlafaxine Hydrochloride; Cytochrome P-450 CYP2C19; Antidepressive Agents; Triglycerides; Cholesterol; United Kingdom
PubMed: 36772859
DOI: 10.1177/02698811231152748 -
Oncotarget Dec 2017The impacts of antidepressants on the pathogenesis of dementia remain unclear despite depression and dementia are closely related. Antidepressants have been reported may...
The impacts of antidepressants on the pathogenesis of dementia remain unclear despite depression and dementia are closely related. Antidepressants have been reported may impair serotonin-regulated adaptive processes, increase neurological side-effects and cytotoxicity. An 'astroglio-centric' perspective of neurodegenerative diseases proposes astrocyte dysfunction is involved in the impairment of proper central nervous system functioning. Thus, defining whether antidepressants are harmful to astrocytes is an intriguing issue. We used an astrocyte cell line, primary cultured astrocytes and neuron cells, to identify the effects of 11 antidepressants which included selective serotonin reuptake inhibitors, a serotonin-norepinephrine reuptake inhibitor, tricyclic antidepressants, a tetracyclic antidepressant, a monoamine oxide inhibitor, and a serotonin antagonist and reuptake inhibitor. We found that treatment with 10 μM sertraline and 20 μM paroxetine significantly reduced cell viability. We further explored the underlying mechanisms and found induction of the [Ca] level in astrocytes. We also revealed that sertraline and paroxetine induced mitochondrial damage, ROS generation, and astrocyte apoptosis with elevation of cleaved-caspase 3 and cleaved-PARP levels. Ultimately, we validated these mechanisms in primary cultured astrocytes and neuron cells and obtained consistent results. These results suggest that sertraline and paroxetine cause astrocyte dysfunction, and this impairment may be involved in the pathogenesis of neurodegenerative diseases.
PubMed: 29383176
DOI: 10.18632/oncotarget.23302 -
Cureus Sep 2020Objective The goal of this study was to compare the efficacy of tramadol and paroxetine in the treatment of primary premature ejaculation (PE). Study design This study...
Objective The goal of this study was to compare the efficacy of tramadol and paroxetine in the treatment of primary premature ejaculation (PE). Study design This study was a randomized controlled trial performed in the outpatient department of Nishtar Hospital, Multan, from January 2017 to January 2018. Methodology One hundred six patients were diagnosed with PE and included in the study. The patients were categorized into two groups receiving either tramadol or paroxetine through a lottery randomization method. The main variables were baseline PE, baseline satisfaction after intercourse, baseline intravaginal ejaculatory latency time (IELT), ejaculation control, difficulty in ejaculation, and after-treatment satisfaction with sexual intercourse and IELT. We used IBM SPSS Statistics for Windows, Version 23.0 (Armonk, NY: IBM Corp.) for data analysis, and p≤0.05 was considered statistically significant. Results Ejaculation control, difficulty in ejaculation, and distress due to ejaculation in patients in the tramadol group was noted as 24.5%, 7.5%, and 7.5%, respectively. Ejaculation control, difficulty in ejaculation, and distress due to ejaculation in the paroxetine group was noted as 49.1%, 17%, and 24.5%, respectively. The differences were statistically significant within the groups at baseline and after treatment of PE (p<0.001). Conclusion Tramadol is an effective and useful drug as compared to paroxetine for the treatment of PE. Tramadol can be used as an alternative to other medications for the treatment of lifelong PE.
PubMed: 33145131
DOI: 10.7759/cureus.10725 -
Frontiers in Psychiatry 2021Depression and post-traumatic stress disorder (PTSD) highly co-occur with alcohol use disorder (AUD). The comparative effects of noradrenergic vs. serotonergic...
Depression and post-traumatic stress disorder (PTSD) highly co-occur with alcohol use disorder (AUD). The comparative effects of noradrenergic vs. serotonergic antidepressants on drinking and depressive outcomes for those with AUD and co-occurring depression and/or PTSD are not well known. This study was an analysis of a randomized control trial of 128 patients with AUD who had co-occurring depression and/or PTSD. They were randomized to treatment with paroxetine vs. desipramine and naltrexone vs. placebo leading to four groups: paroxetine plus naltrexone, paroxetine plus placebo, desipramine plus naltrexone, and desipramine plus placebo. Outcomes were percent of drinking days, percent heavy drinking days, drinks per drinking day (Time Line Follow-back Method), and depressive symptoms (Hamilton Depression Scale). Groups compared were (1) depression without PTSD (depression group; = 35), (2) PTSD without depression (PTSD group; = 33), and (3) both depression and PTSD (comorbid group; = 60). There were no overall significant differences in drinking outcomes by medication in the entire sample, and no significant interaction when diagnostic groups were not considered. However, when diagnostic groups were included in the model, the interactions between time, diagnostic group, and medication (desipramine vs. paroxetine) were significant for percent drinking days ( = 0.042), and percent heavy drinking days ( = 0.036); paroxetine showed better drinking outcomes within the depression group, whereas desipramine showed better drinking outcomes in the PTSD and comorbid groups. Regarding depressive symptoms, paroxetine was statistically superior to desipramine in the total sample ( = 0.007), but there was no significant interaction of diagnostic group and medication. Naltrexone led to a decrease in craving but no change in drinking outcomes. The results of this study suggest that drinking outcomes may respond differently to desipramine and paroxetine depending on comorbid MDD and/or PTSD.
PubMed: 35058816
DOI: 10.3389/fpsyt.2021.768318 -
Journal of Clinical Sleep Medicine :... Jul 2020Sexsomnia is a parasomnia consisting of sexual behavior during non-rapid eye movement sleep. To date, there have been 116 clinical cases of sexsomnia reported and most...
Sexsomnia is a parasomnia consisting of sexual behavior during non-rapid eye movement sleep. To date, there have been 116 clinical cases of sexsomnia reported and most were treated with clonazepam. We present a case of an adult male with sexsomnia that started during his college days. He presented to us because of problems in his current marriage arising from sexual behavior during sleep. Polysomnography revealed no significant sleep-disordered breathing, electroencephalography abnormality, or abnormal movement during non-rapid eye movement and rapid eye movement (REM) sleep. Alcohol consumption was reported to worsen his sexsomnia. To avoid the neuro-depressant effects of benzodiazepines, paroxetine was administered and resulted in complete resolution of sexsomnia.
Topics: Adult; Humans; Male; Parasomnias; Paroxetine; Polysomnography; Sleep; Sleep Apnea Syndromes
PubMed: 32672534
DOI: 10.5664/jcsm.8478 -
Journal of Neurochemistry Sep 2022Selective serotonin reuptake inhibitor (SSRI) antidepressants are commonly prescribed treatments for depression, but their effects on serotonin reuptake and release are...
Selective serotonin reuptake inhibitor (SSRI) antidepressants are commonly prescribed treatments for depression, but their effects on serotonin reuptake and release are not well understood. Drosophila melanogaster, the fruit fly, expresses the serotonin transporter (dSERT), the major target of SSRIs, but real-time serotonin changes after SSRIs have not been characterized in this model. The goal of this study was to characterize effects of SSRIs on serotonin concentration and reuptake in Drosophila larvae. We applied various doses (0.1-100 μM) of fluoxetine (Prozac), escitalopram (Lexapro), citalopram (Celexa), and paroxetine (Paxil), to ventral nerve cord (VNC) tissue and measured optogenetically-stimulated serotonin release with fast-scan cyclic voltammetry (FSCV). Fluoxetine increased reuptake from 1 to 100 μM, but serotonin concentration only increased at 100 μM. Thus, fluoxetine occupies dSERT and slows clearance but does not affect concentration. Escitalopram and paroxetine increased serotonin concentrations at all doses, but escitalopram increased reuptake more. Citalopram showed lower concentration changes and faster reuptake profiles compared with escitalopram, so the racemic mixture of citalopram does not change reuptake as much as the S-isomer. Dose response curves were constructed to compare dSERT affinities and paroxetine showed the highest affinity and fluoxetine the lowest. These data demonstrate SSRI mechanisms are complex, with separate effects on reuptake or release. Furthermore, dynamic serotonin changes in Drosophila are similar to previous studies in mammals. This work establishes how antidepressants affect serotonin in real-time, which is useful for future studies that will investigate pharmacological effects of SSRIs with different genetic mutations in Drosophila.
Topics: Animals; Antidepressive Agents; Citalopram; Drosophila; Drosophila melanogaster; Fluoxetine; Mammals; Paroxetine; Serotonin; Selective Serotonin Reuptake Inhibitors
PubMed: 35736504
DOI: 10.1111/jnc.15658 -
ENeuro Jul 2022There are currently no Food and Drug Administration (FDA)-approved delta opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and...
There are currently no Food and Drug Administration (FDA)-approved delta opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and non-human primates compared to traditional mu opioid receptor (MOR) therapeutics (Vanderah, 2010). Targeting peripheral receptors is an attractive strategy to reduce abuse potential. However, peripheral opioid receptors do not readily respond to agonists unless primed by inflammation, which would limit their efficacy in non-inflammatory pain patients (Stein et al., 1989). It was recently identified that G protein-coupled receptor kinase 2 (GRK2) maintains DOR incompetence in non-inflamed nociceptors (Brackley et al., 2016; Brackley et al., 2017). Here, we report that paroxetine, a selective serotonin reuptake inhibitor and potent GRK2 inhibitor (Thal et al., 2012), reduces chronic GRK2 association with membrane DOR, thereby enhancing peripheral DOR-mediated analgesic competence in the absence of inflammation. Interestingly, paroxetine's effects on GRK2 are limited to peripheral tissues in the male rat. The effects of paroxetine on DOR competence are notably antagonized by GRK2 overexpression. This is the first study to suggest that paroxetine induces peripheral DOR analgesic competence through a GRK2-dependent mechanism, improving analgesic efficacy in non-inflamed tissue. Because paroxetine targets the protein that governs peripheral opioid receptor responsiveness, and does so in the absence of inflammation, we propose that paroxetine may be suitable as a co-therapy with peripherally-restrictive doses of opioids to improve analgesic efficacy in non-inflammatory pain conditions.Opioids that target MOR represent the gold-standard for analgesic healthcare, despite widespread abuse potential and the ongoing opioid-epidemic. Work herein uncovers the therapeutic potential of targeting peripheral DOR for analgesic utility with an FDA-approved GRK2 inhibitor paroxetine to boost efficacy and reduce side effect profiles. Analgesic pain management targeting DOR with increased efficacy through adjuvant paroxetine treatment could reduce over-reliance on MOR agonist opioids for pain relief and usher in new options for analgesia.
PubMed: 35882549
DOI: 10.1523/ENEURO.0063-22.2022 -
Frontiers in Psychiatry 2020Recent interest in the role of microbiota in health and disease has implicated gut microbiota dysbiosis in psychiatric disorders including major depressive disorder....
Recent interest in the role of microbiota in health and disease has implicated gut microbiota dysbiosis in psychiatric disorders including major depressive disorder. Several antidepressant drugs that belong to the class of selective serotonin reuptake inhibitors have been found to display antimicrobial activities. In fact, one of the first antidepressants discovered serendipitously in the 1950s, the monoamine-oxidase inhibitor Iproniazid, was a drug used for the treatment of tuberculosis. In the current study we chronically treated DBA/2J mice for 2 weeks with paroxetine, a selective serotonin reuptake inhibitor, and collected fecal pellets as a proxy for the gut microbiota from the animals after 7 and 14 days. Behavioral testing with the forced swim test revealed significant differences between paroxetine- and vehicle-treated mice. Untargeted mass spectrometry and 16S rRNA profiling of fecal pellet extracts showed several primary and secondary bile acid level, and microbiota alpha diversity differences, respectively between paroxetine- and vehicle-treated mice, suggesting that microbiota functions are altered by the drug. In addition to their lipid absorbing activities bile acids have important signaling activities and have been associated with gastrointestinal diseases and colorectal cancer. Antidepressant drugs like paroxetine should therefore be used with caution to prevent undesirable side effects.
PubMed: 32581888
DOI: 10.3389/fpsyt.2020.00518