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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 -
The Journal of Pharmacology and... Oct 2019Long-term use of selective serotonin reuptake inhibitors (SSRIs) targeting the serotonin transporter (SERT) has been suggested to be associated with an increased risk...
Long-term use of selective serotonin reuptake inhibitors (SSRIs) targeting the serotonin transporter (SERT) has been suggested to be associated with an increased risk for obesity and type 2 diabetes. Previously, using a murine knockout model of SERT, we showed that estrogen suppression is involved in SERT deficiency-induced obesity and glucose intolerance in nonpregnant mice. The present study investigated the effects of chronic paroxetine treatment on adiposity and glucose tolerance in mice before and during pregnancy. Chronic paroxetine treatment in nonpregnant mice resulted in visceral adiposity and glucose intolerance accompanied by reduced circulating 17-estradiol levels and ovarian expression of the aromatase (CYP19a1). Remarkably, pregnancy significantly reduced adiposity and improved glucose tolerance in paroxetine-treated mice by rebooting ovarian CYP19a1 expression and 17-estradiol production. These effects appear to be reversible as ovarian CYP19a1 expression and circulating 17-estradiol returned to prepregnancy levels soon after parturition. As in pregnant mice, 17-estradiol replacement treatment in nonpregnant mice reduced paroxetine-induced adiposity. Our findings further suggested that modulation of estrogen synthesis underlies the observed metabolic adverse effects of SSRIs. Although our data revealed a transient reversal effect of pregnancy on SSRI-induced metabolic abnormalities, these observations are experimental and limited to mice. The use of SSRIs during human pregnancy should be cautioned because of potential adverse effects to the fetuses.
Topics: Adiposity; Animals; Aromatase; Estradiol; Female; Glucose Intolerance; Hormone Replacement Therapy; Mice; Mice, Inbred C57BL; Obesity; Ovary; Paroxetine; Pregnancy; Pregnancy Complications; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 31308195
DOI: 10.1124/jpet.118.255380 -
BMJ (Clinical Research Ed.) Sep 2015To reanalyse SmithKline Beecham's Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To reanalyse SmithKline Beecham's Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine.
DESIGN
Double blind randomised placebo controlled trial.
SETTING
12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998.
PARTICIPANTS
275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality.
INTERVENTIONS
Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo.
MAIN OUTCOME MEASURES
The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified.
RESULTS
The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group.
CONCLUSIONS
Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.
Topics: Adolescent; Adrenergic Uptake Inhibitors; Antidepressive Agents, Second-Generation; Data Interpretation, Statistical; Depressive Disorder, Major; Double-Blind Method; Evidence-Based Medicine; Humans; Imipramine; Paroxetine; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 26376805
DOI: 10.1136/bmj.h4320 -
The American Journal of Managed Care May 1999To compare depression-related treatment costs and total healthcare costs for patients diagnosed with depression and treated with either sertraline, paroxetine, or...
OBJECTIVE
To compare depression-related treatment costs and total healthcare costs for patients diagnosed with depression and treated with either sertraline, paroxetine, or fluoxetine.
PATIENTS AND METHODS
Claims records from a national database of patients diagnosed with depression who began treatment with an SSRI in 1995, following an antidepressant medication-free period of at least 6 months, were included. Treatment course and associated depression-related treatment and total healthcare costs during the subsequent 12-month treatment period were examined using univariate and multivariate methods.
RESULTS
Nine-hundred five (905) patients taking sertraline, 492 on paroxetine, and 945 on fluoxetine met inclusion criteria. The groups were similar and representative with respect to gender and age. Mean dose over the 12-month treatment period increased 24%, indicating significant titration in all cohorts. Patients treated with paroxetine had shorter treatment duration (157.0 days) than did patients treated with fluoxetine (192.6 days) or sertraline (166.9 days, P < 0.001). Patients receiving index treatment with paroxetine were most likely to switch to another SSRI (21.3%); those taking sertraline were second most likely to switch (16.1%); and those on fluoxetine were least likely (12.4%, P = 0.001). Mean costs for depression-related outpatient visits and hospitalizations were similar. Mean antidepressant prescription costs differed, being $586, $419, and $446 for fluoxetine, paroxetine and sertraline cohorts, respectively (P < 0.001). In this sample, the fluoxetine cohort did not have lower nonpharmaceutical healthcare costs to offset higher pharmaceutical acquisition costs. Conclusions from median and multivariate analyses were robust to these findings.
CONCLUSIONS
During this study period when fluoxetine, paroxetine, and sertraline were all well-established agents, similar depression-related treatment courses and cost characteristics among all 3 drugs were observed.
Topics: Adolescent; Adult; Aged; Antidepressive Agents; Antidepressive Agents, Second-Generation; Cost of Illness; Cost-Benefit Analysis; Depressive Disorder; Female; Fluoxetine; Follow-Up Studies; Health Care Costs; Humans; Male; Middle Aged; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; United States
PubMed: 10537866
DOI: No ID Found -
The Cochrane Database of Systematic... Apr 2014Paroxetine is the most potent inhibitor of the reuptake of serotonin of all selective serotonin reuptake inhibitors (SSRIs) and has been studied in many randomised... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Paroxetine is the most potent inhibitor of the reuptake of serotonin of all selective serotonin reuptake inhibitors (SSRIs) and has been studied in many randomised controlled trials (RCTs). However, these comparative studies provided contrasting findings and systematic reviews of RCTs have always considered the SSRIs as a group, and evidence applicable to this group of drugs might not be applicable to paroxetine alone. The present systematic review assessed the efficacy and tolerability profile of paroxetine in comparison with tricyclics (TCAs), SSRIs and newer or non-conventional agents.
OBJECTIVES
1. To determine the efficacy of paroxetine in comparison with other anti-depressive agents in alleviating the acute symptoms of Major Depressive Disorder.2. To review acceptability of treatment with paroxetine in comparison with other anti-depressive agents.3. To investigate the adverse effects of paroxetine in comparison with other anti-depressive agents.
SEARCH METHODS
We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialized Register (CCDANCTR, to 30 September 2012), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). Reference lists of relevant papers and previous systematic reviews were handsearched. Pharmaceutical companies marketing paroxetine and experts in this field were contacted for supplemental data.
SELECTION CRITERIA
All randomised controlled trials allocating participants with major depression to paroxetine versus any other antidepressants (ADs), both conventional (such as TCAs, SSRIs) and newer or non-conventional (such as hypericum). For trials which had a cross-over design, only results from the first randomisation period were considered.
DATA COLLECTION AND ANALYSIS
Two review authors independently checked eligibility and extracted data using a standard form. Data were then entered in RevMan 5.2 with a double-entry procedure. Information extracted included study and participant characteristics, intervention details, settings and efficacy, acceptability and tolerability measures.
MAIN RESULTS
A total of 115 randomised controlled trials (26,134 participants) were included. In 54 studies paroxetine was compared with older ADs, in 21 studies with another SSRI, and in 40 studies with a newer or non-conventional antidepressant other than SSRIs. For the primary outcome (patients who responded to treatment), paroxetine was more effective than reboxetine at increasing patients who responded early to treatment (Odds Ratio (OR): 0.66, 95% Confidence Interval (CI) 0.50 to 0.87, number needed to treat to provide benefit (NNTb) = 16, 95% CI 10 to 50, at one to four weeks, 3 RCTs, 1375 participants, moderate quality of evidence), and less effective than mirtazapine (OR: 2.39, 95% CI 1.42 to 4.02, NNTb = 8, 95% CI 5 to 14, at one to four weeks, 3 RCTs, 726 participants, moderate quality of evidence). Paroxetine was less effective than citalopram in improving response to treatment (OR: 1.54, 95% CI 1.04 to 2.28, NNTb = 9, 95% CI 5 to 102, at six to 12 weeks, 1 RCT, 406 participants, moderate quality of evidence). We found no clear evidence that paroxetine was more or less effective compared with other antidepressants at increasing response to treatment at acute (six to 12 weeks), early (one to four weeks), or longer term follow-up (four to six months). Paroxetine was associated with a lower rate of adverse events than amitriptyline, imipramine and older ADs as a class, but was less well tolerated than agomelatine and hypericum. Included studies were generally at unclear or high risk of bias due to poor reporting of allocation concealment and blinding of outcome assessment, and incomplete reporting of outcomes.
AUTHORS' CONCLUSIONS
Some possibly clinically meaningful differences between paroxetine and other ADs exist, but no definitive conclusions can be drawn from these findings. In terms of response, there was a moderate quality of evidence that citalopram was better than paroxetine in the acute phase (six to 12 weeks), although only one study contributed data. In terms of early response to treatment (one to four weeks) there was moderate quality of evidence that mirtazapine was better than paroxetine and that paroxetine was better than reboxetine. However there was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any time point. Even if some differences were identified, the findings from this review are better thought as hypothesis forming rather than hypothesis testing and it would be reassuring to see the conclusions replicated in future trials. Finally, most of included studies were at unclear or high risk of bias, and were sponsored by the drug industry. The potential for overestimation of treatment effect due to sponsorship bias should be borne in mind.
Topics: Antidepressive Agents; Depression; Humans; Paroxetine; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors
PubMed: 24696195
DOI: 10.1002/14651858.CD006531.pub2 -
Cellular Signalling Oct 2017β-adrenergic receptors (βAR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of βAR has...
β-adrenergic receptors (βAR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of βAR has long been recognized as a maladaptive process in the progression of various disease states. Thus, the development of small molecule inhibitors of GRKs for the study of these processes and as potential therapeutics has been at the forefront of recent research efforts. Via structural and biochemical analyses, the selective serotonin reuptake inhibitor (SSRI) paroxetine was identified as a GRK2 inhibitor that enhances βAR-dependent cardiomyocyte and cardiac contractility and reverses cardiac dysfunction and myocardial βAR expression in mouse models of heart failure. Despite these functional outcomes, consistent with diminished βAR desensitization, the proximal βAR signaling mechanisms sensitive to paroxetine have not been reported. In this study, we aimed to determine whether paroxetine prevents classic βAR desensitization-related signaling mechanisms at a molecular level. Therefore, via immunoblotting, radioligand binding, fluorescence resonance energy transfer (FRET) and microscopy assays, we have performed an assessment of the effect of paroxetine on proximal βAR signaling responses. Indeed, paroxetine treatment inhibited ligand-induced β2AR phosphorylation in a concentration-dependent manner. Additionally, for both β1AR and β2AR, paroxetine decreased ligand-induced βarrestin2 recruitment and subsequent receptor internalization. Thus, paroxetine inhibits βAR desensitization mechanisms consistent with GRK2 inhibition and provides a useful pharmacological tool for studying these proximal GPCR signaling responses.
Topics: Adrenergic beta-Agonists; Cell Line; Endocytosis; Humans; Paroxetine; Phosphorylation; Receptors, Adrenergic, beta; Signal Transduction; beta-Arrestin 2
PubMed: 28711716
DOI: 10.1016/j.cellsig.2017.07.006 -
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 -
Emergency Medicine Journal : EMJ Apr 2007Serotonin syndrome is an under-reported and under-recognised condition that occurs on administration of selective serotonin re-uptake inhibitors alone, or in combination...
Serotonin syndrome is an under-reported and under-recognised condition that occurs on administration of selective serotonin re-uptake inhibitors alone, or in combination with other medication known to increase levels of 5-hydroxytryptamine. This case report demonstrates signs and symptoms associated with their overdose and illustrates the importance of recognition of this syndrome to instigate appropriate treatment for the patient.
Topics: Adult; Diphenhydramine; Drug Overdose; Female; Glasgow Coma Scale; Humans; Paroxetine; Serotonin Syndrome; Temazepam
PubMed: 17384366
DOI: 10.1136/emj.2006.040550 -
The International Journal of Risk &... Sep 2016This is an analysis of the unpublished continuation phase of Study 329, the primary objective of which was to compare the efficacy and safety of paroxetine and... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This is an analysis of the unpublished continuation phase of Study 329, the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The objectives of the continuation phase were to assess safety and relapse rates in the longer term. The objective of this publication, under the Restoring Invisible and Abandoned Trials (RIAT) initiative, was to see whether access to and analysis of the previously unpublished dataset from the continuation phase of this randomized controlled trial would have clinically relevant implications for evidence-based medicine.
METHODS
The study was an eight-week double-blind randomized placebo-controlled trial with a six month continuation phase. The setting was 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. 275 adolescents with major depression were originally enrolled in Study 329, with 190 completing the eight-week acute phase. Of these, 119 patients (43%) entered the six-month continuation phase (paroxetine n = 49; imipramine n = 39; placebo n = 31), in which participants were continued on their current treatment, blinded. As per the protocol, we have looked at rates of relapse (based on Hamilton Depression Scale scores) across both acute and continuation phases, and generated a safety profile for paroxetine and imipramine compared with placebo for up to six months.ANOVA testing (generalized linear model) using a model including effects of site, treatment and site x treatment interaction was applied. Otherwise we used only descriptive statistics.
RESULTS
Of patients entering the continuation phase, 15 of 49 for paroxetine (31%), 12 of 39 for imipramine (31%) and 12 of 31 for placebo (39%) completed as responders. Across the study, 25 patients on paroxetine relapsed (41% of those showing an initial response), 15 on imipramine (26%), and 10 on placebo (21%). In the continuation and taper phases combined there were 211 adverse events in the paroxetine group, 147 on imipramine and 100 on placebo. The taper phase had a higher proportion of severe adverse events per week of exposure than the acute phase, with the continuation phase having the fewest events.
CONCLUSIONS
The continuation phase did not offer support for longer-term efficacy of either paroxetine or imipramine. Relapse and adverse events on both active drugs open up the risks of a prescribing cascade. The previously largely unrecognised hazards of the taper phase have implications for prescribing practice and need further exploration.
Topics: Adolescent; Antidepressive Agents, Second-Generation; Child; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Imipramine; Male; Paroxetine; Psychiatric Status Rating Scales; Recurrence
PubMed: 27662279
DOI: 10.3233/JRS-160728 -
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