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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 -
JAMA Oct 2022Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects.
OBJECTIVE
To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021.
INTERVENTIONS
Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo.
MAIN OUTCOMES AND MEASURES
Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary).
RESULTS
Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -∞ to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -∞ to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -∞ to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -∞ to 6.4]; P = .67). No drug-related serious adverse events were reported.
CONCLUSIONS AND RELEVANCE
In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04310579.
Topics: Adult; Analgesics, Opioid; Antidepressive Agents; Benzodiazepines; Carbon Dioxide; Double-Blind Method; Female; Humans; Hypercapnia; Oxycodone; Paroxetine; Quetiapine Fumarate; Respiration; Respiratory Insufficiency
PubMed: 36219407
DOI: 10.1001/jama.2022.17735 -
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 -
Chinese Journal of Integrative Medicine Apr 2023To evaluate the efficacy and safety of Jianpi Jieyu Decoction (JJD) for treating patients with mild-to-moderate depression of Xin (Heart)-Pi (Spleen) deficiency (XPD)... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of Jianpi Jieyu Decoction for Patients with Mild-to-Moderate Depression of Xin (Heart)-Pi (Spleen) Deficiency Syndrome: A Multi-centre Randomized Controlled Study.
OBJECTIVE
To evaluate the efficacy and safety of Jianpi Jieyu Decoction (JJD) for treating patients with mild-to-moderate depression of Xin (Heart)-Pi (Spleen) deficiency (XPD) syndrome.
METHODS
In this multi-center, randomized, controlled study, 140 patients with mild-to-moderate depression of XPD syndrome were included from Xiyuan Hospital of China Academy of Chinese Medical Sciences and Botou Hospital of Traditional Chinese Medicine from December 2017 to December 2019. They were randomly divided into JJD group and paroxetine group by using a random number table, with 70 cases in each group. The patients in the JJD group were given JJD one dose per day (twice daily at morning and evening, 100 mL each time), and the patients in the paroxetine group were given paroxetine (10 mg/d in week 1; 20 mg/d in weeks 2-6), both orally administration for a total of 6 weeks. The primary outcome was the change of 17-item Hamilton Depression Rating Scale (HAMD-17) score at week 6 from baseline. The secondary outcomes included the Hamilton Anxiety Scale (HAMA) score, Traditional Chinese Medicine Symptom Scale (TCMSS), and Clinlcal Global Impression (CGI) scores at the 2nd, 4th, and 6th weekends of treatment, HAMD-17 response (defined as a reduction in score of >50%) and HAMD-17 remission (defined as a score of ⩽7) at the end of the 6th week of treatment. Adverse events (AEs) were also recorded.
RESULTS
From baseline to week 6, the HAMD-17 scores decreased 10.2 ± 4.0 and 9.1 ± 4.9 points in the JJD and paroxetine groups, respectively (P=0.689). The HAMD-17 response occurred in 60% of patients in the JJD group and in 50% of those in the paroxetine group (P=0.292); HAMD-17 remission occurred in 45.7% and 30% of patients, respectively (P=0.128). The differences of CGI scores at the 6th week were not statistically significant (P>0.05). There were significant differences in HAMD-17 scores between the two groups at 2nd and 4th week (P=0.001 and P=0.014). The HAMA scores declined 8.1 ± 3.0 and 6.9 ± 4.3 points from baseline to week 6 in the JJD and paroxetine groups, respectively (P=0.905 between groups). At 4th week of treatment, there was a significant difference in HAMA between the two groups (P=0.037). TCMSS decreased 11.4 ± 5.1, and 10.1 ± 6.8 points in the JJD and paroxetine groups, respectively (P=0.080 between groups). At the 6th week, the incidence of AEs in the JJD group was significantly lower than that in the paroxetine group (7.14% vs. 22.86%, P<0.05).
CONCLUSION
Compared with paroxetine, JJD was associated with a significantly lower incidence of AEs in patients with mild-to-moderate depression of XPD syndrome, with no difference in efficacy at 6 weeks. (Trial registration No. ChiCTR2000040922).
Topics: Humans; Paroxetine; Spleen; Anxiety; Syndrome; Medicine, Chinese Traditional; Treatment Outcome; Double-Blind Method
PubMed: 36301455
DOI: 10.1007/s11655-022-3685-6 -
Tijdschrift Voor Psychiatrie 2013Tapering strips can be used for the gradual reduction of the dose of certain types of drugs such as antidepressants and benzodiazepines. The strips contain a slightly...
BACKGROUND
Tapering strips can be used for the gradual reduction of the dose of certain types of drugs such as antidepressants and benzodiazepines. The strips contain a slightly lower dose on each consecutive day. This prevents the withdrawal symptoms still experienced by too many patients and lowers the risk of relapse.
AIM
To make tapering strips of antidepressant drugs available for patients in need of a tapering-off procedure.
METHOD
The Consensusgroup Tapering studied the literature and consulted with experts to find out whether the plan to make tapering strips of paroxetine and venlafaxine available for patients is feasible.
RESULTS
The Cinderella Therapeutic Foundation (www.cinderella-tx.org), a not-for-profit organisation which aims to give patients access to orphan drugs and treatments, wants to make tapering strips of paroxetine and venlafaxine available since these are the two antidepressants that cause the most problems. The process of producing, packaging and checking the tapering doses is iso-certified; each strip is provided with a bar-code and can be followed and traced. Therefore the strips will conform to current safety regulations.In view of the large number of patients taking paroxetine and venlafaxine there is likely to be a considerable demand for tapering strips.
CONCLUSION
From a financial, marketing and practical point of view, the introduction of tapering strips is feasable. Patients will derive considerable benefits. The paroxetine strips will be produced first and are expected to be available from December 2013.
Topics: Antidepressive Agents; Cyclohexanols; Depressive Disorder; Dose-Response Relationship, Drug; Feasibility Studies; Humans; Paroxetine; Substance Withdrawal Syndrome; Venlafaxine Hydrochloride
PubMed: 24194351
DOI: No ID Found -
International Journal of Molecular... Jan 2023A considerable amount of literature has been published on antidepressants and cardiac ion channel dysfunction. The antidepressant paroxetine has been associated with...
A considerable amount of literature has been published on antidepressants and cardiac ion channel dysfunction. The antidepressant paroxetine has been associated with Brugada syndrome and long QT syndrome, albeit on the basis of conflicting findings. The cardiac voltage-gated sodium channel (Na1.5) is related to both of these syndromes, suggesting that paroxetine may have an effect on this channel. In the present study, we therefore carried out patch clamp experiments to examine the effect of paroxetine on human Na1.5 channels stably expressed in human embryonic kidney 293 (HEK-293) cells as well as on action potentials of isolated rabbit left ventricular cardiomyocytes. Additionally, computer simulations were conducted to test the functional effects of the experimentally observed paroxetine-induced changes in the Na1.5 current. We found that paroxetine led to a decrease in peak Na1.5 current in a concentration-dependent manner with an IC of 6.8 ± 1.1 µM. In addition, paroxetine caused a significant hyperpolarizing shift in the steady-state inactivation of the Na1.5 current as well as a significant increase in its rate of inactivation. Paroxetine (3 µM) affected the action potential of the left ventricular cardiomyocytes, significantly decreasing its maximum upstroke velocity and amplitude, both of which are mainly regulated by the Na1.5 current. Our computer simulations demonstrated that paroxetine substantially reduces the fast sodium current of human left ventricular cardiomyocytes, thereby slowing conduction and reducing excitability in strands of cells, in particular if conduction and excitability are already inhibited by a loss-of-function mutation in the Na1.5 encoding gene. In conclusion, paroxetine acts as an inhibitor of Na1.5 channels, which may enhance the effects of loss-of-function mutations in .
Topics: Animals; Humans; Rabbits; Action Potentials; Antidepressive Agents; HEK293 Cells; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Paroxetine; Sodium
PubMed: 36768229
DOI: 10.3390/ijms24031904 -
International Journal of Molecular... Jun 2021Thus far, many hypotheses have been proposed explaining the cause of depression. Among the most popular of these are: monoamine, neurogenesis, neurobiology, inflammation...
Thus far, many hypotheses have been proposed explaining the cause of depression. Among the most popular of these are: monoamine, neurogenesis, neurobiology, inflammation and stress hypotheses. Many studies have proven that neurogenesis in the brains of adult mammals occurs throughout life. The generation of new neurons persists throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. For this reason, the search for drugs acting in this mechanism seems to be a priority for modern pharmacotherapy. Paroxetine is one of the most commonly used antidepressants. However, the exact mechanism of its action is not fully understood. The fact that the therapeutic effect after the administration of paroxetine occurs after a few weeks, even if the levels of monoamine are rapidly increased (within a few minutes), allows us to assume a neurogenic mechanism of action. Due to the confirmed dependence of depression on serotonin, norepinephrine, dopamine and γ-aminobutyric acid levels, studies have been undertaken into paroxetine interactions with these primary neurotransmitters using in silico and in vitro methods. We confirmed that paroxetine interacts most strongly with monoamine transporters and shows some interaction with γ-aminobutyric acid transporters. However, studies of the potency inhibitors and binding affinity values indicate that the neurogenic mechanism of paroxetine's action may be determined mainly by its interactions with serotonin transporters.
Topics: Animals; Binding Sites; CHO Cells; Cricetulus; GABA Plasma Membrane Transport Proteins; Humans; Molecular Docking Simulation; Neurotransmitter Agents; Paroxetine; Vesicular Monoamine Transport Proteins
PubMed: 34208199
DOI: 10.3390/ijms22126293 -
The Primary Care Companion For CNS... Apr 2020
Topics: Adult; Betacoronavirus; COVID-19; Clonazepam; Coronavirus Infections; Humans; Male; Pandemics; Panic Disorder; Paroxetine; Pneumonia, Viral; SARS-CoV-2
PubMed: 32369687
DOI: 10.4088/PCC.20l02626 -
Effect of selective serotonin reuptake inhibitor discontinuation on anxiety-like behaviours in mice.Journal of Psychopharmacology (Oxford,... Jul 2022Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms,...
BACKGROUND
Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms, including anxiety. Surprisingly, little is known of the behavioural effect of SSRI discontinuation in animals.
AIM
Here, the effect of SSRI discontinuation on anxiety-like behaviour was systematically investigated in mice.
METHODS
Experiments were based on a three-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed 2 days after SSRI discontinuation over a 5-day period using the elevated plus maze (EPM) and other anxiety tests.
RESULTS
An exploratory experiment found cessation of paroxetine (12 days) was associated with decreased open-arm exploration and reduced total distance travelled, in male but not female mice. Follow-up studies confirmed a discontinuation effect on the EPM in male mice after paroxetine (12 days) and also citalopram (12 days). Mice receiving continued paroxetine (but not citalopram) also showed decreased open-arm exploration but this was dissociable from the effects of discontinuation. The discontinuation response to paroxetine did not strengthen after 28 days of treatment but was absent after 7 days of treatment. A discontinuation response was not discernible in other anxiety and fear-learning tests applied 3-5 days after treatment cessation. Finally, discontinuation effects on the EPM were typically associated with decreased locomotion on the test. However, separate locomotor testing implicated anxiety-provoked behavioural inhibition rather than a general reduction in motor activity.
CONCLUSION
Overall, this study provides evidence for a short-lasting behavioural discontinuation response to cessation of SSRI treatment in mice.
Topics: Animals; Anxiety; Citalopram; Male; Mice; Paroxetine; Selective Serotonin Reuptake Inhibitors
PubMed: 35607713
DOI: 10.1177/02698811221093032 -
Neuropsychopharmacology Reports Mar 2023Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder,...
AIM
Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression-like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect.
METHODS
Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI-treated group data.
RESULTS
Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411).
CONCLUSION
Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant-like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings.
Topics: Mice; Animals; Selective Serotonin Reuptake Inhibitors; Fluoxetine; Paroxetine; Sertraline; Swimming; Depressive Disorder, Major; Escitalopram; Antidepressive Agents
PubMed: 36649966
DOI: 10.1002/npr2.12316