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Tidsskrift For Den Norske Laegeforening... Sep 2011Metoprolol, the most commonly used beta-receptor antagonist in Norway, is eliminated mainly via the enzyme cytochrome P450 (CYP) 2D6. This enzyme is inhibited to a... (Review)
Review
BACKGROUND
Metoprolol, the most commonly used beta-receptor antagonist in Norway, is eliminated mainly via the enzyme cytochrome P450 (CYP) 2D6. This enzyme is inhibited to a varying extent by antidepressants. The aim of this article is to provide an overview of the interactions between metoprolol and antidepressants with an emphasis on CYP2D6 inhibition.
MATERIAL AND METHODS
Relevant literature was identified by a PubMed search using the word "metoprolol" combined with generic names of antidepressant drugs.
RESULTS
The potent CYP2D6 inhibitor paroxetine has been shown to increase the biologically available dose of metoprolol about 4- to 6-fold. The same degree of increase is expected for the two other potent CYP2D6 inhibitors in the class, fluoxetine and bupropion. Severe bradycardia and atroventricular block has been reported in patients who have taken metoprolol in combination with these three drugs. Escitalopram, citalopram and duloxetine are less potent CYP2D6 inhibitors, and have been shown to cause 2- to 3-fold increases in biologically available dose of metoprolol. Other antidepressants, such as sertraline, venlafaxine, mianserin and mirtazapine, inhibit CYP2D6 to little or no extent, and are not expected to cause clinically relevant interactions with metoprolol.
CONCLUSION
Metoprolol should not be used concomitantly with paroxetine, fluoxetine or bupropion due to extensive interactions and the risk of serious adverse effects. Dose reductions of metoprolol should be considered for combined treatment with citalopram, escitalopram or duloxetine, while concurrent use with sertraline, venlafaxine, mianserin and mirtazapine should be safe.
Topics: Adrenergic beta-1 Receptor Antagonists; Antidepressive Agents; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Drug Interactions; Drug Therapy, Combination; Fluoxetine; Humans; Metoprolol; Paroxetine; Risk Factors
PubMed: 21946596
DOI: 10.4045/tidsskr.11.0143 -
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 -
The Cochrane Database of Systematic... Sep 2014Postnatal depression is a common disorder that can have adverse short- and long-term effects on maternal morbidity, the new infant and the family as a whole. Treatment... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Postnatal depression is a common disorder that can have adverse short- and long-term effects on maternal morbidity, the new infant and the family as a whole. Treatment is often largely by social support and psychological interventions. It is not known whether antidepressants are an effective and safe choice for treatment of this disorder. This review was undertaken to evaluate the effectiveness of different antidepressants and to compare their effectiveness with other forms of treatment, placebo or treatment as usual. It is an update of a review first published in 2001.
OBJECTIVES
To assess the effectiveness of antidepressant drugs in comparison with any other treatment (psychological, psychosocial or pharmacological), placebo or treatment as usual for postnatal depression.
SEARCH METHODS
We searched the Cochrane Depression, Anxiety and Neurosis Group's Specialized Register (CCDANCTR) to 11 July 2014. This register contains reports of relevant randomised controlled trials (RCTs) from the following bibliographic databases: The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE, (1974 to date) and PsycINFO (1967 to date). We also searched international trial registries and contacted pharmaceutical companies and experts in the field.
SELECTION CRITERIA
We included RCTs of women with depression with onset up to six months postpartum that compared antidepressant treatment (alone or in combination with another treatment) with any other treatment, placebo or treatment as usual.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data from the trial reports. We requested missing information from investigators wherever possible. We sought data to allow an intention-to-treat analysis. Random effects meta-analyses were conducted to pool data where sufficient comparable studies were identified.
MAIN RESULTS
We included six trials with 596 participants in this review. All studies had a randomised controlled parallel group design, with two conducted in the UK, three in the US and one in Israel. Meta-analyses were performed to pool data on response and remission from studies comparing antidepressants with placebo. No meta-analyses could be conducted for other comparisons due to the small number of trials identified.Four studies compared selective serotonin reuptake inhibitors (SSRIs) with placebo (two using sertraline, one using paroxetine and one using fluoxetine; 233 participants in total). In two of these studies both the experimental and placebo groups also received psychological therapy. Pooled risk ratios based on data from three of these studies (146 participants) showed that women randomised to SSRIs had higher rates of response and remission than those randomised to placebo (response: RR 1.43, 95% CI 1.01 to 2.03; remission: RR 1.79, 95% CI 1.08 to 2.98); the fourth study did not report data on response or remission.One study (254 participants) compared antidepressant treatment with treatment as usual (for the first four weeks) followed by listening visits. The study found significantly higher rates of improvement in the antidepressant group than treatment-as-usual group after the first four weeks, but no difference between antidepressants and listening visits at the later follow-up. In addition, one study comparing sertraline with nortriptyline (a tricyclic antidepressant) found no difference in effectiveness (109 participants).Side effects were experienced by a substantial proportion of women, but there was no evidence of a meaningful difference in the number of adverse effects between treatment arms in any study. There were very limited data on adverse effects experienced by breastfed infants, with no long-term follow-up. All but one of the studies were assessed as being at high or uncertain risk of attrition bias and selective outcome reporting. In particular, one of the placebo-controlled studies had over 50% drop-out.
AUTHORS' CONCLUSIONS
The evidence base for this review was very limited, with a small number of studies and little information on a number of important outcomes, particularly regarding potential effects on the child. Risk of bias, for example from high attrition rates, as well as low representativeness of participants (e.g. exclusion of women with severe or chronic depression in several trials) also limit the conclusions that can be drawn.Pooled estimates for response and remission found that SSRIs were significantly more effective than placebo for women with postnatal depression. However the quality of evidence contributing to this comparison was assessed as very low owing to the small sample size for this comparison (146 participants from three studies), the risk of bias in included studes and the inclusion of one study where all participants in both study arms additionally received psychological therapy. There was insufficient evidence to conclude whether, and for whom, antidepressant or psychological/psychosocial treatments are more effective, or whether some antidepressants are more effective or better tolerated than others. There is also inadequate evidence on whether the benefits of antidepressants persist beyond eight weeks or whether they have short- or long-term adverse effects on breastfeeding infants.Professionals treating women with severe depression in the postnatal period will need to draw on other evidence, including trials among general adult populations and observational studies of antidepressant safety when breastfeeding (although the potential for confounding in non-randomised studies must be considered). More RCTs are needed with larger sample sizes and longer follow-up, including assessment of the impact on the child and safety of breastfeeding. Further larger-scale trials comparing antidepressants with alternative treatment modalities are also required.
Topics: Adult; Antidepressive Agents, Second-Generation; Clinical Trials as Topic; Depression, Postpartum; Female; Fluoxetine; Humans; Nortriptyline; Paroxetine; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Sertraline
PubMed: 25211400
DOI: 10.1002/14651858.CD002018.pub2 -
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 -
Iranian Biomedical Journal Sep 2020Neuropathic pain, due to peripheral nerve damage, has influenced millions of people living all over the world. It has been shown that paroxetine can relieve neuropathic...
BACKGROUND
Neuropathic pain, due to peripheral nerve damage, has influenced millions of people living all over the world. It has been shown that paroxetine can relieve neuropathic pain. Recently, the role of certain proteins like brain-derived neurotrophic factor (BDNF), GABAA receptor, and K+-Cl- cotransporter 2 (KCC2) transporter in the occurrence of neuropathic pain has been documented. In the current study, the expression of these proteins affected by paroxetine was evaluated.
METHODS
Male Wistar rats were allocated into two main groups of pre- and post-injury. Rats in each main group received paroxetine before nerve injury and at day seven after nerve damage till day 14, respectively. The lumbar spinal cord of animals was extracted to assess the expression of target genes and proteins.
RESULTS
In the preventive study, paroxetine decreased BDNF and increased KCC2 and GABAA gene and protein expression, while in the post-injury paradigm, it decreased BDNF and increased KCC2 genes and protein expression. In this regard, an increase in the protein expression of GABAA was observed.
CONCLUSION
It seems that paroxetine with a change in the expression of three significant proteins involved in neuropathic pain could attenuate this type of chronic pain.
Topics: Animals; Brain-Derived Neurotrophic Factor; Calcium-Binding Proteins; Gene Expression Regulation; Male; Microfilament Proteins; Nerve Tissue; Neuralgia; Paroxetine; Rats, Wistar; Receptors, GABA-A; Symporters; K Cl- Cotransporters
PubMed: 32429644
DOI: 10.29252/ibj.24.5.301 -
PloS One 2014Previous meta-analyses of published and unpublished trials indicate that antidepressants provide modest benefits compared to placebo in the treatment of depression; some... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous meta-analyses of published and unpublished trials indicate that antidepressants provide modest benefits compared to placebo in the treatment of depression; some have argued that these benefits are not clinically significant. However, these meta-analyses were based only on trials submitted for the initial FDA approval of the medication and were limited to those aimed at treating depression. Here, for the first time, we assess the efficacy of a selective serotonin reuptake inhibitor (SSRI) in the treatment of both anxiety and depression, using a complete data set of all published and unpublished trials sponsored by the manufacturer.
METHODS AND FINDINGS
GlaxoSmithKline has been required to post the results for all sponsored clinical trials online, providing an opportunity to assess the efficacy of an SSRI (paroxetine) with a complete data set of all trials conducted. We examined the data from all placebo-controlled, double-blind trials of paroxetine that included change scores on the Hamilton Rating Scale for Anxiety (HRSA) and/or the Hamilton Rating Scale for Depression (HRSD). For the treatment of anxiety (k = 12), the efficacy difference between paroxetine and placebo was modest (d = 0.27), and independent of baseline severity of anxiety. Overall change in placebo-treated individuals replicated 79% of the magnitude of paroxetine response. Efficacy was superior for the treatment of panic disorder (d = 0.36) than for generalized anxiety disorder (d = 0.20). Published trials showed significantly larger drug-placebo differences than unpublished trials (d's = 0.32 and 0.17, respectively). In depression trials (k = 27), the benefit of paroxetine over placebo was consistent with previous meta-analyses of antidepressant efficacy (d = 0.32).
CONCLUSIONS
The available empirical evidence indicates that paroxetine provides only a modest advantage over placebo in treatment of anxiety and depression. Treatment implications are discussed.
Topics: Antidepressive Agents, Second-Generation; Anxiety; Anxiety Disorders; Clinical Trials as Topic; Depression; Double-Blind Method; Humans; Panic Disorder; Paroxetine; Placebos; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome
PubMed: 25162656
DOI: 10.1371/journal.pone.0106337 -
The Cochrane Database of Systematic... Jul 2010PTSD is an anxiety disorder related to exposure to a severe psychological trauma. Symptoms include re-experiencing the event, avoidance and arousal as well as distress... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
PTSD is an anxiety disorder related to exposure to a severe psychological trauma. Symptoms include re-experiencing the event, avoidance and arousal as well as distress and impairment resulting from these symptoms.Guidelines suggest a combination of both psychological therapy and pharmacotherapy may enhance treatment response, especially in those with more severe PTSD or in those who have not responded to either intervention alone.
OBJECTIVES
To assess whether the combination of psychological therapy and pharmacotherapy provides a more efficacious treatment for PTSD than either of these interventions delivered separately.
SEARCH STRATEGY
Searches were conducted on the trial registers kept by the CCDAN group (CCDANCTR-Studies and CCDANCTR-References) to June 2010. The reference sections of included studies and several conference abstracts were also scanned.
SELECTION CRITERIA
Patients of any age or gender, with chronic or recent onset PTSD arising from any type of event relevant to the diagnostic criteria were included. A combination of any psychological therapy and pharmacotherapy was included and compared to wait list, placebo, standard treatment or either intervention alone. The primary outcome was change in total PTSD symptom severity. Other outcomes included changes in functioning, depression and anxiety symptoms, suicide attempts, substance use, withdrawal and cost.
DATA COLLECTION AND ANALYSIS
Two or three review authors independently selected trials, assessed their 'risk of bias' and extracted trial and outcome data. We used a fixed-effect model for meta-analysis. The relative risk was used to summarise dichotomous outcomes and the mean difference and standardised mean difference were used to summarise continuous measures.
MAIN RESULTS
Four trials were eligible for inclusion, one of these trials (n =24) was on children and adolescents. All used an SSRI and prolonged exposure or a cognitive behavioural intervention. Two trials compared combination treatment with pharmacological treatment and two compared combination treatment with psychological treatment. Only two trials reported a total PTSD symptom score and these data could not be combined. There was no strong evidence to show if there were differences between the group receiving combined interventions compared to the group receiving psychological therapy (mean difference 2.44, 95% CI -2.87, 7.35 one study, n=65) or pharmacotherapy (mean difference -4.70, 95% CI -10.84 to 1.44; one study, n = 25). Trialists reported no significant differences between combination and single intervention groups in the other two studies. There were very little data reported for other outcomes, and in no case were significant differences reported.
AUTHORS' CONCLUSIONS
There is not enough evidence available to support or refute the effectiveness of combined psychological therapy and pharmacotherapy compared to either of these interventions alone. Further large randomised controlled trials are urgently required.
Topics: Adolescent; Adult; Child; Child Abuse, Sexual; Clonazepam; Cognitive Behavioral Therapy; Combined Modality Therapy; Female; Humans; Male; Paroxetine; Randomized Controlled Trials as Topic; Refugees; Selective Serotonin Reuptake Inhibitors; Sertraline; Stress Disorders, Post-Traumatic
PubMed: 20614457
DOI: 10.1002/14651858.CD007316.pub2 -
Paroxetine and fluoxetine in pregnancy: a prospective, multicentre, controlled, observational study.British Journal of Clinical Pharmacology Nov 2008Recent studies have suggested a possible association between maternal use of selective serotonin reuptake inhibitors (SSRIs) in early pregnancy and cardiovascular... (Comparative Study)
Comparative Study
AIMS
Recent studies have suggested a possible association between maternal use of selective serotonin reuptake inhibitors (SSRIs) in early pregnancy and cardiovascular anomalies. The aim of the present study was to evaluate the teratogenic risk of paroxetine and fluoxetine.
METHODS
This multicentre, prospective, controlled study evaluated the rate of major congenital anomalies after first-trimester gestational exposure to paroxetine, fluoxetine or nonteratogens.
RESULTS
We followed up 410 paroxetine, 314 fluoxetine first-trimester exposed pregnancies and 1467 controls. After exclusion of genetic and cytogenetic anomalies, there was a higher rate of major anomalies in the SSRI groups compared with the controls [paroxetine 18/348 (5.2%), fluoxetine 12/253 (4.7%) and controls 34/1359 (2.5%)]. The main risk applied to cardiovascular anomalies [paroxetine 7/348 (2.0%), crude odds ratio (OR) 3.47, 95% confidence interval (CI) 1.13, 10.58; fluoxetine 7/253 (2.8%), crude OR, 4.81 95% CI 1.56, 14.71; and controls 8/1359 (0.6%)]. On logistic regression analysis only cigarette smoking of >or=10 cigarettes day(-1) and fluoxetine exposure were significant variables for cardiovascular anomalies. The adjusted ORs for paroxetine and fluoxetine were 2.66 (95% CI 0.80, 8.90) and 4.47 (95% CI 1.31, 15.27), respectively.
CONCLUSION
This study suggests a possible association between cardiovascular anomalies and first-trimester exposure to fluoxetine.
Topics: Abnormalities, Drug-Induced; Abortion, Induced; Adult; Antidepressive Agents, Second-Generation; Birth Weight; Case-Control Studies; Confidence Intervals; Drug Administration Schedule; Female; Fluoxetine; Gestational Age; Heart Defects, Congenital; Humans; Infant, Newborn; Maternal Age; Odds Ratio; Paroxetine; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Risk; Selective Serotonin Reuptake Inhibitors
PubMed: 18754846
DOI: 10.1111/j.1365-2125.2008.03261.x -
British Journal of Clinical Pharmacology Apr 2016The aim of this study was to perform an up-to-date meta-analysis on the risk of cardiac malformations associated with gestational exposure to paroxetine, taking into... (Meta-Analysis)
Meta-Analysis Review
AIMS
The aim of this study was to perform an up-to-date meta-analysis on the risk of cardiac malformations associated with gestational exposure to paroxetine, taking into account indication, study design and reference category.
METHOD
A systematic review of studies published between 1966 and November 2015 was conducted using embase and MEDLINE. Studies reporting major malformations with first trimester exposure to paroxetine were included. Potentially relevant articles were assessed and relevant data extracted to calculate risk estimates. Outcomes included any major malformations and major cardiac malformations. Pooled odds ratios and 95% confidence intervals were calculated using random-effects models.
RESULTS
Twenty-three studies were included. Compared with non-exposure to paroxetine, first trimester use of paroxetine was associated with an increased risk of any major congenital malformations combined (pooled OR 1.23, 95% CI 1.10, 1.38; n = 15 studies), major cardiac malformations (pooled OR 1.28, 95% CI 1.11, 1.47; n = 18 studies), specifically bulbus cordis anomalies and anomalies of cardiac septal closure (pooled OR 1.42, 95% CI 1.07, 1.89; n = 8 studies), atrial septal defects (pooled OR 2.38, 95% CI 1.14, 4.97; n = 4 studies) and right ventricular outflow track defect (pooled OR 2.29, 95% CI 1.06, 4.93; n = 4 studies). Although the estimates varied depending on the comparator group, study design and malformation detection period, a trend towards increased risk was observed.
CONCLUSIONS
Paroxetine use during the first trimester of pregnancy is associated with an increased risk of any major congenital malformations and cardiac malformations. The increase in risk is not dependent on the study method or population.
Topics: Abnormalities, Drug-Induced; Female; Heart Defects, Congenital; Humans; Maternal Exposure; Paroxetine; Pregnancy; Pregnancy Trimester, First; Risk Assessment; Selective Serotonin Reuptake Inhibitors
PubMed: 26613360
DOI: 10.1111/bcp.12849 -
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