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British Journal of Clinical Pharmacology Nov 2021The objective of this paper is to systematically review the literature on drug-drug interactions with warfarin, with a focus on patient-important clinical outcomes. (Meta-Analysis)
Meta-Analysis Review
AIMS
The objective of this paper is to systematically review the literature on drug-drug interactions with warfarin, with a focus on patient-important clinical outcomes.
METHODS
MEDLINE, EMBASE and the International Pharmaceutical Abstract (IPA) databases were searched from January 2004 to August 2019. We included studies describing drug-drug interactions between warfarin and other drugs. Screening and data extraction were conducted independently and in duplicate. We synthesized pooled odds ratios (OR) with 95% confidence intervals (CIs), comparing warfarin plus another medication to warfarin alone. We assessed the risk of bias at the study level and evaluated the overall certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
RESULTS
Of 42 013 citations identified, a total of 72 studies reporting on 3 735 775 patients were considered eligible, including 11 randomized clinical trials and 61 observational studies. Increased risk of clinically relevant bleeding when added to warfarin therapy was observed for antiplatelet (AP) regimens (OR = 1.74; 95% CI 1.56-1.94), many antimicrobials (OR = 1.63; 95% CI 1.45-1.83), NSAIDs including COX-2 NSAIDs (OR = 1.83; 95% CI 1.29-2.59), SSRIs (OR = 1.62; 95% CI 1.42-1.85), mirtazapine (OR = 1.75; 95% CI 1.30-2.36), loop diuretics (OR = 1.92; 95% CI 1.29-2.86) among others. We found a protective effect of proton pump inhibitors (PPIs) against warfarin-related gastrointestinal (GI) bleeding (OR = 0.69; 95% CI 0.64-0.73). No significant effect on thromboembolic events or mortality of any drug group used with warfarin was found, including single or dual AP regimens.
CONCLUSIONS
This review found low to moderate certainty evidence supporting the interaction between warfarin and a small group of medications, which result in increased bleeding risk. PPIs are associated with reduced hospitalization for upper GI bleeding for patients taking warfarin. Further studies are required to better understand drug-drug interactions leading to thromboembolic outcomes or death.
Topics: Anticoagulants; Drug Interactions; Gastrointestinal Hemorrhage; Humans; Pharmaceutical Preparations; Randomized Controlled Trials as Topic; Warfarin
PubMed: 33769581
DOI: 10.1111/bcp.14833 -
Progress in Neuro-psychopharmacology &... Jul 2021Gastrointestinal side effects (SEs) are frequently observed in patients with major depressive disorder (MDD) while taking antidepressants and may lead to treatment... (Meta-Analysis)
Meta-Analysis
Gastrointestinal side effects (SEs) are frequently observed in patients with major depressive disorder (MDD) while taking antidepressants and may lead to treatment discontinuation. The aim of this meta-analysis is to provide quantitative measures on short-term rates of gastrointestinal SEs in MDD patients treated with second-generation antidepressants. An electronic search of the literature was conducted by using MEDLINE, ISI Web of Science - Web of Science Core Collection, and Cochrane Library databases. Eligible studies had to focus on the use of at least one of 15 antidepressants commonly used in MDD (i.e., agomelatine, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, mirtazapine, paroxetine, reboxetine, sertraline, venlafaxine, and vortioxetine) and report data on treatment-emergent gastrointestinal SEs (i.e. nausea/vomiting, diarrhoea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite and dry mouth) within 12 weeks of treatment. Overall, 304 studies were included in the meta-analyses. All the considered antidepressants showed higher rates of gastrointestinal SEs than placebo. Escitalopram and sertraline were shown to be the least tolerated antidepressants on the gastrointestinal tract, being associated with all the considered SEs with the exception of constipation and increased appetite, while mirtazapine was shown to be the antidepressant with fewer side effects on the gut, being only associated with increased appetite. In conclusion, commonly used antidepressants showed different profiles of gastrointestinal SEs, possibly related to their mechanisms of action. The specific tolerability profile of each compound should be considered by clinicians when prescribing antidepressants in order to improve adherence to treatment and increase positive outcomes in patients with MDD.
Topics: Antidepressive Agents; Constipation; Depressive Disorder, Major; Diarrhea; Humans; Nausea; Vomiting
PubMed: 33549697
DOI: 10.1016/j.pnpbp.2021.110266 -
Focus (American Psychiatric Publishing) Apr 2020(Reprinted with permission from . 2019 Jul;6(7):601-609).
(Reprinted with permission from . 2019 Jul;6(7):601-609).
PubMed: 33343239
DOI: 10.1176/appi.focus.18204 -
JAMA Psychiatry Mar 2021Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization.
OBJECTIVE
To quantify the difference in the antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers.
DATA SOURCES
PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to June 30, 2020, with no language restrictions.
STUDY SELECTION
Two independent reviewers performed study screening and assessed the following inclusion criteria: (1) appropriate CYP2C19 or CYP2D6 genotyping was performed, (2) genotype-based classification into CYP2C19 or CYP2D6 NM, IM, and PM categories was possible, and (3) 3 patients per metabolizer category were available.
DATA EXTRACTION AND SYNTHESIS
The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and quality, validity, and risk of bias assessments. A fixed-effects model was used for pooling the effect sizes of the included studies.
MAIN OUTCOMES AND MEASURES
Drug exposure was measured as (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady-state plasma level, or (3) reciprocal apparent total drug clearance. The ratio of means (RoM) was calculated by dividing the mean drug exposure for PM, IM, or pooled PM plus IM categories by the mean drug exposure for the NM category.
RESULTS
Based on the data derived from 94 unique studies and 8379 unique individuals, the most profound differences were observed in the patients treated with aripiprazole (CYP2D6 PM plus IM vs NM RoM, 1.48; 95% CI, 1.41-1.57; 12 studies; 1038 patients), haloperidol lactate (CYP2D6 PM vs NM RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; 423 patients), risperidone (CYP2D6 PM plus IM vs NM RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; 1492 patients), escitalopram oxalate (CYP2C19 PM vs NM, RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; 1262 patients), and sertraline hydrochloride (CYP2C19 IM vs NM RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; 917 patients). Exposure differences were also observed for clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride; however, these differences were marginal, ambiguous, or based on less than 3 independent studies.
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations.
Topics: Antidepressive Agents; Antipsychotic Agents; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Humans; Pharmacogenomic Variants
PubMed: 33237321
DOI: 10.1001/jamapsychiatry.2020.3643 -
ESC Heart Failure Dec 2020The aim of this study is to investigate the effect of antidepressant therapy on mortality and cardiovascular outcomes in patients with acute coronary syndrome (ACS).
AIMS
The aim of this study is to investigate the effect of antidepressant therapy on mortality and cardiovascular outcomes in patients with acute coronary syndrome (ACS).
METHODS AND RESULTS
We systematically searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials and performed a Bayesian random-effects meta-analysis of randomized controlled trials that investigated antidepressant pharmacotherapy in patients following ACS. The primary outcome was all-cause mortality. Secondary outcomes were repeat hospitalizations and recurrent myocardial infarctions (MIs). Ten randomized controlled trials with a total of 1935 patients qualified for inclusion. Selective serotonin reuptake inhibitors were investigated in six, bupropion in three, and mirtazapine in one trial. Placebo was used as control in eight trials. There was no difference in all-cause mortality [odds ratio (OR) 0.97, 95% credible interval (CrI) 0.66-1.42] and recurrent MI (OR 0.64, 95% CrI 0.40-1.02) between patients receiving antidepressants compared with controls, whereas antidepressant therapy was associated with less repeat hospitalizations (OR 0.62, 95% CrI 0.40-0.94). In patients with ACS and concomitant depression, antidepressants reduced the odds of recurrent MI compared with usual care/placebo (OR 0.45, 95% CrI 0.25-0.81). Extended funnel plots suggest robustness of the observations.
CONCLUSIONS
Antidepressants in patients following ACS have no effect on mortality but reduce repeat hospitalizations; in patients with depression, there is a reduced risk of recurrent MI with antidepressant therapy.
PubMed: 32935927
DOI: 10.1002/ehf2.12861 -
CNS Drugs Apr 2020Stimulant drugs are second only to cannabis as the most widely used class of illicit drug globally, accounting for 68 million past-year consumers. Dependence on... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Stimulant drugs are second only to cannabis as the most widely used class of illicit drug globally, accounting for 68 million past-year consumers. Dependence on amphetamines (AMPH) or methamphetamine (MA) is a growing global concern. Yet, there is no established pharmacotherapy for AMPH/MA dependence. A comprehensive assessment of the research literature on pharmacotherapy for AMPH/MA dependence may inform treatment guidelines and future research directions.
METHODS
We systematically reviewed the peer-reviewed literature via the electronic databases PubMed, EMBASE, CINAHL and SCOPUS for randomised controlled trials reported in the English language examining a pharmacological treatment for AMPH/MA dependence or use disorder. We included all studies published to 19 June 2019. The selected studies were evaluated for design; methodology; inclusion and exclusion criteria; sample size; pharmacological and (if included) psychosocial interventions; length of follow-up and follow-up schedules; outcome variables and measures; results; overall conclusions and risk of bias. Outcome measures were any reported impact of treatment related to AMPH/MA use.
RESULTS
Our search returned 43 studies that met our criteria, collectively enrolling 4065 participants and reporting on 23 individual pharmacotherapies, alone or in combination. Disparate outcomes and measures (n = 55 for the primary outcomes) across studies did not allow for meta-analyses. Some studies demonstrated mixed or weak positive signals (often in defined populations, e.g. men who have sex with men), with some variation in efficacy signals dependent on baseline frequency of AMPH/MA use. The most consistent positive findings have been demonstrated with stimulant agonist treatment (dexamphetamine and methylphenidate), naltrexone and topiramate. Less consistent benefits have been shown with the antidepressants bupropion and mirtazapine, the glutamatergic agent riluzole and the corticotropin releasing factor (CRF-1) antagonist pexacerfont; whilst in general, antidepressant medications (e.g. selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs]) have not been effective in reducing AMPH/MA use.
CONCLUSIONS
No pharmacotherapy yielded convincing results for the treatment of AMPH/MA dependence; mostly studies were underpowered and had low treatment completion rates. However, there were positive signals from several agents that warrant further investigation in larger scale studies; agonist therapies show promise. Common outcome measures should include change in use days. Future research must address the heterogeneity of AMPH/MA dependence (e.g. coexisting conditions, severity of disorder, differences between MA and AMPH dependence) and the role of psychosocial intervention.
Topics: Amphetamine; Amphetamine-Related Disorders; Animals; Central Nervous System Stimulants; Humans; Methamphetamine; Substance-Related Disorders
PubMed: 32185696
DOI: 10.1007/s40263-020-00711-x -
Journal of Affective Disorders Apr 2020The efficacy ranking of antidepressants for post-stroke depression (PSD) has not been assessed thoroughly yet due to the lack of network meta-analyses with sufficiently... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The efficacy ranking of antidepressants for post-stroke depression (PSD) has not been assessed thoroughly yet due to the lack of network meta-analyses with sufficiently large sample size.
METHODS
Seven databases including PubMed, Embase, CENTRAL, CBM, CNKI, WanFang and VIP were systematically searched for eligible randomized controlled trials (RCTs) regarding nine antidepressants (citalopram, escitalopram, venlafaxine, paroxetine, duloxetine, amitriptyline, doxepin, sertraline and mirtazapine) treating PSD patients. Stata 15 software and R software were utilized for statistical analyses.
RESULTS
51 RCTs were included in this NMA. For the key efficacy outcomes, escitalopram, mirtazapine, sertraline, citalopram, venlafaxine and paroxetine were associated with larger reduction of the Hamilton Depression Scale (HAMD) total score compared with placebo at 2 weeks. Among the nine antidepressants, escitalopram ranked the best while amitriptyline was the least helpful. At 4 weeks, citalopram ranked higher than placebo and the other eight antidepressants. In contrast, amitriptyline and doxepin were associated with minimal reduction of HAMD score. At 8 weeks, changes in HAMD score were significantly greater in nine antidepressants groups compared to placebo group. Besides, mirtazapine ranked higher than citalopram and escitalopram. At endpoint, mirtazapine was related to the highest response rate, followed by venlafaxine and escitalopram, respectively.
LIMITATIONS
No restriction was imposed on doses of every antidepressant.
CONCLUSIONS
Escitalopram was associated with a quicker relief of depression, but mirtazapine was probably the best option when it comes to the efficacy of 8-week treatment duration. Amitriptyline and doxepin were nearly the worst choice regardless of the duration (2, 4 or 8 weeks).
Topics: Antidepressive Agents; China; Citalopram; Depression; Depressive Disorder, Major; Humans; Network Meta-Analysis; Selective Serotonin Reuptake Inhibitors; Stroke; Treatment Outcome
PubMed: 32056924
DOI: 10.1016/j.jad.2020.02.005 -
American Family Physician Feb 2020
Topics: Aged; Bupropion; Depressive Disorder, Major; Female; Humans; Male; Mirtazapine; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors
PubMed: 32003957
DOI: No ID Found -
Acta Psychiatrica Scandinavica May 2020In fixed-dose antidepressant trials, the lower range of the licensed dose achieves the optimal balance between efficacy and tolerability. Whether flexible upward...
BACKGROUND
In fixed-dose antidepressant trials, the lower range of the licensed dose achieves the optimal balance between efficacy and tolerability. Whether flexible upward titration while side-effects permit provides additional benefits is unknown.
METHODS
We did a systematic review of placebo-controlled randomized trials that examined selective serotonin reuptake inhibitors (SSRIs), venlafaxine or mirtazapine in the acute treatment of major depression. Our primary outcome was response, defined as 50% or greater reduction in depression severity. Secondary outcomes included drop-outs due to adverse effects and drop-outs for any reason. We conducted random-effects meta-analyses to calculate the ratios of odds ratios (RORs) between trials comparing the flexible dose titrating above the minimum licensed dose against placebo and those comparing the fixed minimum licensed dose against placebo.
RESULTS
We included 123 published and unpublished randomized controlled trials (29 420 participants). There was no evidence supporting efficacy of the flexible dosing over the fixed low dose of SSRIs (ROR 0.96, 95% CI: 0.73 to 1.25), venlafaxine (1.24, 0.96 to 1.60) or mirtazapine (0.77, 0.33 to 1.78). No important differences were noted for tolerability or for any subgroup analyses except the superior efficacy of venlafaxine flexible dosing between 75 and 150 mg over the fixed 75 mg (1.30, 1.02 to 1.65).
CONCLUSION
There was no evidence to support added value in terms of efficacy, tolerability or acceptability of flexibly titrating up the dosage over the minimum licensed dose of SSRIs or mirtazapine. For venlafaxine, increased efficacy can be expected by flexibly titrating up to 150 mg.
Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Mirtazapine; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Venlafaxine Hydrochloride
PubMed: 31891415
DOI: 10.1111/acps.13145 -
What is the evidence for mirtazapine in treating cancer-related symptomatology? A systematic review.Supportive Care in Cancer : Official... Apr 2020Cancer patients often experience multiple distressing symptoms which are challenging to manage. It would therefore be helpful to find a treatment that alleviates more... (Review)
Review
PURPOSE
Cancer patients often experience multiple distressing symptoms which are challenging to manage. It would therefore be helpful to find a treatment that alleviates more than one symptom, to avoid polypharmacy: mirtazapine has been used in several studies for this purpose. The objective of this study was to assess the effectiveness and safety of mirtazapine in alleviating one or more frequently encountered cancer-related symptoms.
METHODS
Systematic review of clinical trials in English or French. Eight databases were searched. Included studies assessed the effectiveness of mirtazapine in alleviating one or more frequently encountered cancer-related symptoms. Comparator and validated assessment tools were required. Studies were independently appraised by two investigators before data synthesis.
RESULTS
The search yielded 1898 references, from which we identified 12 relevant articles evaluating highly heterogeneous outcomes. These were two randomised-controlled (RCTs), three non-randomised controlled, and seven non-randomised non-controlled trials. In total, 392 participants were included and 185 were in RCTs. No study assessed the effectiveness of mirtazapine in alleviating symptoms at the same time, but some considered more than one symptom. Overall, the data was of poor quality, limited by small sample size and bias. However, mirtazapine showed effectiveness in treating depression, anxiety, sleep disorders, emesis and neuropathic pain. Across all studies, mirtazapine is safe to use, with drowsiness and dizziness the most common side-effects.
CONCLUSION
Study design and small sample sizes limit the ability to interpret results. Trials to assess the impact of mirtazapine or other medicines in alleviating multiple symptoms would be valuable.
Topics: Adrenergic alpha-2 Receptor Antagonists; Antidepressive Agents; Clinical Trials as Topic; Depression; Humans; Mirtazapine; Neoplasms; Palliative Care; Randomized Controlled Trials as Topic
PubMed: 31858251
DOI: 10.1007/s00520-019-05229-7