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The Lancet. Psychiatry Jul 2024Antidepressant discontinuation symptoms are becoming an increasingly important part of clinical practice, but the incidence of antidepressant discontinuation symptoms... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antidepressant discontinuation symptoms are becoming an increasingly important part of clinical practice, but the incidence of antidepressant discontinuation symptoms has not been quantified. An estimate of antidepressant discontinuation symptoms incidence could inform patients and clinicians in the discontinuation of treatment, and provide useful information to researchers in antidepressant treatments. We aimed to assess the incidence of antidepressant discontinuation symptoms in patients discontinuing both antidepressants and placebo in the published literature.
METHODS
We systematically searched Medline, EMBASE, and CENTRAL from database inception until Oct 13, 2022 for randomised controlled trials (RCTs), other controlled trials, and observational studies assessing the incidence of antidepressant discontinuation symptoms. To be included, studies must have investigated cessation or tapering of an established antidepressant drug (excluding antipsychotics, lithium, or thyroxine) or placebo in participants with any mental, behavioural, or neurodevelopmental disorder. We excluded studies in neonates, and those using antidepressants for physical conditions such as pain syndromes due to organic disease. After study selection, summary data extraction, and risk of bias evaluation, data were pooled in random-effects meta-analyses. The main outcome was the incidence of antidepressant discontinuation symptoms after discontinuation of antidepressants or placebo. We also analysed the incidence of severe discontinuation symptoms. Sensitivity and meta-regression analyses tested a selection of methodological variables.
FINDINGS
From 6095 articles screened, 79 studies (44 RCTs and 35 observational studies) covering 21 002 patients were selected (72% female, 28% male, mean age 45 years [range 19·6-64·5]). Data on ethnicity were not consistently reported. 16 532 patients discontinued from an antidepressant, and 4470 patients discontinued from placebo. Incidence of at least one antidepressant discontinuation symptom was 0·31 (95% CI 0·27-0·35) in 62 study groups after discontinuation of antidepressants, and 0·17 (0·14-0·21) in 22 study groups after discontinuation of placebo. Between antidepressant and placebo groups of included RCTs, the summary difference in incidence was 0·08 [0·04-0·12]. The incidence of severe antidepressant discontinuation symptoms after discontinuation of an antidepressant was 0·028 (0·014-0·057) compared with 0·006 (0·002-0·013) after discontinuation of placebo. Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequencies of discontinuation symptoms, and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms. Heterogeneity of results was substantial.
INTERPRETATION
Considering non-specific effects, as evidenced in placebo groups, the incidence of antidepressant discontinuation symptoms is approximately 15%, affecting one in six to seven patients who discontinue their medication. Subgroup analyses and heterogeneity figures point to factors not accounted for by diagnosis, medication, or trial-related characteristics, and might indicate subjective factors on the part of investigators, patients, or both. Residual or re-emerging psychopathology needs to be considered when interpreting the results, but our findings can inform clinicians and patients about the probable extent of antidepressant discontinuation symptoms without causing undue alarm.
FUNDING
None.
Topics: Humans; Antidepressive Agents; Incidence; Substance Withdrawal Syndrome; Randomized Controlled Trials as Topic
PubMed: 38851198
DOI: 10.1016/S2215-0366(24)00133-0 -
Basic & Clinical Pharmacology &... Nov 2023Monoamine transporters are of great interest for their role in the physiological activity of the body and their link to mental and behavioural disorders. Currently,...
Monoamine transporters are of great interest for their role in the physiological activity of the body and their link to mental and behavioural disorders. Currently, static well-plate assays or manual perfusion systems are used to characterize the interaction of psychostimulants, antidepressants and drugs of abuse with the transporters but still suffer from significant drawbacks caused by lack of automation, for example, low reproducibility, non-comparability of results. An automated microfluidic platform was developed to address the need for more standardized procedures for cell-based assays. An automated system was used to control and drive the simultaneous perfusion of 12 channels on a microfluidic chip, establishing a more standardized protocol to perform release assays to study monoamine transporter-mediated substrate efflux. D-Amphetamine, GBR12909 (norepinephrine transporter) and p-chloroamphetamine, paroxetine (serotonin transporter) were used as control compounds to validate the system. The platform was able to produce the expected releasing (D-Amphetamine, p-chloroamphetamine) or inhibiting (GBR12909, paroxetine) profiles for the two transporters. The reduction of manual operation and introduction of automated flow control enabled the implementation of stronger standardized protocols and the possibility of obtaining higher throughput by increasing parallelization.
Topics: Microfluidics; p-Chloroamphetamine; Paroxetine; Reproducibility of Results; Membrane Transport Proteins; Perfusion; Dextroamphetamine
PubMed: 37658634
DOI: 10.1111/bcpt.13940 -
Globalization and Health Sep 2023This paper examines the events and conditions that led to the creation of the International Clinical Trials Registry Platform (ICTRP) in 2006 by the World Health...
BACKGROUND
This paper examines the events and conditions that led to the creation of the International Clinical Trials Registry Platform (ICTRP) in 2006 by the World Health Organization (WHO), and how the WHO addressed the issue of transparency in global pharmaceutical research. Using historical textual analysis, I trace the scientific debates that advocated for the establishment of official clinical trial registries in medical journals, and the sequence of actions following the GSK Paxil scandal in 2004, identifying the major ethical and scientific arguments that led to the involvement of the WHO as a key actor in trial registration in the context of the Big Pharma business model.
RESULTS
Through the questions "Why register?" and "Why registries?" as a roadmap, I examine the issues of publication bias and selective reporting by the industry, scrutinizing two ways in which the practice of publication bias damaged transparency in industry-sponsored research. The first involved ethical concerns regarding human subject exploitation and concealing of negative results. The second addresses the deterioration of the certainty of evidence due to incomplete access to trials results. By reviewing the series of events that occurred between 2004 and 2006 -between the Paxil scandal and the launch of the ICTRP-, I analyze the actions taken by the different actors involved: (1) the International Committee of Medical Journal Editors (ICMJE) and the creation of the Ottawa Group; (2) the WHO, beginning with the Ministerial Summit on Health Research held in November of 2004, and (3) the responses of the pharmaceutical industry and specifically GSK to the call for transparency and trial registration.
CONCLUSIONS
The history of trial registration through the ICTRP as a dataveillance apparatus shows the difficulty of regulating a health enterprise turned into a global business. Moreover, it shows the challenges of globalization and how easier and faster it is to globalize business compared to good practices, raising the question of why it has been so hard to undo these trends. Indeed, the history of the movement for trial registration is not a history of regulation success, or at least not yet.
Topics: Humans; Commerce; Drug Industry; Paroxetine; Registries; World Health Organization; Clinical Trials as Topic
PubMed: 37723473
DOI: 10.1186/s12992-023-00970-5 -
Drugs associated with a risk of supraventricular tachycardia: analysis using the OpenVigil database.The Journal of International Medical... Mar 2024The OpenVigil database can be used to assess medications that may cause supraventricular tachycardia (SVT) and to produce a reference for their safe use in clinical...
OBJECTIVE
The OpenVigil database can be used to assess medications that may cause supraventricular tachycardia (SVT) and to produce a reference for their safe use in clinical settings.
METHODS
We analyzed first-quarter data from 2004 to 2023, obtained by searching the OpenVigil database using the keyword "supraventricular tachycardia." Trade names and generic names were obtained by querying the RxNav database, and the proportions were summarized. The proportionate reporting ratio (PRR), reporting odds ratio, and chi-square values were also summarized. We created Asahi diagrams and set the screening criteria to drug events ≥30, PRR >2, and chi-square >4. Outcomes were evaluated using the Side Effect Resource database, several scientific literature databases, and the Hangzhou Yiyao Rational Medication System.
RESULTS
A total of 2435 distinct medications were found to induce SVT between the first quarter of 2004 and 2023, leading to 22,375 documented adverse events related to SVT. Further investigation revealed that salbutamol, paroxetine, formoterol, paclitaxel, venlafaxine, and theophylline were most likely to cause SVT.
CONCLUSION
We conducted signal mining of adverse drug events using the OpenVigil database and evaluated the six drugs most likely to cause SVT. The results of this research can serve as a drug safety reference in the clinic.
Topics: Humans; Tachycardia, Supraventricular; Albuterol; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Formoterol Fumarate
PubMed: 38530149
DOI: 10.1177/03000605241238077 -
Journal of Clinical Medicine Jan 2024: Histamine intolerance manifests when there is an imbalance between the production of histamine and the body's capacity to metabolise it. Within the gastrointestinal...
Exploring the Relationship between Diamine Oxidase and Psychotropic Medications in Fibromyalgia Treatment, Finding No Reduction in Diamine Oxidase Levels and Activity except with Citalopram.
: Histamine intolerance manifests when there is an imbalance between the production of histamine and the body's capacity to metabolise it. Within the gastrointestinal tract, diamine oxidase (DAO) plays a pivotal role in breaking down ingested histamine. Insufficient levels of DAO have been linked to various diseases affecting the respiratory, cardiovascular, nervous, muscular, and digestive systems; some of these symptoms are evidenced in fibromyalgia syndrome. This underscores the crucial role of DAO in maintaining the histamine balance and highlights its association with diverse physiological systems and health conditions. The management of fibromyalgia commonly involves the use of psychotropic medications; however, their potential interactions with DAO remain not fully elucidated. : This study delved into the influence of various psychotropic medications on DAO activity through experiments. Additionally, we explored their impact on the human intestinal cell line Caco-2, examining alterations in DAO expression at both the mRNA and protein levels along with DAO activity. : Notably, the examined drugs-sertraline, pregabalin, paroxetine, alprazolam, and lorazepam-did not exhibit inhibitory effects on DAO activity or lead to reductions in DAO levels. In contrast, citalopram demonstrated a decrease in DAO activity in assays without influencing DAO levels and activity in human enterocytes. : These findings imply that a collaborative approach involving psychotropic medications and DAO enzyme supplementation for individuals with fibromyalgia and a DAO deficiency could offer potential benefits for healthcare professionals in their routine clinical practice.
PubMed: 38337486
DOI: 10.3390/jcm13030792 -
Drug Metabolism and Disposition: the... Oct 2023Atomoxetine is a cytochrome P450 (P450) 2D6 probe substrate and an approved medicine for attention-deficit/hyperactivity disorder. In this humanized-liver mouse study,...
Atomoxetine is a cytochrome P450 (P450) 2D6 probe substrate and an approved medicine for attention-deficit/hyperactivity disorder. In this humanized-liver mouse study, interactions between atomoxetine and the P450 2D6 probe drug paroxetine were observed. Human physiologically based pharmacokinetic (PBPK) models were established by scaling up humanized-liver mouse data obtained in the absence or presence of paroxetine. These models could explain the drug monitoring results of atomoxetine and its primary 4-hydroxylated and -demethylated metabolites in Japanese children aged 8-14 years and could be used to help establish the correct dosage and for the evaluation of clinical outcomes. The results of simple PBPK models (using input parameters that reflected the subjects' small body size and normal or reduced P450 2D6-dependent clearance) were in general agreement with one-point measured plasma concentrations of atomoxetine and its 4-hydroxylated and -demethylated metabolites in 13 pediatric participants. Unexpectedly high hepatic exposure, possibly in intermediate-metabolizer patients harboring or alleles might in part explain the adverse effects of atomoxetine prescribed alone recorded in a Japanese adverse-event database. The steady-state, one-point drug monitoring data from the participants indicated extensive biotransformation of atomoxetine to 4-hydroxyatomoxetine under individually prescribed doses of atomoxetine. These results also suggest that a relatively narrow range of 4-hydroxyatomoxetine and -desmethylatomoxetine concentration ratios in spot urine and/or plasma samples from pediatric patients could be a simple semiquantitative determinant factor for P450 2D6 intermediate metabolizers, compared with the wide range of concentrations of the two primary metabolites and substrate in extensive metabolizers. Validated simple pharmacokinetic models are able to predict steady-state plasma concentrations of the approved medicine atomoxetine and its primary metabolites in the majority of pediatric patients. The package insert advises careful dose escalation, especially for poor metabolizers; however, no simple way exists to determine P450 2D6 phenotypes. A relatively narrow range ratio of 4-hydroxyatomoxetine and -desmethylatomoxetine in spot urine/plasma samples could be a simple semi-quantitative determinant factor for P450 2D6 intermediate metabolizers to optimize or confirm the correct dosage.
PubMed: 37879849
DOI: 10.1124/dmd.123.001481 -
Biological & Pharmaceutical Bulletin 2024Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such...
Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such as antidepressants, hypnotics, and anxiolytics. If these drugs also inhibit acetylcholinesterase (AChE) activity, they may contribute to the suppression of AD progression by increasing brain acetylcholine concentrations. We tested the potential inhibitory effects of 31 antidepressants, 21 hypnotics, and 12 anxiolytics on recombinant human AChE (rhAChE) activity. At a concentration of 10 M, 22 antidepressants, 19 hypnotics, and 11 anxiolytics inhibited rhAChE activity by <20%, whereas nine antidepressants (clomipramine, amoxapine, setiptiline, nefazodone, paroxetine, sertraline, citalopram, escitalopram, and mirtazapine), two hypnotics (triazolam and brotizolam), and one anxiolytic (buspirone) inhibited rhAChE activity by ≥20%. Brotizolam (≥10 M) exhibited stronger inhibition of rhAChE activity than the other drugs, with its pIC value being 4.57 ± 0.02. The pIC values of the other drugs were <4, and they showed inhibitory activities toward rhAChE at the following concentrations: ≥3 × 10 M (sertraline and buspirone), ≥10 M (amoxapine, nefazodone, paroxetine, citalopram, escitalopram, mirtazapine, and triazolam), and ≥3 × 10 M (clomipramine and setiptiline). Among these drugs, only nefazodone inhibited rhAChE activity within the blood concentration range achievable at clinical doses. Therefore, nefazodone may not only improve the depressive symptoms of BPSD through its antidepressant actions but also slow the progression of cognitive symptoms of AD through its AChE inhibitory actions.
Topics: Humans; Anti-Anxiety Agents; Acetylcholinesterase; Hypnotics and Sedatives; Sertraline; Clomipramine; Mirtazapine; Paroxetine; Citalopram; Escitalopram; Amoxapine; Buspirone; Triazolam; Antidepressive Agents
PubMed: 38296462
DOI: 10.1248/bpb.b23-00719 -
Pharmaceutics Nov 2023The successful integration of hot-melt extrusion (HME) and fused deposition modelling (FDM) depends on a better understanding of the impact of environmental conditions...
The successful integration of hot-melt extrusion (HME) and fused deposition modelling (FDM) depends on a better understanding of the impact of environmental conditions on the printability of formulations, since they significantly affect the properties of the raw materials, whose control is crucial to enable three-dimensional printing (3DP). Hence, the objective of this work was to investigate the correlation between the environmental settings and the properties of paroxetine (PRX)-loaded filaments, previously produced by HME, which affect printability by FDM. The influence of different drying methods of the physical mixtures (PMs) and HME-filaments (FILs) on the quality and printability of these products was also assessed. The printability of FILs was evaluated in terms of the water content, and the mechanical and thermal properties of the products. Stability studies and physicochemical, thermal, and in vitro dissolution tests were carried out on the 3D-printed tablets. Stability studies demonstrated the high ductility of the PRX loaded FILs, especially under high humidity conditions. Under low humidity storage conditions (11% RH), the FILs became stiffer and were successfully used to feed the FDM printer. Water removal was slow when carried out passively in a controlled atmosphere (desiccator) or accelerated by using active drying methods (heat or microwave). Pre-drying of the PRX/excipients and/or PMs did not show any positive effect on the printability of the FIL. On the contrary, dry heat and, preferably, microwave mediated drying processes were shown to reduce the holding time required for successful FDM printing, enabling on-demand production at the point of care.
PubMed: 38004614
DOI: 10.3390/pharmaceutics15112636 -
The Science of the Total Environment Nov 2023Paroxetine (PAR) is a selective serotonin reuptake inhibitor (SSRI) antidepressant increasingly detected in surface waters worldwide. Its environmental presence raises...
Paroxetine (PAR) is a selective serotonin reuptake inhibitor (SSRI) antidepressant increasingly detected in surface waters worldwide. Its environmental presence raises concerns about the potential detrimental effects on non-target organisms. Thus, this study aimed to increase knowledge on PAR's potential environmental impacts, assessing the effects of commercial formulation (PAR-c) and active ingredient (PAR-a) on fish. Therefore, the short-term exposure effects of PAR-c and PAR-a were assessed on zebrafish (Danio rerio) embryos/larvae to determine the most toxic formulation [through median lethal (LC) and effective concentrations (EC)]. PAR-c and PAR-a induced morphological abnormalities (scoliosis) in a dose-dependent manner from 96 hours post-fertilization onwards, suggesting the involvement of a fully functional biotransformation system. As PAR-c exhibited higher toxicity, it was selected to be tested in the subsequent stage (juvenile stage), which was more sensitive (lower LC). PAR-c significantly decreased fish swimming activity and disrupted fish stress response. Overall, the results highlight the ability of PAR-c to adversely affect fish swimming performance, an effect that persisted even after exposure ceases (21-day depuration), suggesting that PAR-c may impair individual fitness.
Topics: Animals; Zebrafish; Paroxetine; Embryo, Nonmammalian; Selective Serotonin Reuptake Inhibitors; Lethal Dose 50; Larva; Water Pollutants, Chemical
PubMed: 37499832
DOI: 10.1016/j.scitotenv.2023.165706 -
Journal of Affective Disorders Jun 2024Preclinical studies suggested that drugs that functionally inhibit acid sphingomyelinase (FIASMA)may enhance immune cell longevity and potentially offer protection... (Observational Study)
Observational Study
BACKGROUND
Preclinical studies suggested that drugs that functionally inhibit acid sphingomyelinase (FIASMA)may enhance immune cell longevity and potentially offer protection against infections. Many antidepressants have shown FIASMA activity.
METHODS
We conducted a cohort study using primary-care data from the UK-based Clinical Practice Research Datalink (2000-2021). We assessed the association of composite diagnosed acute infections in new users of fluoxetine, sertraline, paroxetine, or venlafaxine aged 18-80 years compared to citalopram. We compared SARS-CoV-2 infections between groups in a secondary analysis. We estimated incidence rates (IR) and IR ratios (IRR) of acute infections in four pairwise comparisons using negative binomial regression. We applied propensity score (PS) fine stratification to control for confounding.
RESULTS
In the PS-weighted cohorts, we included 353,138 fluoxetine, 222,463 sertraline, 69,963 paroxetine, 32,608 venlafaxine, and between 515,996 and 516,583 new citalopram users. PS-weighted IRs ranged between 76.8 acute infections /1000 person-years (py) (sertraline) and 98.9 infections/1000 py (citalopram). We observed PS-weighted IRRs around unity for paroxetine (0.97, 95 % CI, 0.95-1.00), fluoxetine (0.94, 95 % CI, 0.92-0.95), and venlafaxine (0.90, 95 % CI, 0.87-0.94) vs citalopram. Reduced IRR for sertraline vs citalopram (0.84, 95 % CI, 0.82-0.85), became null within subgroups by cohort entry date. In the analysis of SARS-CoV-2 infection, no statistically relevant risk reduction was seen.
LIMITATIONS
Analysis not limited to patients with diagnosed depression, possible underestimation of infection incidence, and unclear FIASMA activity of citalopram.
CONCLUSIONS
Fluoxetine, sertraline, paroxetine, and venlafaxine were not associated with a reduced risk of acute infection when compared with the presumably weak FIASMA citalopram.
Topics: Humans; Sertraline; Paroxetine; Fluoxetine; Citalopram; Selective Serotonin Reuptake Inhibitors; Venlafaxine Hydrochloride; Cohort Studies; Antidepressive Agents
PubMed: 38479501
DOI: 10.1016/j.jad.2024.03.002