Norepinephrine Reuptake Inhibitor Research Articles

PSUN28 Factors Associated with False-positive Fractionated Metanephrines in Plasma and Urine

Abstract Context Plasma and 24-hr urine metanephrine (M) and normetanephrine (NM) are the standard of care tests used in the biochemical diagnosis of pheochromocytoma and paraganglioma (PPGL). Considering the rarity of PPGL, false positive (FP) results represent a challenge because they lead to additional investigations, healthcare burden, and uncertainty for the patient. The impact of medications on the rate of FP results is not fully established. Objective We aimed to identify the medications associated with the FP rate of 24-hr urine and plasma M and NM measured by the HPLC-MS/MS method. Methods We conducted a single-center study of patients who had 24-hour urine or plasma M and NM testing between 09/27/2015 and 02/15/2021, and who had a follow-up of at least 6 months. Results were considered FP if M/NM were > upper limit of the normal ranges (ULN) and there was absence of PPGL. Results were considered true negative (TN) when M/NM were within the reference ranges in patients without PPGL. Age- and sex-adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression models. Results Plasma M/NM testing was performed in 3152 patients and 24-hr urine M/NM was performed in 2008 patients. The FP rate for the M fraction (plasma: 0.8%, urine: 1.3%) was much lower than the FP rate for NM (plasma: 16%, urine: 4.4%); thus, the impact of medications on FP rate was examined only for NM. In those with FP NM, the median degrees of elevation were 24% (IQR 10-46) >ULN in plasma and 26% (IQR 11-45) >ULN in urine. When compared to patients with TN results, patients with FP plasma NM were more likely to be treated with opioids (OR=1.29, 95%CI, 1.04-1.60), tricyclic antidepressants (OR=1.61, 95%CI,1.14-2.27), serotonin–norepinephrine reuptake inhibitors (OR=1.85, 95%CI, 1.35-2.53), second generation antipsychotics (OR=2.32, 95%CI, 1.28-4.20), but not first generation antipsychotics (OR=1.23, 95% CI, 0.86-1.75) when compared to the TN group. When compared to patients with TN results, patients with FP urine NM were more likely to be treated with opioids (OR=1.96 95%CI, 1.26-3.06), tricyclic antidepressants (OR=2.61, 95%CI, 1.47-4.65), serotonin–norepinephrine reuptake inhibitors (OR=2.20, 95%CI, 1.20-4.02), and both first (OR=3.06, 95%CI, 1.74-5.38) and second generation antipsychotics (OR=2.51, 95%CI, 1.03-6.13). Conclusion The plasma NM FP rate was 16% and 3-fold higher than the same measurement in urine (4.4%). Several classes of medications had a significant impact on the rate of FP NM. Clinicians should consider use of 24-hr urine M and NM in low suspicion cases of PPGL where the diagnosis simply needs to be excluded. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Integrated Module of Multidimensional Omics for Peripheral Biomarkers (iMORE) in patients with major depressive disorder: rationale and design of a prospective multicentre cohort study

IntroductionMajor depressive disorder (MDD) represents a worldwide burden on healthcare and the response to antidepressants remains limited. Systems biology approaches have been used to explore the precision therapy. However, no...

The effect of selective serotonin and norepinephrine reuptake inhibitors on clinical outcome of COVID-19 patients: A systematic review and meta-analysis.

Background and AimDue to the high social and economic burden and also mortality and morbidity caused by coronavirus disease 2019 (COVID‐19) in the past few years, researchers have aimed at finding solutions to suppressing the severity of infection. Recently, selective serotonin and serotonin‐norepinephrine reuptake inhibitors (SSRI/SNRI) have been investigated as an adjuvant treatment for COVID‐19. The aim of the current study was to investigate the impact of SSRI/SNRIs on outcomes of COVID‐19 patients.MethodsIn this systematic review and meta‐analysis, a comprehensive search strategy consisting of relevant words was performed by two researchers in PubMed, Scopus and EMBASE libraries. Studies reporting the effect of SSRI and/or SNRI use in COVID‐19 patients' outcome were included. Hospitalization, mortality, hospitalization event, and length of hospital stay were considered as main outcomes of this study. Analysis was carried out using Comprehensive Meta‐Analysis (CMA‐version 2) and final data were reported as odds ratio (OR) and 95% confidence interval (CI).ResultsOur search led to the final selection of 9 articles including 15,287 patients. The effect of fluvoxamine, fluoxetine, and the overall effect of SSRI/SNRI use on mortality of COVID‐19 patients were investigated in 3, 2, and 7 articles, respectively. The results of our analyses showed that these medications could significantly decrease mortality of COVID‐19 patients (OR and 95% [CI]: 0.595 [0.467–0.758], 0.620 [0.469–0.821], and 0.596 [0.437–0.813]). The effect of SSRI/SNRIs on hospitalization events of COVID‐19 patients was not significant (OR: 0.240% and 95% CI: 0.041–1.4). Also, length of hospital stay was longer in patients who administrated SSRIs.ConclusionAccording to this study's results, SSRI/SNRIs may be effective in reducing mortality of COVID‐19 patients, suggesting the superiority of fluvoxamine to fluoxetine. The safety profile and affordable cost of SSRI/SNRIs for a short‐term use may be other reasons to propose them as beneficial medications in preventing mortality in COVID‐19.

Special Report: Women’s Reproductive Mental Health—A Clinical Framework

Special Report: Women’s Reproductive Mental Health—A Clinical Framework

Inflammatory Bowel Disease and Pregnancy

Inflammatory Bowel Disease and Pregnancy

Viloxazine for the Treatment of Attention Deficit Hyperactivity Disorder.

Attention deficit hyperactivity disorder (ADHD) is a widely diagnosed neurodevelopmental disorder giving rise to symptoms of hyperactivity, impulsivity, and inattentiveness that can impair daily functioning. Stimulants, such as methylphenidate and amphetamines, are the mainstay of treatment for ADHD. However, nonstimulant drugs such as viloxazine, atomoxetine, guanfacine, and clonidine are becoming more popular due to minimal adverse effects when compared to stimulants. Viloxazine is a selective norepinephrine reuptake inhibitor (NRI) originally used to treat depression in adults with activity in both the noradrenergic as well as serotonergic pathways. Studies have demonstrated its efficacy for its use in the treatment of ADHD. Unlike stimulants, viloxazine has a decreased chance of substance abuse, drug dependance, and withdrawal symptoms upon the cessation of therapy. Additionally, dopamine levels in the nucleus accumbens after treatment with viloxazine are elevated considerably less in comparison with traditional stimulant ADHD treatments. Viloxazine provides an alternative, nonstimulant approach to treating ADHD. Viloxazine is a recently approved, non-stimulant medication functions by inhibiting the uptake of norepinephrine which has been seen to be decreased in patients with ADHD. When patients do not respond to first-line stimulants, cannot tolerate the side effects, or have contraindications to stimulants, viloxazine may be a nonstimulant option offering patients an increasing arsenal of medications to treat ADHD.

Depressive disorder and antidepressants from an epigenetic point of view.

Depressive disorder is a complex, heterogeneous disease that affects approximately 280 million people worldwide. Environmental, genetic, and neurobiological factors contribute to the depressive state. Since the nervous system is susceptible to shifts in activity of epigenetic modifiers, these allow for significant plasticity and response to rapid changes in the environment. Among the most studied epigenetic modifications in depressive disorder is DNA methylation, with findings centered on the brain-derived neurotrophic factor gene, the glucocorticoid receptor gene, and the serotonin transporter gene. In order to identify biomarkers that would be useful in clinical settings, for diagnosis and for treatment response, further research on antidepressants and alterations they cause in the epigenetic landscape throughout the genome is needed. Studies on cornerstone antidepressants, such as selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, norepinephrine, and dopamine reuptake inhibitors and their effects on depressive disorder are available, but systematic conclusions on their effects are still hard to draw due to the highly heterogeneous nature of the studies. In addition, two novel drugs, ketamine and esketamine, are being investigated particularly in association with treatment of resistant depression, which is one of the hot topics of contemporary research and the field of precision psychiatry.

Can bupropion treat COVID-19-induced brain fog? A case series.

COVID-19-induced neurocognitive complications that include brain fog have affected a large portion of individuals who survived COVID-19. These symptoms can include inattention, mental fatigue, forgetfulness, amotivation, and distractibility. This can cause significant anxiety and depression, which may worsen disease progression. To date, there are no known specific treatments that target COVID-19-related brain fog. Here, two patients are presented that develop symptoms of brain fog that persisted after they recovered from an acute COVID-19 infection. Both had memory impairment, mental exhaustion, and inattention with associated depressed mood. They were given bupropion extended release and though varied with dosing and time to resolution, they recovered dramatically. The dopamine and norepinephrine reuptake inhibitor is known to have effects on the brain that may treat symptoms of brain fog including blocking hippocampal cell loss, increased neural activity in the cingulate cortex, and decreasing proinflammatory cytokines. Bupropion may be a possible option for those suffering from this growing and debilitating post-COVID-19 complication.

Influence of cerebral infarction on both bladder and urethral activities and changes after tramadol administration in rats.

We investigated the changes in bladder and urethral function after cerebral infarction (CI) and the influence of tramadol on these functions. Twenty-eight female Sprague Dawley rats were divided into normal and CI groups. In the awake condition, metabolic cage study and blood pressure were evaluated. Under urethane anesthesia, the intravenous effect of tramadol (0.01-1 mg/kg), which has both µ-opioid receptor stimulation and inhibition of norepinephrine and serotonin reuptake, on continuous cystometry, and simultaneous measurements of bladder and urethral perfusion pressure (UPP) were recorded. Infarcted lesions were examined by staining with triphenyltetrazolium chloride, a marker of mitochondrial enzyme activity. CI rats showed impaired sympathetic activity with Horner's syndrome and lower blood pressure. In metabolic cage study, urinary frequency during the dark phase was increased in CI rats. On bladder activity, in CI rats, the baseline pressure threshold for inducing bladder contractions was significantly lower (p < 0.01), and the intercontraction interval was prolonged after tramadol administration. On urethral activity, the baseline UPP was significantly lower in CI rats than in normal rats and it did not change after tramadol administration. Residual urine rate was significantly increased in normal rats, but not in CI rats. CI rats showed brain infarction including the cortex and hypothalamus, which is a center of the autonomic nervous system. CI-induced ischemic brain damage results in impairment of both bladder and urethral functions, in addition to decreased sympathetic activity. Bladder overactivity after CI can be improved by tramadol; however, urethral activity cannot be improved by it.

The Risk of Fatal Arrhythmias in Post-Myocardial Infarction Depression in Association With Venlafaxine.

Venlafaxine is a second line anti-depressant and the most commonly used in the treatment of selective serotonin reuptake inhibitor nonresponders in major depression; due to its effects on the noradrenergic and serotonergic systems as a serotonin and norepinephrine reuptake inhibitor, there has been considerable apprehension regarding its use in patients with cardiovascular diseases, particularly post-myocardial infarction depression, some of the feared adverse effects include QT prolongation, arrhythmias including torsades de pointes and sudden cardiac death. We tried to resolve the facts regarding the risks associated with venlafaxine use in cardiac patients. We have reviewed all the relevant information up to May 2022 regarding the risks of venlafaxine use in cardiovascular disease, particularly with a focus on post-myocardial infarction depression, and gathered around 350 articles in our research and narrowed it down to 49 articles. The database used was PubMed and the keywords used were venlafaxine, arrhythmia, major depression, post-myocardial infarction, and ventricular tachycardia. We carefully screened all relevant articles and found articles supporting and refuting the effects of venlafaxine in increasing cardiovascular morbidity and mortality. We have concluded that there is a significant variability due to confounding factors affecting individual cases. Overall there is no increased arrhythmia risk in comparison with other anti-depressants except in high-risk cases such as with pre-existing cardiovascular disease, certain genotypes, and other co-morbidities. Any patient with a high risk of arrhythmias due to any etiology should receive a screening electrocardiogram before venlafaxine prescription for baseline QT interval and periodically while on therapy to check for changes. We encourage further research, including randomized clinical trials and post-marketing surveillance regarding the use of venlafaxine in high-risk cases such as patients with multiple co-morbidities, elderly patients, or patients with certain genotypes.

Bupropion - an antidepressant drug with broad therapeutic potential

Introduction: Bupropion is currently mainly used as an atypical antidepressant due to its psychotropic effects. In addition, it shows high potential in reducing withdrawal cravings in addicts, which is also used in the treatment of nicotinism. However, studies in recent years have shown that it may also be useful in other conditions.Aim of the study: Our aim was to review the known usage of bupropion in the fields of psychiatry, neurology and internal medicine, and to identify potential directions for further research. Methods and materials: We reviewed the literature available in the PubMed database, using the key words: "bupropion"; "depression"; "smoking cessation"; "obesity"; "ADHD".Results: Bupropion- an antidepressant drug belonging to the group of selective norepinephrine and dopamine reuptake inhibitors. Bupropion is approved by the FDA(Food and Drug Administration) for the treatment of depression, seasonal affective disorder and nicotinism. The literature shows that it is also effective in off-label indications - treatment of antidepressant-induced sexual dysfunction, attention deficit hyperactivity disorder (ADHD), depression in bipolar disorder, obesity, neuropathic pain and cancer-related fatigue syndrome.Conclusion: Due to the specific effects of bupropion, there are many more usage for the drug than the primary indications for which it is usually used. The usage of the drug described in the literature require additional studies on a larger group of patients.

Consensus of the Brazilian Headache Society (SBCe) for prophylactic treatment of episodic migraine: part II.

Migraine affects 1 billion people worldwide and > 30 million Brazilians; besides, it is an underdiagnosed and undertreated disorder. The need to disseminate knowledge about the prophylactic treatment of migraine is known, so the Brazilian Headache Society (SBCe, in the Portuguese acronym) appointed a committee of authors with the objective of establishing a consensus with recommendations on the prophylactic treatment of episodic migraine based on articles from the world literature as well as from personal experience. Meetings were held entirely online, with the participation of 12 groups that reviewed and wrote about the pharmacological categories of drugs and, at the end, met to read and finish the document. The drug classes studied in part II of this Consensus were: antihypertensives, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, calcium channel blockers, other drugs, and rational polytherapy. From this list of drugs, only candesartan has been established as effective in controlling episodic migraine. Flunarizine, venlafaxine, duloxetine, and pizotifen were defined as likely to be effective, while lisinopril, enalapril, escitalopram, fluvoxamine, quetiapine, atorvastatin, simvastatin, cyproheptadine, and melatonin were possibly effective in prophylaxis of the disease. Despite an effort by the scientific community to find really effective drugs in the treatment of migraine, given the large number of drugs tested for this purpose, we still have few therapeutic options.

Pharmacological Treatment for Pediatric Anxiety Disorders.

Pediatric anxiety disorders (PADs) occur in up to 20% of youth and can cause impairment across the lifespan. Coronavirus disease 2019 (COVID-19) added unique pressures on those with PADs, as children and adolescents endured the longest pandemic restrictions, stymieing their ability to develop socially, emotionally, and cognitively. Although first-line treatment for PADs is psychotherapy, those with severe anxiety symptoms will require pharmacological interventions. Selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor (SNRI) medications are effective in treating PADs, yet only duloxetine (a SNRI) is approved by the U.S. Food and Drug Administration for children aged >7 years with generalized anxiety disorder. Treatment of children and adolescents with benzodiazepines for PADs presents unique challenges with potential paradoxical reactions. Caution must be observed as well due to risk for misuse related to long-term use of benzodiazepines with PADs. [Journal of Psychosocial Nursing and Mental Health Services, 60(9), 6-9.].

The Effect of Neuromodulatory Drugs on the Intensity of Chronic Pelvic Pain in Women: A Systematic Review.

To evaluate the effect of neuromodulatory drugs on the intensity of chronic pelvic pain (CPP) in women. Searches were carried out in the PubMed, Cochrane Central, Embase, Lilacs, OpenGrey, and Clinical Trials databases. The searches were carried out by two of the authors, not delimiting publication date or original language. The following descriptors were used: chronic pelvic pain in women OR endometriosis, associated with MESH/ENTREE/DeCS: gabapentinoids, gabapentin, amitriptyline, antidepressant, pregabalin, anticonvulsant, sertraline, duloxetine, nortriptyline, citalopram, imipramine, venlafaxine, neuromodulation drugs, acyclic pelvic pain, serotonin, noradrenaline reuptake inhibitors, and tricyclic antidepressants, with the Boolean operator OR. Case reports and systematic reviews were excluded. The following data were extracted: author, year of publication, setting, type of study, sample size, intervention details, follow-up time, and results. A total of 218 articles were found, with 79 being excluded because they were repeated, leaving 139 articles for analysis: 90 were excluded in the analysis of the titles, 37 after reading the abstract, and 4 after reading the articles in full, and 1 could not be found, therefore, leaving 7 articles that were included in the review. Most of the studies analyzed have shown pain improvement with the help of neuromodulators for chronic pain. However, no improvement was found in the study with the highest statistical power. There is still not enough evidence that neuromodulatory drugs reduce the intensity of pain in women with CPP.

THE EXISTING LANDSCAPE OF DEPRESSION: REVIEW

Introduction: Depression is a global health problem that has been increasing in recent years, but it is still underdiagnosed and it’s not taken seriously enough. For this reason, it is vital for health workers to know their correct diagnosis and treatment to prevent patients from reaching their worst outcome, which is suicide. Objective: To examine how these patients have been approached and managed, and the effectiveness of both pharmacological and non-pharmacological therapies, based on review articles from the last five years. Methodology: a total of 43 original and review articles, collected from the Cochrane Library, PubMed and Google Scholar databases, were searched for the term Depression. The documents were found in Spanish and English. Some articles were excluded due to lack of updated information and lack of relevance for our literature review. Results: there is a fundamental pillar for the treatment of depression, based on psychological therapies (primary and fundamental element), pharmacotherapy and, as a last line, electroconvulsive therapy. The drugs generally used are serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors. There are other therapies such as acupuncture, music therapy, which have shown some benefit. Conclusions: throughout this time, it has been determined that current diagnostic modalities have made it possible to diagnose early and a greater number of people suffering from depression, starting with psychotherapy, and administering antidepressant drugs in the absence of response to psychotherapy. KEY WORDS: depression, dysthymia, psychotherapy, Serotonin Uptake Inhibitors, Serotonin and Norepinephrine Reuptake Inhibitors.

Trends in dispensing and utilisation of sustained-release tapentadol in Australia.

ObjectivesTapentadol is a µ-opioid agonist, moderate noradrenaline reuptake inhibitor (NRI) and very weak serotonin reuptake inhibitor. The sustained release (SR) formulation is indicated for relief of chronic moderate to severe pain. We examined utilisation trends and concordance with prescribing guidelines of prescription SR tapentadol in Australia between 2014-2021. ApproachWe used a 10% sample of Australian Pharmaceutical Benefits Scheme dispensing data linked to death records. We assessed incidence, prevalence, and trends in monthly dispensed prescriptions between June 2014 (date of public subsidy) and September 2021. We defined incident users in adults aged ≥18 years as no tapentadol dispensings in the previous year. We assessed characteristics of initiators and patterns of utilization in the year following initiation, including prescription strengths, concurrent dispensing of tapentadol and medicines with known interactions or contraindications, and switching to other opioids. Results4,883,840 prescriptions of tapentadol were dispensed during the study period. Total monthly dispensed prescriptions increased from 2,040 (June 2014) to 91,300 (September 2021). The lowest strength formulations (50mg, 100mg) comprised nearly three quarters of all dispensed prescriptions (3,628,400; 74.3%). We identified 66,334 new episodes of tapentadol use. Incidence rose from 0.8/1000 population in 2014 to a high of 8.4/1000 in 2019, dropping to 5.5/1000 in 2020. Most people initiating tapentadol were aged 45-84 years (48,464; 73.1%) and female (37,709; 56.9%). More than half (38,157; 57.5%) did not receive a second tapentadol dispensing within 90 days of initiation. 10,868 (16.4%) were dispensed a non-opioid medicine with known interaction on the same day as initiation, and 23,205 (35.0%) were concurrently dispensed tapentadol and other opioids. ConclusionThe only approved subsidized indication is tapentadol SR for chronic pain. However, the very high prevalence of single dispensings of tapentadol SR suggests it may be being used off-label for acute pain instead of tapentadol immediate-release; this would be less safe, less effective and also against Australian therapeutic guidelines.

Shared and unique imaging-derived endo-phenotypes of two typical antidepressant-applicative depressive patients.

Determining the clinical homogeneous and heterogeneous sets among depressive patients is the key to facilitate individual-level treatment decision. The diffusion tensor imaging (DTI) data of 62 patients with major depressive disorder (MDD) and 39 healthy controls were used to construct a Latent Dirichlet Allocation (LDA) Bayesian model. Another 48 MDD patients were used to verify the robustness. The LDA model was employed to identify both shared and unique imaging-derived factors of two typically antidepressant-targeted depressive patients, selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Furthermore, we applied canonical correlation analysis (CCA) between each factor loading and Hamilton depression rating scale (HAMD) sub-score, to explore the potential neurophysiological significance of each factor. The results revealed the imaging-derived connectional fingerprint of all patients could be situated along three latent factor dimensions; such results were also verified by the out-of-sample dataset. Factor 1, uniquely expressed by SNRI-targeted patients, was associated with retardation (r = 0.4, p = 0.037) and characterized by coupling patterns between default mode network and cognitive control network. Factor 3, uniquely expressed by SSRI-targeted patients, was associated with cognitive impairment (r = 0.36, p = 0.047) and characterized by coupling patterns within cognitive control and attention network, and the connectivity between threat and reward network. Shared factor 2, characterized by coupling patterns within default mode network, was associated with anxiety (r = 0.54, p = 0.005) and sleep disturbance (r = 0.37, p = 0.032). Our findings suggested that quantification of both homogeneity and heterogeneity within MDD may have the potential to inform rational design of pharmacological therapies. • The shared and unique manifestations guiding pharmacotherapy of depressive patients are caused by the homogeneity and heterogeneity of underlying structural connections of the brain. • Both shared and unique factor loadings were found in different antidepressant-targeted patients. • Significant correlations between factor loading and HAMD sub-scores were found.

Antidepressant use and risk of self-harm among people aged 40 years or older: A population-based cohort and self-controlled case series study

SummaryBackgroundStudies on the association between antidepressants and self-harm in adults were mostly conducted over a decade ago and have inconsistent findings. We aimed to compare self-harm risks by antidepressant classes among people aged 40 years or older with depression.MethodsIndividuals aged ≥40 years with depression who initiated antidepressant treatment between 2001 and 2015 were retrieved from the Hong Kong Clinical Data Analysis & Reporting system, and were followed up until December 31, 2016. We conducted self-controlled case series (SCCS) analyses to estimate the incidence rate ratio (IRR) of self-harm comparing the pre-exposure (90 days before the first antidepressant use), index exposure (the first antidepressant use), and subsequent exposure (subsequent antidepressant use) periods to nonexposed periods. We applied Cox proportional hazard regressions to estimate the hazard ratio (HR) of self-harm comparing five antidepressant classes (tricyclic and related antidepressant drugs [TCAs], selective serotonin reuptake inhibitors [SSRIs], noradrenergic and specific serotonergic antidepressants [NaSSAs], serotonin–norepinephrine reuptake inhibitors [SNRIs], and others).FindingsA total of 48,724 individuals were identified. SCCS analyses (N = 3,846) found that the increased self-harm risk occurred during the pre-exposure (IRR: 22.24; 95% CI, 20.25-24.42), index exposure (7.03; 6.34-7.80), and subsequent exposure periods (2.47; 2.18-2.79) compared to the unexposed period. Cohort analyses (N = 48,724) found an association of higher self-harm risks in short-term (one year) for NaSSAs vs. TCAs (HR, 2.13; 95% CI, 1.53-2.96), SNRIs vs. TCAs (1.64; 1.01-2.68), and NaSSAs vs. SSRIs (1.75; 1.29-2.36) in the 40-64 years group. The higher risk remained significant in long-term (> one year) for NaSSAs vs. TCAs (1.55; 1.26-1.91) and NaSSAs vs. SSRIs (1.53; 1.26-1.87). In the 65+ group, only short-term differences were observed (SSRIs vs. TCAs [1.31; 1.03-1.66], SNRIs vs. SSRIs [0.44; 0.22-0.87], and SNRIs vs. NaSSAs [0.43; 0.21-0.87]).InterpretationWithin-person comparisons did not suggest that antidepressant exposure is causally associated with an increased risk of self-harm in people with depression. Between-person comparisons revealed differences in self-harm risks between certain pairs of antidepressant classes. These findings may inform clinicians’ benefit-risk assessments when prescribing antidepressants.FundingNil.

Drug-Associated Parosmia: New Perspectives from the WHO Safety Database.

Parosmia is a qualitative distortion of smell perception. Resulting from central causes, sinonasal diseases, and infections, parosmia has also been associated with medications. Therefore, we aimed to investigate potential signals for drugs associated with parosmia. VigiBase® (the WHO pharmacovigilance database) was queried for all reports of “Parosmia” (MedDRA Preferred Term), registered up to 23 January 2022. Disproportionality analysis relied on the reporting odds ratio and the information component. A signal is detected when the lower end of the 95% confidence interval of the information component is positive. We found 14,032 reports of parosmia, with a median patient age of 53 years. Most reported drugs were antiinfectives, among which COVID-19 vaccines accounted for 27.1% of reports. Antibiotics and corticosteroids were involved in 6.8% and 4.6% of reports. Significant disproportionate reporting was detected for corticosteroids, antibiotics, drugs used in nicotine dependence, COVID-19 and HPV vaccines, serotonin–norepinephrine reuptake inhibitors (SNRI), and incretin mimetics. We suggest potential safety signals involving nicotine replacement therapies and vaccines. We also highlight the potential role of less suspected classes, such as SNRIs and incretin mimetics. An iatrogenic etiology should be evoked when parosmia occurs, especially in the elderly.

Activity dependent inhibition of TRPC1/4/5 channels by duloxetine involves voltage sensor-like domain.

Transient receptor potential canonical 5 (TRPC5) is a polymodal, calcium-permeable, nonselective ion channel that is expressed in the brain and 75 % of human sensory neurons. Its pharmacological or genetic inhibition leads to the relief of neuropathic and inflammatory pain. The clinically approved drug duloxetine is superior to other serotonin and norepinephrine reuptake inhibitors at managing painful neuropathies, but it is not known why. Here we ask whether the TRPC5 receptor is modulated by duloxetine and may contribute to its analgesic effect. Electrophysiological measurements of heterologously expressed human TRPC5 in HEK293T cells were performed to evaluate the effect of duloxetine. The interaction site was identified by molecular docking and molecular dynamics simulations in combination with point mutagenesis. We found that duloxetine inhibits TRPC5 in a concentration-dependent manner with a high potency (IC50 = 0.54±0.03µM). Our data suggest that duloxetine binds into a voltage sensor-like domain. For the interaction, Glu418 exhibited particular importance due to putative hydrogen bond formation. Duloxetine effectively inhibits TRPC5 currents induced by cooling, voltage, direct agonists and by the stimulation of the PLC pathway. The finding that this TRPC5 inhibitor is widely used and well tolerated provides a scaffold for new pain treatment strategies.