Concurrent administration of serotonergic antidepressants and ozanimod in participants with relapsing multiple sclerosis from the open-label extension DAYBREAK trial.

BACKGROUND: Monoamine oxidase (MAO) inhibitors can interact with selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs). There is clinical interest surrounding use of ozanimod with SSRIs/SNRIs because the major metabolites of ozanimod are weak inhibitors of MAO-B in vitro. OBJECTIVE: To evaluate the incidence of treatment-emergent adverse events (TEAEs) potentially related to serotonin accumulation (SA) during concomitant ozanimod and SSRI/SNRI use by performing analyses of data from an open-label, oral ozanimod 0.92 mg trial (DAYBREAK; NCT02576717). METHODS: SA narrow (serotonin syndrome, neuroleptic malignant syndrome, and hyperthermia malignant) and broad (terms potentially associated with SA) MedDRA v24.0 searches were performed using TEAE data from participants with relapsing multiple sclerosis who entered DAYBREAK from phase 3 studies (cutoff February 1, 2022). Incidences of TEAEs matching terms from each search were stratified by SSRI/SNRI use. RESULTS: Of 2257 DAYBREAK participants, 274 (12.1%) used an SSRI/SNRI. No participants had TEAEs matching the SA narrow search terms. There was no significant difference in the percentage of participants with ⩾1 TEAE matching the SA broad search for those on versus off SSRIs/SNRIs (on: 12.4%, n = 34/274; off: 15.6%, n = 310/1982, nominal p = 0.1630). CONCLUSION: MedDRA searches showed no increase in TEAEs potentially associated with SA with concomitant SSRI/SNRI and ozanimod use.

Antidepressant nonadherence and sexual dysfunction among young adult males: the cross-sectional YAMAN study.

PURPOSE: Selective serotonin reuptake inhibitors are associated with high rates of nonadherence and sexual dysfunction, yet the correlation between these findings in young adult men is poorly characterized. We aimed to evaluate if young adult men are less willing to adhere to antidepressant treatment due to intolerable side effects, such as sexual dysfunction. METHODS: Deidentified, compensated survey that assessed baseline demographics, PHQ-8 and GAD-7 scores, attitudes towards antidepressant medication side effects, and perceptions of antidepressant medications including selective serotonin reuptake inhibitors, bupropion, and mirtazapine. RESULTS: From 665 delivered surveys, 505 respondents completed their survey (response rate: 76%), of which 486 were included for final analysis. After seeing common side effect profiles, our sample's willingness to take sexual function-sparing agents, such as bupropion or mirtazapine, was significantly greater than selective serotonin reuptake inhibitors (p < 0.001), with no significant difference between bupropion and mirtazapine (p = 0.263). The negative influence of erectile dysfunction and anorgasmia scored significantly higher than other common antidepressant side effects like weight gain, nausea, and dry mouth (range: p < 0.001, p = 0.043). With the exception of insomnia, participants indicated that experiencing sexual dysfunction while taking an antidepressant medication would lead to nonadherence at a significantly higher frequency than any other side effect assessed (range: p < 0.001, p = 0.005). CONCLUSION: The risk of experiencing sexual side effects when taking antidepressants could lead young adult men to become nonadherent to these medications. Strategies to augment the effectiveness of antidepressants, such as shared decision-making and the use of sexual function-sparing agents, are critical.

Greater Apathy Associated With Selective Serotonin Reuptake Inhibitor Use in Parkinson's Disease.

OBJECTIVE: Apathy, a motivational disorder, is common in Parkinson's disease (PD) and often misdiagnosed as depression. Use of selective serotonin reuptake inhibitors (SSRIs) has been associated with increased apathy in adolescents and adults with depression. Based on observations that serotonin may downregulate dopaminergic systems, we examined the relationship between apathy and SSRI use in individuals with PD. METHODS: Medications, mood/motivation scales, and clinical data were collected from a convenience sample of 400 individuals with PD. Depression and apathy were measured using the Beck Depression Inventory-II (BDI-Il) and the Apathy Scale (AS). Antidepressant medications were grouped by mechanism type. RESULTS: Of the 400 PD patients, 26% were on SSRIs. On standard mood/motivation scales, 38% of the sample exceeded clinical cut-offs for apathy and 28% for depression. Results of hierarchical regression analyses revealed that SSRIs were the only antidepressant that were significantly associated with higher apathy scores (ß = .1, P = .02). Less education (ß = -.1, P = .01) worse cognition (ß = -.1, P = .01), and greater depressive symptoms (ß = .5, P < .001) were also significant predictors of apathy. CONCLUSION: These findings suggest that use of SSRIs, but not other antidepressants, is associated with greater apathy in PD. Given the interactive relationship between serotonin and dopamine, the current findings highlight the importance of considering apathy when determining which antidepressants to prescribe to individuals with PD. Similarly, switching a SSRI for an alternative antidepressant in individuals with PD who are apathetic may be a potential treatment for apathy that needs further study.

Poststroke Depression: An Update.

The presence of neuropsychiatric disorders after stroke has been recognized for more than 100 years, but controlled systematic studies did not begin until the 1970s. The most clinically important advances, however, have been in the treatment and prevention of poststroke depression (PSD). Recent meta-analyses of randomized controlled trials (RCTs) for the treatment of PSD have demonstrated the efficacy of antidepressants. Similarly, RCTs for the prevention of PSD have shown that antidepressants significantly decrease the incidence of PSD compared with placebo. Early treatment of PSD with antidepressants also appears to enhance both physical and cognitive recovery from stroke and may increase survival up to 10 years. Genetic and epigenetic variations, white matter disease, cerebrovascular deregulation, altered neuroplasticity, and changes in glutamate neurotransmission may be relevant etiological factors.

Association between selective serotonin reuptake inhibitor use and developing irritable bowel syndrome through retrospective analysis.

BACKGROUND AND AIM: Serotonin affects the balance and integrity of the gut microbiome; however, studies have confirmed the influence of selective serotonin reuptake inhibitors (SSRIs) on irritable bowel syndrome (IBS). We evaluated the association between SSRI use and subsequent IBS occurrence in a real-world setting. METHODS: A multivariate Cox proportional hazard model was adopted, and the National Health Insurance Service cohort claims database between 2010 and 2019 was used. Non-SSRI users were selected using the propensity score matching method. Subgroup analyses were performed using the point of use, cumulative dose, and duration of SSRI use. Additional analysis was performed using a control group without psychiatric medications. RESULTS: We included 2901 SSRI users and 2727 non-SSRI users. After adjusting covariates, the risk of developing IBS in SSRI users was 1.54 times that in non-SSRI users (95% confidence interval [CI]: 1.01-2.33). The hazard ratio (HR) of the recent, heavy, and short-term user groups were 3.19 (95% CI: 2.03-4.99), 2.22 (95% CI: 1.50-3.29), and 4.83 (95% CI: 3.02-7.73), respectively, compared with that of non-users. In patients without a history of psychiatric medications, the risk of IBS incidence after SSRI use increased significantly (HR: 1.61, 95% CI: 1.06-2.42), whereas HR was insignificant in patients with a history of psychiatric medications (HR: 1.25, 95% CI: 0.98-1.60). CONCLUSIONS: The risk of subsequent IBS occurrence following SSRI use was high in patients who initially took a heavy SSRI dose and those who did not have a history of psychiatric drug use.

Comparing the effect of fluoxetine, escitalopram, and sertraline, on the level of BDNF and depression in preclinical and clinical studies: a systematic review.

Brain-derived neurotrophic factor (BDNF) dysfunction is one of the most important mechanisms underlying depression. It seems that selective serotonin reuptake inhibitors (SSRIs) improve depression via affecting BDNF level. In this systematic review, for the first time, we aimed to review the effect of three SSRIs including fluoxetine, escitalopram, and sertraline, on both depression and BDNF level in preclinical and clinical studies. PubMed electronic database was searched, and 193 articles were included in this study. After reviewing all manuscripts, only one important difference was found: subjects. We found that SSRIs induce different effects in animals vs. humans. Preclinical studies showed many controversial effects, while human studies showed only two effects: improvement of depression, with or without the improvement of BDNF. However, most studies used chronic SSRIs treatment, while acute SSRIs were not effectively used and evaluated. In conclusion, it seems that SSRIs are reliable antidepressants, and the improvement effect of SSRIs on depression is not dependent to BDNF level (at least in human studies).

The effect of drug holidays on sexual dysfunction in men treated with selective serotonin reuptake inhibitors (SSRIs) other than fluoxetine: an 8-week open-label randomized clinical trial.

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of various mental disorders. Sexual dysfunction is one of the most common side effects of SSRIs, and often leads to poor adherence and treatment discontinuation. While several strategies have been employed to manage SSRI-induced sexual dysfunction, drug holidays has not been extensively studied for this purpose. This clinical trial aims to assess the effect of drug holidays on sexual dysfunction in married men under treatment with SSRIs other than fluoxetine (as its long half-life makes drug holidays ineffective). METHODS: This 8-week double-center, randomized, open-label, controlled trial was conducted in the outpatient clinics of Iran Psychiatric Hospital and Tehran Institute of Psychiatry, from January 2022 to March 2023. We included married men aged between18 and 50 years who had experienced sexual dysfunction during treatment with SSRIs, other than fluoxetine. The Male Sexual Health Questionnaire (MSHQ) and the 28-Question General Health Questionnaire (GHQ-28) were used for the assessment of sexual function and mental health status. The drug holidays group was instructed not to take their medications on the weekends. The control group was asked to continue their regular medication regimen without any changes. Both groups were assessed at baseline, and weeks 4 and 8. RESULTS: Sixty-three patients were included and randomly assigned to the drug holidays group (N = 32) or the control group (N = 31). Fifty patients (25 in each group) completed the trial. Drug holidays significantly improved erection, ejaculation, satisfaction, and the overall sexual health of the participants (P < 0.001). No significant change was observed in their mental health status. No major side effects were recorded. CONCLUSIONS: Drug holidays significantly improved the MSHQ scores in 'erection', 'ejaculation', 'satisfaction' and 'total' in married men with sexual dysfunction induced by SSRIs, other than fluoxetine, without causing any significant changes in their mental health status. Further research is needed to reach a certain conclusion. TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials on 2021.10.25 ( www.irct.ir ; IRCT ID: IRCT20170123032145N6) before the trial.

Effect of l-arginine compared to placebo on sexual function in women with major depressive disorder: a randomized controlled trial.

BACKGROUND: While some evidence suggests that l-arginine may improve sexual function and alleviate depression, it has not been investigated in women with depression to assess both its effects on the depression and sexual function concurrently. METHODS: Patients who had received a diagnosis of major depressive disorder, as determined by predetermined inclusion and exclusion criteria, were enrolled in this triple-blind clinical trial. Patients were divided into two groups: group A, received L-arginine 1 gram twice daily, and group B, received a placebo for four weeks. They were evaluated at baseline, after four and eight weeks with the Hamilton Depression Rating Scale (HDRS), and Rosen's questionnaire or Female Sexual Function Index (FSFI). RESULTS: A decrease in the severity of depression was observed in all patients, which was determined due to Hamilton's questionnaire (P-value < 0.001). During the time in group A, FSFI increased. Based on the FSFI questionnaire, they had improvement in some domains, including the lubrication index and orgasm index, which significantly changed in the eighth week compared to the baseline (P-value < 0.05). However, these two indicators did not change statistically significantly compared to the placebo group. CONCLUSION: L-arginine supplementation can improve sexual function, particularly lubrication and orgasm, and mood in women with depression, with minimal side effects observed. Additional research is necessary to validate these results by examining the effects of higher dosages, extended durations, and larger populations of depressed patients. TRIAL REGISTRATION: Iranian Registry of Clinical Trial: IRCT20100127003210N26.

Prescribing patterns in patients with obsessive-compulsive disorder: Retrospective, single-center study.

INTRODUCTION: Obsessive-compulsive disorder (OCD) is marked by a high rate of treatment resistance. Patients are often left trialing medications within multiple drug classes with little response, causing heterogeneity to emerge in prescribing patterns. This analysis seeks to investigate the selection and dosing of the pharmacotherapy utilized, to portray an overview of prescribing trends in the United States. METHODS: This retrospective, single center, review of electronic medical records investigated the pharmacotherapy utilization of patients with a primary diagnosis of OCD. Two hundred and ninety-five patients who received OCD treatment at an urban, academic medical center were included in the study. Patients were included in the review if they were at least eighteen years of age and were assigned a diagnosis of OCD according to DSM-5 criteria. RESULTS: Psychotropic pharmacotherapy was integrated into the care of 93% of patients. Selective serotonin reuptake inhibitors were the most utilized medication class at 85% followed by benzodiazepines (47%) and second-generation antipsychotics (37%). Tricyclic antidepressants and first-generation antipsychotics were the two medication classes utilized the least at 13% and 2% respectively. Additionally, mood stabilizers and serotonin-norepinephrine reuptake inhibitors were utilized at rates of 8% and 16%, respectively. CONCLUSIONS: Evidence-based treatment guidelines are being followed with varying augmentation strategies widely prevalent, thus displaying the heterogeneity in treating OCD. A high rate of benzodiazepine utilization highlights a practice trend with potential ties to clinical factors, such as the latency to treatment effect of other first-line pharmacotherapies. Future prospective studies are required to determine the cultural, pharmacoeconomic and pharmacogenomic factors that contribute to the variation in prescribing practices and whether these variations influence treatment outcomes.

Frequency of self-reported persistent post-treatment genital hypoesthesia among past antidepressant users: a cross-sectional survey of sexual and gender minority youth in Canada and the US.

PURPOSE: Persistent post-treatment genital hypoesthesia (PPTGH) is a primary symptom of post-SSRI sexual dysfunction (PSSD), an iatrogenic syndrome characterized by enduring sexual dysfunction following the discontinuation of some antidepressants. We aimed to estimate the frequency of PPTGH among past users of psychiatric treatments, particularly antidepressants. METHODS: We used a subsample of UnACoRN, a US/Canada survey of sexual and gender minority youth aged 15 to 29. We included participants with a history of psychiatric drug use. We excluded individuals with genital surgeries or without sexual experience. The analysis involved chi-square tests for initial group comparisons, post hoc tests for multiple comparisons, and logistic regression among those who had stopped taking medication. We exponentiated the regression to estimate the odds of PPTGH by drug type, adjusting for age, sex-assigned-at-birth, hormone treatment, and depression severity in three nested models. RESULTS: 574 of 2179 survey participants reported genital hypoesthesia. They were older and more likely to report male sex assignment at birth, hormonal therapy history, and psychiatric drug history. The frequency of PPTGH among antidepressant users was 13.2% (93/707) compared to 0.9% (1/102) among users of other medications; adjusted odds ratio: 14.2 (95% CI: 2.92 to 257). CONCLUSION: Antidepressant discontinuation is strongly associated with PPTGH in the US and Canada where SSRI/SNRI medications account for 80% of antidepressant prescriptions. We call for standardized international warnings and transparent, informed consent. Future research should expand upon our efforts to estimate the risk of PSSD by including all the proposed diagnostic criteria, including documentation of temporal changes in PSSD-related symptoms before and after treatment (≥3 months).

This study explored the long-lasting sexual side effects­specifically, reduced genital sensitivity­of certain antidepressants, even after stopping the medication, in a diverse group of young people, primarily those identifying as sexual and gender minorities. We analyzed responses from a large survey, focusing on participants with a history of psychiatric drug use but without genital surgeries. Our findings indicate that those who used antidepressants experienced a substantial increase in reports of reduced genital sensitivity­13.2% of antidepressant users compared to 0.9% of users of other medications. This symptom is more common among individuals who had used antidepressants and sedatives. Our results emphasize the necessity for clear warnings and proper consent processes about potential long-term sexual side effects, particularly for young patients, and standardization of these procedures across countries. Further research is needed to explore this condition more deeply, including studies of all related symptoms and their development over time before and after treatment.

The antidepressant, sertraline, impacts growth and reproduction in the benthic deposit feeder, Tubifex tubifex.

Among emerging contaminants, pharmaceuticals are considered one of the most pertinent substances that may threaten aquatic ecosystems. Pharmaceuticals are designed to be directed at specific metabolic- and molecular pathways. Thus, they are assumed to be still biologically active when entering the ecosystem and may result in unpremeditated impacts on non-target organisms. One of the most widely used selective serotonin reuptake inhibitors, sertraline (an antidepressant), is regularly found in aquatic environments. However, knowledge about the effects, and in particular, of sediment-associated sertraline in benthic invertebrates is limited. We examined the impacts of chronic exposure (28 d) to sediment-associated sertraline (3.3, 33, 330 µg/g dw sed.) on survival, growth and reproduction in the deposit-feeding oligochaete, Tubifex tubifex. Sertraline significantly decreased T. tubifex survival and growth. Worms exposed to high sertraline concentrations (330 µg/g) had a lower growth rate and reproduction, as indicated by a significantly lower number of cumulated cocoons. Worms exposed to an environmentally relevant concentration (3.3 µg/g) decreased growth but maintained a reproduction rate similar to that of the control. The implications are that adult worms exposed to high sertraline concentrations presumably required more energy for maintenance and detoxification, thereby reducing available energy for reproduction and growth. This represents a trade-off between survival, reproduction and growth. In contrast, T. tubifex exposed to environmentally relevant concentrations allocated more energy to reproduction by slightly increasing the number of cocoons produced and reducing growth. However, the quantity and quality of offspring may be impacted as we observed fewer juveniles in the environmentally relevant treatment than in the control. Overall, the results indicate that sediment-associated sertraline is bioavailable and negatively impacts T. tubifex survival, growth, and reproduction even at environmentally relevant concentrations.

The Association Between Oral Bone Mineral Density-Reducing Medications and the Risk of 2-Year Implant-Related Complications Following Total Knee Arthroplasty.

BACKGROUND: Certain medications interfere with the bone remodeling process and may potentially increase the risk of complications after total knee arthroplasty (TKA). As patients undergoing TKA may be taking these bone mineral density (BMD)-reducing medications, it is unclear as to whether and which medications impact TKA outcomes. Therefore, the purpose of this study was to observe the impact of various BMD-reducing medications on 2-year implant-related complications following TKA. METHODS: A retrospective analysis of patients undergoing primary TKA was conducted using a national administrative claims database. Patients were identified if they were taking any known BMD-reducing medication and were compared to control patients. To control for confounders associated with taking multiple agents, multivariable logistic regression analyses were conducted for each 2-year outcome (all-cause revision, loosening-indicated revision, and periprosthetic fracture--indicated revision), with the output recorded as odds ratios (ORs). RESULTS: In our study, 502,927 of 1,276,209 TKA patients (39.4%) were taking at least one BMD-reducing medication perioperatively. On multivariable analysis, medications associated with a higher likelihood of 2-year all-cause revision included first- and second-generation antipsychotics (SGAs) (OR: 1.42 and 1.26, respectively), selective serotonin reuptake inhibitors (SSRIs) (OR: 1.14), glucocorticoids (1.13), and proton pump inhibitors (PPIs) (OR: 1.23) (P < .05 for all). Medications associated with a higher likelihood of 2-year periprosthetic fracture included SGAs (OR: 1.51), SSRIs (OR: 1.27), aromatase inhibitors (OR: 1.29), and PPIs (OR: 1.42) (P < .05 for all). CONCLUSIONS: Of the drug classes observed, the utilization of perioperative PPIs, SSRIs, glucocorticoids, first-generation antipsychotics, and SGAs was associated with the highest odds of all-cause revision. Our findings suggest a relationship between these medications and BMD-related complications; however, further studies should seek to determine the causality of these relationships.

Advances in Therapeutics to Alleviate Cognitive Decline and Neuropsychiatric Symptoms of Alzheimer's Disease.

Dementia exists as a 'progressive clinical syndrome of deteriorating mental function significant enough to interfere with activities of daily living', with the most prevalent type of dementia being Alzheimer's disease (AD), accounting for about 80% of diagnosed cases. AD is associated with an increased risk of comorbidity with other clinical conditions such as hypertension, diabetes, and neuropsychiatric symptoms (NPS) including, agitation, anxiety, and depression as well as increased mortality in late life. For example, up to 70% of patients diagnosed with AD are affected by anxiety. As aging is the major risk factor for AD, this represents a huge global burden in ageing populations. Over the last 10 years, significant efforts have been made to recognize the complexity of AD and understand the aetiology and pathophysiology of the disease as well as biomarkers for early detection. Yet, earlier treatment options, including acetylcholinesterase inhibitors and glutamate receptor regulators, have been limited as they work by targeting the symptoms, with only the more recent FDA-approved drugs being designed to target amyloid-ß protein with the aim of slowing down the progression of the disease. However, these drugs may only help temporarily, cannot stop or reverse the disease, and do not act by reducing NPS associated with AD. The first-line treatment options for the management of NPS are selective serotonin reuptake inhibitors/selective noradrenaline reuptake inhibitors (SSRIs/SNRIs) targeting the monoaminergic system; however, they are not rational drug choices for the management of anxiety disorders since the GABAergic system has a prominent role in their development. Considering the overall treatment failures and side effects of currently available medication, there is an unmet clinical need for rationally designed therapies for anxiety disorders associated with AD. In this review, we summarize the current status of the therapy of AD and aim to highlight novel angles for future drug therapy in our ongoing efforts to alleviate the cognitive deficits and NPS associated with this devastating disease.

Effectiveness of antidepressants in improving the prognosis of COVID-19: A systematic review and meta-analysis.

OBJECTIVE, AND MATERIAL AND METHODS: A systematic review and meta-analysis was performed to evaluate the effectiveness of antidepressants in reducing the poor evolution of COVID-19 disease (a composite variable including death, hospitalization and need for mechanical ventilation), and mortality, according the guidelines for Systematic Reviews of Interventions published by the Cochrane library. SOURCE OF DATA: MEDLINE, EMBASE and COCHRANE LIBRARY were consulted up to February 25, 2022. Unpublished studies were searched on clinicaltrials.gov platform. SELECTION OF STUDIES: Seven masked and unmasked, observational and experimental studies evaluating death, hospitalization and need for mechanical ventilation were selected. A second subgroup analysis with mortality variable was performed. DATA EXTRACTION: A full risk of bias assessment was performed addressing issues such as information and confounding bias. ROB2 and Robins-I tools for randomized and no randomized studies were employed respectively. In the quantitative analysis, the risk of publication bias, heterogeneity, estimation of pooled measure and a sensitivity analysis was performed. The pooled final measure was calculated as odds ratio with its correspondent 95% confidence interval. A random effects model was used for this purpose due to the heterogeneity between included studies. Finally, a sensitivity analysis was performed to assess the robustness of final pooled measure. RESULTS: Seven studies were finally considered to calculate the final pooled measure. The effect of intervention was OR 0.73; 95% CI 0.56-0.94. CONCLUSIONS: The use of antidepressants, and specially SSRI could be effective for reducing the risk of poor progression of COVID-19 disease.

Sertraline-Induced Hypoglycemia in Drug-Induced Liver Injury.

Sertraline, a selective serotonin reuptake inhibitor, is a medication recommended as a third line treatment of cholestatic liver injury pruritis. We report a case of a young male who developed liver injury secondary to self-administration of anabolic steroids and who complained of persistent pruritis leading to a treatment by sertraline. Two days later, the patient was admitted to the hospital with a severe hypoglycemia, while the liver function tests were in amelioration. Clinical and biological evaluation were in favor of sertraline-induced hypoglycemia, a side effect rarely reported in non-diabetic patients, and in the context of hepatic injury.

AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Diarrhea.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder associated with significant disease burden. This American Gastroenterological Association Guideline is intended to support practitioners in decisions about the use of medications for the pharmacological management of IBS with predominant diarrhea (IBS-D) and is an update of a prior technical review and guideline. METHODS: The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence and make recommendations. The technical review panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of the following agents: eluxadoline, rifaximin, alosetron, loperamide, tricyclic antidepressants, selective serotonin reuptake inhibitors, and antispasmodics. The guideline panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. CONCLUSIONS: The panel agreed on 8 recommendations for the management of patients with IBS-D. The panel made conditional recommendations for eluxadoline, rifaximin, alosetron, (moderate certainty), loperamide (very low certainty), tricyclic antidepressants, and anstispasmodics (low certainty). The panel made a conditional recommendation against the use of selective serotonin reuptake inhibitors (low certainty).

The inhibitory effect of escitalopram on mouse detrusor contractility: The role of L-type calcium channels.

Selective serotonin reuptake inhibitors (SSRIs) are associated with urinary problems attributed to their central effects. ESC is a preferred SSRI and several case reports described that ESC is related to urinary retention. However, the direct effect of ESC on detrusor contractility is still not completely elucidated. Thus, we investigated the effect of ESC on detrusor contractility and mechanism(s) of its action in isolated mouse detrusor strips. Molecular docking and measurement of intracellular calcium were performed to determine the possible calcium channel blocking effect of ESC. The contractile responses to carbachol (CCh), KCl and electrical field stimulation of detrusor strips were significantly abolished by ESC (10 or 100 µM). ESC relaxed KCl-precontracted detrusor strips concentration-dependently, which was not affected by tetraethylammonium, glibenclamide, 4-aminopyridine, propranolol, L-NAME or methylene blue. ESC (10 or 100 µM) reduced both the CaCl2- and CCh-induced contractions under calcium-free conditions, indicating the role of calcium-involved mechanisms in ESC-mediated relaxation. Furthermore, ESC significantly decreased Bay K8644-induced contraction and the cytosolic calcium level in fura-2-loaded A7r5 cells. Molecular docking study also revealed the potential of ESC to bind L-type calcium (Cav1) channels. Our results demonstrate that ESC inhibits detrusor contractility via blocking Cav1 channels, which provides evidence for the direct effect of ESC on detrusor contractility and its mechanism.

Risk of Fractures With Concomitant Use of Calcium Channel Blockers and Selective Serotonin Reuptake Inhibitors.

BACKGROUND: Despite their frequent concurrent use, little is known about the concomitant use of calcium channel blockers (CCBs) and selective serotonin reuptake inhibitors (SSRIs) on fracture risk. We compared risk of fractures in patients concomitantly treated with CCBs and SSRIs versus CCB-only users. We compared risk of fractures among concomitant CCB-SSRI users initiating cytochrome P450 3A4 (CYP3A4)-inhibiting SSRIs versus non-CYP3A4 inhibiting SSRIs. METHODS: This retrospective cohort study used IBM MarketScan commercial claims and Medicare Supplemental database (2007-2019). We included adults diagnosed with hypertension and depression, newly initiating SSRIs while being treated with CCBs (ie, concomitant CCB-SSRI users) and those who did not (ie, CCB-only users). Primary outcome was the first occurrence of any fracture. We used stabilized inverse probability of treatment weighting (sIPTW) based on propensity scores to balance baseline risk between groups. Cox proportional hazard regression modeling was used to compare fracture risk. RESULTS: We identified 191 352 concomitant CCB-SSRI and 956 760 CCB-only users (mean age = 56 years, 50.1% males). After sIPTW, compared with CCB-only users, CCBs-SSRIs users had a higher risk of fractures (hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.22-1.66). No difference in the risk of fractures between concomitant users of CCB-CYP3A4-inhibiting SSRIs and those of CCB-non-CYP3A4 inhibiting SSRIs (HR: 1.10, 95% CI: 0.87-1.40) was observed. CONCLUSION AND RELEVANCE: Short-term concomitant CCB-SSRI use was associated with increased fracture risk. Concomitant CCBs and CYP3A4-inhibiting SSRIs compared with CCBs and non-CYP3A4 inhibiting SSRIs use was not associated with increased risk.

Co-prescribing of Central Nervous System-Active Medications for COPD Patients: Impact on Emergency Room Visits and Hospitalization.

BACKGROUND: Anxiety and chronic pain are common comorbidities in patients with chronic obstructive pulmonary disease (COPD), which are frequently managed with benzodiazepines (BZDs) and opioids, respectively. OBJECTIVE: The purpose of this study was to determine whether different combinations of opioids, BZD, and their substitutes-gabapentinoids (GABA) and selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs)-are associated with lower risk of acute respiratory events in COPD patients with co-occurring chronic pain and anxiety. METHODS: This retrospective cohort study used a nationally representative sample of Medicare beneficiaries with COPD, chronic pain, and anxiety. Patients were grouped based on drug combination (opioid + BZD/Z-hypnotics, opioid + GABA, opioid + SSRI/SNRI, BZD/Z-hypnotics + GABA, BZD/Z-hypnotics + SSRI/SNRI, GABA + SSRI/SNRI, or ≥3 drugs). The primary outcome was emergency room (ER) visit or hospitalization due to acute respiratory events assessed up to 180 days following initiation of drug combination. Overdose secondary to central nervous system (CNS)-related drugs was also assessed up to 180 days following initiation of drug combination. RESULTS: The drug combination opioid + GABA was associated with decreased risk for ER visit (hazard ratio [HR] = 0.73; 95% CI = 0.61-0.87) and hospitalization (HR = 0.69; 95% CI = 0.55-0.85). Opioid + SSRI/SNRI also showed decreased risk for ER visit (HR = 0.84; 95% CI = 0.71-0.99). There was no significant difference in risk for CNS-related drug overdose among different drug combinations compared with opioid + BZD/Z-hypnotics. CONCLUSION AND RELEVANCE: Opioids in combination with GABA and SSRI/SNRI demonstrate relatively lower risk for acute respiratory events among patients with COPD and comorbid chronic pain and anxiety. The findings emphasize the need for multimodal management in this vulnerable population.

Evaluation of Bleeding in Orthopedic Surgery With Perioperative Use of Serotonergic Antidepressants.

BACKGROUND: The use of serotonergic antidepressants (SADs) is associated with an increase in bleeding, and their exposure during the perioperative period increases the potential bleeding risk in patients undergoing surgical operations. OBJECTIVE: The purpose of this study was to compare the rates of bleeding between patients on perioperative SADs and those not on SADs in patients undergoing orthopedic surgical procedures. METHODS: A retrospective cohort study was conducted with patients who were admitted to a single tertiary care county teaching hospital for orthopedic surgery. Outcomes evaluated were requirements of ≥ 2 units of packed red blood cells (PRBCs) and length of hospital stay for those requiring ≥ 2 units of PRBCs. RESULTS: Of 273 patients, a significantly higher percentage of patients who received SADs required ≥ 2 units of PRBCs (19.3% vs 6.9%; P = 0.0049). Patients who required transfusion had a higher median (interquartile range [IQR]) age (79 [64-84.6] vs 65 [59-75]; P < 0.0001). The risk of requiring ≥ 2 units of PRBCs transfusion was greater for individuals having an anemia comorbidity (odds ratio [OR], 4.55; 95% CI, 1.95-10.62, P = 0.0004). Patients who required ≥ 2 units of PRBCs had a longer median hospital stay than those who did not receive ≥ 2 units of PRBCs (8 [5-10.1] vs 4 [3-5]; P < 0.0001). CONCLUSION AND RELEVANCE: Receiving SADs in the perioperative period is associated with a higher transfusion requirement in patients undergoing orthopedic surgery. Clinicians should be aware of this increased risk for patients who are taking SADs while undergoing surgical procedures.