Serotonin-norepinephrine Reuptake Inhibitors Research Articles

Patients on Antidepressants Are at an Increased Risk of Adverse Events following Total Knee Arthroplasty.

A large proportion of total knee arthroplasty (TKA) patients are on antidepressant medications at the time of surgery. Postoperative outcomes of this patient demographic have not been characterized. This study compared the risk of 90-day adverse events and 5-year survival to revision surgery between patients on antidepressants and those not on antidepressants at the time of surgery. TKA patients were identified from the PearlDiver M151Ortho data set. Of these patients, those taking antidepressants (selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors) and those not taking antidepressants were identified and matched 1:1 based on patient age, sex, and Elixhauser Comorbidity Index scores. The incidence of 90-day adverse events was determined for the two groups and compared by multivariate analyses. Five-year survival to revision surgery was compared between TKA patients on antidepressants and those not on antidepressants. In total, 21.8% of TKA patients were taking antidepressants; 209,320 matched TKA patients on antidepressants and 837,066 not on antidepressants were extracted from the data set. Controlling for patient age, sex, and Elixhauser Comorbidity Index, those on antidepressants at the time of surgery had markedly higher odds of experiencing any (odds ratio [OR] 1.50), severe (OR 1.23), and minor (OR 1.61) adverse events in the 90 days following TKA (P < 0.0001 for all). Five-year survival to revision surgery of TKA patients on antidepressants was 96.4% (95% CI, 96.3% to 96.5%), compared with 96.9% (95% CI 96.8% to 96.9%) for patients not on antidepressants. TKA patients on antidepressants at the time of surgery were found to have markedly greater odds of experiencing 90-day postoperative adverse events but not clinically notable differences in five-year revision surgeries. TKA patients taking antidepressants could constitute a patient population at risk for inferior perioperative outcomes following surgery and thus may require additional counseling and mitigation strategies. Retrospective database study. Level III.

Neuroplasticity and Mechanisms of Action of Acute and Chronic Treatment with Antidepressants in Preclinical Studies

Pharmacotherapy for depression includes drugs such as monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors (NaSSAs), and atypical antidepressants; these drugs exert differentially beneficial effects on symptoms of depression after acute and chronic treatment in animal models. Said effects are established through neuroplastic mechanisms involving changes in neurogenesis and synaptogenesis as result of the activation of intracellular signaling pathways associated with neurochemical and behavioral changes. Antidepressants increase the synaptic availability of monoamines (monoaminergic hypothesis) such as 5-HT, NA, and gamma-aminobutyric acid (GABA) by inhibiting their reuptake or degradation and activating intracellular signaling pathways such as the responsive element binding protein (cAMP-CREB) cascade, which regulates the expression of genes related to neuroplasticity and neurogenesis, such as brain-derived neurotrophic factor (BDNF), in various brain structures implicated in depression. The aim of this review is to analyze the mechanisms of action of different antidepressants and to compare the effects of acute and chronic treatment on neuroplasticity in animal models of depression. A thorough search was conducted in PubMed, Scopus, and Web of Science, focusing on studies since 1996 with keywords like antidepressants, acute and chronic treatment, neuroplasticity, and experimental depression. Studies included had to investigate antidepressant effects experimentally, with full-text access, while excluding those that did not. Data extraction focused on study design, findings, and relevance to understanding treatment differences. Only high-quality, peer-reviewed studies were considered to ensure a comprehensive synthesis of current knowledge.

Hyponatremia Associated with the Use of Common Antidepressants in the All of Us Research Program.

Selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), and norepinephrine-dopamine reuptake inhibitor (NRI) antidepressants can cause hyponatremia through syndrome of inappropriate antidiuretic hormone secretion (SIADH). This study assesses the differential risks of hyponatremia associated with commonly prescribed SSRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram), SNRIs (duloxetine, venlafaxine) and NRI (bupropion), as well as omeprazole as a reference, with a retrospective observational cohort study in the All of Us Research Program, a national multicenter research cohort containing de-identified electronic health records (EHR). Participants who had been prescribed monotherapy with any of eight common antidepressants were included, with each drug considered as a separate arm indexed with a start date. Events were defined as the first occurrence of a low plasma sodium measurement or a clinical diagnosis recorded for either hyponatremia or SIADH. Those who did not have events were censored at their last plasma sodium measurement. A total of 17,439 individuals were exposed to one of the eight antidepressants as monotherapy. The overall incidences for hyponatremia were 0.87% in the first 30 days and 10.5% in the first 3 years in the antidepressant arms. Compared to sertraline, duloxetine (hazard ratio [HR] = 1.37 [1.19-1.58]) and escitalopram (HR = 1.16 [1.01-1.33]) were associated with the highest overall risk of hyponatremia, and bupropion (HR = 0.83 [0.73-0.94]) and paroxetine (HR = 0.78 [0.65-0.93]) were associated with the lowest risk. The risks were unchanged after adjusting for comorbidity and polypharmacy. Such information could help guide providers in managing patients and their risks of hyponatremia when on common antidepressants.

DDDR-44. REPURPOSING SSRI/SNRI TARGETING NEUROTRANSMITTER SIGNALING TO OVERCOME RESISTANCE TO CDK9 INHIBITORS IN DIFFUSE MIDLINE GLIOMA

Abstract Diffuse midline glioma (DMG) is a subset of aggressive brain tumors with few effective therapies. Cyclin-dependent kinase 9 (CDK9i) inhibitors such as zotiraciclib (ZTR) are in clinical trials for glioma, but CDK9i treatment alone may be ineffective due to the development of resistance. To identify CDK9i resistance mechanisms, we analyzed the transcriptomes of DMG xenograft tumors after three weeks of treatment with ZTR, which revealed that transcripts encoding synaptic signaling regulators such as glutamate receptors were overexpressed in surviving cells, suggesting that altered regulation of synaptic signaling may mediate CDK9i resistance. We also performed drug synergy screens using a library of FDA-approved and bioactive compounds and found that drugs that modulate neurotransmitter signaling, such as SSRIs and SNRIs (selective serotonin and serotonin/norepinephrine reuptake inhibitors), increased DMG sensitivity to an IC25 dose of ZTR. Follow-up studies confirm that combinations of structurally distinct CDK9i (ZTR, AZD4573) and SSRI/SNRI (sertraline, duloxetine) synergistically reduce DMG growth in neurospheres by BLISS analysis and show that co-treatment with CDK9i and SSRI/SNRI strongly induces the apoptotic marker cleaved caspase 3 and reduces the CDK9 target phos-Pol2Ser2. Additional phospho-proteomic analyses identified differentially phosphorylated proteins following CDK9i+SSRI treatment, including chromatin regulators, Pol2 elongation factors, and splicing regulators. Further RNAseq studies reveal that CDK9i+SSRI treatment resulted in more robust transcriptional changes than either drug alone, including the downregulation of transcripts associated with ZTR resistance such as GRIA3/4, and SYT12. These observations suggest that CDK9i +SSRI/SNRI drug combinations may overcome some of the transcriptional changes underlying CDK9i resistance. Finally, preclinical studies show that co-treatment with low doses of AZD4573 and sertraline reduces the growth of orthotopic DMG xenografts and prolongs overall survival. Taken together, these data suggest that SSRI/SNRI and CDK9i might be used in combination to synergistically reduce DMG growth and overcome CDK9i resistance.

An overview of the non-procedural treatment options for peripheral neuropathic pain.

Peripheral neuropathic pain is common in patients with peripheral nerve injury and can significantly impact both their function and quality of life. There is a wide variety of non-interventional treatment approaches, including pharmacologic therapy, physical/occupational therapy, modalities (therapeutic, mechanical, thermal, etc.), psychology, and lifestyle modification. First line pharmacologic therapy for peripheral neuropathic pain includes gabapentinoids, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors. Other classes of medications, such as topical treatments, opioids, and cannabinoids, have more limited usefulness in treatment but remain part of a treatment regimen. Physical and occupational therapy, psychological interventions, and lifestyle medicine are important adjuncts in the treatment and prevention of future peripheral neuropathic pain. The strength of the evidence supporting each intervention varies, with that for pharmacologic intervention being the strongest. A combination of these options tailored to the individual needs of the patient likely will result in the best treatment outcome for peripheral neuropathic pain.

Retrospective study on the use of venlafaxine in 176 cats diagnosed with behavioral disorders

Behavioral disorders in cats can severely affect their well-being and the owner-pet relationship, sometimes resulting in relinquishment or euthanasia. While selective serotonin reuptake inhibitors (SSRIs) and tricyclic anti-depressants (TCAs) have been routinely used, venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI) that has been effective in treating various human psychiatric conditions, offers potential for veterinary use in addressing feline behavioral disorders.This retrospective study evaluates the use of venlafaxine in 176 cats diagnosed with a variety of behavioral disorders to assess its efficacy, safety, and ease of administration within privately owned-cats. Cats were from multiple veterinary practices which collected data on dosage, administration, adverse effects, and overall treatment outcomes. Both quantitative and qualitative data were gathered through veterinary records and owner surveys, allowing for a comprehensive analysis of venlafaxine’s effect on cat behavior and wellbeing.Findings from this study highlight venlafaxine as an effective treatment for a broad spectrum of behavioral disorders in cats, with a noteworthy rate of owner compliance in administering the drug, facilitated by its convenient formulation. Adverse effects were reported in 35.4% of the cats (N=61), they were primarily minor and of short duration. Dosage adjustments based on individual responses and specific behavioral diagnoses improved treatment outcomes and minimized adverse effects. A significant portion of the treated population exhibited substantial behavioral improvement, with 20% (N=35) of cats successfully weaned off the medication without a relapse of clinical signs.Venlafaxine represents a promising pharmacological intervention for behavioral disorders in cats, meriting further investigation in prospective studies.

Deprescribing Antidepressants in Children and Adolescents: A Systematic Review of Discontinuation Approaches, Cross-Titration, and Withdrawal Symptoms.

Background: Antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly used to treat depressive, anxiety, and obsessive-compulsive disorders in youth. Yet, data on discontinuing these medications, withdrawal symptoms, and strategies to switch between them are limited. Methods: We searched PubMed and ClinicalTrials.gov through June 1, 2024, to identify randomized controlled trials assessing antidepressant discontinuation in youth. We summarized pediatric pharmacokinetic data to inform tapering and cross-titration strategies for antidepressants and synthesized these data with reports of antidepressant withdrawal. Results: Our search identified 528 published articles, of which 28 were included. In addition, 19 records were obtained through other methods, with 14 included. The corpus of records included 13 randomized, double-blind, placebo-controlled trials (3026 patients), including SSRIs (K = 10), SNRIs (K = 4), andTCAs (K = 1), ranging from 4 to 35 weeks. Deprescribing antidepressants requires considering clinical status, treatment response, and, in cross-titration cases, the pharmacokinetics and pharmacodynamics of both medications. Antidepressant withdrawal symptoms are related to the pharmacokinetics of the medication, which vary across antidepressants and may include irritability, palpitations, anxiety, nausea, sweating, headaches, insomnia, paresthesia, and dizziness. These symptoms putatively involve changes in serotonin transporter expression and receptor sensitivity, impacting the serotonin, dopamine, and norepinephrine pathways. Conclusions: Although approaches to deprescribing antidepressants in pediatric patients are frequently empirically guided, accumulating data related to the course of relapse and withdrawal symptoms, as well as the pharmacokinetic and pharmacodynamic properties of medications, should inform these approaches. Recommendations within this review support data-informed discussions of deprescribing-including when and how-that are critically important in the clinician-family-patient relationship.

Current Developments in the Treatment of Postpartum Depression: Zuranolone.

Pregnancy is a period in a woman's life during which she experiences physiological, psychological, and social changes. These changes can lead to various mental illnesses, including postpartum depression (PPD), which is common during the perinatal period. Postpartum depression is a significant cause of morbidity and mortality for both the mother and baby. A peripartum-onset major depressive episode is defined as PPD when it occurs during pregnancy or up to 4 weeks postpartum. The frequency of this condition is extremely high. Its etiology is influenced by biological, psychological, and sociocultural factors. Depressed mood, anhedonia, feelings of guilt, irritability, lack of concentration, psychomotor agitation or retardation, sleep disturbance, and changes in appetite and weight can all be symptoms of PPD. There are various treatment options available, many of which are adapted from those used for major depression. Selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants, estradiol, progesterone, psychotherapies, electroconvulsive therapy, and brexanolone can be used to treat PPD. In addition, the newest drug approved by the FDA (Food and Drug Administration) for this condition is oral zuranolone. This review aims to analyze recent developments on zuranolone, the latest drug approved by the FDA for PPD, based on current studies.

The Association of Antidepressants in Late Pregnancy with Postpartum Hemorrhage: Systematic Review of Controlled Observational Studies.

Introduction: Despite advances in obstetric care, postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide. Prior reviews of studies published through 2016 suggest an association of antidepressant use during late pregnancy and increased risk of PPH. However, a causal link between prenatal antidepressants and PPH remains controversial. Objectives: This systematic literature review aimed to synthesize the empirical evidence on the association of antidepressant exposure in late pregnancy with the risk of PPH, including studies published before and after 2016. Methods: A systematic literature search was conducted using PubMed, OVID Medline, EMBASE, SCOPUS, PsycINFO, and CINAHL from inception to September 9, 2023. Original, peer-reviewed studies (published in English) that reported on the frequency or risk of PPH in women with evidence of antidepressant use during pregnancy and included at least one control group were included. Results: Twenty studies (eight published after 2016) met inclusion criteria, most of which focused on the risks of PPH associated with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). The main findings from the individual studies were mixed, but the majority documented statistically significant associations of PPH with late prenatal exposure, especially for exposures occurring within 30 days of delivery, compared with unexposed deliveries. Fourteen studies addressed underlying antidepressant indications or their correlates. Few studies focused on prenatal antidepressants and the risk of well-defined severe PPH or on antidepressant dose changes and general PPH risk. None examined competing risks of antidepressant discontinuation on mental health outcomes. Conclusions: Late pregnancy exposure to antidepressants may be a minor risk factor for PPH, but it is unclear to what extent reported associations are causal in nature, as opposed to correlational (effects related to nonpharmacological factors including maternal indication). For patients needing antidepressants during pregnancy, current evidence does not favor routinely discontinuing antidepressants specifically to reduce the risk of PPH.

Risk of osteoporotic fractures in menopausal women with common mental health diagnoses prescribed SSRIs/SNRIs: cohort and self-controlled case series analyses

SummaryIn a population-based cohort study of menopausal women with common mental health diagnoses, SSRIs/SNRIs were associated with a 32% increased risk of osteoporotic fractures. The risk of osteoporotic fractures was particularly increased for longer periods of treatment with SSRIs/SNRIs (> 5 years) and in younger menopausal women (< 50 years old).PurposeTo investigate the association between selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and the risk of osteoporotic fractures (OF) in menopausal women with common mental health diagnoses (CMHD).MethodsWe conducted the study with two designs (cohort and self-controlled case series [SCCS]), using the IQVIA Medical Research Database (IMRD) UK. The source population comprised women aged ≥ 50 years and women with a record indicating menopause (< 50 years). All women had a recorded CMHD. For the cohort analysis, the risk of OFs was estimated by comparing women prescribed SSRIs/SNRIs (exposed) to those not exposed. Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CIs). For the SCCS, women acted as their own controls; periods of exposure to SSRIs/SNRIs were compared to periods of non-exposure using conditional Poisson regression to estimate incidence rate ratios (IRR) with 95% CIs.ResultsWe identified 292,848 women, of whom 35,222 experienced OFs within a median follow-up of 6.01 years. We found strong evidence of an association between SSRIs/SNRIs and the risk of OFs (adjusted HR = 1.32, 95% CI:1.29–1.35). Compared to periods of no exposure, SSRIs/SNRIs increased the risk of OFs during the first 30 days (IRR = 1.38, 95% CI:1.26–1.51), during the first 90 days (IRR = 1.58, 95% CI: 1.48–1.69), and the remaining exposure (IRR = 1.42, 95% CI:1.37–1.48).ConclusionsIn a population of menopausal women with CMHDs, the prescribing of SSRIs/SNRIs antidepressants was associated with a higher risk of OFs. Careful assessment of osteoporosis risk needs to be considered when treating menopausal women with SSRIs/SNRIs antidepressants.

Zuranolone for the Treatment of Postpartum Depression.

To review the safety, efficacy, and tolerability of zuranolone for the treatment of postpartum depression. A literature search was conducted through PubMed using the following terms: zuranolone, postpartum depression, perinatal depression, SAGE-217, and allopregnanolone analogue. Articles describing the pharmacology, pharmacokinetics, efficacy, safety, and/or tolerability of zuranolone were included in this review. Zuranolone is an allopregnanolone analogue that works through modulation of the GABAA receptor. Clinical trials have demonstrated that compared with placebo, zuranolone is effective in treating patients with postpartum depression. Common adverse events associated with zuranolone include fatigue, somnolence, headache, dizziness, diarrhea, sedation, upper respiratory tract infection, and nausea. Pharmacotherapeutic options to treat postpartum depression include selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, with the medication brexanolone (the first allopregnanolone analogue) reserved for severe postpartum depression. Zuranolone, the newest medication in its class, is without the same limitations as brexanolone, thus affording providers an additional easy-to-use option for treating postpartum depression.

Pharmacologic and Nonpharmacologic Management of Neuropathic Pain.

Disorders of the somatosensory nervous system that cause neuropathic pain are treated in a variety of ways. Herein, we introduce a stepwise approach to treating neuropathic pain. We then summarize the available data and guidelines for treating neuropathic pain, both with pharmacologic and nonpharmacologic methods, and provide a synthesized algorithm highlighting the similarities and differences between recent guidelines on the management of neuropathic pain. Pharmacologic treatments are primarily antiseizure medications (e.g., gabapentinoids, sodium channel blockers) and antidepressant medications (e.g., tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors), though other medications and interventional pharmacologic therapies can also be considered. There are a wide variety of nonpharmacologic treatments for neuropathic pain including neuromodulation, nerve stimulation, physiotherapy, movement therapies, lifestyle modification, nutritional supplements, acupuncture, and mind-body techniques.

Incidence and risk factors of antidepressant withdrawal symptoms: a meta-analysis and systematic review.

Antidepressants are among the most extensively prescribed psychotropic drugs worldwide. Discontinuation induced withdrawal symptoms have been reported for almost all antidepressants. The incidence of antidepressant withdrawal syndrome (AWS) and other characteristics remain unknown. We searched the PubMed, Embase, PsycINFO, MEDLINE, CINAHL, and Cochrane Central Register of Controlled Trials databases from inception to December 31, 2023. Randomized double-blinded trials, longitudinal or cross-sectional studies that reported the incidence and other characteristics of antidepressant withdrawal symptoms were included. The pooled incidence of AWS was calculated by a random effects model. We included 35 studies, of which 2 studies just provided incidence of specific withdrawal symptoms, and 4 studies only described other characteristics. The pooled incidence of AWS from all available studies was 42.9%, from 11 RCTs was 44.4%, in studies in which the treatment duration was mostly 8-12 weeks, which usually appear within 2 weeks, and were generally measured for <4 weeks. The incidence in selective serotonin-norepinephrine reuptake inhibitors was the lowest (29.7%), followed by selective serotonin reuptake inhibitors (45.6%) and tricyclic antidepressants (59.7%), without significant differences (p = 0.221). Treatment duration showed a dose-response to the incidence of AWS (6-12 W: 35.1%, 12-24 W: 42.7%, >24 W: 51.4%). The half-life did not show such a simple dose-dependent relationship. The pooled estimate was robust regardless whether withdrawal symptoms were measured in RCTs or observational studies (including face-to-face and online survey studies). Tapering the dose reduced the incidence of AWS compared with abrupt stoppage (34.5% vs 42.5%), without a significant difference (p = 0.484). Risk factors for withdrawal symptoms included being female, younger, experiencing adverse effects early in treatment, taking higher doses or longer duration of medication, abrupt cessation of drugs, and those with a lower clearance of drugs or with serotonin 1A receptor gene variation. The findings suggest the incidence of AWS are common and some clinical characteristics and risk factors which can help clinicians identify who is at greater risk of experiencing AWS. Discontinuation studies on long-term antidepressant users with long follow-up periods are required in the future.

Association between psychopharmacotherapy and postpartum hemorrhage

BackgroundPrior studies evaluating the relationship between psychopharmacotherapy (PPT), and postpartum hemorrhage (PPH) have yielded inconsistent findings. Clarifying this potential relationship is important for effective counseling and risk stratification. ObjectivesOur primary objective was to evaluate the association between prenatal exposure to PPT (any drug class) and the occurrence of PPH requiring transfusion of packed red blood cells (PPH+pRBC) after systematically adjusting for known hemorrhage risk factors at the time of admission for delivery. Secondary objectives were to evaluate the association between individual PPT drug classes and PPH+pRBC, and the association between treatment intensity of mental health condition and PPH+pRBC. Finally, we evaluated the association between PPT and a broader definition of PPH that included deliveries requiring multiple uterotonic drugs. Study designThis is a retrospective cross-sectional study of all pregnancies delivered at 23 weeks of gestational age or greater at seven hospitals within a large academic health system in New York between January 2019 and December 2022. There were no exclusion criteria, as postpartum hemorrhage risk assessment is necessary for all patients admitted for delivery. We assessed exposure to prenatal PPT, including selective serotonin reuptake inhibitors (SSRIs: escitalopram, fluoxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (SNRIs: duloxetine, venlafaxine), dopamine-norepinephrine reuptake inhibitors (DNRIs: buproprion), benzodiazepines (alprazolam, diazepam, lorazepam), and others (buspirone, trazodone, zolpidem). Multivariable logistic regression was performed to evaluate the relationship between PPT and PPH+pRBC, while systematically adjusting for known hemorrhage risk factors at the time of hospital admission. Similar regression analyses were performed to address the secondary objectives. ResultsA total of 107,425 deliveries were included. Non-Hispanic White patients constituted the largest race and ethnicity group (43.4%), followed by Hispanic patients (18.7%), Asian or Pacific Islander patients (13.2%), and non-Hispanic Black patients (12.3%). Prenatal exposure to PPT occurred in 3.6% of pregnancies (n=3,834). The overall rate of PPH+pRBC was 2.9% (n=3,162). PPH+pRBC occurred more frequently in pregnancies exposed to PPT than in pregnancies which were not exposed (5.5% vs. 2.8%, respectively; aOR 2.10, 95% CI: 1.79–2.44). SSRIs and benzodiazepine monotherapy were each associated with higher odds of PPH+pRBC than nonexposure. Compared to patients without a mental health condition, monotherapy was associated with nearly 2-fold increased odds and combination PPT was associated with nearly 4-fold greater odds of PPH+pRBC after adjustment for confounding variables (monotherapy: aOR 1.94, 95% CI: 1.64–2.28; combination PPT: aOR 3.96, 95% CI: 2.61–5.79). Patients with untreated mental health conditions (no PTT) had no increased odds of PPH+pRBC compared to those without mental health conditions. Finally, after adjusting for covariates, a positive association was found between PPT and PPH requiring pRBC transfusion and/or the use of two additional uterotonic agents beyond routine postpartum oxytocin (aOR 1.53, 95% CI: 1.35–1.73). ConclusionsPrenatal PPT exposure is associated with increased odds of clinically significant PPH+pRBC after adjusting for other hemorrhage risk factors. Combination PPT was associated with greater odds of PPH+pRBC than monotherapy.

Postpartum Psychiatric Outcomes and Sick Leave After Discontinuing SSRI or SNRI in Pregnancy

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are consistently reported to be discontinued by approximately half of pregnant women. Little is known about how this may be associated with postpartum psychiatric health. To investigate associations of SSRI or SNRI discontinuation in pregnant women with depression or anxiety and psychiatric health and sick leave absence after childbirth. This population-based cohort study was conducted between 2006 and 2019 using data from Swedish population-based registers. Pregnant women with a filled prescription of an SSRI or SNRI in the 90 days before pregnancy without recorded comorbid or severe psychiatric conditions were included. Analyses were performed in November 2023. K-means for longitudinal data was used to cluster trajectories of SSRI and SNRI use during pregnancy, resulting in 2 trajectory groups based on the number of days covered, defined as continued and discontinued use groups. The primary outcome was psychiatric-related hospitalizations by 90 days after childbirth. Secondary outcomes included psychiatric-related outpatient visits, self-harm and suicide, and any-cause mortality by 90 days after childbirth and all outcomes plus sick leave absence by 1.5 years after childbirth. Among 27 773 pregnant women (17 241 aged ≥30 years [62.1%] at childbirth), 13 184 women (47.5%) had discontinued SSRI or SNRI use and 14 589 individuals (52.5%) had continued use. Individuals in the discontinued compared with continued use group were younger (5588 women [42.4%] vs 4944 women [33.9%] aged <30 years), less educated (4281 women [32.5%] vs 5821 women [39.9%] who completed postsecondary education or above), and more likely to have smoked in early pregnancy (1445 individuals [11.0%] vs 1180 individuals [8.1%]), been born in a non-Nordic country (1641 individuals [12.4%] vs 975 individuals [6.7%]), and used anxiolytics (1301 individuals [9.9%] vs 1119 individuals [7.7%]) and hypnotics and sedatives (1609 individuals [12.2%] vs 1510 individuals [10.4%]). Psychiatric-related hospitalizations occurred in 49 individuals (0.4%) in the discontinued vs 59 individuals (0.5%) in the continued use group in the 90 days after childbirth, with an adjusted hazard ratio (aHR) of 1.28 (95% CI, 0.85-1.91), while at 1.5 years after childbirth, the aHR was 0.81 (95% CI, 0.66-1.00). Lower hazard rates for psychiatric-related outpatient visits in the discontinued vs continued use group at 90 days (aHR, 0.59; 95% CI, 0.53-0.66) and 1.5 years (aHR, 0.60; 95% CI, 0.57-0.64) after childbirth were found. No difference in sick leave absence was found; however, individuals who discontinued had fewer days of sick leave by 1.5 years after childbirth than those who continued (mean [SD], 44.6 [70.6] days vs 53.1 [82.3] days). In this study, approximately half of pregnant women discontinued SSRIs or SNRIs, and discontinuation during pregnancy was not associated with adverse psychiatric-related outcomes, including hospitalizations, outpatient visits, suicidal behavior, or sick leave absence in the 90 days or 1.5 years after childbirth.

Estimating the benefit of esketamine nasal spray versus real-world treatment on patient-reported functional remission: results from the ICEBERG study.

Treatment resistant depression (TRD) affects approximately 10-30% of patients with major depressive disorder, and most patients with TRD do not respond to real-world treatments (RWT). Treatment with esketamine nasal spray (NS) plus a selective serotonin or serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) has significant long-term clinical benefit over RWT in patients with TRD. However, the impact on patient-reported function remains to be determined. The ICEBERG analysis was an indirect treatment comparison performed using data from two studies of patients with TRD: SUSTAIN-2 (esketamine NS; NCT02497287) and the European Observational TRD Cohort (EOTC; RWT; NCT03373253; clinicaltrials.gov). Here, patient-reported functional remission, assessed using the Sheehan Disability Scale (SDS), was defined as SDS ≤6 at Month 6. Analyses were conducted using propensity score re-weighting and multivariable models based on 18 covariates. At Month 6, the probability of functional remission in esketamine NS-treated patients from SUSTAIN-2 (n=512) was 25.6% (95% confidence interval [CI] 21.8-29.4), while the adjusted probability for RWT patients from the EOTC (n=184) was 11.5% (95% CI 6.9-16.1; relative risk: 2.226 [95% CI 1.451-3.416]; p=0.0003). In the total combined population (N=696), patients who did not achieve clinical response or remission had a low probability of achieving functional remission (5.84% and 8.76%, respectively). However, for patients who did achieve clinical response or remission, the probability of achieving functional remission was greater (43.38% and 54.15%, respectively), although many still did not achieve this status. For patients with TRD, esketamine NS had a significant functional benefit versus RWT after 6 months of treatment. Irrespective of treatment, achievement of clinical response or remission was insufficient to attain functional remission. Nevertheless, clinical remission increased the likelihood of achieving functional remission, further supporting an important role for clinical remission in for the path towards functional recovery.

Serotonergic Antidepressants are Associated With Higher Rates of Hematoma After Anterior Cervical Spine Surgery: A Large Propensity-matched Cohort Analysis.

Large database propensity-matched retrospective cohort analysis. This study aimed to investigate the potential effects of serotonergic antidepressants on outcomes after anterior cervical spine surgery (ACSS). It was hypothesized that the perioperative use of serotonergic antidepressants would be associated with higher rates of hematoma formation and worse outcomes after ACSS. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been associated with worse outcomes after orthopaedic procedures. A retrospective cohort analysis was performed using TriNetX, an aggregated and de-identified electronic health record platform. Patients who underwent anterior cervical surgery were included via Current Procedural Terminology (CPT) codes and the International Classification of Disease (ICD-10) encounter diagnosis codes. Cohorts were 1:1 propensity matched across seven demographic and medical comorbidity parameters, and outcomes were compared. The incidence of adverse outcomes, as well as healthcare utilization, within 14 days, 30 days, 90 days and 2-years post-operatively was evaluated. Following propensity matching, each cohort consisted of 9,249 patients, for a total of 18,498 patients included in final statistical analysis. SSRI/SNRI's were associated with higher odds of hematoma formation within 7-days (0.69% vs. 0.46%, OR 1.5 [95% CI 1.02-2.2], P=0.04) and within 14-days postoperatively (0.81% vs. 0.52%, OR 1.6 [95% CI 1.1-2.3], P=0.01. Within 30- and 90-days, SSRI/SNRI's were associated with higher risk of emergency department utilization (30-day OR 1.30 [1.1-1.4]; 90-day OR 1.3 [1.2-1.4]) and irrigation & debridement (I&D) (30-day OR 1.9 [1.2-3.0]). SSRIs/SNRIs were also associated with significantly higher risk of I&D within 2-years (OR 1.3 [1.1-1.6]). The use of serotonergic antidepressants perioperatively was associated with higher odds and risk of numerous outcomes, including hematoma formation, emergency department utilization and the need for irrigation & debridement. Future prospective studies are required to confirm these results. III; retrospective cohort analysis.

The Impact of Antidepressants on COVID-19 and Post-Acute COVID-19 Syndrome: A Scoping-Review Update

On May 20, 2024, this systematic scoping review in PUBMED identified 1016 articles related to AD and COVID-19, Long COVID and SARS-COV-2. These included 10 retrospective "large scale" studies (> 20000 chart reviews), 8 prospective clinical trials (plus 4 regarding Long COVID), 11 placebo-controlled randomized (RCT) (plus 2 regarding Long COVID) and 15 meta-analyses. COVID-19: Retrospective studies with cohorts taking AD primarily for psychiatric comorbidities or chronic pain conditions directly prior to SARS-COV-2 infection described that this substance class (most studied: Selective Serotonin Re-Uptake Inhibitors (SSRI) and Selective Serotonin Noradrenaline Re-Uptake Inhibitors (SSNRI)) were associated with (i) significantly fewer SARS-COV-2 infections and (ii) a milder course of COVID-19 ("COVID-19 protection"). Ten of the 11 RCTs found regarding COVID-19 tested fluvoxamine, as this old AD appeared suitable as a prophylactic agent against severe COVID-19, taking into account its in vitro potency against the progression of intracellular sepsis cascades. Therefore, most (12 out of 15) meta-analyses also referred to fluvoxamine. They found (iii) a significant (40-70% reduction) in mortality, intubation and hospitalization rates when fluvoxamine was used as an add-on to standard therapy for mild to moderate COVID-19. When this AD was used in the early stages of the disease, it was more successful than when it was given later in advanced, severe COVID-19 (e.g. severe pneumonia, final sepsis stages). A dose dependency was observed: 2x50 mg fluvoxamine over 15 days was less effective than 2x100 or even 3x100 mg with an adverse event profile still at the placebo level. Direct comparisons with drugs approved for COVID-19 do not yet exist. A first indirect meta-analytical comparison showed an advantage of paxlovid or molnupiravir versus fluvoxamine against the development of severe COVID-19: risk reduction of 95% (I2 = N/A, but only one study) or 78% (I2=0) versus 5+-5% (I2=48). However, an add-on of fluvoxamine was still significantly more efficacious than symptom-oriented standard therapy alone. Long COVID: A common Long COVID phenotype with dominant anxiety and depression symptoms, which responds to AD, relaxation therapy and/or psychotherapy, has now been identified. Casuistics report positive effects of AD on fatigue, cognitive and autonomic dysfunctions. A first large prospective open-label RCT has just shown significantly more favourable courses, less viral load and less pro-inflammatory cytokines in the treatment of mild to moderate COVID-19 with fluvoxamine versus standard treatment, also with regard to the subsequent development of neuropsychiatric and pulmonary Long COVID or fatigue. Overall, there is promising evidence of a preventive effect of AD (especially fluvoxamine) against progression to severe COVID-19 and against the development of Long COVID. It is likely, that the entire AD substance class could be effective here. This assumption is based on the results of retrospective large scale studies, but awaits verification by better controlled studies. The potential effectiveness/efficacy (currently low and moderate confidence of the evidence for the entire substance class and specifically fluvoxamine, respectively) of fluvoxamine as an add-on against COVID-19 and possibly also directly against Long COVID could stimulate similar projects in other infectious diseases that also have the potential to pose a lasting threat to the health of those affected. We consider the evidence to date to be sufficient to be able to emphasize a possible positive effect of these substances in the psychoeducation of patients with COVID-19 or Long COVID who are already receiving AD for other conditions - especially also against the symptoms associated with the viral disease or its consequences. In regions where neither vaccines nor antiviral agents currently approved for the prevention or treatment of COVID-19 are available, AD and in particular fluvoxamine would be a cost-effective alternative to protect against a severe course, even if this AD appears to have a smaller effect against COVID-19 than the currently approved antiviral agents, but with presumably better tolerability. A direct comparative clinical trial with approved antiviral agents is still pending and should be positive to further open the door for a guideline-based recommendation of fluvoxamine (or perhaps even AD) for COVID-19 or its aftermath.

Selective Serotonin Reuptake Inhibitors and Solitary Rectal Ulcer Syndrome: A Bloody Relationship.

Solitary rectal ulcer syndrome (SURS) is a poorly understood and uncommon benign disorder of the lower gastrointestinal tract. It presents with various symptoms, often misinterpreted as inflammatory bowel disease. To date, there is no association between the use of selective serotonin reuptake inhibitors (SSRIs) and SURS. A 29-year-old male on paroxetine for six months and with a non-contributory surgical history presented to the clinic due to three months of haematochezia, abdominal pain and mucoid discharge. Physical examination and a review of systems were unremarkable; a colonoscopy demonstrated a suspicious ulcerated lesion in the rectum, which was identified as SURS on biopsy. The patient was advised lifestyle and dietary modifications. In addition, paroxetine was discontinued, and patient was switched to venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Subsequently, the patient's symptoms resolved gradually, and he did not report any signs of recurrence on follow-up. Literature confirms that SSRIs can increase the occurrence of GI ulceration yet focuses specifically on upper gastrointestinal bleeding rather than rectal bleeding. This finding raises the need for further research. SURS is often underdiagnosed or misdiagnosed as inflammatory bowel disease.The pathophysiology and aetiology behind SURS remain obscure.This case points to a potential correlation between SSRIs use and SURS development.

The impact of antidepressant medications on the course of inflammatory bowel diseases

Introduction and Objective: Inflammatory bowel diseases (IBD) and anxiety, as well as depressive disorders, can coexist. Depression may affect IBD symptoms and vice versa. The aim of our study is to determine the impact of different classes of antidepressant medications in the treatment of IBD with comorbid depressive episodes, to summarize the most commonly used therapies, and to identify the most effective practices in treating inflammatory diseases with coexisting depressive episodes. Materials and Methods: A review of the available literature was conducted by searching the PubMed and Google Scholar databases using the following keywords: inflammatory bowel diseases, depression, antidepressants, in both English and Polish, up until July 19, 2024. To ensure the high quality of the narrative review, the SANRA scale (a scale for the quality assessment of narrative review articles) was used. Results: Studies indicate that depressive symptoms occur in approximately 25-27.5% of patients with inflammatory bowel diseases (IBD). Treatment of depression in IBD patients often includes the use of antidepressant medications, such as selective serotonin reuptake inhibitors (SSRIs), which not only reduce depression but also exhibit anti-inflammatory effects. SSRIs may also be effective in improving patients' quality of life; however, they may cause side effects such as diarrhea and an increased risk of bleeding. In addition to SSRIs, other antidepressants, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and atypical antipsychotics, are also used and may have a beneficial impact on the course of the disease. Conclusions: In patients with IBD and comorbid depression, SSRIs are most commonly used, followed by TLPDs, SNRIs, and atypical antipsychotics. Drugs from these groups may have a beneficial effect on depressive symptoms, but also affect the course of IBD. Further clinical studies are needed to establish precise guidelines for the use of these drugs in patients with IBD.