Long-term Use Of Selective Serotonin Reuptake Inhibitors Research Articles

SSRI Induced Sleep Bruxism and Jaw Muscle Dystonia- Management with Low Dose Quetiapine Along with Occlusal Guards (D9944, D9945)- Two Case Reports

Background: Long term use of SSRIs (selective serotonin re uptake inhibitors) sometimes induces a problem called nocturnal or sleep bruxism which is nothing but uncoordinated jaw muscle movements which leads to grinding and clenching of teeth. The undesired effect of SSRIs produces a muscle stiffness, jaw and neck muscle tenderness, continuous toothache, hypersensitivity, tooth fracture and TMJ pain. Different treatment modalities are there to manage this kind of problem without hampering the psychiatric prognosis of the patient. Here two cases of SSRI induced sleep bruxism along with successful managements are discussed which will throw some light to the potential treatment approaches of such rare disorders.

Dysregulation of adipogenesis and disrupted lipid metabolism by the antidepressants citalopram and sertraline

Selective Serotonin Reuptake Inhibitors (SSRIs) are widely used medications for the treatment of major depressive disorder. However, long-term SSRI use has been associated with weight gain and altered lipid profiles. These findings suggest that SSRIs may have negative effects on metabolism. Exposure to certain chemicals called ‘obesogens’ is known to promote lipid accumulation and obesity by modulating adipogenesis. Here, we investigated whether citalopram (CIT) and sertraline (SER) interfere with the process of adipogenesis, using human mesenchymal stem cells (MSCs) in a 2D and a 3D model. Assessment of intracellular lipid accumulation by fluorescence staining was used as a measure for enhanced adipogenesis. To explore possible mechanisms behind SSRIs' effects, receptor mediated activity was studied using responsive cell lines for various nuclear receptors. Furthermore, RNA sequencing was performed in the 3D model, followed by differential gene expression and pathway analysis. A dose dependent increase in lipid accumulation was observed in both models with CIT and SER. For the 3D model, the effect was seen in a range close to reported steady-state plasma concentrations (0.065–0.65 μM for SER and 0.12–0.92 μM for CIT). Pathway analysis revealed unexpected results of downregulation in adipogenesis-related pathways and upregulation in phospholipids and lysosomal pathways. This was confirmed by an observed increase in lysosomes in the 2D model. Our findings suggest lysosomal dysfunction and disrupted lipid metabolism in mature adipocytes, leading to excessive phospholipid synthesis. Moreover, important adipogenic processes are inhibited, potentially leading to dysfunctional adipocytes, which might have implications in the maintenance of a healthy metabolic balance.

Cardiovascular toxicity induced by SSRIs: Analysis of spontaneous reports submitted to FAERS

Depression diagnoses have surged recently, and selective serotonin reuptake inhibitors (SSRIs) are the go-to treatment. However, studies indicate that long-term use of SSRIs can increase cardiovascular risk without systematic evaluation of the drug class. To offer clinical guidance, we performed an evaluation of the association between the six most commonly prescribed SSRIs and cardiovascular adverse events. Using the FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q2 2022, we conducted a disproportionality analysis and determined the magnitude of significant signals using statistical shrinkage transformations. Our study revealed that arrhythmias, torsades de pointes/QT prolongation, cardiomyopathy, and hypertension were among the most prevalent adverse events linked to SSRIs. Our analysis also showed a significant association between SSRIs and the aforementioned adverse events, with higher incidence in middle-aged and elderly patients and women. We further observed a rising trend in the incidence of arrhythmias, torsades de pointes/QT prolongation, and hypertension, highlighting the need for heightened cardiac monitoring in patients on SSRIs.

Selective Serotonin Reuptake Inhibitors: How Long Is Long Enough?

Selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications. They are among the first-line medications for several chronic or relapsing-remitting psychiatric conditions, including major depressive disorder and anxiety disorders. The advantages of SSRI use include ease of titration and their tolerability and safety profile. Guidelines for the short-term use of SSRIs are widely available, but there is no well-organized guidance on how and whether to maintain a patient on SSRIs for the long-term. In this article, we discuss the benefits and possible adverse consequences of long-term SSRI use, as well as clinical practice considerations when using SSRIs chronically. The major benefit of long-term SSRI use is relapse prevention. The current literature suggests that the general health risks of long-term SSRI use are low; however, further research, particularly in special populations including youth and the elderly, is needed. Long-term SSRI use increases the risk of tachyphylaxis and discontinuation syndrome. Recognizing that many patients may remain on SSRIs for many years, there are several factors that prescribers should consider if they choose to use an SSRI when initiating treatment and during long-term monitoring. The decision to continue or to discontinue an SSRI should be an active one, involving both the patient and prescriber, and should be revisited periodically. Patients who remain on SSRIs for the long-term should also have periodic monitoring to reassess the risk-benefit ratio of remaining on the SSRI, as well as to assess the safety, tolerability, and efficacy of the medication.

Compliance With Fluoxetine Use in Men With Primary Premature Ejaculation

BackgroundPremature ejaculation (PE) is a common sexual dysfunction for which selective serotonin reuptake inhibitors (SSRIs) have been used effectively for treatment. However, compliance with therapy and predictors of long-term SSRI use in the treatment of PE are not well known. AimTo analyze our experience with drop-out rates with fluoxetine in the primary PE population and to identify predictors of continued use of this agent. MethodsMen with primary PE constituted who used fluoxetine and had at least 12 months follow-up constituted the study population. Subjects underwent a comprehensive interview to ascertain self-reported (non-stopwatch) intravaginal ejaculatory latency time (IELT), self-rated control over ejaculation, and personal and patient-reported partner distress due to PE. Patients were treated with fluoxetine 20 mg daily, with the possibility of dose titration up or down based on efficacy and side effects. OutcomesThe PE parameters of interest included self-reported IELT, self-rated control over ejaculation, personal and partner distress due to PE, and medication adherence. Results130 men were included in the study. Dropout rates at 6 and 12 months were 56% and 72%. Self-rated “poor” ejaculatory control decreased from 98%–41% (P < .01), high personal distress from 47%–11% (P < .01), and high partner distress rates from 72%–27% (P < .01). Predictors of continued use at 12 months included high partner distress, being unpartnered, and having a post-treatment IELT ≥5 minutes (P < .01). Overall side effects included headache (5%), dizziness (4%), nausea (5%), nervousness (5%), and sleepiness (8%); however, moderate to severe side effects reported included nausea (2%), sleepiness (2%), headache (2%), and dizziness (2%). Clinical ImplicationsCompliance with SSRIs is a well-described problem in the depression literature, but data are sparse regarding continued use of SSRIs in the treatment of PE. Strengths and LimitationsWe report on 12-month compliance with SSRIs for the treatment of PE. Our early compliance rates were more encouraging than what has been reported in the past. However, IELT was self-reported and not measured objectively, and we did not use validated patient-reported outcomes but rather self-reported ejaculatory control and distress levels, which have limitations. ConclusionsFluoxetine is an effective agent for the treatment of PE with significant improvement realized in IELT, ejaculatory control, and distress levels for both men and their partners. Despite its efficacy, continued use of fluoxetine beyond 6 months is poor.Jenkins LC, Gonzalez J, Tal R, et al. Compliance with Fluoxetine Use in Men with Primary Premature Ejaculation. J Sex Med 2020;16:1895–1899.

Selective serotonin reuptake inhibitor, fluoxetine, impairs E-cadherin-mediated cell adhesion and alters calcium homeostasis in pancreatic beta cells

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed drugs for mood disorders. Long term use of SSRIs is associated with an increased risk of diabetes, but the underlying mechanism(s) remains elusive. E-cadherin-mediated cell-cell adhesion and elevated [Ca2+]i are important for insulin release and pancreatic β cell functions. This study aims to investigate whether a SSRI, fluoxetine (Prozac), induces pancreatic β cell dysfunction through affecting E-cadherin and/or [Ca2+]i. Here we show that fluoxetine significantly reduces glucose stimulated insulin secretion (GSIS). MIN6 cells, an established murine immortalized β cell line, form smaller colonies of loosely packed cells with reduced cell-cell contact after fluoxetine treatment. Immunofluorescence staining reveals that fluoxetine increases cytoplasmic accumulation of E-cadherin and reduces the membrane-localized E-cadherin probably due to increase of its endocytosis. Fluoxetine inhibits spreading of β cells on E-cad/Fc coated slides and also disrupts E-cadherin-mediated actin filaments. Additionally, fluoxetine significantly suppresses endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through reduction of ER calcium storage and inhibition of stromal interaction molecule 1 (STIM1) trafficking. These data suggest that exposure to fluoxetine results in impaired β cell functions, occurring in concert with reduction of E-cadherin-dependent cell adhesion and alterations of calcium homeostasis.

Effects of selective serotonin reuptake inhibitors on intraocular pressure and anterior segment parameters in open angle eyes

Purpose: To evaluate the short- and long-term effects of selective serotonin reuptake inhibitors (SSRIs) on intraocular pressure (IOP) and anterior segment parameters in open angle eyes.Materials and methods: This cross-sectional study included 325 eyes of 166 subjects. Subjects were divided into three groups: Group 1 included 116 eyes of 58 patients receiving SSRIs for 1 week–6 months, Group 2 included 102 eyes of 53 patients receiving SSRIs for longer than 6 months and Group 3 included 107 eyes of 55 healthy subjects not receiving any drugs. All of the patients receiving SSRIs were diagnosed as major depressive disorder. All groups were chosen to be similar in terms of age and gender. All patients underwent a detailed ophthalmologic examination including IOP measurement by Goldmann applanation tonometer and gonioscopy. Anterior segment parameters including pupil diameter (PD), central corneal thickness (CCT), anterior chamber depth (ACD), anterior chamber volume (ACV), and anterior chamber angle (ACA) were assessed by a Scheimpflug system.Results: Pupil diameter was significantly larger in patients receiving SSRIs for <6 months and ≥6 months than the control subjects (3.53 ± 0.71 mm, 3.48 ± 0.60 mm versus 3.11 ± 0.72 mm, p < 0.05) but this effect was independent from the duration of SSRI treatment. IOP was significantly lower in patients receiving SSRIs for <6 months and ≥6 months than the control group (16.04 ± 2.17 mm Hg, 16.11 ± 2.13 mm Hg versus 17.34 ± 2.15 mmHg, p < 0.05), but there were no statistically significant differences between the patients receiving SSRIs for <6 months and ≥6 months. There were no statistically significant differences between the patient and the control group in values of CCT, ACD, ACV and ACA. The ACAs were measured between 25° and 55° with Scheimpflug system and also classified as grade 3–4 (Shaffer system) by gonioscopy.Conclusions: Selective serotonin reuptake inhibitors cause mydriasis which is persistent during the treatment. In depression patients with open angle eyes, short- and long-term use of SSRIs leads to decrease in IOP.

Selective Serotonin Reuptake Inhibitors and Cataract Risk: A Case-Control Analysis

Use of selective serotonin reuptake inhibitors (SSRIs) has been associated with an increased cataract risk. We aimed to assess cataract risk after exposure to SSRI or to other antidepressant drugs in a large electronic primary care database. Case-control study. The study population was derived from the UK-based Clinical Practice Research Datalink (CPRD). We included patients with first-time cataract aged ≥40 years between 1995 and 2015 and an equal number of cataract-free controls matched on age, sex, general practice, date of cataract recording (i.e., index date), and years of history in the CPRD before the index date. We conducted conditional logistic regression analyses adjusted for body mass index, smoking, hypertension, diabetes, and systemic steroid use. Exposure of interest was the number of SSRI prescriptions and prescriptions for other antidepressant drugs. We further explored mutually exclusive use of single SSRI substances. In sensitivity analyses, we shifted the index date backwards by 2 years, and we restricted our analyses to cases and controls without a prior glaucoma diagnosis. Relative risk estimates as odds ratios (ORs) with 95% confidence intervals (CIs). We identified 206 931 cataract cases and the same number of matched controls. Current long-term use of SSRI (≥20 prescriptions) was not associated with an increased cataract risk (adjusted OR, 0.99; 95% CI, 0.94-1.03). However, in a subset of patients aged 40 to 64 years, we found a slightly increased risk of cataract for long-term SSRI users (adjusted OR, 1.24; 95% CI, 1.15-1.34) compared with nonusers. In these data, use of SSRI was not associated with an increased risk of cataract. The slightly increased OR for individuals younger than 65 years of age in association with long-term SSRI use needs to be investigated in further studies.

Prenatal Exposure to Folic Acid and Antidepressants and Language Development: A Population-Based Cohort Study.

The aim of the study was to determine the effect of simultaneous use of folic acid supplements and selective serotonin reuptake inhibitors (SSRIs) by pregnant women on language development in their offspring at the age of 3 years. We conducted a cohort study of 45,266 women with 51,747 singleton pregnancies in the population-based Norwegian Mother and Child Cohort study (1999-2008). The association between the use of SSRIs with and without concomitant folic acid and language competence in the offspring was investigated using multinomial logistic regression. Self-reported use of folic acid supplements and SSRIs was prospectively collected in 4-week intervals during pregnancy and validated with prescription data and plasma concentrations, respectively. The children's language competence was measured by a validated language grammar rating scale and classified into 3 categories. Women reported the use of folic acid in 44,417 (85.8%) and SSRI in 372 (0.7%) of the pregnancies, 260 used the 2 simultaneously. Compared with women who used folic acid and no SSRIs, the adjusted relative risk ratio of lower language competence rose with the increased duration of simultaneous use of folic acid and SSRIs. After simultaneous use at 4 to 8 four-week intervals, the relative risk ratio reached 4.5 (95% confidence interval, 2.5-8.0) and 5.7 (2.5-13.0) for the intermediate and most delayed category, respectively, using the best language competence category as the reference. The use of SSRIs without folic acid was not significantly associated with an increased risk. We detected a significant association between long-term use of SSRIs during pregnancy and delayed language competence in the offspring only when folic acid supplementation was used concomitantly. This surprising result warrants further studies.

Long-Term Use of Selective Serotonin Reuptake Inhibitors and Risk of Glaucoma in Depression Patients

This study investigated whether the long-term use of selective serotonin reuptake inhibitors (SSRIs) influences the risk of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) in the Chinese ethnic population in Taiwan.The authors retrieved the data under analysis from the National Health Insurance Research Database in Taiwan and identified 26,186 newly diagnosed depression patients without preexisting glaucoma. The study cohort included 13,093 patients with over 1 year of SSRI use, and a comparison cohort of 13,093 patients who had never used SSRIs. The main outcome was a diagnosis of POAG or PACG during follow-up. The authors used univariable and multivariable Cox proportional hazards regression models to assess the effects of SSRIs on the risk of POAG and PACG.The cumulative incidences of POAG and PACG between the SSRI and comparison cohorts exhibited nonsignificant differences (log-rank test P = .52 for POAG, P = .32 for PACG). The overall incidence of POAG in the SSRI cohort was nonsignificantly higher than that in the comparison cohort (1.51 versus 1.39 per 1000 person-years), with an adjusted hazard ratio of 1.07 (95% confidence interval = 0.82–1.40). The overall incidence of PACG in the SSRI cohort was nonsignificantly lower than that in the comparison cohort (0.95 versus 1.11 per 1000 person-years), with an adjusted hazard ratio of 0.85 (95% confidence interval = 0.62–1.18).The long-term use of SSRIs does not influence the risk of POAG or PACG in depression patients.

Prenatal exposure to antidepressants and language competence at age three: results from a large population-based pregnancy cohort in Norway.

To examine the association between maternal use of selective serotonin reuptake inhibitors (SSRI) in pregnancy and language competence in their children at age three taking into account maternal symptoms of anxiety and depression. Population-based prospective pregnancy cohort study. The Norwegian Mother and Child Cohort Study; recruited pregnant women from 1999 through 2008. 45,266 women with 51,748 singleton pregnancies. The association between short- or long-term use of SSRI during pregnancy and language competence in the child was investigated using multinomial logistic regression with three outcome categories: long, complicated sentences, fairly complete sentences and language delay. Children's language competence at age three measured by maternal report on a validated language grammar scale. Women reported use of SSRI in 386 (0.7%) pregnancies. Of these, 161 (42%) reported long-term use. Compared with children whose mothers took no SSRI, using the best language category as the reference, adjusted relative risk ratios (RRR) of having fairly complete sentences were 1.21 (95% CI 0.85-1.72) and 2.28 (1.54-3.38) for short- and long-term SSRI use, respectively. The adjusted RRRs of language delay were 0.86 (0.42-1.76) and 2.30 (1.21-4.37). Symptoms of anxiety and depression in pregnancy were independently related to language delay, adjusted RRR 1.25 (1.03-1.50) and 1.83 (1.40-2.40) for short- and long-term symptoms, respectively. Prolonged use of SSRI during pregnancy was associated with lower language competence in children by age three independently of depression. Having symptoms of depression throughout pregnancy had an independent effect.

Long-term use of fluoxetine and multiple skeleton fractures

Dear Editor: We report a 33-year-old female patient treated with fluoxetine for 8 years for depression. She had the first depression attack 14 years ago. She was treated with fluoxetine 20 mg/day and used that dose continuously for 5 years. After quitting the medication, her depression returned and fluoxetine was begun at 20 mg/day and increased to 40 mg/day and used at that dose for 3 months, than lowered to the original dose. At the end of 8 years of using fluoxetine 20 mg/day, three fractures occured within a short interval. The first fracture appeared on the right radius and distal third of the ulna. After 8 months, a second fracture at the left distal third of the spinal cruris emerged. One and a half years later, a fragmented fracture was seen at the collum chirurgicum and tuberculum majus in the proximal third of the right humerus. The patient was operated on four times due to those fractures. At the time of the fractures, there were no biochemical abnormalities other than slight elevations in the levels of LH and FSH. The bone densitometry was within normal limits. A poor densitometry rating was found (−1.5) only for the corpus femoris. Based on that finding, the patient was considered to be in the initial stages of osteopenia. All of those fractures however could not be explained by this diagnosis. Lerner [1] documented that there could be osteoporosis due to the administration of selective serotonin reuptake inhibitors (SSRIs) because serotonin might work as a signal molecule in the brain and there are serotonin receptors on osteoblasts and osteoclasts. There would be a decrease in the bone mass when the serotonin gene transporter was left out of the circuit in gene knock-out studies. These findings reveal that osteoporosis may occur secondary to the use of SSRIs and can cause bone fractures. Ziere et al. [2] reported that SSRIs and tricyclic antidepressants (TSAs) can cause fractures, especially in the bones of older patients, and fractures have appeared in the vertebrae of patients using SSRIs for long periods but not with TSAs. In the presented case, the patient was relatively young and had fractures one after another. It is also interesting that the fractures appeared in the eighth year of using an SSRI. This is in keeping with Ziere’s report that the long-term use of SSRIs may provoke formation of fractures. The fractures due to the use of SSRIs occur without any change in the hormonal regulations in the metabolism of bones, and the deficiency in the bone mass cannot be caught with bone densitometry scans because the pathology is related to the loss of the function of serotonin as a signal molecule in the brain. We propose that rather than continuing the use of SSRIs for more than 5 years, the medication might be shifted to different types of drugs such as MAOIs that are relatively benign to bone mass.

Treating children and adolescents with selective serotonin reuptake inhibitors: how long is appropriate?

This article addresses a key question on the use of selective serotonin reuptake inhibitors (SSRIs) among children and adolescents. As briefly reviewed, recent randomized controlled trials have established the safety and efficacy of SSRIs in the acute treatment of major depression and anxiety disorders among children and adolescents. Major questions emerge in light of these data concerning the potential risks and benefits of long-term SSRI use among children and adolescents who receive significant short-term benefits from SSRI treatment. The current review summarizes research on longitudinal outcomes, neuroscience, and psychopharmacology to formulate a set of preliminary recommendations on long-term SSRI use. A review of data in these areas supports three conclusions. First, for children who achieve marked reduction in anxiety or depressive symptoms on an SSRI, clinicians should consider recommending a medication-free trial. Second, when indicated, this medication-free trial should coincide with the first low-stress period occurring after 1 year of continual SSRI treatment. Third, SSRI treatment should be reinitiated in children who exhibit signs of relapse during this medication-free trial.

Selective serotonin reuptake inhibitors for premenstrual dysphoric disorder: the emerging gold standard?

There have been a large number of studies conducted investigating the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of patients with premenstrual dysphoric disorder (PMDD). The 12 randomised, controlled trials with continuous dose administration of SSRIs and the eight randomised, controlled trials with luteal phase dose administration (from ovulation to menses) are reviewed. All the treatment studies on fluoxetine, sertraline, paroxetine and citalopram have reported positive efficacy. Fluoxetine and sertraline have the largest literature, with a smaller number of studies endorsing paroxetine and citalopram. Mixed efficacy results have been reported with fluvoxamine. In general, adverse effects from the use of SSRIs in women with PMDD are the usual mild and transient adverse effects from SSRIs including anxiety, dizziness, insomnia, sedation, nausea and headache. Sexual dysfunction and weight gain can be problematic long-term adverse effects of SSRIs, but these effects have not been systematically evaluated with long-term SSRI use in women with PMDD. Serotonergic antidepressants have differential superiority over nonserotonergic antidepressants in the treatment of PMDD. Treatments that enhance serotonergic action improve premenstrual irritability and dysphoria with a rapid onset of action, suggesting a different mechanism of action than in the treatment of depression. It is possible that neurosteroids, such as progesterone metabolites, are involved in the rapid action of serotonergic antidepressants in PMDD. Future research needs to address less frequent dose administration regimens, such as 'symptom-onset' dose administration, and the recommended length of treatment.