Selective Serotonin Reuptake Inhibitors Research Articles

The Effect of Adding Agomelatine to Escitalopram in the Treatment of Major Depressive Disorder

Major Depressive Disorder (MDD) is a psychiatric illness that imposes a high cost on the patient and the community. Over the past few decades, a variety of treatments have been used to treat depression. One of the most common treatments for depression is medication. Today, specific serotonin reuptake inhibitors are the first line of treatment for major depression. Another drug that has been considered in the treatment of depression is agomelatine.Objective of this study was to evaluate the effect of adding agomelatine to Escitalopram in treatment of major depressive disorder.Materials and methods. This study was a double-blind randomized clinical trial with before and after designs (b and a). In this study, 70 patients with MDD referred to psychiatric clinics affiliated with Yazd University of Medical Sciences were studied. Patients were randomly divided into two groups of 35 patients (agomelatine + Escitalopram and Escitalopram + placebo) and were treated for 12 weeks. Depression Scale was the Hamilton Depression Inventory and was assessed before treatment, 1, 2, and 3 months after treatment. Variables such as gender, age, marital status, level of education, occupation, and duration of illness were also collected. The data were entered into SPSS version 18 software and analyzed using statistical tests.Results. Of the 70 patients studied, 31 (44.3%) were male and 39 (55.7%) were female. There was not significant difference between gender distribution (p=0.810), marital status(p=0.789), job (p=0.651) and educational level (p=0.794). Also, no significant difference was found between the mean variables: age (p=0.563) and duration of depression (p=0.958). There was a statistically significant difference between the mean score of depression 2 months after treatment (p=0.10) and 3 months after treatment (p=0.023) in the two groups. Also the mean depression score after treatment compared to before, was significantly lower in both groups (p=0.000). Also, no significant difference was found between the frequency of drug side effects in the two groups (p=0.970).Conclusion. Adding agomelatine to Escitalopram is more effective than mood-boosting depression as a result of depression or depressive disorder alone.Future researchers in the field of MDD treatment could consider investigating the long-term effects and comparative efficacy of combining agomelatine with other antidepressants beyond Escitalopram to further enhance treatment outcomes for patients with MDD.

Sertraline-Induced 5-HT Dysregulation in Mouse Cardiomyocytes and the Impact on Calcium Handling.

Selective serotonin reuptake inhibitors (SSRIs) are prescribed in 15% of pregnancies in the United States for depression. Maternal use of SSRIs has been linked to an increased risk of congenital heart defects, but the exact mechanism of pathogenesis is unknown. SSRIs, including sertraline, are permeable to the placenta and can produce direct fetal exposure. Previously, we have shown decreased cardiomyocyte proliferation, left ventricle size, and cardiac expression of the serotonin receptor 5-HT2B in offspring of mice exposed to the SSRI sertraline relative to offspring of saline-exposed mice. Using a mouse model of in utero plus neonatal sertraline exposure, we observed lengthened peak-to-peak time of calcium oscillation (saline 784 ±76 ms; sertraline 1121 ± 130 ms, p<0.001) and decreased expression of critical genes in calcium regulation. We also observed significant up-regulation of specific miRNAs that modulate serotonin signaling in neonatal cardiac tissues (Slc6a4: miR-223-5p, miR-92a-2-5p, miR-182-5p; Htr2a: miR-34b-5p, miR-182-5p; Htr2b: miR-223-5p, miR-92a-2-5p, miR-337-5p) (p<0.05) with corresponding levels of the target mRNAs down-regulated (Slc6a4 0.73 ± 0.05; Htr2a 0.67 ± 0.04; Htr2b 0.72 ± 0.03; all p< 0.01), resulting in decreased production of the cognate proteins. Adult mice at 10 weeks showed altered cardiac parameters including decreased heart rates in males (saline 683 ± 8 vs sertraline 666 ± 6 beats per minute, p< 0.05) and ejection fraction in females (saline 83.9 ± 0.6% vs sertraline 80.6 ± 1.1%, p<0.05). These findings raise the question if sertraline exposure during development may increase the potential risk for cardiac disease when subjected to stress.

Assessing the Neurodevelopmental Impact of Fluoxetine, Citalopram, and Paroxetine on Neural Stem Cell-Derived Neurons

Background/Objectives: Many pregnant women globally suffer from depression and are routinely prescribed selective serotonin reuptake inhibitors (SSRIs). These drugs function by blocking the re-uptake of serotonin by the serotonin transporter (SERT) into neurons, resulting in its accumulation in the presynaptic cleft. Despite a large amount of research suggesting a potential link to neurodevelopmental disorders in children whose mothers took these drugs during pregnancy, their possible adverse effects are still debated, and results are contradictory. On the other hand, there is an immediate need for improved cell-based models for developmental neurotoxicity studies (DNT) to minimize the use of animals in research. Methods: In this study, we aimed to assess the effects of clinically relevant concentrations of paroxetine (PAR), fluoxetine (FLX), and citalopram (CIT)—on maturing neurons derived from human neural stem cells using multiple endpoints. Results: Although none of the tested concentrations of FLX, CIT, or PAR significantly affected cell viability, FLX (10 µM) exhibited the highest reduction in viability compared to the other drugs. Regarding neurite outgrowth, CIT did not have a significant effect. However, FLX (10 µM) significantly reduced both mean neurite outgrowth and mean processes, PAR significantly reduced mean processes, and showed a trend of dysregulation of multiple genes associated with neuronal development at therapeutic-relevant serum concentrations. Conclusions: Transcriptomic data and uptake experiments found no SERT activity in the system, suggesting that the adverse effects of FLX and PAR are independent of SERT.

Therapy strategies for repetitive vocalizations in dementia : Asystematic review

Vocalizations in dementia patients are repetitive verbal expressions that, due to their volume, frequency, and/or social inappropriateness, cause negative effects on patients and other individuals present. The prevalence ranges up to 30%. Given the increasing global incidence of dementia and the limited number of randomized controlled trials about treating repetitive vocalizations, this systematic review provides asummary of existing works on the effectiveness of potential pharmacotherapeutic and nonpharmacological therapies. The systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered on the International Prospective Register of Systematic Reviews (PROSPERO) registration page (registration number: CRD42023486344). Literature search was conducted in PubMed and Embase databases. Due to insufficient data, case reports were also included. Of 2635 articles, 25studies were included in the review. Efficacy was demonstrated for selective serotonin reuptake inhibitors (SSRIs), pregabalin, gabapentin, and the antipsychotics haloperidol and risperidone based on afew case reports, albeit with associated side effects. Nonpharmacological interventions also showed efficacy. Both pharmacological and nonpharmacological interventions are effective treatment approaches for repetitive vocalizations in dementia patients. Due to the fact that there are hardly any randomized controlled studies available, the results of this systematic review must be interpreted with caution. The results of this review show that randomized controlled trials are required for many interventions.

Fluoxetine and Sertraline Inhibit Height Growth and Growth Hormone Signaling During Puberty.

The aim of this study was to examine the effect of fluoxetine and sertraline on height growth and insulin-like growth factor-1 (IGF-1) during puberty. In this 6-month cohort study, electronic medical records were used to identify 8- to 15-year-old participants, within 1 month of starting fluoxetine (n = 39) or sertraline (n = 27), and sexual maturation stages 2 to 4 were confirmed. Conditions that interfere with height growth led to exclusion. Participants underwent anthropometric assessments and phlebotomy. Healthy, unmedicated children (n = 36) also provided anthropometric data. After the baseline height Z-score, sex, Tanner stage, daily selective serotonin reuptake inhibitor (SSRI) dose, and time were accounted for, the interaction effect of dose by time was inversely associated with height Z-score in SSRI-treated participants (β = -0.18; 95% confidence interval [CI]: -0.35, -0.02). Sertraline and fluoxetine did not differ in their effect on height growth. Compared with being unmedicated, SSRI treatment was associated with a smaller growth in height (time × dose 2-way interaction effect β = -1.30; 95% CI: -2.52, -0.09). The interaction effect of dose by time was significant for body mass index Z-score (β = 0.35; 95% CI: 0.06, 0.64) but not weight Z-score (β = 0.24; 95% CI: -0.01, 0.49). Body mass index Z-score increased more with sertraline compared with fluoxetine (time × dose × SSRI type 3-way interaction effect P < 0.05). SSRI dose was inversely associated with IGF-1 (β = -63.5; 95% CI: -112.2, -14.7) but not insulin growth factor binding protein-3 concentration (β = -207.3; 95% CI: -536.2, 121.5). Fluoxetine and sertraline reduce height gain and IGF-1 concentration, in a dose-dependent manner. Longer-term studies are necessary.

Exploring Effective Interventions for Postpartum Blues: A Review of Current Literature

Postpartum blues, or "baby blues," is a common condition affecting 50-80% of new mothers, marked by mood swings, tearfulness, anxiety, and fatigue. It typically emerges within the first two weeks postpartum and can impact mother-infant bonding and maternal well-being. Left untreated, it may escalate into more severe postpartum mood disorders. This review aims to assess the efficacy, accessibility, and feasibility of various interventions for postpartum blues, synthesizing current research to inform clinical practices and future studies. A systematic review of peer-reviewed articles from 2010 to 2024 was conducted using PubMed, CINAHL, and PsycINFO databases. Articles were selected based on relevance, methodological rigor, and focus on postpartum blues interventions. After screening, 72 articles met the inclusion criteria and were included in the final analysis. The review identified several effective interventions across different domains: Psychosocial intervention particularly peer support programs and cognitive-behavioral therapy (CBT) were most effective in reducing postpartum blues symptoms; Hormonal and pharmacological interventions, including neuroactive steroids and selective serotonin reuptake inhibitors (SSRIs), showed mixed but promising results; Nutritional interventions, particularly omega-3 supplementation, demonstrated significant preventive effects; Mind-body interventions, such as mindfulness-based therapies, were effective in improving mood stability; Technology-based interventions, including mobile health applications and AI-driven support, showed potential for scalable and accessible solutions. Psychosocial interventions provide the strongest evidence for managing postpartum blues, while emerging research on hormonal, nutritional, and technology-based interventions offers promising new directions. A personalized, multimodal approach integrating these strategies is recommended for improving maternal mental health during the postpartum period.

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.

Zuranolone for the Treatment of Postpartum Depression

Objective To review the safety, efficacy, and tolerability of zuranolone for the treatment of postpartum depression. Data Sources: A literature search was conducted through PubMed using the following terms: zuranolone, postpartum depression, perinatal depression, SAGE-217, and allopregnanolone analogue. Study Selection and Data Extraction Articles describing the pharmacology, pharmacokinetics, efficacy, safety, and/or tolerability of zuranolone were included in this review. Data Synthesis 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. Conclusions: 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.

Effects of selective serotonin reuptake inhibitors on platelet functions: a literature review.

Many epidemiological studies have evidenced an increased bleeding risk associated with selective serotonin reuptake inhibitors (SSRIs), yet the underlying mechanisms remain unclear. This review summarizes data on SSRIs' effects on platelet functions assessed with assays used in clinical practice and highlights the areas that deserve further investigation. Conflicting results of SSRI effects on platelet aggregation were observed irrespectively of the agonist used, the antidepressant drug or the study type. Alike, discrepant results were reported with flow-cytometry-based assays assessing either platelet surface glycoprotein levels, integrin activation, agonist-induced secretion of intraplatelet granule content or membrane anionic phospholipid exposure. Other tests may have detected a platelet function defect in SSRIs samples, however, results were largely inconsistent. Critical literature examination unveils very low certainty of evidence on potential SSRI effect on platelet functions. Findings are often inconsistent even when similar methods are used, most likely because of differences in study design, included patients (age, comorbid conditions), SSRIs' type and dose, uncontrolled confounding factors, and statistical analysis power. Further studies are needed to disentangle any intrinsic antiplatelet effect of SSRIs and the multiple confounding factors, mainly the depression control itself and the degree of platelet SERT inhibition.

Perception of the Capixaba population regarding the use and benefits of antidepressants and anxiolytics

Depression is a routine disorder characterized by at least two weeks of loss of pleasure, mood, and interest in basic daily activities. Treatment involves psychotherapy, lifestyle changes, and medication therapy with antidepressants. These medications increase the availability of neurotransmitters in the central nervous system through different mechanisms of action, such as Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, Selective Serotonin Reuptake Inhibitors, and Atypicals. Studies indicate that, after the pandemic, mental health issues such as anxiety and depression became more frequent in society, leading to greater use of antidepressants, especially clonazepam, sertraline, and amitriptyline. This project aims to investigate this usage, focusing on the benefits and drawbacks from the user’s perspective. To this end, it was submitted to the Ethics and Human Research Council of UNESC, with a bibliographic review conducted in the PubMed, Lilacs, and Scielo databases during the approval period. After approval, the research was conducted through structured questionnaires, made available online to the Capixaba society. The study evaluated the rate of use of these psychotropic drugs in the region, the benefits, risks, and behaviors regarding the use of antidepressants and anxiolytics from the perspective of patients. The use of psychotropic drugs by the population can be satisfactory for treating mental disorders, but it is essential that these medications are used with caution and under the guidance of a healthcare professional. Regular monitoring helps to manage adverse effects, ensure the medication is working properly, and prevent long-term medication-related problems.

Combined Methylphenidate and Selective Serotonin Reuptake Inhibitors in Adults With Attention-Deficit/Hyperactivity Disorder.

Depression is a common comorbidity of adult attention-deficit/hyperactivity disorder (ADHD), and the combination of methylphenidate and selective serotonin reuptake inhibitors (SSRIs) is a frequently prescribed treatment. However, there is limited clinical evidence on the safety of this medication combination in adults with ADHD. To evaluate the safety of administering a combination of SSRI and methylphenidate in adults with ADHD and comorbid depression. This cohort study obtained data from a nationwide claims database in South Korea from January 2016 to February 2021. Participants were adults aged 18 years or older with a diagnosis of ADHD and depressive disorder who were prescribed methylphenidate. Comparisons of 4 groups who received prescriptions were conducted: (1) SSRI plus methylphenidate (hereafter, SSRI) group vs methylphenidate-only group and (2) methylphenidate plus fluoxetine (hereafter, fluoxetine) group vs methylphenidate plus escitalopram (hereafter, escitalopram) group (compared to find a preferable treatment option). Data analysis was conducted between July and December 2023. New users of the methylphenidate and SSRI combination among adults with both ADHD and depressive disorder. A total of 17 primary and secondary outcomes, including neuropsychiatric and other events, were assessed, with respiratory tract infection used as a control outcome. Groups were matched at a 1:1 ratio using a propensity score to balance confounders. A Cox proportional hazards regression model was used to calculate hazard ratio (HRs) and 95% CIs. Subgroup analysis by sex and sensitivity analyses in varying epidemiologic settings were conducted. The study included 17 234 adults with ADHD (mean [SD] age at study entry, 29.4 [10.8] years; 9079 females [52.7%]). There was no difference in the risk of outcomes between the methylphenidate-only and SSRI groups, except for a lower risk of headache in the SSRI group (HR, 0.50; 95% CI, 0.24-0.99). In sensitivity analyses of fluoxetine vs escitalopram, the risk of hypertension (HR: 1:n matching, 0.26; 95% CI, 0.08-0.67) and hyperlipidemia (HR: 1:n matching, 0.23; 95% CI, 0.04-0.81) was lower in the fluoxetine group than in the escitalopram group. Results of this study revealed no significant increase in adverse event risk associated with use of SSRI plus methylphenidate vs methylphenidate alone in adults with ADHD and comorbid depression. Instead, the combination was associated with a lower risk of headache.

New Role of the Serotonin as a Biomarker of Gut-Brain Interaction.

Serotonin (5-hydroxytryptamine: 5-HT), a neurotransmitter that regulates mood in the brain and signaling in the gut, has receptors throughout the body that serve various functions, especially in the gut and brain. Selective serotonin reuptake inhibitors (SSRIs) are used to treat depression, but their efficacy is uncertain. Depression is often associated with early gastrointestinal symptoms. Gut disorders such as functional dyspepsia (FD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are linked to elevated serotonin levels. In this review, we would like to discuss the approach of using serotonin as a biomarker for gut-brain, and body-wide organ communication may lead to the development of preventive and innovative treatments for gut-brain disorders, offering improved visibility and therapeutic monitoring. It could also be used to gauge stress intensity for self-care and mental health improvement.

Bruxism and Sleep Disorders in Patients Diagnosed With Depressive Disorder and Anxiety Disorder UsingAntidepressants.

To investigate the frequency of bruxism, factors associated with bruxism and sleep disorders in patients diagnosed with depressive disorder and anxiety disorder who use antidepressants. A total of 273 patients diagnosed with anxiety disorder or depression who had been using antidepressants for at least 1 month were included, along with 273 healthy control groups. The patient and control groups completed a sociodemographic data form, Epworth Daytime Sleepiness Scale (EDSS), Pittsburgh Sleep Quality Index (PSQI) and a bruxism questionnaire. Additionally, the clinician confirmed the diagnosis of bruxism through a clinical interview. Bruxism was detected in 73.3% of the patient group and 28.2% of the control group (p < 0.001). The most commonly used antidepressants among patients were selective serotonin reuptake inhibitors (SSRIs) such as escitalopram and sertraline. Within the patient group, individuals with bruxism had higher family history rates of teeth grinding (p = 0.034), PSQI scores (p < 0.001) and EDSS scores (p < 0.001) compared to those without bruxism. Positive correlations were found between the presence of bruxism and PSQI (p < 0.001) scores as well as EDSS scores (p < 0.001) in both the patient group and all participants. Regression analysis conducted on the entire sample revealed that family history rates of teeth grinding (p < 0.001), antidepressant use (p < 0.001) and PSQI score (p = 0.004) were associated with bruxism. The findings from this study suggest that a majority of patients diagnosed with depressive or anxiety disorders may experience bruxism, particularly those using SSRI-type antidepressants. Furthermore, individuals with bruxism may have poor sleep quality and excessive daytime sleepiness tendencies.

Association between Drug Use and Perception of Mental Health in Women Diagnosed with Fibromyalgia: An Observational Study.

Fibromyalgia (FM) is a chronic syndrome characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and mental health issues. It affects approximately 1.78% of the general population; an estimated 4:1 ratio between women and men is observed. It significantly impacts quality of life and carries both clinical and social stigma. This study aims to evaluate the relationship between drug use and mental health in female patients with fibromyalgia. This study is prospective, observational, and cross-sectional. A questionnaire was administered to 544 subjects, achieving a representative sample size from a population of 800,000 subjects by using an algorithm for proportion estimation with a known sampling frame. The selection was non-random, making the sampling non-probabilistic. Logistic regression models were applied to assess the effect of drug use on perception of mental health; presence of symptoms such as comprehension and memory problems, insomnia, depression, and anxiety; and severity of cognitive symptoms and non-restorative sleep. To quantify the impact, odds ratios and confidence intervals have been observed. The findings indicate the non-recommended use of medications and reveal the ineffectiveness and adverse effects of drug interactions on mental health. The use of benzodiazepines and sedative-hypnotics is significantly associated with a negative perception of mental health. Benzodiazepines do not improve symptoms or significantly reduce their severity. SSRI antidepressants do not enhance mental health perception; however, when used exclusively, they are effective in reducing the severity, but not the prevalence, of cognitive symptoms. The results highlight the complexity of pharmacological management in FM and raise concerns about the inappropriate use of ineffective or counterproductive drug interactions affecting patients' mental health. They underscore the need for multidisciplinary and personalized strategies that include close and careful monitoring, as well as the simultaneous use of non-pharmacological treatments that have demonstrated evidence in improving quality of life without negatively affecting mental health, such as patient education, psychological therapy, physiotherapy, and mindfulness.

SSRI use during acute COVID-19 and risk of long COVID among patients with depression

BackgroundLong COVID, also known as post-acute sequelae of COVID-19 (PASC), is a poorly understood condition with symptoms across a range of biological domains that often have debilitating consequences. Some have recently suggested that lingering SARS-CoV-2 virus particles in the gut may impede serotonin production and that low serotonin may drive many Long COVID symptoms across a range of biological systems. Therefore, selective serotonin reuptake inhibitors (SSRIs), which increase synaptic serotonin availability, may be used to prevent or treat Long COVID. SSRIs are commonly prescribed for depression, therefore restricting a study sample to only include patients with depression can reduce the concern of confounding by indication.MethodsIn an observational sample of electronic health records from patients in the National COVID Cohort Collaborative (N3C) with a COVID-19 diagnosis between September 1, 2021, and December 1, 2022, and a comorbid depressive disorder, the leading indication for SSRI use, we evaluated the relationship between SSRI use during acute COVID-19 and subsequent 12-month risk of Long COVID (defined by ICD-10 code U09.9). We defined SSRI use as a prescription for SSRI medication beginning at least 30 days before acute COVID-19 and not ending before SARS-CoV-2 infection. To minimize bias, we estimated relationships using nonparametric targeted maximum likelihood estimation to aggressively adjust for high-dimensional covariates.ResultsWe analyzed a sample (n = 302,626) of patients with a diagnosis of a depressive condition before COVID-19 diagnosis, where 100,803 (33%) were using an SSRI. We found that SSRI users had a significantly lower risk of Long COVID compared to nonusers (adjusted causal relative risk 0.92, 95% CI (0.86, 0.99)) and we found a similar relationship comparing new SSRI users (first SSRI prescription 1 to 4 months before acute COVID-19 with no prior history of SSRI use) to nonusers (adjusted causal relative risk 0.89, 95% CI (0.80, 0.98)).ConclusionsThese findings suggest that SSRI use during acute COVID-19 may be protective against Long COVID, supporting the hypothesis that serotonin may be a key mechanistic biomarker of Long COVID.

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.

Optimizing Antidepressant Efficacy: Generalizable Multimodal Neuroimaging Biomarkers for Prediction of Treatment Response.

Major depressive disorder (MDD) is a common and often severe condition that profoundly diminishes quality of life for individuals across ages and demographic groups. Unfortunately, current antidepressant and psychotherapeutic treatments exhibit limited efficacy and unsatisfactory response rates in a substantial number of patients. The development of effective therapies for MDD is hindered by the insufficiently understood heterogeneity within the disorder and its elusive underlying mechanisms. To address these challenges, we present a target-oriented multimodal fusion framework that robustly predicts antidepressant response by integrating structural and functional connectivity data (sertraline: R-squared = 0.31; placebo: R-squared = 0.22). Remarkably, the sertraline response biomarker is further tested on an independent escitalopram-medicated cohort of MDD patients, validating its generalizability (p = 0.01) and suggesting an overlap of psychopharmacological mechanisms across selective serotonin reuptake inhibitors. Through the model, we identify multimodal neuroimaging biomarkers of antidepressant response and observe that sertraline and placebo show distinct predictive patterns. We further decompose the overall predictive patterns into constitutive network constellations with generalizable structural-functional co-variation, which exhibit treatment-specific association with personality traits and behavioral/cognitive task performance. Our innovative and interpretable multimodal framework provides novel and reliable insights into the intricate neuropsychopharmacology of antidepressant treatment, paving the way for advances in precision medicine and development of more targeted antidepressant therapeutics.

PET Imaging of the Serotonin 1A Receptor in Major Depressive Disorder: Hierarchical Multivariate Analysis of [11C]WAY100635 Overcomes Outcome Measure Discrepancies

Abstract The serotonin 1A receptor has been linked to both the pathophysiology of major depressive disorder (MDD) and the antidepressant action of serotonin reuptake inhibitors. Most PET studies of the serotonin 1A receptor in MDD used the receptor antagonist radioligand, [carbonyl-11C]WAY100635; however the interpretation of the combined results has been contentious owing to reports of higher or lower binding in MDD with different outcome measures. The reasons for these divergent results originate from several sources, including properties of the radiotracer itself, which complicate its quantification and interpretation; as well as from previously reported differences between MDD and healthy volunteers in both reference tissue binding and plasma free fraction, which are typically assumed not to differ. Recently, we have developed two novel hierarchical multivariate methods which we validated for the quantification and analysis of [11C]WAY100635, which show better accuracy and inferential efficiency compared to standard analysis approaches. Importantly, these new methods should theoretically be more resilient to many of the factors thought to have caused the discrepancies observed in previous studies. We sought to apply these methods in the largest [11C]WAY100635 sample to date, consisting of 160 individuals, including 103 MDD patients, of whom 50 were not-recently-medicated and 53 were antidepressant-exposed, as well as 57 healthy volunteers. While the outcome measure discrepancies were substantial using conventional univariate analysis, our multivariate analysis techniques instead yielded highly consistent results across PET outcome measures and across pharmacokinetic models, with all approaches showing higher serotonin 1A autoreceptor binding potential in the raphe nuclei of not-recently-medicated MDD patients relative to both healthy volunteers and antidepressant-exposed MDD patients. Moreover, with the additional precision of estimates afforded by this approach, we can show that while binding is also higher in projection areas in this group, these group differences are approximately half of those in the raphe nuclei, which are statistically distinguishable from one another. These results are consistent with the biological role of the serotonin 1A autoreceptor in the raphe nuclei in regulating serotonin neuron firing and release, and with preclinical and clinical evidence of deficient serotonin activity in MDD due to over expression of autoreceptors resulting from genetic and/or epigenetic effects. These results are also consistent with downregulation of autoreceptors as a mechanism of action of selective serotonin reuptake inhibitors. In summary, the results using multivariate analysis approaches therefore demonstrate both face and convergent validity, and may serve to provide a resolution and consensus interpretation for the disparate results of previous studies examining the serotonin 1A receptor in MDD.

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.

8429 Serotonin Receptor Antagonist Alleviates Vascular Defects Produced by Selective Serotonin Reuptake Inhibitor Treatment During Gestation

Abstract Disclosure: L.P. Agnew: None. R. Domingues: None. A. Weichmann: None. L.L. Hernandez: None. Maternal mental health is critical for both mother and infant and often antidepressant therapy outweighs the potential risks of selective serotonin reuptake inhibitor (SSRI) treatment; however, SSRI use is associated with adverse neonatal outcomes. Preliminary work in our laboratory revealed placental apoptosis in pregnant dams treated with fluoxetine (FLX) and dams genetically deficient for the serotonin transporter gene. We hypothesize that SSRIs decrease placental blood flow, causing apoptosis and organ death via signaling through the serotonin 2A/2C receptors. Pregnant female C57BL6 mice were randomized to be treated daily, via I.P. injection, from E10-17.5 with saline (CON; n=6), 2 mg/kg FLX (n=5), or 2 mg/kg ketanserin plus 2 mg/kg FLX (n=5). On E17.5, using high-resolution ultrasound imaging, we identified the uterine artery, individual umbilical cords, and placental disc blood vessels. We calculated blood pressure, blood volume, blood flow rate, and heart rate in the uterine artery, umbilical cord, and placental disc. FLX (decreased blood volume in the uterine artery compared to ketanserin plus FLX (48.42 ± 18.26, 116.54 ± 45.25; p=0.0077), and decreased average (89.38 ± 31.50) and peak (130.36 ± 39.05) blood velocity in the uterine artery compared to ketanserin plus FLX average (162.76 ± 68.46; p=0.0322) and peak (236.77 ± 92.43; p=0.0242) blood velocity. FLX decreased average (0.04 + 0.02) and peak (0.07 ± 0.04) blood pressure in the uterine artery compared to ketanserin and FLX treated animals average (0.12 ± 0.10; p=0.0634) and peak (0.25 ± 0.19; p=0.0412) blood pressure. Ketanserin plus FLX (391 ± 38.29) decreased heart rate (BPM) in the placental disc compared to untreated controls (450.67 ± 26.08; p=0.0128). In the umbilical cord, ketanserin plus FLX (393 ± 28.25) decreased BPM compared to CON (450.17 ± 29.44; p=0.0078) and compared to FLX treatment alone (437.20 ± 17.28; p=0.0450). FLX treatment of dams during pregnancy reduces blood flow volume, heart rate, and blood flow velocity to the placenta via the uterine artery. The use of ketanserin, an inhibitor of serotonin receptor 2A/2C signaling, in combination with FLX, reduced the effects of FLX on the uterine artery. These data suggest that treatment with ketanserin could be utilized to alleviate the reproductive side effects of antidepressant usage for pregnant mothers while allowing the mother to remain on antidepressants. Future research should further investigate the effects of SSRI and ketanserin on blood flow to the fetus through the umbilical cord. Presentation: 6/2/2024