Selective Serotonin Reuptake Inhibitors within Cells: Temporal Resolution in Cytoplasm, Endoplasmic Reticulum, and Membrane.

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatment for individuals experiencing major depressive disorder. The therapeutic mechanisms that take place before, during, or after SSRIs bind the serotonin transporter (SERT) are poorly understood, partially because no studies exist on the cellular and subcellular pharmacokinetic properties of SSRIs in living cells. We studied escitalopram and fluoxetine using new intensity-based, drug-sensing fluorescent reporters targeted to the plasma membrane, cytoplasm, or endoplasmic reticulum (ER) of cultured neurons and mammalian cell lines. We also used chemical detection of drug within cells and phospholipid membranes. The drugs attain equilibrium in neuronal cytoplasm and ER at approximately the same concentration as the externally applied solution, with time constants of a few s (escitalopram) or 200-300 s (fluoxetine). Simultaneously, the drugs accumulate within lipid membranes by ≥18-fold (escitalopram) or 180-fold (fluoxetine), and possibly by much larger factors. Both drugs leave cytoplasm, lumen, and membranes just as quickly during washout. We synthesized membrane-impermeant quaternary amine derivatives of the two SSRIs. The quaternary derivatives are substantially excluded from membrane, cytoplasm, and ER for >2.4 h. They inhibit SERT transport-associated currents sixfold or 11-fold less potently than the SSRIs (escitalopram or fluoxetine derivative, respectively), providing useful probes for distinguishing compartmentalized SSRI effects. Although our measurements are orders of magnitude faster than the therapeutic lag of SSRIs, these data suggest that SSRI-SERT interactions within organelles or membranes may play roles during either the therapeutic effects or the antidepressant discontinuation syndrome.SIGNIFICANCE STATEMENT Selective serotonin reuptake inhibitors stabilize mood in several disorders. In general, these drugs bind to SERT, which clears serotonin from CNS and peripheral tissues. SERT ligands are effective and relatively safe; primary care practitioners often prescribe them. However, they have several side effects and require 2-6 weeks of continuous administration until they act effectively. How they work remains perplexing, contrasting with earlier assumptions that the therapeutic mechanism involves SERT inhibition followed by increased extracellular serotonin levels. This study establishes that two SERT ligands, fluoxetine and escitalopram, enter neurons within minutes, while simultaneously accumulating in many membranes. Such knowledge will motivate future research, hopefully revealing where and how SERT ligands engage their therapeutic target(s).

Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression.

BACKGROUND: Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PT's therapeutic action. METHODS: In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up. RESULTS: PT was associated with decreases in neuroticism (B = -0.63), introversion (B = -0.38), disagreeableness (B = -0.47), impulsivity (B = -0.40), and increases in absorption (B = 0.32), conscientiousness (B = 0.30), and openness (B = 0.23) at week 6, with neuroticism (B = -0.47) and disagreeableness (B = -0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decreases in neuroticism (B = -0.38), disagreeableness (B = -0.26), impulsivity (B = -0.35), and increases in openness (B = 0.28) at week 6, with neuroticism (B = -0.46) remaining decreased at month 6. No significant between-condition differences were observed. CONCLUSIONS: Personality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (v. ET) on personality; however, post-ET changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.

Combined effect of CYP2C19 and CYP2D6 genotypes on escitalopram serum concentration and its metabolic ratio in a European patient population.

AIMS: The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real-world population. METHODS: Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N-desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype-predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration-to-dose (CD) ratio and metabolite-to-parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal-Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. RESULTS: A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P < .001), 28% in CYP2C19 IMs (P < .001) and 31% in CYP2C19 PMs (P = .04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. CONCLUSIONS: CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone.

Forensic investigation on a combined death by food aspiration and acute escitalopram intoxication occurred to a psychiatric subject in a nursing home.

Food aspiration is one of the major health risks for elderly people in nursing homes which could lead to death. Moreover, misconducts in pharmacotherapy may represent a potential risk of adverse drug reactions. It is reported here the toxicological evaluation of a combined death by food aspiration and acute escitalopram intoxication of a psychiatric subject, occurred in a nursing home. An 89-year-old man, suffering from dysphagia and Alzheimer's, was resident in a nursing home. He was fed with a liquid diet administered directly in mouth using a syringe. The man was also being treated with escitalopram 10 mg tablet. One evening, after receiving the meal in the usual way, the man complained of sudden illness. Carried to the emergency room, the man died about 3 h later with a diagnosis of cardiogenic shock subsequentially to ab ingestis. The histological findings revealed the presence of exogenous material, probably food, up to the finest bronchial branches. The toxicological examination revealed the presence of escitalopram and its main metabolite, desmethylcitalopram: in the blood 1972 ng/ml and 285 ng/ml, in the brain 4657 ng/g and 1025 ng/g, in the gastric content 2317 ng/g and 423 ng/g, in the lung 21,771 ng/g and 468 ng/g, respectively. The bad practice of the nurses to dissolve the escitalopram tablet in the liquefied food and to administer the therapy with a syringe directly into the mouth emerged thanks this investigation. Following food aspiration, escitalopram was absorbed by inhalation route, reaching high concentrations in blood and tissues. The death occurred due to a combined mechanism between food aspiration and the escitalopram toxic action.

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

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

Identifying subgroups with differential response to CBASP versus Escitalopram during the first eight weeks of treatment in outpatients with persistent depressive disorder.

There exists little empirical evidence helping clinicians to select the most effective treatment for individual patients with persistent depressive disorder (PDD). This study identifies and characterizes subgroups of patients with PDD who are likely to benefit more from an acute treatment with psychotherapy than from pharmacotherapy and vice versa. Non-medicated outpatients with PDD were randomized to eight weeks of acute treatment with the Cognitive Behavioral Analysis System of Psychotherapy (CBASP; n = 29) or escitalopram plus clinical management (ESC/CM; n = 31). We combined several baseline variables to one composite moderator and identified two subgroups of patients: for 56.0%, ESC/CM was associated with a greater reduction in depression severity than CBASP, for the remaining 44.0%, it was the other way around. Patients likely to benefit more from ESC/CM were more often female, had higher rates of moderate-to-severe childhood trauma, more adverse life events and more previous suicide attempts. Patients likely to benefit more from CBASP were older, had more often an early illness onset and more previous treatments with antidepressants. Symptomatic response, remission, and reductions in symptom severity occurred more often in those patients treated with their likely more effective treatment condition. The findings suggest that the baseline phenotype of patients with PDD moderates their benefit from acute treatment with CBASP relative to ESC/CM. Once confirmed in an independent sample, these results could serve to guide the choice between primarily psychotherapeutic or pharmacological treatments for outpatients with PDD.

The safety and efficacy of escitalopram and sertraline in post-stroke depression: a randomized controlled trial.

OBJECTIVES: This study aims to evaluate the safety and efficacy of escitalopram and sertraline in post-stroke depression (PSD) patients, to provide more reliable therapeutics for cardiovascular and psychiatric clinical practice. METHODS: We recruited 60 patients (aged 40-89 years old) with an ICD-10 diagnosis of PSD, who were then randomly assigned to two groups and treated with flexible doses of escitalopram (10 to 20 mg/day, n = 30) or sertraline (50 to 200 mg/day, n = 30) for consecutive 8 weeks, respectively. The 24-item Hamilton Depression Rating Scale (HAMD-24), the 14-item Hamilton Anxiety Rating Scale (HAMA-14), the Treatment Emergent Symptom Scale (TESS), the Montreal Cognitive Assessment Scale (MOCA), and the Activity of Daily Living scale (ADL) were used to assess patients before, during, and after treatment for depression, anxiety, adverse effects, cognitive function, and daily living activities. Repeated measures ANOVA, the Mann-Whitney U test, the chi-square test (χ2), or Fisher's exact test was employed to assess baseline demographics, response rate, adverse effects rate, and changes in other clinical variables. RESULTS: Significant reduction in HAMD-24 and HAMA-14 scores was evaluated at baseline, as well as 1, 3, 4, 6, and 8 weeks of drug intervention (p < 0.01). There was a significant group difference in post-treatment HAMD-24 scores (p < 0.05), but no difference was observed in HAMA-14 scores (p > 0.05). Further analysis showed a significant variance in the HAMD-24 scores between the two groups at the end of the first week (p < 0.01). The incidence of adverse effects in both patient groups was mild, but there was a statistically significant difference between the two groups (p < 0.05). The improvement in cognitive function and the recovery of daily living abilities were comparable between both groups (p > 0.05). CONCLUSION: Escitalopram and sertraline showed comparable efficacy for anxiety symptoms, cognitive function, and daily living abilities in PSD patients. In addition, escitalopram was more appropriate for alleviating depressive symptoms. To validate the conclusion, trials with a larger sample size are in demand in the future. The registration number is ChiCTR1800017373.

Effects of antidepressant on FKBP51 mRNA expression and neuroendocrine hormones in patients with panic disorder.

OBJECTIVE: The purpose of this study was to investigate the effects of escitalopram on the peripheral expression of hypothalamic-pituitary-adrenal (HPA) axis-related genes (FKBP51, HSP90, NR3C1 and POMC) and HPA-axis hormones in patients with panic disorder (PD). METHODS: Seventy-seven patients with PD were treated with escitalopram for 12 weeks. All participants were assessed for the severity of panic symptoms using the Panic Disorder Severity Scale (PDSS). The expression of HPA-axis genes was measured using real-time quantitative fluorescent PCR, and ACTH and cortisol levels were measured using chemiluminescence at baseline and after 12 weeks of treatment. RESULTS: At baseline, patients with PD had elevated levels of ACTH and cortisol, and FKBP51 expression in comparison to healthy controls (all p < 0.01). Correlation analysis revealed that FKBP51 expression levels were significantly positively related to cortisol levels and the severity of PD (all p < 0.01). Furthermore, baseline ACTH and cortisol levels, and FKBP51 expression levels were significantly reduced after 12 weeks of treatment, and the change in the PDSS score from baseline to post-treatment was significantly and positively related to the change in cortisol (p < 0.01). CONCLUSIONS: The results suggest that PD may be associated with elevated levels of ACTH and cortisol, and FKBP51 expression, and that all three biomarkers are substantially decreased in patients who have received escitalopram treatment.

Influence of CYP2C19, CYP2D6, and ABCB1 Gene Variants and Serum Levels of Escitalopram and Aripiprazole on Treatment-Emergent Sexual Dysfunction: A Canadian Biomarker Integration Network in Depression 1 (CAN-BIND 1) Study.

OBJECTIVES: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6, and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample. METHODS: A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n = 91), while responders continued ESC (i.e., ESC-Only, n = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models. RESULTS: In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F(2,54) = 8.00, p < 0.001, q = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF (r = -0.42, p = 0.004, q = 0.034) and SS (r = -0.43, p = 0.003, q = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction (r = -0.39, p = 0.009, q = 0.052). CONCLUSIONS: CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.

Comparative Efficacy of Augmenting Escitalopram with Modified Electroconvulsive Therapy or High-Frequency Repetitive Transcranial Magnetic Stimulation on Depressive Symptoms, Quality of Life, and Cognitive Function in Treatment-Resistant Depression.

Treatment-resistant depression (TRD) poses significant therapeutic challenges despite available interventions. Escitalopram (ESC) is a highly selective antidepressant. This study aimed to compare ESC alone and ESC combined with modified electroconvulsive therapy (MECT) or high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in TRD patients. Ninety participants were randomized into ESC alone, ESC + MECT, and ESC + HF-rTMS groups. Notable differences were observed in Hamilton Depression Rating Scale (HDRS-17) scores at 12 weeks among ESC (14.37), ESC + MECT (10.27), and ESC + HF-rTMS (10.77) groups (P = 0.006). In terms of overall quality of life (QoL) evaluated using the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) at 12 weeks, the ESC, ESC + MECT, and ESC + HF-rTMS groups scored 2, 3, and 3.5, respectively. ESC + MECT/HF-rTMS groups showed reduced depressive symptoms compared to the ESC group, accompanied by higher overall QoL scores and increased satisfaction with health. Patients receiving ESC + MECT demonstrated no significant alterations in short-term memory and orientation, as measured by the Montreal Cognitive Assessment (MoCA), before and after treatment. Moreover, a decline in language was observed compared to baseline (12 weeks: median 2, IQR 2-3; baseline: median 1, IQR 1-3; P = 0.022). The positive impact of ESC with HF-rTMS on cognitive function was evidenced by improvements in all domines MoCA.Combining ESC with MECT or HF-rTMS exhibited enhanced effectiveness in alleviating depressive symptoms and enhancing QoL compared to ESC monotherapy. Specifically, the ESC + HF-rTMS combination displayed potential as a comprehensive treatment strategy for TRD, addressing both emotional and cognitive aspects.

Unraveling the potential of vitamins C and D as adjuvants in depression treatment with escitalopram in an LPS animal model.

Depression is linked with oxidative stress and inflammation, where key players include nitric oxide (NO), nuclear factor erythroid 2-related factor 2 (Nrf2), Brain-Derived Neurotrophic Factor (BDNF), and Heme Oxidase-1 (HO-1). Augmenting the efficacy of antidepressants represents a compelling avenue of exploration. We explored the potential of vitamins C and D as adjuncts to escitalopram (Esc) in a lipopolysaccharide (LPS)-induced depression model focusing on the aforementioned biomarkers. Male Swiss albino mice were stratified into distinct groups: control, LPS, LPS + Esc, LPS + Esc + Vit C, LPS + Esc + Vit D, and LPS + Esc + Vit C + Vit D. After a 7-day treatment period, a single LPS dose (2 mg/kg), was administered, followed by comprehensive assessments of behavior and biochemical parameters. Notably, a statistically significant (p < 0.05) alleviation of depressive symptoms was discerned in the Esc + Vit C + Vit D group versus the LPS group, albeit with concomitant pronounced sedation evident in all LPS-treated groups (p < 0.05). Within the cortex, LPS reduced (p < 0.05) the expression levels of NOx, Nrf2, BDNF, and HO-1, with only HO-1 being reinstated to baseline in the LPS + Esc + Vit D and the LPS + Esc + Vit C + Vit D groups. Conversely, the hippocampal NOx, Nrf2, and HO-1 levels remained unaltered following LPS administration. Notably, the combination of Esc, Vit C, and Vit D effectively restored hippocampal BDNF levels, which had been diminished by Esc alone. In conclusion, vitamins C and D enhance the therapeutic effects of escitalopram through a mechanism independent of Nrf2. These findings underscore the imperative need for in-depth investigations.

Unraveling the Potential of Isorhamnetin as an Adjuvant in Depression Treatment with Escitalopram.

Oxidative stress and inflammation are implicated in depression. While selective serotonin reuptake inhibitors (SSRIs) like escitalopram are commonly prescribed as first-line treatments, their inconsistent efficacy and delayed onset of action necessitates the exploration of adjunctive therapies. Isorhamnetin, a flavonol, has shown antioxidant and anti-inflammatory properties that makes exploring its antidepressant effect attractive. This study aims to investigate the adjuvant potential of isorhamnetin in combination with escitalopram to enhance its antidepressant efficacy in a lipopolysaccharide (LPS)-induced depression model using Swiss albino mice. Behavioral paradigms, such as the forced swim test and open field test, were employed to assess depressive symptoms, locomotion, and sedation. Additionally, enzyme-linked immunosorbent assays were utilized to measure Nrf2, BDNF, HO-1, NO, and IL-6 levels in the prefrontal cortex and hippocampus. The results demonstrate that isorhamnetin significantly improves the antidepressant response of escitalopram, as evidenced by reduced floating time in the forced swim test. Moreover, isorhamnetin enhanced antidepressant effects of escitalopram and effectively restored depleted levels of Nrf2, BDNF, and HO-1 in the cortex caused by LPS-induced depression. Isorhamnetin shows promise in enhancing the efficacy of conventional antidepressant therapy through antioxidant and anti-inflammatory effects.

VE-MMODE - A randomized controlled trial of Venlafaxine versus Escitalopram for treatment of mild to moderate depression in persons with epilepsy.

OBJECTIVES: Depression in persons with epilepsy (PWE) goes undiagnosed and untreated. Despite being common, there are no direct efficacy comparisons of available antidepressants in PWE. Our aim was to compare the effectiveness of Venlafaxine (VEN) and Escitalopram (ESCIT) in comorbid depression in PWE. METHODS: In a single-center, prospective, double-blinded randomized controlled trial (RCT) 90 PWE (age ≥18 years) with mild to moderate depression, were randomized in a 1:1 ratio to receive ESCIT (5-20 mg/day) or VEN (37.5-150 mg/day) for 8 weeks. The primary outcome was to study differences in the efficacy, based on the change in scores of the Hamilton depression rating scale (HAM-D) at 8 weeks. Seizure frequency, QOLIE-31, adverse event profile, and medication adherence were secondary outcome measures. RESULTS: Using the NDDI-E scale, we screened 350 PWE, 90 were enrolled. ITT analysis included all participants and the PP analysis included 40 participants to VEN group and 42 to ESCIT group. Baseline mean (±SD) HAM-D scores for both groups were similar (13.53 ± 3.27; 13.02 ± 3.57). The mean difference (95%CI) on HAM-D scores at 8 weeks was found to be significant within both groups (ITT/PP- VEN: 7.75(6.75, 8.79)/7.92 (7.06, 8.78); p < 0.001, ESCIT: 8.21 (7.39, 9.03)/8.23(7.43, 9.04); p < 0.001). However, there was no significant difference in the efficacy of VEN versus ESCIT at 8 weeks. A significant improvement in QOLIE-31 index and seizure frequency was observed from baseline in both the groups. 90% of those on VEN and 92.9% of those using ESCITadhered to the treatment at week 8. Adverse events were more in VEN group than the ESCIT group. CONCLUSIONS: This study found that HAMD scores improved significantly in the ESCIT and VEN groups, despite the fact that there was no clinically meaningful difference observed between the two groups. Trials with a larger sample size and longer duration are required to establish whether ESCIT or VEN is superior.

Selective serotonin reuptake inhibitors regulate the interrelation between 5-HT and inflammation after myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is a main cause of death all around the world. There is a close relationship between myocardial infarction (MI) and depression. MI patients with untreated depression had higher mortality than those without depression. Therefore, this study aimed to explore the effect of escitalopram in treating a model under MI and unpredictable chronic mild stress (UCMS). METHODS: Male C57BL/6J mice were treated with sham surgery, or MI surgery, or UCMS, or escitalopram (ES) for a consecutive two weeks. And the mice were divided into Sham group, MI group, MI + UCMS group, MI + UCMS + ES group (n = 8 in each group). After treatment, the mice went through open field test for anxiety behavior, sucrose preference test for depressive behavior. After sacrificed, the blood, heart, hippocampus, and cortex were collected. RESULTS: The escitalopram badly increased the area of cardiac fibrosis size. The sucrose preference test demonstrated that escitalopram treatment showed significant effect in improving depressive behaviors of mice under MI + UCMS. The potential mechanism involved the interrelation between 5-HT system and inflammation. MI significantly affected the level of cardiac SERT. Both UCMS and ES significantly affected the level of cortex TNF-α. UCMS significantly affected the level of cardiac IL-33. In the hippocampus tissue, TNF-α was positively correlated with SERT, and IL-10 was positively correlated with SERT. In the cortex tissue, IL-33 was positively correlated with 5-HT4R, and sST2 was positively correlated with 5-HT. CONCLUSIONS: Two-week escitalopram treatment might worsen myocardial infarction. But escitalopram could benefit depressive behaviors, which may be related with the interrelationship between the 5-HT system and inflammatory factors in the brain.

Concentrations of escitalopram in blood of patients treated in a naturalistic setting: focus on patients with alcohol and benzodiazepine use disorder.

The selective serotonin reuptake inhibitor escitalopram (ESC) is indicated for the treatment of major depressive disorder (MDD) and of generalized anxiety disorder (GAD). Monitoring of blood levels (BLs) is strongly indicated due to ESC's high interindividual pharmacokinetic variability. The aim of this study was to analyse clinical efficacy and pharmacokinetic influences on ESC BLs, in patients with depressive disorder alone and with comorbid alcohol or benzodiazepine use disorder. Data were collected from patients treated under naturalistic conditions for whom Therapeutic Drug Monitoring (TDM) was requested to guide antidepressant drug therapy and analysed retrospectively. Particular emphasis was given to patients with alcohol or benzodiazepine use disorder. Responders according to the clinical global impression (CGI) scale were compared with nonresponders for their ESC blood level (BL). The patient sample included 344 patients from 16 psychiatric hospitals in Germany. Influencing factors that could explain 22% of ESC BLs were dose, sex and age. Variability was high between individuals, and doses up to 40 mg were common in real-world settings. Patients treated with ESC monotherapy who responded showed a trend towards higher BLs compared to nonresponders with a concentration of 15 ng/mL separating both groups. Pathological changes in liver function (indicated by elevated GGT in combination with an AST/ALT ratio ≥ 1) resulted in higher dose-corrected ESC concentrations. Influencing factors that could explain 22% of ESC blood levels were dose, sex, and age. Our findings confirm the currently recommended lower threshold level and support the need for standard TDM analyses in everyday clinical practice. The ICD 10 diagnosis alcohol dependence alone does not lead to pharmacokinetic changes in the metabolism of ESC, but altered liver function does.

Escitalopram versus other antidepressive agents for major depressive disorder: a systematic review and meta-analysis.

BACKGROUND: Escitalopram is selective serotonin reuptake inhibitors (SSRIs) and one of the most commonly prescribed newer antidepressants (ADs) worldwide. We aimed to explore the efficacy, acceptability and tolerability of escitalopram in comparison with other ADs in the acute-phase treatment of major depressive disorder (MDD). METHODS: Medline/PubMed, EMBASE, the Cochrane Library, CINAHL, and Clinical Trials.gov were searched from inception to July 10, 2023. Trial databases of drug-approving agencies were hand-searched for published, unpublished and ongoing controlled trials. All randomized controlled trials comparing escitalopram against any other antidepressant for patients with MDD. Responders and remitters to treatment were calculated on an intention-to-treat basis. For dichotomous data, risk ratios (RRs) were calculated with 95% confidence intervals (CI). Continuous data were analyzed using standardized mean differences (with 95% CI) using the random effects model. RESULTS: A total of 30 studies were included in this meta­analysis, among which sixteen trials compared escitalopram with another SSRI and 14 compared escitalopram with a newer AD. Escitalopram was shown to be significantly more effective than citalopram in achieving acute response (RR 0.67, 95% CI 0.50-0.87). Escitalopram was also more effective than citalopram in terms of remission (RR 0.53, 95% CI 0.30-0.93). CONCLUSIONS: Escitalopram was superior to other ADs for the acute phase treatment of MDD in terms of efficacy, acceptability and tolerability. However, no significant difference was found between escitalopram and other ADs in early response or follow-up response to treatment of MDD.

Transcutaneous electrical cranial-auricular acupoint stimulation versus escitalopram for mild-to-moderate depression: An assessor-blinded, randomized, non-inferiority trial.

AIM: Transcutaneous electrical cranial-auricular acupoint stimulation (TECAS) is a novel non-invasive therapy that stimulates acupoints innervated by the trigeminal and auricular vagus nerves. An assessor-blinded, randomized, non-inferiority trial was designed to compare the efficacy of TECAS and escitalopram in mild-to-moderate major depressive disorder. METHODS: 468 participants received two TECAS sessions per day at home (n = 233) or approximately 10-13 mg/day escitalopram (n = 235) for 8 weeks plus 4-week follow-up. The primary outcome was clinical response, defined as a baseline-to-endpoint ≥50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Secondary outcomes included remission rate, changes in the severity of depression, anxiety, sleep and life quality. RESULTS: The response rate was 66.4% on TECAS and 63.2% on escitalopram with a 3.2% difference (95% confidence interval [CI], -5.9% to 12.9%) in intention-to-treat analysis, and 68.5% versus 66.2% with a 2.3% difference (95% CI, -6.9% to 11.4%) in per-protocol analysis. The lower limit of 95% CI of the differences fell within the prespecified non-inferiority margin of -10% (P ≤ 0.004 for non-inferiority). Most secondary outcomes did not differ between the two groups. TECAS-treated participants who experienced psychological trauma displayed a markedly greater response than those without traumatic experience (81.3% vs 62.1%, P = 0.013). TECAS caused much fewer adverse events than escitalopram. CONCLUSIONS: TECAS was comparable to escitalopram in improving depression and related symptoms, with high acceptability, better safety profile, and particular efficacy in reducing trauma-associated depression. It could serve an effective portable therapy for mild-to-moderate depression.

Combined Administration of Escitalopram Oxalate and Nivolumab Exhibits Synergistic Growth-Inhibitory Effects on Liver Cancer Cells through Inducing Apoptosis.

Liver cancer is one of the most lethal malignant cancers worldwide. However, the therapeutic options for advanced liver cancers are limited and reveal scant efficacy. The current study investigated the effects of nivolumab (Niv) and escitalopram oxalate (Esc) in combination on proliferation of liver cancer cells both in vitro and in vivo. Significantly decreased viability of HepG2 cells that were treated with Esc or Niv was observed in a dose-dependent manner at 24 h, 48 h, and 72 h. Administration of Esc (50 µM) + Niv (20 µM), Esc (75 µM) + Niv (5 µM), and Esc (75 µM) + Niv (20 µM) over 24 h exhibited synergistic effects, inhibiting the survival of HepG2 cells. Additionally, treatment with Esc (50 µM) + Niv (1 µM), Esc (50 µM) + Niv (20 µM), and Esc (75 µM) + Niv (20 µM) over 48 h exhibited synergistic effects, inhibiting the survival of HepG2 cells. Finally, treatment with Esc (50 µM) + Niv (1 µM), Esc (50 µM) + Niv (20 µM), and Esc (75 µM) + Niv (20 µM) for 72 h exhibited synergistic effects, inhibiting HepG2 survival. Com-pared with controls, HepG2 cells treated with Esc (50 µM) + Niv (20 µM) exhibited significantly increased sub-G1 portion and annexin-V signals. In a xenograft animal study, Niv (6.66 mg/kg) + Esc (2.5 mg/kg) significantly suppressed the growth of xenograft HepG2 tumors in nude mice. This study reports for the first time the synergistic effects of combined administration of Niv and Esc for inhibiting HepG2 cell proliferation, which may provide an alternative option for liver cancer treatment.

Kappa Opioid Receptors Reduce Serotonin Uptake and Escitalopram Efficacy in the Mouse Substantia Nigra Pars Reticulata.

The serotonin and kappa opioid receptor (KOR) systems are strongly implicated in disorders of negative affect, such as anxiety and depression. KORs expressed on axon terminals inhibit the release of neurotransmitters, including serotonin. The substantia nigra pars reticulata (SNr) is involved in regulating affective behaviors. It receives the densest serotonergic innervation in the brain and has high KOR expression; however, the influence of KORs on serotonin transmission in this region is yet to be explored. Here, we used ex vivo fast-scan cyclic voltammetry (FSCV) to investigate the effects of a KOR agonist, U50, 488 (U50), and a selective serotonin reuptake inhibitor, escitalopram, on serotonin release and reuptake in the SNr. U50 alone reduced serotonin release and uptake, and escitalopram alone augmented serotonin release and slowed reuptake, while pretreatment with U50 blunted both the release and uptake effects of escitalopram. Here, we show that the KOR influences serotonin signaling in the SNr in multiple ways and short-term activation of the KOR alters serotonin responses to escitalopram. These interactions between KORs and serotonin may contribute to the complexity in the responses to treatments for disorders of negative affect. Ultimately, the KOR system may prove to be a promising pharmacological target, alongside traditional antidepressant treatments.

THERAPY OF POST-COVID DEPRESSION: A PROACTIVE PSYCHOSOMATIC APPROACH.

OBJECTIVE: Aim: Evaluation of the effectiveness of the early 8-week monotherapy with escitalopram as a form of proactive psychosomatic intervention for patients with post-COVID depression. PATIENTS AND METHODS: Materials and methods: 44 patients with post-COVID depression were involved in a proactive psychosomatic intervention in the form of an 8-week intake of escitalopram (Medogram, Medochemiе Ltd) for 2-8 weeks in the case of a diagnosis of severe depression. Hamilton Depression Scale (HAM-D), Somatic Symptom Scale (SSS-8), Quality of Life Scale (CQLS) were used to assess symptoms and status dynamics. RESULTS: Results: Patients with post-COVID depression after an 8-week course of escitalopram therapy showed a significant reduction in mental and somatic symptoms of depression and an improvement in quality of life. At the time of enrollment in the study, 12 (28.58%) individuals had mild depression, 15 (35.71%) had moderate depression, and 15 (35.71%) had severe depression. At the end of the 8th weeks of taking the drug in 24 (57.14%) there were no signs of depression on the HAM-D scale, in 18 people there were subclinical manifestations of depression. The effectiveness of escitalopram in reducing the symptoms of depression in this study was 66%. CONCLUSION: Conclusions: With the introduction of pharmacotherapy with escitalopram there was a significant reduction in mental and so¬matic symptoms of depression and an improvement in quality of life. Escitalopram (Medochemie Ltd) may be an effective drug for psychopharmacotherapy of depressive symptoms in patients who have had COVID-19. Further studies are promising its effective¬ness in the treatment of post-COVID depression.