Search

Objective: There is growing evidence that adding non-steroidal anti-inflammatory drugs to some psychopharmacological treatments may help to improve symptoms in patients suffering from major depressive disorder. The present study examined the therapeutic efficacy of adding celecoxib to escitalopram and the safety of doing so., Method: In this double-blind randomized controlled trial, 60 patients with major depressive disorder were randomly assigned to either treatment with escitalopram plus celecoxib (intervention group) or escitalopram and placebo. All patients were evaluated blind to treatment group with the Hamilton Depression Rating Scale (HDRS) before the intervention as well at 4 and 8 weeks after initiating treatment. Chi-square and paired t-test were used to examine between-group differences at those assessment times., Results: There was no significant difference in depressive symptoms between intervention and placebo groups at baseline. However, at 4 and 8 weeks after the beginning of treatment, there were significant between-group differences in HDRS scores, favoring the intervention group. No between-group differences were found in treatment-related side effects., Conclusions: Adding celecoxib to escitalopram may improve symptoms of depression in patients with major depressive disorder without increasing the risk of drug-related side effects., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To study the effects of selective serotonin reuptake inhibitors (SSRIs) on cognitive functions, mental improvements, and adverse effects in patients with Alzheimer's disease (AD)., Methods: Registered in INPLASY (INPLASY202450004), five drugs (citalopram, s-citalopram, quetiapine, olanzapine, and sertraline) were selected as representatives. A comprehensive search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Library up to May 15, 2024. Search terms were combined using Boolean operators, specifically 'AND' between different categories (e.g., 'Alzheimer's Disease' AND 'SSRIs') and 'OR' within the same category (e.g., 'citalopram OR s-citalopram OR quetiapine OR olanzapine OR sertraline'), to ensure a thorough retrieval of relevant studies. The selection followed rigorous inclusion and exclusion criteria for meta-analysis., Results: Fourteen articles from 1118 were selected for meta-analysis. The indicators, including Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), Brief Psychiatric Rating Scale (BPRS), and Cornell Scale for Depression in Dementia (CSDD), were used to assess the effects of the drugs on AD treatment. According to the results of NPI, CSDD, BPRS, MMSE, and security assessments, the five antidepressants have significant advantages in AD treatment compared with placebo, while the MMSE of the patient treated with the antidepressants did not show notable changes compared with patients treated only with placebo. Statistical analyses were conducted using Review Manager 5.3, employing random-effects models to account for study heterogeneity and sensitivity analyses to test the robustness of our findings., Conclusion: This study suggests that SSRI-related antidepressants have great potential values in AD treatment, and further research on the application of SSRI-related antidepressants in AD treatment is necessary., (© 2024. The Author(s).)

Background: Antidepressants are among the most commonly prescribed medications, but evidence on comparative weight change for specific first-line treatments is limited., Objective: To compare weight change across common first-line antidepressant treatments by emulating a target trial., Design: Observational cohort study over 24 months., Setting: Electronic health record (EHR) data from 2010 to 2019 across 8 U.S. health systems., Participants: 183 118 patients., Measurements: Prescription data determined initiation of treatment with sertraline, citalopram, escitalopram, fluoxetine, paroxetine, bupropion, duloxetine, or venlafaxine. The investigators estimated the population-level effects of initiating each treatment, relative to sertraline, on mean weight change (primary) and the probability of gaining at least 5% of baseline weight (secondary) 6 months after initiation. Inverse probability weighting of repeated outcome marginal structural models was used to account for baseline confounding and informative outcome measurement. In secondary analyses, the effects of initiating and adhering to each treatment protocol were estimated., Results: Compared with that for sertraline, estimated 6-month weight gain was higher for escitalopram (difference, 0.41 kg [95% CI, 0.31 to 0.52 kg]), paroxetine (difference, 0.37 kg [CI, 0.20 to 0.54 kg]), duloxetine (difference, 0.34 kg [CI, 0.22 to 0.44 kg]), venlafaxine (difference, 0.17 kg [CI, 0.03 to 0.31 kg]), and citalopram (difference, 0.12 kg [CI, 0.02 to 0.23 kg]); similar for fluoxetine (difference, -0.07 kg [CI, -0.19 to 0.04 kg]); and lower for bupropion (difference, -0.22 kg [CI, -0.33 to -0.12 kg]). Escitalopram, paroxetine, and duloxetine were associated with 10% to 15% higher risk for gaining at least 5% of baseline weight, whereas bupropion was associated with 15% reduced risk. When the effects of initiation and adherence were estimated, associations were stronger but had wider CIs. Six-month adherence ranged from 28% (duloxetine) to 41% (bupropion)., Limitation: No data on medication dispensing, low medication adherence, incomplete data on adherence, and incomplete data on weight measures across time points., Conclusion: Small differences in mean weight change were found between 8 first-line antidepressants, with bupropion consistently showing the least weight gain, although adherence to medications over follow-up was low. Clinicians could consider potential weight gain when initiating antidepressant treatment., Primary Funding Source: National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2742.

BACKGROUND Rhabdomyolysis, an uncommon but recognized adverse effect of selective serotonin reuptake inhibitor (SSRI) antidepressants, can precipitate acute renal injury (AKI), especially when combined with risk factors such as alcohol consumption. This report describes a 68-year-old man with acute renal failure due to rhabdomyolysis associated with alcohol intoxication while taking low-dose escitalopram, an SSRI antidepressant. CASE REPORT The patient, with a history of bipolar affective disorder managed with escitalopram, presented with symptoms of general malaise, diarrhea, myalgias, and transient loss of consciousness following substantial ethanol consumption. Laboratory tests indicated severe rhabdomyolysis with a creatine kinase level of 37 672 U/L and myoglobin level >5710 ng/ml, leading to an AKI diagnosis. The discontinuation of escitalopram, along with hydration and renal replacement therapy, facilitated renal recovery. However, the reintroduction of escitalopram resulted in the recurrence of rhabdomyolysis, suggesting a probable causal link, confirmed using the Naranjo Adverse Drug Reaction Probability Scale. CONCLUSIONS This report highlights the importance of identifying the medication history in patients presenting with acute renal failure and rhabdomyolysis and the association with SSRIs, which can be exacerbated by alcohol. This case underscores the importance of vigilant medication history assessment in patients presenting with AKI and rhabdomyolysis, particularly concerning the use of SSRIs like escitalopram, which can pose heightened risks in the context of alcohol use. It highlights the need for clinical caution in managing patients on long-term SSRI therapy, especially when reintroducing such medications after an episode of rhabdomyolysis.

Background: Selective Serotonin Reuptake Inhibitors (SSRIs) represent a diverse class of medications widely prescribed for depression and anxiety. Despite their common use, there is an absence of large-scale, real-world evidence capturing the heterogeneity in their effects on individuals. This study addresses this gap by utilizing naturalistic search data to explore the varied impact of six different SSRIs on user behavior., Methods: The study sample included ∼508 thousand Bing users with searches for one of six SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) from April-December 2022, comprising 510 million queries. Cox proportional hazard models were employed to examine 30 topics (e.g., shopping, tourism, health) and 195 health symptoms (e.g., anxiety, weight gain, impotence), using each SSRI as a reference. We assessed the relative hazard ratios between drugs and, where feasible, ranked the SSRIs based on their observed effects. We used Cox proportional hazard models in order to account for both the likelihood of users searching for a particular topic or symptom and the associated time to that search. The temporal aspect aided in distinguishing between potential symptoms of the disorder, short-term medication side effects, and later appearing side effects., Results: Differences were found in search behaviors associated with each SSRI. E.g., fluvoxamine was associated with a significantly higher likelihood of searching weight gain compared to all other SSRIs (HRs 1.85-2.93). Searches following citalopram were associated with significantly higher rates of later impotence queries compared to all other SSRIs (HRs 5.11-7.76), except fluvoxamine. Fluvoxamine was associated with a significantly higher rate of health related searches than all other SSRIs (HRs 2.11-2.36)., Conclusions: Our study reveals new insights into the varying SSRI impacts, suggesting distinct symptom profiles. This novel use of large-scale, naturalistic search data contributes to pharmacovigilance efforts, enhancing our understanding of intra-class variation among SSRIs, potentially uncovering previously unidentified drug effects., Competing Interests: Declaration of competing Interest NCJ has a received grant from Boehringer-Ingelheim. NCJ has edited a book through Academic Press and receives book royalties, and NCJ also receives speaking fees related to his research. MVH has worked as a paid consultant for Artisight and ChatNexus. EYT was previously employed by Microsoft Research., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: The study aimed to conduct a multidimensional evaluation of potential adverse events (AEs) of escitalopram oxalate based on the FDA adverse event reporting system (FAERS) database., Methods: This study utilized the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma-poisson shrinker (MGPS) to mine and analyze data from the FAERS database from the first quarter of 2004 to the second quarter of 2023., Results: There was a total of 19,854 AE reports related to escitalopram oxalate, extracting 625 preferred terms (PTs), and covering 27 system organ classes (SOCs). The results showed that the number of reports by females was significantly higher than males, accounting for 57.68%. The reporting number was higher in 2018 and 2019, accounting for 9.50% and 10.18% of the total reports, respectively. The main reporters were consumers and other health professionals, accounting for 26.99% and 26.75% respectively. The majority of the reports were primarily from the United States. Newly emerging AE signals such as intentional overdose ( n  = 691, ROR 8.51, PRR 8.45, IC 3.05, Empirical Bayesian Geometric Mean (EBGM) 8.35), suicide attempt ( n  = 665, ROR 8.58, PRR 8.52, IC 3.06, EBGM 8.42), serum serotonin ( n  = 5, ROR 1044.78, PRR 1044.71, IC 2.56, EBGM 392.39), anti-actin antibody positive ( n  = 5, ROR 626.87, PRR 626.83, IC 2.56, EBGM 313.91), among others, were not mentioned in the drug's label., Conclusion: While escitalopram oxalate has clear benefits in the treatment of depression and other mental health disorders, the presence of AEs also suggests risks associated with its use. Particularly concerning are risks of suicide and changes in serum serotonin levels., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Typical antipsychotics are known to produce extrapyramidal side effects such as drug induced parkinsonism, acute dystonia, akathisia, tardive dyskinesias and rabbit syndrome. Rabbit syndrome is characterized by vertical rhythmic motion of the mouth and lips, resembling chewing movements of a rabbit., Reason for the Report: Rabbit syndrome seen in patients on antidopaminergic therapies is characterized by vertical rhythmic movements of perioral region, has a late onset, and characteristically spares the tongue. The main aim of the report is to highlight atypical manifestation of antipsychotic associated Rabbit syndrome in the presence of a serotonergic antidepressant. An elderly patient presented with atypical rabbit syndrome with relatively acute onset, horizontal movements of jaw and marked tongue involvement after haloperidol-escitalopram initiation., Outcome: The patient improved with discontinuation of antipsychotic. The tongue involvement was believed to be secondary to escitalopram use., (© 2023. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

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 (χ 2 ), 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., (© 2024. The Author(s).)

Background: Restless arms syndrome (RAS) is the most common variant of restless legs syndrome (RLS), which is easy to be ignored in clinical practice due to the lack of specific diagnostic criteria. When effective therapeutic agents induced RAS and symptoms persisted after briefly observation, clinicians will face the challenge of weighing efficacy against side effects., Case Presentation: A 67-year-old woman was admitted to a geriatric psychiatric ward with depression. Upon admission, the escitalopram dose was reduced from 15 mg to 10 mg per day, and the duloxetine dose was increased from 60 mg to 80 mg per day. The next night before bedtime, she developed itching and creeping sensations deep inside bilateral shoulders and arms, with the urge to move, worsening at rest, and alleviation after hammering. The symptoms persisted when escitalopram was discontinued. A history of RLS was confirmed. Treatment with 40 mg of duloxetine and 0.125 mg of pramipexole significantly improved depression, and the paresthesia disappeared, with no recurrence occurring 6 months after discharge., Discussion and Conclusions: This case suggests that psychiatrists should pay attention to RLS variants when increasing doses of duloxetine. Long-term improvement can be achieved through dosage reduction combined with dopaminergic drugs instead of immediate discontinuation., (© 2024. The Author(s).)

Selective serotonin reuptake inhibitors (SSRI) are the first-line pharmacologic treatment for anxiety and depressive disorders in children and adolescents. Many patients experience side effects that are difficult to predict, are associated with significant morbidity, and can lead to treatment discontinuation. Variation in SSRI pharmacokinetics could explain differences in treatment outcomes, but this is often overlooked as a contributing factor to SSRI tolerability. This study evaluated data from 288 escitalopram-treated and 255 sertraline-treated patients ≤ 18 years old to develop machine learning models to predict side effects using electronic health record data and Bayesian estimated pharmacokinetic parameters. Trained on a combined cohort of escitalopram- and sertraline-treated patients, a penalized logistic regression model achieved an area under the receiver operating characteristic curve (AUROC) of 0.77 (95% confidence interval (CI): 0.66-0.88), with 0.69 sensitivity (95% CI: 0.54-0.86), and 0.82 specificity (95% CI: 0.72-0.87). Medication exposure, clearance, and time since the last dose increase were among the top features. Individual escitalopram and sertraline models yielded an AUROC of 0.73 (95% CI: 0.65-0.81) and 0.64 (95% CI: 0.55-0.73), respectively. Post hoc analysis showed sertraline-treated patients with activation side effects had slower clearance (P = 0.01), which attenuated after accounting for age (P = 0.055). These findings raise the possibility that a machine learning approach leveraging pharmacokinetic data can predict escitalopram- and sertraline-related side effects. Clinicians may consider differences in medication pharmacokinetics, especially during dose titration and as opposed to relying on dose, when managing side effects. With further validation, application of this model to predict side effects may enhance SSRI precision dosing strategies in youth., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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.

Objective: We assessed pharmacokinetic correlates of treatment response to escitalopram using a large therapeutic drug monitoring database., Methods: A large naturalistic sample of patients receiving escitalopram was analyzed. Responders were defined as 'very much improved' or 'much improved' based on the Clinical Global Impression - Improvement score, CGI-I. We compared responders ( n  = 83) vs. non-responders ( n = 388) with the primary outcome being the escitalopram plasma concentration and concentration corrected by the daily dose (C/D ratio). Effects of age, sex, body-mass-index (BMI), and C/D ratio were assessed in a multivariate logistic regression model predicting response., Results: There were no statistically significant differences in clinical and demographic characteristics between responders vs. non-responders. There were also no differences between escitalopram daily doses or plasma concentrations, while C/D ratios were significantly higher in non-responders than in responders (1.6 ± 1.7 vs. 1.2 ± 0.9 (ng/mL)/(mg/day), p  = 0.007); C/D ratios (odds ratio 0.52, 95% confidence interval 0.34-0.80, p < 0.003) were associated with response to escitalopram, after controlling for age, sex, and BMI., Conclusions: Patients with low clearance of escitalopram as reflected upon high C/D ratios may be less likely respond to escitalopram. Identifying these patients during dose titration may support clinical decision-making, including switching to a different antidepressant instead of increasing daily dose.

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes ( CYP2C19 or CYP2D6 ), the serotonin transporter ( SLC6A4 ), and the serotonin receptor 2A subtype ( HTR2A ). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC 0-24 ; p  = 0.025), trough concentrations (C trough ; p  = 0.013), and elimination half-lives (t 1/2 ; p  < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia ( p  = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores ( p  = 0.017). Escitalopram maximum concentration, AUC 0-24 , CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.

Objectives: To explore the effect of escitalopram combined with aripiprazole on cognitive function in patients with major depressive disorder (MDD), and to evaluate the clinical efficacy of the combination therapy., Method: A total of 70 patients with first-episode MDD were randomly divided into the study group or the control group, receiving escitalopram combined with aripiprazole (5 mg/day) or escitalopram monotherapy respectively for 8 weeks. The severity of illness was assessed by using the Hamilton Rating Scale for Depression (HAMD) at baseline, at the end of 4 th and 8 th week, and cognitive function was assessed by using the THINC integrated tool (THINC-it), the Wisconsin Card Sorting Test (WCST), and the Continuous Performance Test (CPT). Rating Scale for Extrapyramidal Side Effects (RSESE) was applied to assess adverse reactions., Results: The average HAMD-17 and HAMA scores decreased over time in both the control and the study groups, but the reductions were not statistically different between two groups with the passage of time. In WCST, total number of response (TR) of the study group decreased relative to the baseline at the end of the eighth week, but the control group did not significantly change during whole eight weeks. Perseverative errors (PE) in the control group eventually decreased at the end of Week 8 compared to that at Week 4, but in the study group, it was a continuous trend of decrease. In CPT, the decrease of leakage responses (LR) in the study group was higher than that of the control group in 2-digit number, and LR of the control group was higher than that of the study group at the end of Week 8 in 4-digit number. The downtrend of LR in 4-digit number kept for the whole period in study group, while in the control group, the LR did not decrease significantly until the end of Week 8 compared to that at baseline., Conclusion: Escitalopram combined with a low-dose of aripiprazole, and escitalopram monotherapy could both enhance cognitive function of MDD patients, while the improvements of combination therapy might happen relatively earlier. The combined use of escitalopram and aripiprazole might be more beneficial to the domains of executive function (EF) and continuous attention compared to escitalopram monotherapy. There was no significant differences between two treatment options in alleviating depressive and anxiety symptoms., Competing Interests: Declaration of competing interest All authors declare no conflict of interest with this work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Citalopram is a selective serotonin re-uptake inhibitor (SSRI) antidepressant; it exhibits the greatest cardiotoxic effect among SSRIs. Citalopram can cause drug-induced long QT syndrome (LQTS) and ventricular arrhythmias. We investigated the protective effect of nicorandil, a selective mitochondrial K ATP (mito-K ATP ) channel opener, on LQTS and myocardial damage caused by citalopram in male rats. In a preliminary study, we determined that the minimum citalopram dose that prolonged the QT interval was 102 mg/kg injected intraperitoneally. For the main study, rats were divided randomly into five experimental groups: untreated control, normal saline + citalopram, nicorandil + citalopram, 5-hydroxydecanoate (5-HD) + citalopram, 5-HD + nicorandil + citalopram. Biochemical and histologic data from blood and heart tissue samples from six untreated control rats were evaluated. Electrocardiographic parameters including QRS duration, QT interval, corrected QT interval (QTc) and heart rate (HR) were assessed, and biochemical parameters including malondialdehyde, reduced glutathione, glutathione peroxidase, superoxide dismutase were measured. We also performed histomorphologic and immunohistochemical examination of heart tissue. Citalopram prolonged QT-QTc intervals significantly and increased significantly the histomorphologic score and proportion of apoptotic cells, but produced no differences in the oxidant and antioxidant parameters. Nicorandil did not prevent citalopram induced QT-QTc interval prolongation and produced no significant changes in oxidant and antioxidant parameters; however, it did reduce histologic damage and apoptosis caused by citalopram.

Background: Breast cancer is the most common cancer in women worldwide. Premature menopause and hot flashes are the main complications of breast cancer treatments. About 40 to 50 percent of breast cancer women who undergo chemotherapy are experiencing premature menopause symptoms, including hot flashes. Some endocrine therapies such as tamoxifen and aromatase inhibitors are associated with induction or aggravating hot flashes. Hot flashes are often debilitating and significantly impair daily functions. Therefore many therapeutic options have been studied so far for the management of this adverse effect. However, there are still some clinical challenges in managing hot flashes in patients with breast cancer., Objective: We aimed to evaluate and compare the efficacy of venlafaxine and citalopram on hot flashes in breast cancer women receiving tamoxifen., Design: We conducted a double-blind, placebo-controlled trial in forty-one, 35 to 65 years old female patients. The study lasted for four weeks, and the follow-up was for two months. Venlafaxine and citalopram treatments started with doses of 37.5 mg or 10 mg, respectively. Venlafaxine and citalopram dosages were increased in the second week to 75 and 20 mg, respectively. The study was conducted during the year 2017., Key Results: The results indicated that the total efficacy was significantly different in groups receiving citalopram, venlafaxine, and placebo. Total efficacy in the placebo group, venlafaxine, and citalopram was 14.3, 53.8, and 64.3%, respectively (p=0.02). During the second week, the efficacy in groups receiving citalopram, venlafaxine, and placebo was 57.1, 53.8, and 14.3%, respectively (p=0.04). Generally, both citalopram and venlafaxine were well tolerated. The associated adverse effects were mild to moderate in both groups., Conclusions: Although citalopram was associated with more adverse effects, including constipation, it was more effective in reducing the frequency of hot flashes when compared to venlafaxine or placebo., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objectives: Depression is often accompanied by various degrees of cognitive decline, with a high incidence. Guidelines recommend medication combined with psychological therapy. Solution focused group therapy (SFGT) is a newer group psychotherapy technique. This study aims to explore the difference between SFGT combined with escitalopram and only use escitalopram in treating depression., Methods: A total of 84 patients who met the diagnostic criteria of international classification of diseases-10 (ICD-10) were enrolled into the combined group (SFGT combined with escitalopram, n =42) and the control group (only escitalopram, n =42) for an 8-week treatment. Patients were measured with the 24-item Hamilton Depression Scale (HAMD-24) and the Cognitive Flexibility Inventory (CFI) at baseline (T 0 ), week 4 (T 1 ), and week 8 (T 2 ), respectively. Differences in depressive symptoms and cognitive flexibility between the 2 groups were compared and analyzed., Results: At T 2 , 8 patients were dislodged in the combined group and 10 in the control group. There was no difference in the subscales and total scores of HAMD-24 and CFI between the 2 groups at T 0 (all P> 0.05). At T 1 and T 2 , compared with the control group, the total scores and anxiety somatization, cognitive impairment, delay, and a sense of despair subscales scores of HAMD-24 were lower, and the total scores and subscales scores of CFI in the combined group were higher (all P <0.05)., Conclusions: SFGT combined with escitalopram is more effective than monotherapy for improving the anxiety somatization symptoms, cognitive impairment, retardation symptoms and despair symptoms, and increasing the cognitive flexibility.

Background: For a decade, patients have been advised against using high citalopram- and escitalopram-doses due to risk for ventricular arrhythmia and cardiac arrest. Still, these drugs are widely used to treat depression and anxiety especially in older patients. It is unclear why they are cardiotoxic and at what serum concentrations patients are at risk for arrhythmias. Thus, how many patients that are at risk for iatrogenic cardiac arrest is unknown., Methods: We studied the arrhythmogenic effects of citalopram, escitalopram and their metabolites on human cardiomyocytes. Concentrations showing pro-arrhythmic activity were compared with observed drug and metabolite serum concentrations in a cohort of 19,742 patients (age 12-105 years) using escitalopram or citalopram in Norway (2010-2019). As arrhythmia-risk is related to maximum serum concentration, this was simulated for different age-groups from the escitalopram patient material., Findings: Therapeutic concentrations of both citalopram and escitalopram but not their metabolites showed pro-arrhythmic changes in the human cardiac action potential. Due to age-dependent reduction of drug clearance, the proportion of patients above threshold for arrhythmia-risk increased with age. 20% of patients >65 years were predicted to reach potentially pro-arrhythmic concentrations, following intake of 10 mg escitalopram., Interpretation: All patients that are using escitalopram or citalopram and have genetic disposition for acquired long-QT syndrome, are >65 years, are using additional pro-arrhythmic drugs or have predisposition for arrhythmias, should be monitored with therapeutic drug monitoring (TDM) to avoid exposure to potentially cardiotoxic concentrations. Serum concentrations should be kept below 100 nM, to reduce arrhythmia-risk., Funding: This study was funded by The Research Council of Norway (project number: 324062)., Competing Interests: Declaration of interests The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

This longitudinal study examines the association between fetal Selective Serotonergic Reuptake Inhibitor antidepressant exposure and infant sleep behaviours at six and 12 months of age and focus on three of the most commonly prescribed antidepressants in pregnancy. This study utilises data on 698 women recruited at less than 20 weeks of pregnancy and are followed up at six and 12 months postpartum. Women were recruited into one of three groups: those taking either sertraline, citalopram or escitalopram antidepressants in pregnancy (n = 85); women with a depressive disorder who were not taking antidepressants (non-medicated depressed, NMD; n = 82); and, and a control group of women (n = 531). At six and 12 months, data were collected on breastfeeding and sleep location and infant sleep was measured using the Brief Infant Sleep Questionnaire. Antidepressants sertraline, escitalopram and citalopram were not associated with increased infant waking or time awake. However, sertraline was associated with longer time for an infant to go to sleep. This study provides reassurance that SSRI antidepressants and, in particular, sertraline, escitalopram and citalopram are not associated with infant sleep behaviours that are commonly regarded as problematic including night waking. Further replication of these findings, including with direct measures of infant sleep, are recommended., Competing Interests: Disclosure of Interests The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Antidepressants, specifically Selective Serotonin Re-uptake Inhibitors (SSRIs), that alter serotonin metabolism are currently the most commonly prescribed drugs for the treatment of depression. There is some evidence to suggest these drugs contribute to birth defects. As jaw development is often altered in craniofacial birth defects, the purpose of this study was to interrogate the effects of in utero SSRI exposure in a preclinical model of mandible development., Materials and Methods: Wild-type C57BL6 mice were used to produce litters that were exposed in utero to an SSRI, Citalopram (500 μg/day). Murine mandibles from P15 pups were analysed for a change in shape and composition., Results: Analysis indicated an overall shape change with total mandibular length and ramus height being shorter in exposed pups as compared to controls. Histomorphometric analysis revealed that first molar length was longer in exposed pups while third molar length was shorter in exposed as compared to control. Histological investigation of molars and surrounding periodontium revealed no change in collagen content of the molar in exposed pups, some alteration in collagen composition in the periodontium, increased alkaline phosphatase in molars and periodontium and decreased mesenchymal cell marker presence in exposed mandibles., Conclusion: The results of this study reveal SSRI exposure may interrupt mandible growth as well as overall dental maturation in a model of development giving insight into the expectation that children exposed to SSRIs may require orthodontic intervention., (© 2022 The Authors. Orthodontics & Craniofacial Research published by John Wiley & Sons Ltd.)

Background: Evidence is limited regarding the optimal therapeutic approach for neuropsychiatric symptoms associated with Parkinson's disease dementia (PDD). Selective serotonin reuptake inhibitors (SSRIs) are widely used for mood disorders and behavioral symptoms in older adults with cognitive impairment, but they have limited efficacy in patients with PDD. The effect of SSRIs on hemostasis is also unclear. This report describes a patient with PDD who developed deep venous thrombosis (DVT) and hyponatremia after initiating citalopram treatment., Case Presentation: An 86-year-old woman with PDD presented to our emergency department with altered mental status, generalized weakness, and left lower leg swelling. Citalopram was begun 4 weeks previously for behavioral changes and was discontinued 2 days before presentation because of excessive fatigue. At presentation, her plasma sodium level was 123 mg/dL. Brain computed tomography showed age-related changes. Doppler ultrasound revealed a DVT in the left lower leg. The patient was treated with hypertonic saline and intravenous heparin. After normalization of her sodium, she was discharged on donepezil and apixaban. At follow-up, her sodium remained normal, and her cognition and behavior were noticeably improved., Conclusion: Older adults with Parkinson's disease are sensitive to adverse effects of psychotropic agents, including SSRIs, which are not recommended first-line agents for behavioral symptoms in PDD. Upon initiating SSRIs in older patients with functional decline and multiple comorbidities, physicians need to evaluate the patient's risk factors for bleeding or thrombosis. Physical activities should also be maintained as much as possible., (© 2023. The Author(s).)

Studies assessing associations between prenatal exposure to antidepressants, maternal depression, and offspring DNA methylation (DNAm) have been inconsistent. Here, we investigated whether prenatal exposure to citalopram or escitalopram ((es)citalopram) and maternal depression is associated with differences in DNAm. Then, we examined if there is an interaction effect of (es)citalopram exposure and DNAm on offspring neurodevelopmental outcomes. Finally, we investigated whether DNAm at birth correlates with neurodevelopmental trajectories in childhood. We analyzed DNAm in cord blood from the Norwegian Mother, Father and Child Cohort Study (MoBa) biobank. MoBa contains questionnaire data on maternal (es)citalopram use and depression during pregnancy and information about child neurodevelopmental outcomes assessed by internationally recognized psychometric tests. In addition, we retrieved ADHD diagnoses from the Norwegian Patient Registry and information on pregnancies from the Medical Birth Registry of Norway. In total, 958 newborn cord blood samples were divided into three groups: (1) prenatal (es)citalopram exposed (n = 306), (2) prenatal maternal depression exposed (n = 308), and (3) propensity score-selected controls (n = 344). Among children exposed to (es)citalopram, there were more ADHD diagnoses and symptoms and delayed communication and psychomotor development. We did not identify differential DNAm associated with (es)citalopram or depression, nor any interaction effects on neurodevelopmental outcomes throughout childhood. Trajectory modeling identified subgroups of children following similar developmental patterns. Some of these subgroups were enriched for children exposed to maternal depression, and some subgroups were associated with differences in DNAm at birth. Interestingly, several of the differentially methylated genes are involved in neuronal processes and development. These results suggest DNAm as a potential predictive molecular marker of later abnormal neurodevelopmental outcomes, but we cannot conclude whether DNAm links prenatal (es)citalopram exposure or maternal depression with child neurodevelopmental outcomes., (© 2023. The Author(s).)

Objective: Generalized anxiety disorder (GAD) in children and adolescents is associated with substantial morbidity and increases the risk of future psychopathology. However, relatively few psychopharmacologic studies have examined treatments for GAD in pediatric populations, especially in prepubertal youth. Methods: Children and adolescents aged 7-17 years of age with a primary diagnosis of GAD were treated with flexibly dosed escitalopram (10-20 mg daily, n  = 138) or placebo ( n  = 137) for 8 weeks. Efficacy measures included the Pediatric Anxiety Rating Scale (PARS) for GAD, Clinical Global Impression of Severity (CGI-S) scale, Children's Global Assessment Scale (CGAS); safety measures included the Columbia-Suicide Severity Rating Scale (C-SSRS) as well as adverse events (AEs), vital signs, and electrocardiographic and laboratory monitoring. Results: Escitalopram was superior to placebo in reducing anxiety symptoms of GAD, as seen in the difference in mean change from baseline to week 8 on the PARS severity for GAD score (least squares mean difference = -1.42; p  = 0.028). Functional improvement, as reflected by CGAS score, was numerically greater in escitalopram-treated patients compared with those receiving placebo ( p  = 0.286), and discontinuation owing to AEs did not differ between the two groups. Vital signs, weight, laboratory, and electrocardiographic results were consistent with previous pediatric studies of escitalopram. Conclusions: Escitalopram reduced anxiety symptoms and was well tolerated in pediatric patients with GAD. These findings confirm earlier reports of escitalopram efficacy in adolescents aged 12-17 years and extend the safety and tolerability data to children with GAD aged 7-11 years. ClinicalTrials.gov Identifier: NCT03924323.

We present a case of Torsades de Pointes (TdP) in a patient with COVID-19 infection and multiple TdP risk factors including QT-interval prolongation, hemodialysis, bradycardia, and treatment with remdesivir, citalopram, and quetiapine. The case was complicated by post-resuscitation anxiety superimposed on a history of medical trauma since childhood. Top experts in the field of consultation-liaison psychiatry, trauma informed care, and cardiac electrophysiology provide perspectives on this case with a review of the literature. Key teaching topics include identification of TdP risk factors in patients with a complex illness; the necessity for prompt electrophysiology consultation in clinical scenarios with high risk for TdP; and the approach to patients with medical trauma using a trauma-informed lens. We highlight the contributions of COVID-19, the pharmacokinetics of QT-interval-prolonging psychotropic medications, the risks of hemodialysis, and the role of remdesivir-induced bradycardia in this first reported case of TdP in a patient treated with remdesivir., (Copyright © 2022 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: To investigate the association between exposure to antidepressants (ADs) and the risk of epilepsy among patients exposed to ADs., Method: We conducted a case-control study using Taiwan's National Health Insurance Research Database between 1998 and 2013. A total of 863 patients with epilepsy and 3,452 controls were included. The dose of ADs was categorized according to the cumulative defined daily dose (cDDD). The risk of epilepsy was assessed using conditional logistic regression analysis., Results: Compared with cDDD < 90, ADs exposure with cDDD > 365 (odds ratio [OR]: 1.37, 95% confidence interval [CI]:1.12-1.68) was associated with an increased risk of epilepsy, but not for those with cDDD 90-365 (OR: 1.07,95% CI: 0.87-1.30) after adjustment for several comorbidities and indications of ADs use. Other identified risk factors include cerebrovascular disease, traumatic brain injury, and central nervous system infection. Subgroup analysis of individual ADs showed that escitalopram (OR: 1.93, 95% CI: 1.12-3.31), venlafaxine (OR: 1.62, 95% CI: 1.13-2.31), mirtazapine (OR: 1.56, 95% CI: 1.00-2.43), paroxetine (OR: 1.44, 95% CI: 1.08-1.94), and fluoxetine (OR: 1.25, 95% CI: 1.01-1.56) had a significantly higher risk of epilepsy. Sertraline, fluvoxamine, citalopram, duloxetine, milnacipran, and bupropion did not show any proconvulsant effects., Conclusions: The study found an increased risk of epilepsy among patients who were exposed to any ADs, particularly longer-term users. Given the nature of observational studies with residual bias, interpretation should be cautious., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Major depressive disorder (MDD) is closely associated with sexual dysfunction, which may worsen during treatment with selective serotonin reuptake inhibitors (SSRIs) due to the side effects of pharmacologic treatment., Aim: To examine the association between sexual function and severity of MDD in drug-naïve patients as compared with healthy controls and how treatment with SSRIs affects sexual function over time in individuals with MDD. Interaction with gender and treatment response was examined., Methods: In 92 patients with MDD, we measured MDD severity with 6- and 17-item versions of the Hamilton Depression Rating Scale (HDRS6 and HDRS17) and the level of sexual function with the Changes in Sexual Functioning Questionnaire at baseline and 4, 8, and 12 weeks after initiating treatment with escitalopram. Baseline sexual function was compared with the sexual function of 73 healthy controls. Linear regression models were used to assess differences in sexual function between healthy controls and patients and change in sexual function from baseline to week 12. Linear mixed models were used to assess differences in change in sexual function between treatment response groups., Outcomes: Outcomes included total scores on the HDRS6, HDRS17, and Changes in Sexual Functioning Questionnaire and changes in total scores from baseline to week 12., Results: Unmedicated patients with MDD reported impaired sexual function as compared with healthy controls. Level of sexual function was not associated with severity of MDD at baseline. Patients' sexual function improved significantly during treatment, which was coupled with amelioration of depressive symptoms. Treatment response groups (remitters, intermediate responders, nonresponders) did not predict change in sexual function. Gender had no effect on sexual dysfunction symptoms during treatment., Clinical Implications: Major depression is a risk factor for sexual problems, and improvement in sexual function was coupled with amelioration of depressive symptoms., Strengths and Limitations: Among its strengths, this was a naturalistic study reflecting real-world settings in clinical practice. It additionally included a baseline measurement of sexual function and MDD severity on drug-naïve patients prior to the initiation of treatment. Finally, the follow-up of 12 weeks extends beyond the acute phase of treatment in which previous research has observed a peak in sexual side effects. In terms of limitations, there was no placebo arm; thus, the study cannot attribute the effects on sexual function to treatment with antidepressants per se. Also, the patients were young, which may have served as a protective factor against sexual side effects., Conclusion: Sexual dysfunction was strongly associated with MDD and improved in parallel with overall symptoms of depression across a standard 12-week treatment with SSRI antidepressants., Clinical Trial Registration: NCT02869035 (https://clinicaltrials.gov/ct2/show/NCT02869035)., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dear Doctor Letters (DDLs, Direct Healthcare Professional Communications) from 2011 provided guidance regarding QTc-prolonging effects with risk of torsade de pointes during treatment with citalopram and escitalopram. This study examines the DDLs' effects on prescription behavior. Data from 8842 inpatients treated with citalopram or escitalopram with a primary diagnosis of major depressive disorder (MDD) were derived from a European pharmacovigilance study (Arzneimittelsicherheit in der Psychiatrie, AMSP) from 2001 to 2017. It was examined to what extent new maximum doses were adhered to and newly contraindicated combinations with QTc-prolonging drugs were avoided. In addition, the prescriptions of psychotropic drugs before and after DDLs were compared in all 43,480 inpatients with MDD in the data set. The proportion of patients dosed above the new limit decreased from 8 to 1% in patients ≤ 65 years and from 46 to 23% in patients > 65 years old for citalopram versus 14-5% and 47-31% for escitalopram. Combinations of es-/citalopram with other QTc-prolonging psychotropic drugs reduced only insignificantly (from 35.9 to 30.9%). However, the proportion of patients with doses of quetiapine > 150 mg/day substantially decreased within the combinations of quetiapine and es-/citalopram (from 53 to 35%). After the DDLs, prescription of citalopram decreased and of sertraline increased. The DDLs' recommendations were not entirely adhered to, particularly in the elderly and concerning combination treatments. This might partly be due to therapeutic requirements of the included population. Official warnings should consider clinical needs., (© 2022. The Author(s).)

Background: Major depressive disorders represent a significant burden to society, and it is recommended that antidepressant therapy should last at least 6 months. In Italy, antidepressant use in clinical practice was reported to increase by 1.7% in 2020 compared to 2019, but only 40% of new prescriptions are characterized by a treatment duration longer than 3 months., Objective: The study aims to describe adherence and persistence to therapy in a subset of antidepressants (citalopram, duloxetine, escitalopram, paroxetine, sertraline, venlafaxine) vs. vortioxetine in Italy during a 2-year period from 2017 to 2019., Methods: A retrospective analysis of the longitudinal patient database reporting data from general practitioners on drug prescriptions in Italy was carried out in a cohort of 8,235 adult patients who were prescribed antidepressants., Results: Overall, 32.4% of the patients adhered to treatment for ≥6 months over a 1-year period. Vortioxetine had a lower risk of low adherence compared to duloxetine, paroxetine, and venlafaxine and a higher risk compared to citalopram, escitalopram, and sertraline. 68.7% of patients discontinued treatment during follow-up. The greatest percentage of patients continuing therapy was seen with duloxetine, while citalopram was associated with the highest proportion of patients discontinuing therapy. No significant differences in discontinuation were observed when comparing vortioxetine to the other antidepressants., Conclusion: Adherence results were considerably less than the 6-month recommendation in this real- world analysis of antidepressant therapies. Also, persistence to therapy was low, with most patients discontinuing treatment. Thus, there is a need for interventions to help patients adhere to their planned therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To evaluate the effectiveness and safety of escitalopram in the form of oral dispersible tablets (Elicea Q-Tab) in real-life clinical practice in patients with depressive and anxiety disorders., Material and Methods: The study included 1.892 outpatient patients, 1.860 of whom completed participation in accordance with the protocol and entered the statistical analysis. Most patients were diagnosed with depressive and anxiety disorders of varying severity, as a rule, these diagnoses were established for the first time. The drug was most often prescribed at a dosage of 10 mg/day. The patients were monitored for 90 days and at each of the 3 visits, scales were used to assess the clinical condition (CGI-S and CGI-I), scales «Interaction with people, maintaining relationships (social functioning)» and «Availability of work, task completion, school attendance (professional functioning)», scales satisfaction with the convenience of admission/appointment and the effectiveness of treatment, various indicators of quality of life (autonomy, social and professional functioning, hobbies and hobbies), as well as the severity of cognitive disorders were measured., Results: Patients treated with escitalopram in the form of oral tablets dispersible in the oral cavity (Elicea Q-Tab) showed an improvement in their clinical condition (a decrease in CGI-S scores from 3.65 at visit 1 to 2.63 by visit 3, by 28%; a decrease in CGI-I scores from 2.39 at visit 1 to 1.57 to visit 3, by 34%), as well as improving the quality of life, social (from 2.74 points on 1 visit to 4.32 on 2 visits, by 58%) and professional functioning (from 2.81 on 1 visit to 4.35 on 2 visits, by 55%), the level of concentration (from 3.28 points on 1 visit up to 4.5 on 3 visits, by 37%). Doctors and patients noted high satisfaction with the effectiveness and convenience of using the drug, the frequency of adverse events was low., Conclusion: The study showed that escitalopram in the form of oral tablets dispersible in the oral cavity (Elicea Q-Tab) is an efficient and safe treatment for depressive and anxiety disorders in real-world clinical settings. Patients and physicians have evaluated the drug positively and it can be considered as an effective agent in psychiatric practice.

Background: Emotional blunting is theorized to be an adverse effect of antidepressants, particularly serotonin reuptake inhibitors, but this has not been firmly established. Another possibility is that emotional blunting represents a residual depressive symptom., Methods: We analyzed data from adult outpatients with acute major depressive disorder who participated in three 8-week randomized controlled trials. Trials 1 and 2 were pooled (venlafaxine, n = 378; bupropion, n = 389; placebo, n = 383) and Trial 3 (escitalopram, n = 254; bupropion, n = 260) was analyzed separately. Emotional blunting was measured with the "inability to feel" item from the Montgomery-Åsberg Depression Rating Scale., Results: Emotional responsiveness improved, on average, in all treatment groups. Only a minority of participants (≤6 %) experienced more emotional blunting post-treatment, compared to baseline, with no significant differences between treatment groups, although roughly 20-25 % continued to report an inability to feel normal emotions at the final assessment. In Trials 1 and 2, emotional blunting was associated with poorer outcomes in terms of depressive symptoms, suicidal ideation, and sexual function, but these correlations were nearly identical in the placebo group., Limitations: The trials were short and cannot speak to the possibility of emotional blunting from long-term treatment. Emotional blunting was measured with a single item., Conclusions: The study medications did not significantly decrease emotional responsiveness, and there was no evidence that emotional blunting mediated treatment response. In acute treatment, emotional blunting may be better conceptualized as a residual symptom than as an adverse drug effect., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: In 2011, direct healthcare professional communication (DHPC) letters on citalopram and escitalopram were sent out to address the risk of QTc prolongation in the ECG. Healthcare professionals were informed about a reduction of the maximum recommended daily dose. Furthermore, a contraindication for QTc-prolonging co-medication was given. Previous studies noted that these instructions were implemented incompletely., Aim: For the first time, this study analyzed how the DHPC affected the prescription of citalopram and escitalopram in patients with anxiety disorders., Methods: Drug utilization data from the project "Arzneimittelsicherheit in der Psychiatrie e. V." (AMSP) was used to examine whether the proportion of patients treated with a higher-than-recommended daily dose ("high dose") and the proportion of patients with QTc-prolonging co-medication would decrease post-DHPC (combined category of citalopram/escitalopram)., Results: Drug utilization data of n = 364 patients pre- and n = 262 patients post-DHPC were compared. The proportion of patients with high dose declined from 10.7% to 5.4% (p = 0.019). The proportion of patients with QTc-prolonging co-medication did not change significantly from pre- (54.7%) to post-DHPC (51.5%, p = 0.437)., Discussion: In accordance with previous studies, the proportion of high-dose patients decreased after DHPC publication while the proportion of patients with QTc-prolonging co-medication remained widely unchanged. The specific recommendation on daily dosage seems to have been better implemented than the broadly formulated contraindication of QTc-prolonging co-medication. Hence, DHPCs should be written precisely and give advice for specific clinical situations., (© 2022. Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature.)

Background: Hypokalemia is a risk factor for drug-induced QT prolongation. Larger serum-to-dialysate potassium gradients during hemodialysis (HD) may augment the proarrhythmic risks of selective serotonin reuptake inhibitors (SSRIs)., Methods: We conducted a cohort study using 2007-2017 data from the United States Renal Data System and a large dialysis provider to examine if the serum-to-dialysate potassium gradient modifies SSRI cardiac safety. Using a new-user design, we compared 1-year sudden cardiac death (SCD) risk among HD patients newly treated with higher (citalopram, escitalopram) versus lower (fluoxetine, fluvoxamine, paroxetine, sertraline) QT-prolonging potential SSRIs, overall and stratified by baseline potassium gradient (≥4 versus &lt;4 mEq/l). We used inverse probability of treatment-weighted survival models to estimate weighted hazard ratios (HRs) and 95% confidence intervals (CIs) and conducted a confirmatory nested case-control study., Results: The study included 25 099 patients: 11 107 (44.3%) higher QT-prolonging potential SSRI new users and 13 992 (55.7%) lower QT-prolonging potential SSRI new users. Overall, higher versus lower QT-prolonging potential SSRI use was not associated with SCD [weighted HR 1.03 (95% CI 0.86-1.24)]. However, a greater risk of SCD was associated with higher versus lower QT-prolonging potential SSRI use among patients with baseline potassium gradients ≥4 mEq/l but not among those with gradients &lt;4 mEq/l [weighted HR 2.17 (95% CI 1.16-4.03) versus 0.95 (0.78-1.16)]. Nested case-control analyses yielded analogous results., Conclusions: The serum-to-dialysate potassium gradient may modify the association between higher versus lower QT-prolonging SSRI use and SCD among people receiving HD. Minimizing the potassium gradient in the setting of QT-prolonging medication use may be warranted., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: There is currently conflicting evidence of the association between the use of selective serotonin reuptake inhibitors (SSRIs) and acute pancreatitis. The SSRI fluoxetine has been suspected to be the driver of this serious outcome. Therefore, this study aims to investigate the potential association between fluoxetine use and the occurrence of acute pancreatitis., Methods: We conducted a nationwide cohort study using Danish register-based data from 1996 to 2016. The exposed group were new users of fluoxetine (1-year washout). The control subjects were new users of citalopram or SSRIs, excluding fluoxetine. The outcome was an incident diagnosis of acute pancreatitis with a 5-year washout. We used an intention-to-treat approach following patients for a maximum of 6 months. Cox regression analyses were performed, estimating hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age/sex, comorbidities and co-medications, using propensity score adjustment and matching., Results: In the propensity score-matched analyses, 61 783 fluoxetine users were included. The incidence rates among users of fluoxetine and other SSRIs were 5.33 (3.05-8.66) and 5.36 (3.06-8.70) per 10 000 person-years, respectively. No increased risk of acute pancreatitis was identified following fluoxetine exposure compared with either citalopram [HR 1.00, 95% CI 0.50-2.00) or other SSRIs (0.76, 0.40-1.46)., Conclusions: Fluoxetine use was not associated with an increased risk of acute pancreatitis compared with citalopram or other SSRIs. The absolute risk of acute pancreatitis was low and did not vary between different SSRIs. Further research is needed to determine whether there is a class effect on the risk of acute pancreatitis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

The selective serotonin reuptake inhibitors (SSRIs) citalopram and escitalopram are associated with QT prolongation, which increases the risk of serious arrhythmia. Consequently, regulatory agencies issued safety warnings in 2011. This study aimed to investigate the risk of serious arrhythmia following initiation of citalopram or escitalopram compared to other SSRIs and the risk in the periods before and after the warnings were issued. We conducted a series of nationwide cohort studies emulating a target trial using Danish healthcare register data from January 1, 2002, to December 31, 2016. We included patients (aged ≥65 years) who filled an SSRI prescription with a 1-year washout period before the index date. The outcome was an event of serious arrhythmia. Individuals were followed for a maximum of 6 months using an intention-to-treat approach. Log-binomial regression analyses were performed, estimating risk ratios (RRs) and 95% confidence intervals (CIs) adjusting for age and sex, comorbidities, and comedications with propensity scores. Dose-response effects were not investigated because dosage instructions were not available. We included 167,366 (146,014 individuals), 40,113 (37,069 individuals), and 50,281 (44,754 individuals) person-trials of citalopram, escitalopram, and other SSRIs, respectively. In total, there were 228 events of serious arrhythmia. No difference in risk was observed in the entire study period for either citalopram (0.87 [0.62-1.22]) or escitalopram (0.85 [0.53-1.40]). We identified lower point estimates after the safety warning, RR 0.54 (95% CI 0.31-0.93) for citalopram and 0.58 (0.20-1.63) for escitalopram. Initiation of citalopram and escitalopram was not associated with an increased risk of serious arrhythmia. However, lower point estimates were observed after the safety warning., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Although obsessive-compulsive personality disorder (OCPD) is one of the most prevalent personality disorders, it is one of the least studied. There is debate as to whether pharmacotherapy is efficacious for OCPD. We aimed to systematically evaluate the efficacy and tolerability of pharmacotherapy for OCPD., Areas Covered: This systematic review found two randomized controlled trials investigating pharmacotherapy of OCPD. In a study of major depression (n = 308) with comorbid OCPD (n = 71), citalopram was more effective for OCPD than sertraline with fewer drop-outs from treatment. In a small study of OCPD (n = 24), fluvoxamine was more effective than placebo, and there was a low drop-out rate. Risk of bias and quality assessment of these studies was not possible, and findings have very low levels of certainty., Expert Opinion: Two studies provide preliminary evidence in support of citalopram and fluvoxamine for OCPD. Further randomized controlled trials are required before firm conclusions can be drawn regarding efficacy of pharmacotherapy for OCPD.

Aims: Urethral closure function is essential for urinary continence in women and decreased urethral pressure is associated with stress urinary incontinence (SUI). For decades, the effects of serotonergic drugs on central neural control of urethral closure have been investigated and discussed. Epidemiological studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is associated with SUI. However, the literature findings are conflicting. This study aimed to evaluate citalopram's effect on opening urethral pressure (OUP) in healthy women., Methods: We conducted a randomized, double-blind, placebo- and active-controlled crossover study in 24 healthy women. On three study days, which were separated by 8 days of washout, the subjects received single doses of either 40 mg citalopram (and placebo reboxetine ), 8 mg reboxetine (and placebo citalopram ), or two placebos. Study drugs were administered at a 1-h interval due to a difference in estimated time to peak plasma concentration (t max ). We measured OUP with urethral pressure reflectometry under both resting and squeezing conditions of the pelvic floor at estimated t max for both study drugs (one timepoint)., Results: Compared to placebo, citalopram increased OUP by 6.6 cmH 2 0 (95% confidence interval [CI] 0.04-13.1, p = 0.048) in resting condition. In squeezing condition, OUP increased by 7.1 cmH 2 0 (95% CI: 1.3-12.9, p = 0.01). Reboxetine increased OUP by 30.0 cmH 2 0 in resting condition compared to placebo (95% CI: 23.5-36.5, p < 0.001), and 27.0 cmH 2 0 (95% CI: 21.2-32.8, p < 0.001) in squeezing condition., Conclusion: Citalopram increased OUP slightly compared to placebo suggesting that SSRI treatment does not induce or aggravate SUI., (© 2022 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Conflicting results have been reported regarding the association between antidepressant use and out-of-hospital cardiac arrest (OHCA) risk. We investigated whether the use of antidepressants is associated with OHCA., Methods: We conducted a nationwide nested case-control study to assess the association of individual antidepressant drugs within drug classes with the hazard of OHCA. Cases were defined as OHCA from presumed cardiac causes. Cox regression with time-dependent exposure and time-dependent covariates was conducted to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. Also, we studied antidepressants with and without sodium channel blocking or potassium channel blocking properties separately., Results: During the study period from 2001 to 2015 we observed 10 987 OHCA cases, and found increased OHCA rate for high-dose citalopram (>20 mg) and high-dose escitalopram (>10 mg; HR:1.46 [95% CI:1.27-1.69], HR:1.43 [95% CI:1.16-1.75], respectively) among selective serotonin reuptake inhibitors (reference drug sertraline), and for high-dose mirtazapine (>30; HR:1.59 [95% CI:1.18-2.14]) among the serotonin-norepinephrine reuptake inhibitors or noradrenergic and specific serotonergic antidepressants (reference drug duloxetine). Among tricyclic antidepressants (reference drug amitriptyline), no drug was associated with significantly increased OHCA rate. Increased OHCA rate was found for antidepressants with known potassium channel blocking properties (HR:1.14 [95% CI:1.05-1.23]), but for not those with sodium channel blocking properties. Citalopram, although not statistically significant, and mirtazapine were associated with increased OHCA rate in patients without cardiac disease and cardiovascular risk factors., Conclusion: Our findings indicate that careful titration of citalopram, escitalopram and mirtazapine dose may have to be considered due to drug safety issues., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Escitalopram is commonly prescribed to patients with recurrent depressive disorder. Some of them do not show adequate response to treatment with escitalopram, while many of them experience adverse drug reactions., Objective: The objective of our study was to evaluate the impact of -806C>T polymorphism of CYP2C19 (CYP2C19*17) on the concentration/dose ratio of escitalopram in patients with recurrent depressive disorder., Material and Methods: Our study enrolled 267 patients with recurrent depressive disorder (average age -40.2 ± 16.4 years). Treatment regimen included escitalopram in an average daily dose of 12.5 ± 5.0 mg per day. The efficacy and safety rates of treatment were evaluated using the international psychometric scales. For genotyping, we performed the real-time polymerase chain reaction. Therapeutic drug monitoring has been performed using HPLC-MS/MS., Results: Our findings revealed the statistically significant results in terms of both treatment efficacy evaluation (HAMD scores at the end of the treatment course): (CC) 9.0 [7.0; 11.0], (CT) 4.0 [2.0; 6.0] and (TT) 2.0 [1.0; 4.0], p < 0.001; and safety profile (the UKU scores): (CC) 7.0 [7.0; 8.0], (CT) 3.0 [3.0; 4.0] and (TT) 3.0 [2.0; 3.0], p < 0.001. We revealed no statistically significant results for the concentration/dose ratio of escitalopram in patients with different genotypes: (CC) 5.762 [3.939; 9.076], (CT) 5.714 [3.485; 8.533] and (TT) 7.388 [4.618; 10.167], p = 0.268)., Conclusion: The CYP2C19*17 genetic variant significantly affected the efficacy and safety profiles of escitalopram in a group of 267 patients with recurrent depressive disorder but did not greatly affect its equilibrium plasma concentration., (Copyright © 1964–2022 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Purpose: Polypharmacy is common in the hemodialysis population and increases the likelihood that patients will be exposed to clinically significant drug-drug interactions. Concurrent use of proton pump inhibitors (PPIs) with citalopram or escitalopram may potentiate the QT-prolonging effects of these selective serotonin reuptake inhibitors through pharmacodynamic and/or pharmacokinetic interactions., Methods: We conducted a retrospective cohort study using data from the U.S. Renal Data System (2007-2017) and a new-user design to examine the differential risk of sudden cardiac death (SCD) associated with citalopram/escitalopram initiation vs. sertraline initiation in the presence and absence of PPI use among adults receiving hemodialysis. We studied 72 559 patients:14 983 (21%) citalopram/escitalopram initiators using a PPI; 26 503 (36%) citalopram/escitalopram initiators not using a PPI;10 779 (15%) sertraline initiators using a PPI; and 20 294 (28%) sertraline initiators not using a PPI (referent). The outcome of interest was 1-year SCD. We used inverse probability of treatment weighted survival models to estimate weighted hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Compared with sertraline initiators not using a PPI, citalopram/escitalopram initiators using a PPI had the numerically highest risk of SCD (HR [95% CI] = 1.31 [1.11-1.54]), followed by citalopram/escitalopram initiators not using a PPI (HR [95% CI] = 1.22 [1.06-1.41]). Sertraline initiators using a PPI had a similar risk of SCD compared with those not using a PPI (HR [95% CI] = 1.03 [0.85-1.26])., Conclusions: Existing PPI use may elevate the risk of SCD associated with citalopram or escitalopram initiation among hemodialysis patients., (© 2022 John Wiley & Sons Ltd.)

Background: One in five older adults (age 65+) uses an antidepressant medication. However, little is known about how fall risk differs between commonly prescribed medications. We examine the comparative association between individual selective serotonin reuptake inhibitors (SSRI) and self-reported falls in older adults., Methods: We used data from 2010-2017 Medicare Current Beneficiary Surveys, a nationally representative survey of Medicare beneficiaries. We included participants from three different panels surveyed over two successive years. Participants were limited to community-dwelling Medicare beneficiaries 65+, enrolled in Medicare Part D, and taking an SSRI (n = 1023) during baseline years. Participants were asked about demographic and health characteristics, medication use (including dose, frequency, duration of use) and self-reported falls as any fall or recurrent falls in the past year. We compared individual SSRI (citalopram or escitalopram vs sertraline) use by the average monthly total standardized daily dose (TSDD) and self-reported falling, controlling for potential confounders. Descriptive analysis and multivariable logistic regressions were conducted using SAS-callable SUDAAN., Results: Citalopram/escitalopram (n = 460 users; 45.0% of all SSRI users) and sertraline (n = 294 users; 28.7% of all SSRI users) were the most commonly prescribed SSRIs. Overall, 36.3% of citalopram/escitalopram users and 39.4% of sertraline users reported a fall in the year following medication use. There were no statistically significant differences between sertraline and citalopram/escitalopram users of either low or medium TSDD levels in the risk of self-reported any or recurrent falls. However, users of high TSDD of sertraline (>75 mg) had a lower risk of recurrent falls compared to high TSDD citalopram (>30 mg) or escitalopram (>15 mg) daily for 30 days., Conclusion: These findings suggest a potential comparative safety benefit of sertraline compared to citalopram/escitalopram at high doses related to recurrent falls. Additional comparative studies of individual antidepressants may better inform fall risk management and prescribing for older adults., (© 2022 The American Geriatrics Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Treatment with SSRI have a high frequency of treatment of emergent sexual dysfunction. The mechanism is thought to be through serotoninergic inhibition of the sexual response. More than 70% of patients treated with sertraline, citalopram or paroxetine experience sexual side effects, while escitalopram and fluvoxamine yield the lowest degree of sexual dysfunction within the group. This review suggests management strategies including dose reduction, change of medication and add-on treatment. A small group of patients experience post-SSRI dysfunction, in which sexual dysfunction persists after treatment termination.

The psychedelic psilocybin is being investigated for the treatment of depression and anxiety. Unclear is whether antidepressant treatments interact with psilocybin. The present study used a double-blind, placebo-controlled, crossover design with two experimental test sessions to investigate the response to psilocybin (25 mg) in healthy subjects after pretreatment with escitalopram or placebo. The treatment order was random and counterbalanced. Pretreatment consisted of 10 mg escitalopram daily for 7 days, followed by 20 mg daily for 7 days, including the day of psilocybin administration, or 14 days of placebo pretreatment before psilocybin administration. Psilocybin treatments were separated by at least 16 days. The outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor (BDNF) levels, electrocardiogram QTc time, whole-blood HTR2A and SCL6A4 gene expression, and pharmacokinetics. Escitalopram pretreatment had no relevant effect on positive mood effects of psilocybin but significantly reduced bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects of psilocybin compared with placebo pretreatment. Escitalopram did not alter the pharmacokinetics of psilocin. The half-life of psychoactive free (unconjugated) psilocin was 1.8 hours (range 1.1-2.2 hours), consistent with the short duration of action of psilocybin. Escitalopram did not alter HTR2A or SCL6A4 gene expression before psilocybin administration, QTc intervals, or circulating BDNF levels before or after psilocybin administration. Further studies are needed with a longer antidepressant pretreatment time and patients with psychiatric disorders to further define interactions between antidepressants and psilocybin., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Some data suggests that citalopram has more risk of corrected QT interval (QTc) prolongation than other selective serotonin reuptake inhibitors. Consequently the U.S. Food and Drug Administration distributed a safety warning limiting the maximum dose for citalopram. There is also a suggestion that bupropion may decrease QTc in patients on drugs that increase QTc. The goals of this cross-sectional study were to examine (1) effects on QTc of citalopram compared to sertraline, bupropion, and tricyclic antidepressants; (2) dose dependent effects of citalopram; and (3) effects of bupropion on citalopram-mediated changes in QTc., Methods: Records of subjects who received an EKG while taking one of the specified antidepressants were reviewed to collect demographic information, antidepressant history, and information about other confounders. Linear regression was used to examine the relationship between QTc and antidepressants., Results: 487 subjects provided 798 EKG records. The sample was 95% male with an average age of 61 years. No differences were found in QTc between citalopram and other antidepressants. No dose relationship was detected between citalopram and QTc. Bupropion did not affect the relationship between citalopram and QTc (coefficient = -3.4; 95%CI = -14.2, 7.5; p = 0.54)., Limitations: Observational study designs are prone to biases from retrospective data collection. Some data subsets had small numbers of subjects., Conclusions: No effect of citalopram on QTc was found at therapeutic doses. Neither was there evidence of a "QTc-sparing" effect of bupropion. The risk of adverse cardiovascular effects from citalopram at doses of 60 mg per day or less appears minimal., (Published by Elsevier B.V.)

Objective: To compare associations between individual antidepressants and newborn outcomes., Design: Retrospective cohort study., Setting: Deliveries in a large, US medical system., Population: Women who received at least one antidepressant prescription 3 months prior to conception through delivery., Methods: Eligible women had maternal characteristics and newborn outcomes extracted from medical record data. Exposure was defined by the timing of the prescription during pregnancy., Main Outcome Measures: Newborn outcomes (any adaptation syndrome, neonatal intensive care unit (NICU) admission) were analyzed for each antidepressant and compared using standard statistics and multivariable regression compared to exposure to bupropion. Odds of outcomes based on timing of exposure were also explored., Results: A total of 3,694 women were analyzed. Rates of any adaptation syndrome (p < 0.001), NICU admission (p < 0.001), and transient tachypnea of newborn (TTN) (p = 0.006) were significantly different between drugs. Infants exposed to duloxetine had the highest rates of NICU admissions (39.6%) and adaptation syndromes (15.1%). Venlafaxine-exposed infants had the highest rates of TTN (18.2%). Controlling for maternal age, race, insurance, and gestational age at delivery, early pregnancy antidepressant exposure was associated with adaptation syndrome and NICU admission for both duloxetine (adjusted odds ratio (aOR) 2.31 [95% Confidence Interval (CI) 1.11-4.80] and aOR 2.47 [95% CI 1.40-4.34], respectively) and escitalopram (aOR 1.72 [95% CI 1.09-2.70] and aOR 1.64 [95% CI 1.21-2.22], respectively). Exposure in the third trimester was associated with any adaptation syndrome for citalopram, duloxetine, escitalopram, fluoxetine, sertraline, and venlafaxine and NICU admission for bupropion, citalopram, duloxetine, escitalopram, and fluoxetine., Conclusion: Duloxetine and escitalopram appear to have the strongest associations with any adaptation syndrome and NICU admission whereas bupropion and sertraline tended to have among the lowest risks of these outcomes. These results can help providers and patients discuss choice of individual antidepressant drugs during pregnancy., (© 2021 Pharmacotherapy Publications, Inc.)

Objectives: Genome-wide analyses of antidepressant response have suggested that genes initially associated with risk for schizophrenia may also serve as promising candidates for selective serotonin reuptake inhibitor (SSRI) efficacy. Protein tyrosine phosphatase, receptor-type, zeta-1 (PTPRZ1) has previously been shown to be associated with schizophrenia, but it has not been investigated as a predictor of antidepressant efficacy. The main objective of the study was to assess whether SSRI-mediated depressive and anxiety symptom remission in Chinese patients with major depressive disorder (MDD) are associated with specific PTPRZ1 variants., Methods: Two independent cohorts were investigated, the first sample (N = 344) received an SSRI (i.e. fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, or paroxetine) for 8 weeks. The second sample (N = 160) only received escitalopram for 8 weeks. Hamilton Depression and Hamilton Anxiety Rating Scale scores at 8-weeks post-baseline in both cohorts were used to determine remission status. Five PTPRZ1 variants (rs12154537, rs6466810, rs6466808, rs6955395, and rs1918031) were genotyped in both cohorts., Results: Anxiety symptom remission was robustly associated with PTPRZ1 rs12154537 (P = 0.004) and the G-G-G-G haplotype (rs12154537-rs6466810-rs6466808-rs6955395; P = 0.005) in cohort 2 but not cohort 1 (mixed SSRI use). Associations with depressive symptom remission did not survive correction for multiple testing., Conclusions: These findings suggest that PTPRZ1 variants may serve as a marker of escitalopram-mediated anxiety symptom remission in MDD., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Daridorexant (ACT-541468) is a new dual orexin receptor antagonist being evaluated for the treatment of insomnia, which is a common comorbidity of depression and anxiety. Therefore, daridorexant is likely to be administered concomitantly with agents (e.g., citalopram) used to treat these disorders. In this single-centre, single-blind, randomized, placebo-controlled, sequential design Phase 1 study with the inclusion of two double-blind crossover parts, the pharmacokinetic (PK; blood sampling at regular intervals) and pharmacodynamic (PD; battery of objective and subjective PD tests performed at regular intervals) interactions between daridorexant (50 mg) and citalopram (20 mg, single dose and at steady state) as well as the safety/tolerability in healthy subjects were investigated. There were no relevant effects of citalopram (single dose/steady state) on daridorexant exposure and vice versa. PD variables measured after morning administration of daridorexant alone showed effects consistent with a sleep-promoting compound. Only co-administration of daridorexant with citalopram at steady state led to relevant changes in objective (unstable tracking) and subjective (visual analogue scale alertness and Karolinska Sleepiness Scale) PD endpoints compared to daridorexant alone. No serious or severe adverse events were reported, while no clinically relevant treatment-emergent effects on ECG parameters, clinical laboratory, or vital signs were observed. In conclusion, the co-administration of daridorexant and citalopram lead to only minor changes in PK parameters, while performance of PD assessments following co-administration were mainly driven by the expected central nervous system effects of daridorexant. Doses up to 50 mg daridorexant can be safely co-administered with citalopram., Competing Interests: Declaration of Competing Interest BB and JD were full time employees of Idorsia Pharmaceuticals Ltd at the time of study conduct. JD owns stocks and stock options of Idorsia Pharmaceuticals Ltd. RK was an employee of Parexel International GmbH at the time of study conduct. There are no other relationships or activities that could appear to have influenced the submitted work. Parexel International GmbH received financial compensation for the clinical conduct., (Copyright © 2021. Published by Elsevier B.V.)

Side effects to antidepressant medications are common and can impact the prognosis of successful treatment outcome in people with major depressive disorder (MDD). However, few studies have investigated the severity of side effects over the course of treatment and their association with treatment outcome. Here we assessed the severity of side effects and the impact of treatment type and anxiety symptoms over the course of treatment, as well as whether side effects were associated with treatment outcome. Participants were N = 1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic MDD. Participants were randomised to receive escitalopram, sertraline, or venlafaxine-extended release with equal probability and reassessed at 8 weeks regarding Hamilton Rating Scale Depression (HRSD 17 ) and Quick Inventory of Depressive Symptomatology (QIDS-SR 16 ) remission and response. Severity of side effects were assessed using the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) scale and assessed at day 4 and weeks 2, 4, 6, and 8. Frequency, intensity, and burden of side effects were greatest at week 2, then only frequency and intensity of side effects gradually decreased up to week 6. Treatment type and anxiety symptoms did not impact the severity of side effects. A greater burden-but not frequency or intensity-of side effects was associated with poorer treatment outcome and as early as 4 days post-treatment. Together, this work provides an informative mapping of the progression of side effects throughout the treatment course and their association with treatment outcome. Importantly, the burden of side effects that are present as early as 4 days post-treatment predicts poorer treatment outcome and should be monitored closely. iSPOT-D: Registry name: ClinicalTrials.gov. Registration number: NCT00693849., (© 2021. The Author(s).)