Selective Serotonin Reuptake Inhibitor Citalopram Research Articles

Citalopram & escitalopram: Mechanisms of cardiotoxicity, toxicology predisposition and risks of use in geriatric & hemodialysis populations.

The selective serotonin reuptake inhibitors (SSRIs) citalopram and escitalopram are extensively prescribed for various psychopathies. Despite their reputation for safety compared to older antidepressants, concerns have arisen regarding their cardiotoxic potential, notably in prolonging the QTc interval. In this comprehensive review, we investigate the intricate mechanisms of cardiotoxicity induction by citalopram/escitalopram, with a special focus on their interactions with ion channels like Kv11.1, Nav1.5, and Cav1.2 which may contribute to QTc-prolongation, increasing the risk of life-threatening arrhythmias such as Torsades de Pointes (TdP). Moreover, we explore the predisposing factors to their associated cardiotoxicity along with an investigation of the QRS/QTc ratio as a potential biomarker for identifying patients at risk of ventricular arrhythmias, taking into consideration the impact of genetic variations and drug interactions, especially those involving the liver CYP2C19 metabolism. Our review extends to the geriatric population's use of citalopram and escitalopram, emphasizing the significance of assessing a patient's medical history and cumulative drug use to evaluate their susceptibility to cardiac adverse events. Finally, we scrutinize the compound relationship between QTc-prolongation, proton pump inhibitors (PPIs) and serum-to-dialysate potassium gradients in influencing the proarrhythmic potential of citalopram/escitalopram in hemodialysis patients.

The Influence of CYP2C19 Gene Polymorphism on Selective Serotonin Reuptake Inhibitors In Patients with Major Depressive Disorder: A Pharmacogenetic Prospecting Approach

Major Depressive Disorder (MDD) is a chronic disorder characterized by at least a two-week-long major depressive episode. Selective Serotonin Reuptake Inhibitors (SSRIs) remain the primary prescribed antidepressants to treat MDD. However, SSRIs themselves are found to be ineffective in some individuals or may even lead to adverse side effects. These variable responses have been linked to the drug being metabolized by CYP2C19, which exhibited various polymorphisms. Understanding how gene polymorphism affects drug metabolism is essential since these insights can revolutionize clinical practice, allowing for more precise and personalized treatment approaches that optimize efficacy while minimizing side effects. This issue is particularly pertinent in Indonesia, where research in this area lags behind the pressing need for such studies. In this review, the impact of CYP2C19 polymorphism on the effectiveness of SSRI class drugs, namely citalopram, escitalopram, and sertraline, are explored. Nine relevant articles related to the topic have been studied in Japan, China, Turkey, Russia, Scandinavia, and Australia. The results concluded that CYP2C19 polymorphism can influence the metabolism of SSRIs (citalopram, escitalopram, and sertraline) due to its variability in enzyme activities, which includes both loss-of-function (*2, *3) and gain-of-function (*17) polymorphisms. Consequently, these genetic variations can lead to significant changes in drug efficacy and safety changes within individual patients. This review sheds light on the importance of considering genetic factors when prescribing SSRIs for MDD in the future treatment strategies.

Current Understanding of Compulsive Sexual Behavior Disorder and Co-occurring Conditions: What Clinicians Should Know about Pharmacological Options.

Compulsive sexual behavior disorder (CSBD) has recently been recognized as a psychiatric disorder. Pharmacological treatments for CSBD have received little study and thus have limited empirical support. The main objective of the present work is to review existing literature on the efficacy of different drugs on the symptomatology of CSBD, including the subtype of problematic pornography use (PPU). The main pharmacological approaches to treating CSBD have included opioid antagonists (naltrexone and nalmefene), selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, and sertraline), mood stabilizers (topiramate), tricyclic antidepressants (clomipramine), serotonin antagonist and reuptake inhibitors (nefazodone), and N-acetylcysteine. Since people with CSBD may experience different co-occurring disorders, these should be considered when choosing the best pharmacological treatment. Pharmacological therapy for CSBD/PPU has been suggested as an adjunct to psychological therapies, which, for the moment, have the most empirical evidence. However, to evaluate the efficacy of most of the drugs presented in this narrative review, data to date have only been available from case studies. Thus, empirical support is scant and generalizability of results is limited, highlighting the need for more research in this area.

Comparable roles for serotonin in rats and humans for computations underlying flexible decision-making

Serotonin is critical for adapting behavior flexibly to meet changing environmental demands. Cognitive flexibility is important for successful attainment of goals, as well as for social interactions, and is frequently impaired in neuropsychiatric disorders, including obsessive–compulsive disorder. However, a unifying mechanistic framework accounting for the role of serotonin in behavioral flexibility has remained elusive. Here, we demonstrate common effects of manipulating serotonin function across two species (rats and humans) on latent processes supporting choice behavior during probabilistic reversal learning, using computational modelling. The findings support a role of serotonin in behavioral flexibility and plasticity, indicated, respectively, by increases or decreases in choice repetition (‘stickiness’) or reinforcement learning rates following manipulations intended to increase or decrease serotonin function. More specifically, the rate at which expected value increased following reward and decreased following punishment (reward and punishment ‘learning rates’) was greatest after sub-chronic administration of the selective serotonin reuptake inhibitor (SSRI) citalopram (5 mg/kg for 7 days followed by 10 mg/kg twice a day for 5 days) in rats. Conversely, humans given a single dose of an SSRI (20 mg escitalopram), which can decrease post-synaptic serotonin signalling, and rats that received the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which destroys forebrain serotonergic neurons, exhibited decreased reward learning rates. A basic perseverative tendency (‘stickiness’), or choice repetition irrespective of the outcome produced, was likewise increased in rats after the 12-day SSRI regimen and decreased after single dose SSRI in humans and 5,7-DHT in rats. These common effects of serotonergic manipulations on rats and humans—identified via computational modelling—suggest an evolutionarily conserved role for serotonin in plasticity and behavioral flexibility and have clinical relevance transdiagnostically for neuropsychiatric disorders.

Real-World Evidence on Clinical Outcomes of Commonly Used Antidepressants in Older Adults Initiating Antidepressants for Depression: A Nationwide Cohort Study in Denmark.

The authors investigated the clinical outcomes of commonly used antidepressants among older adults who initiated first-time antidepressants for depression by analyzing the 1-year risk of selected clinically relevant outcomes. This cohort study used nationwide Danish registry data and included all older adults who redeemed a first-time (since 1995) antidepressant prescription with an indication of depression between 2006 and 2017. Only the 10 most frequently redeemed antidepressants were included in the analyses. Outcomes included discontinuation, switching, augmentation, psychiatric hospital contacts, suicide attempt or self-harm, fall-related injuries, cardiovascular events, and all-cause mortality. Incidence rate ratios (IRRs) and 95% confidence intervals were estimated using Poisson regression models, controlling for potential confounders. The study sample included 93,883 older adults (mean age, 78.0 years, SD=7.5 years; 56% female). The most frequently prescribed antidepressants were selective serotonin reuptake inhibitors (citalopram, 47.04%; escitalopram, 11.81%; fluoxetine, 0.55%; paroxetine, 0.52%; sertraline, 11.17%), serotonin-norepinephrine reuptake inhibitors (duloxetine, 0.71%; venlafaxine, 1.54%), a tricyclic antidepressant (amitriptyline, 1.86%), and two atypical antidepressants (mianserin, 1.93%; mirtazapine, 22.87%). Compared with users of sertraline (the reference drug in this analysis, as Danish guidelines recommend it as the first-choice treatment for depression), users of most of the other nine antidepressants had a significantly higher risk of discontinuation (e.g., mirtazapine: IRR=1.55, 95% CI=1.50-1.61; venlafaxine: IRR=1.22, 95% CI=1.12-1.32), switching (amitriptyline: IRR=1.45, 95% CI=1.15-1.81; venlafaxine: IRR=1.47, 95% CI=1.20-1.80), augmentation, cardiovascular events, and mortality. Overall, mirtazapine and venlafaxine users had the most adverse outcomes compared with sertraline users. These results remained consistent in analyses stratified by sex and age (≤75 years vs. >75 years). This real-world evidence suggests that clinical outcomes may vary among initiators of commonly used antidepressants in older adults, which may inform benefit-risk evaluation at treatment initiation, and highlights the importance of careful selection of antidepressant treatment.

Using machine learning to develop a clinical prediction model for SSRI-associated bleeding: a feasibility study

IntroductionAdverse drug events (ADEs) are associated with poor outcomes and increased costs but may be prevented with prediction tools. With the National Institute of Health All of Us (AoU) database, we employed machine learning (ML) to predict selective serotonin reuptake inhibitor (SSRI)-associated bleeding.MethodsThe AoU program, beginning in 05/2018, continues to recruit ≥ 18 years old individuals across the United States. Participants completed surveys and consented to contribute electronic health record (EHR) for research. Using the EHR, we determined participants who were exposed to SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vortioxetine). Features (n = 88) were selected with clinicians’ input and comprised sociodemographic, lifestyle, comorbidities, and medication use information. We identified bleeding events with validated EHR algorithms and applied logistic regression, decision tree, random forest, and extreme gradient boost to predict bleeding during SSRI exposure. We assessed model performance with area under the receiver operating characteristic curve statistic (AUC) and defined clinically significant features as resulting in > 0.01 decline in AUC after removal from the model, in three of four ML models.ResultsThere were 10,362 participants exposed to SSRIs, with 9.6% experiencing a bleeding event during SSRI exposure. For each SSRI, performance across all four ML models was relatively consistent. AUCs from the best models ranged 0.632–0.698. Clinically significant features included health literacy for escitalopram, and bleeding history and socioeconomic status for all SSRIs.ConclusionsWe demonstrated feasibility of predicting ADEs using ML. Incorporating genomic features and drug interactions with deep learning models may improve ADE prediction.

The Role of Serotonergic and Noradrenergic Descending Pathways on Performance-Based Cognitive Functioning at Rest and in Response to Exercise in People with Chronic Whiplash-Associated Disorders: A Randomized Controlled Crossover Study.

(1) Background: Dysregulation in serotonergic and noradrenergic systems may be implicated in the neurobiophysiological mechanisms underlying pain-related cognitive impairment in chronic whiplash-associated disorders (CWAD). This study aimed to unravel the role of serotonergic and noradrenergic descending pathways in cognitive functioning at rest and in response to exercise in people with CWAD. (2) Methods: 25 people with CWAD were included in this double-blind, randomized, controlled crossover study. Endogenous descending serotonergic and noradrenergic inhibitory mechanisms were modulated by using a single dose of a selective serotonin reuptake inhibitor (Citalopram) or a selective norepinephrine reuptake inhibitor (Atomoxetine). Cognitive performance was studied at rest and in response to exercise (1) without medication intake; (2) after intake of Citalopram; and (3) after intake of Atomoxetine. (3) Results: After Atomoxetine intake, selective attention improved compared with the no medication day (p < 0.05). In contrast, a single dose of Citalopram had no significant effect on cognitive functioning at rest. When performing pairwise comparisons, improvements in selective attention were found after exercise for the no medication condition (p < 0.05). In contrast, after intake of Citalopram or Atomoxetine, selective and sustained attention worsened after exercise. (4) Conclusions: A single dose of Atomoxetine improved selective attention only in one Stroop condition, and a single dose of Citalopram had no effect on cognitive functioning at rest in people with CWAD. Only without medication intake did selective attention improve in response to exercise, whereas both centrally acting medications worsened cognitive performance in response to a submaximal aerobic exercise bout in people with CWAD.

Effects of three serotonin reuptake inhibitors on sign-tracking in male Sprague-Dawley rats

Sign-tracking is a behavior with relevance to cue-triggered relapse addiction, a Pavlovian conditioned approach behavior directed at the conditioned stimulus. The study examined one strategy for reducing the magnetic pull of drug-associated conditioned stimuli, using selective serotonin reuptake inhibitors (SSRIs) citalopram (0, 10, and 20 mg/kg), escitalopram (0, 10, and 20 mg/kg) and fluoxetine (0, 5, and 10 mg/kg). Male Sprague-Dawley rats were first trained in a standard sign-tracking task and then acutely administered these drugs in a series of three experiments. In each study, it was found that measures of sign-tracking were reduced, although effects on goal-tracking were different between drugs. This study provides evidence that administration of serotonergic antidepressants is effective in reducing sign-tracking and may have some efficacy in preventing cue-triggered relapse.

Investigating Population-Level Toxicity of the Antidepressant Citalopram in Harpacticoid Copepods Using In Vivo Methods and Bioenergetics-Based Population Modeling.

Recent research has revealed various lethal and sublethal effects of the selective serotonin reuptake inhibitor citalopram hydrobromide on the harpacticoid copepod Nitocra spinipes. In the present study, an individual-based model (IBM) grounded in the dynamic energy budget (DEB) theory was developed to extrapolate said effects to the population level. Using a generic DEB-IBM as a template, the model was designed to be as simple as possible, keeping model components that are outside the scope of the core DEB theory to a minimum. To test the model, a 56-day population experiment was performed at 0, 100, and 1000 μg citalopram hydrobromide L-1 . In the experiment, the populations quickly reached a plateau in the control and at 100 μg L-1 , which was correctly reproduced by the model and could be explained by food limitations hindering further population growth. At 1000 μg L-1 , a clear mismatch occurred: Whereas in the experiment the population size increased beyond the supposed (food competition-induced) capacity, the model predicted a suppression of the population size. It is assumed that the IBM still misses important components addressing population density-regulating processes. Particularly crowding effects may have played an important role in the population experiment and should be further investigated to improve the model. Overall, the current DEB IBM for N. spinipes should be seen as a promising starting point for bioenergetics-based copepod population modeling, which-with further improvements-may become a valuable individual-to-population extrapolation tool in the future. Environ Toxicol Chem 2023;42:1094-1108. © 2023 SETAC.

Patient iPSC-derived neurons reveal mechanisms underlying antidepressant response: a potential diagnostic tool

IntroductionDepression is a leading cause of disability worldwide despite dozens of approved antidepressants. There are currently no clear guidelines to assist the physician in their choice of drug, with existing tools limited to pharmacogenetics that have shown suboptimal response prediction outcomes resulting in a subscription process that is largely a trial and error one. Consequently, the majority of depressed patients do not respond to their first prescribed antidepressant, with &gt;30% not responding to subsequent drugs. We report here on molecular readouts from an in vitro-based platform that provides patient-specific information on antidepressant mechanisms using cortical neurons derived individually from each patient.ObjectivesTo assess gene expression differences in prefrontal cortex neurons derived from responders and non-responders to two commonly used antidepressants, the selective serotonin reuptake inhibitor Citalopram and the atypical antidepressant Bupropion.MethodsPatient-derived lymphoblastoid cell lines from the Sequenced Treatment Alternatives to Relieve Depression (STARD) study with known response to Citalopram or Bupropion were reprogrammed and then differentiated to cortical neurons. Differential gene expression analysis was preformed to identify genes that are differentially expressed between drug responders and non-responders.ResultsSignificant differential expression was shown in 359 genes between Bupropion responders and non-responders (Fig1A) and 12 genes between Citalopram responders and non-responders (Fig1B). Clustering on the differentially expressed genes showed high agreement with the known response to both drugs (Fig1). Functional enrichment analysis revealed biologically relevant pathways that differ between responders and non-responders in Bupropion versus Citalopram.Image:Figure 1.Heatmap of the expression of genes that show significant differential expression between neurons derived from Bupropion (A) and Citalopram (B) responders and non-responders. Color is the scaled gene expression; lines are genes and columns are samples. Column side colors represent the known response of the patient. Colum and line dendrograms are unsupervised hierarchical clustering.ConclusionsGene expression patterns of neurons derived from patients with depression differ according to their response to two common antidepressants from different groups. The identification of distinct drug response dependent expression patterns in derived neurons can help elucidate mechanisms underlying antidepressant activity, supporting new drug development and response prediction.Disclosure of InterestNone Declared

Selective Serotonin Reuptake Inhibitors and 5-HT2 Receptor Agonists Have Distinct, Sleep-state Dependent Effects on Postictal Breathing in Amygdala Kindled Mice

Seizures can cause profound breathing disruptions. Seizures arising from sleep cause greater breathing impairment than those emerging from wakefulness and more often result in sudden unexpected death in epilepsy (SUDEP). The neurotransmitter serotonin (5-HT) plays a major role in respiration and sleep-wake regulation. 5-HT modulates seizure susceptibility and severity and is dysregulated by seizures. Thus, the impact of seizures on breathing dysregulation may be due to impaired 5-HT neurotransmission. We examined whether pharmacologically increasing 5-HT neurotransmission prior to seizures improves postictal breathing and how sleep-state during seizure induction contributes to these effects. We assessed breathing with whole-body plethysmography in 84 amygdala-kindled mice pre-treated with selective serotonin reuptake inhibitors (SSRI) or 5-HT2 receptor agonists. SSRIs and 5-HT2 agonists increased postictal breathing frequency (fR), tidal volume (VT), and minute ventilation (VE) at different timepoints following seizures induced during wakefulness. These effects were not observed following seizures induced during NREM sleep. SSRIs suppressed ictal and postictal apnea regardless of sleep state. The SSRI citalopram and the 5-HT2 agonists TCB-2 and MK-212 decreased breathing variability following wake-occurring seizures at different postictal timepoints. Only MK-212 decreased breathing variability when seizures were induced during NREM sleep. The 5-HT2A antagonist MDL-11939 reduced the effect of citalopram on fR, VT, and VE, and enhanced its effect on breathing variability in the initial period following a seizure. These results suggest that 5-HT mechanisms that are dependent on or independent from the 5-HT2 family of receptors impact breathing on different timescales during the recovery of eupnea, and that certain serotonergic treatments may be less effective at facilitating postictal breathing following seizures emerging from sleep.

Psychiatric Diagnoses and Medications in Wolfram Syndrome.

Wolfram Syndrome is a rare genetic disorder usually resulting from pathogenic variation in the WFS1 gene, which leads to an exaggerated endoplasmic reticulum (ER) stress response. The disorder is typically characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy, hearing loss, and neurodegenerative features. Existing literature suggests it may also have psychiatric manifestations. To examine lifetime psychiatric diagnoses and medication history in Wolfram Syndrome. Child, adolescent, and young adult Wolfram Syndrome participants (n=39) were assessed by a child & adolescent psychiatrist to determine best estimate DSM-5 lifetime psychiatric diagnoses as well as psychoactive medication history. In addition, the Child & Adolescent Symptom Inventory-5 (CASI-5) Parent Checklist was used to determine likely psychiatric diagnoses based on symptom counts in Wolfram Syndrome patients (n=33), type 1 diabetes (n=15), and healthy comparison (n=18) groups. Study participants with Wolfram Syndrome had high lifetime rates of anxiety disorders (77%). Also, 31% had an obsessive-compulsive spectrum disorder, 33% had a mood disorder, 31% had a neurodevelopmental or disruptive behavior disorder, and 31% had a sleep-wake disorder. More than half of Wolfram Syndrome participants had taken at least one psychoactive medication, and one third had taken at least one selective serotonin reuptake inhibitor (SSRI). Some individuals reported poor response to sertraline but better response after switching to another SSRI (fluoxetine or citalopram). In general, people with Wolfram Syndrome often reported benefit from psychotherapy and/or commonly used psychoactive medications appropriate for their psychiatric diagnoses. Wolfram Syndrome may be associated with elevated risk for anxiety and obsessive-compulsive spectrum disorders, which seem generally responsive to usual treatments for these disorders.

Skepticism about Recent Evidence That Psilocybin "Liberates" Depressed Minds.

A recent paper in Nature Medicine found that psilocybin therapy in patients with depression decreased brain network modularity (measured with task-free functional magnetic resonance imaging), an effect supposedly not found with the selective serotonin reuptake inhibitor S-citalopram. This decrease in network modularity also correlated with depression. Here, we raise several issues with this paper, including inconsistencies in reports of the primary clinical outcome, statistical flaws including a one-tailed test, nonsignificant interaction, and regression to the mean, the ambiguity and overinterpretation of "resting state" data, and a missing reference for a conceptually similar study that exemplifies why a one-tailed test cannot be justified. Together, these issues make us question the uniqueness and impact of these findings, as well as the unwarranted media hype that they generated.

Long-Term Exposure to SSRI Citalopram Induces Neurotoxic Effects in Zebrafish.

Residual antidepressants are of increasing concern worldwide, yet critical information on their long-term neurotoxic impacts on nontarget aquatic animals is lacking. Here, we investigated the long-term effects (from 0 to 150 days postfertilization) of the selective serotonin reuptake inhibitor citalopram (0.1-100 μg/L) on motor function, learning, and memory in zebrafish over two generations and explored the reversibility of the effect in F1 larvae. Unlike F0+ larvae, we found that F1+ larvae displayed decreased sensorimotor performance when continuously exposed to citalopram at 100 μg/L. No adverse effects were found in F1- larvae after they were transferred to a clean medium. Whole-mount immunofluorescence assays suggested that the motor impairments were related to axonal projections of the spinal motor neurons (MNs). For F0+ adults, long-term citalopram exposure mainly caused male-specific declines in motor, learning, and memory performance. Analysis of serotonergic and cholinergic MNs revealed no significant changes in the male zebrafish spinal cord. In contrast, the number of glutamatergic spinal MNs decreased, likely associated with the impairment of motor function. Additionally, treatment with 100 μg/L citalopram significantly reduced the number of dopaminergic neurons, but no significant neuronal apoptosis was observed in the adult telencephalon. Overall, this study provides neurobehavioral evidence and novel insights into the neurotoxic mechanisms of long-term citalopram exposure and may facilitate the assessment of the environmental and health risks posed by citalopram-containing antidepressant drugs.

Risks of Digestive System Side-Effects of Selective Serotonin Reuptake Inhibitors in Patients with Depression: A Network Meta-Analysis.

PurposeSelective serotonin reuptake inhibitors (SSRIs) are the preferred treatments for depression. The most common adverse drug reactions are symptoms involving the digestive system, leading to low compliance in patients with depression. Therefore, it is important to assess the safety of SSRIs with respect to the digestive system. Several meta-analyses have compared the risks of digestive side effects of SSRIs and other antidepressants. We aimed to compare the risks of various SSRIs (fluoxetine, escitalopram, citalopram, paroxetine, and sertraline) for adverse reactions of the digestive system.MethodsSystematic searches returned 30 randomized controlled trials (n = 5004) of five antidepressants and placebos.ResultsFluoxetine had the lowest probability of digestive side effects, ranking fifth at 0.548. Sertraline had the highest probability of digestive side effects, with a probability of 0.611. For gastrointestinal tolerability, escitalopram was better than paroxetine (odds ratio [OR] =0.62, 95% confidence interval [CI] 0.43–0.87) and sertraline (OR=0.56, 95% CI 0.32–0.99).ConclusionFluoxetine exhibited distinct advantages compared to other SSRIs, while sertraline had the greatest likelihood of digestive system side effects. These findings will help doctors understand the relative advantages of various antidepressants.

Serious arrhythmia in initiators of citalopram, escitalopram, and other selective serotonin reuptake inhibitors: A population-based cohort study in older adults.

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.

Modafinil acquires reinforcing effects when combined with citalopram

Modafinil (MOD) is a wakefulness promoter used to treat sleep disorders such as narcolepsy and obstructive sleep apnea. Its action mechanism consists in inhibiting dopamine (DAT) and norepinephrine (NET) transporters, but it has no affinity for the serotonin transporter (SERT). Modafinil's addictive potential is not yet clear, but one feature that differentiates it from potentially addictive drugs like cocaine revolves around affinity for SERT. The aims of the present study were to determine whether co-administration of MOD with the selective serotonin reuptake inhibitor citalopram (CIT) can increase MOD's psychostimulant effects on motor activity (MA), verify the effects of subsequent self-administration of MOD mixed with CIT, and document the presence of any symptoms of withdrawal. At 60 postnatal days (PD), male Wistar rats were treated chronically (16 days) with MOD at 30 or 60 mg/kg, with MOD+CIT at four dosage combinations administered to four groups (30MOD + CIT3, 30MOD + CIT5, 60MOD + CIT3, 60MOD + CIT5 mg/kg), or with a vehicle. After 40 min of daily drug administration, MA was measured on the open field test. MA increased only in the 60MOD group. The rats co-administered with 30MOD + 3CIT and 60MOD + 3CIT showed a decrease in the motivation to seek a pleasurable stimulus (lower consumption of sweet solution) after treatment concluded. The 60MOD and 60MOD + 3CIT groups showed MA sensitization after MOD intake. Additionally, higher self-administration of the mixture was observed in the groups pre-treated with 30MOD + 3CIT and 60MOD + 3CIT. Results suggest that serotonergic activity enhances modafinil's psychostimulant effects.

A Focus on Abuse/Misuse and Withdrawal Issues with Selective Serotonin Reuptake Inhibitors (SSRIs): Analysis of Both the European EMA and the US FAERS Pharmacovigilance Databases.

Despite increasing reports, antidepressant (AD) misuse and dependence remain underestimated issues, possibly due to limited epidemiological and pharmacovigilance evidence. Thus, here we aimed to determine available pharmacovigilance misuse/abuse/dependence/withdrawal signals relating to the Selective Serotonin Reuptake Inhibitors (SSRI) citalopram, escitalopram, paroxetine, fluoxetine, and sertraline. Both EudraVigilance (EV) and Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) datasets were analysed to identify AD misuse/abuse/dependence/withdrawal issues. A descriptive analysis was performed; moreover, pharmacovigilance measures, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the empirical Bayesian geometric mean (EBGM) were calculated. Both datasets showed increasing trends of yearly reporting and similar signals regarding abuse and dependence. From the EV, a total of 5335 individual ADR reports were analysed, of which 30% corresponded to paroxetine (n = 1592), 27% citalopram (n = 1419), 22% sertraline (n = 1149), 14% fluoxetine (n = 771), and 8% escitalopram (n = 404). From FAERS, a total of 144,395 individual ADR reports were analysed, of which 27% were related to paroxetine, 27% sertraline, 18% citalopram, 16% fluoxetine, and 13% escitalopram. Comparing SSRIs, the EV misuse/abuse-related ADRs were mostly recorded for citalopram, fluoxetine, and sertraline; conversely, dependence was mostly associated with paroxetine, and withdrawal to escitalopram. Similarly, in the FAERS dataset, dependence/withdrawal-related signals were more frequently reported for paroxetine. Although SSRIs are considered non-addictive pharmacological agents, a range of proper withdrawal symptoms can occur well after discontinuation, especially with paroxetine. Prescribers should be aware of the potential for dependence and withdrawal associated with SSRIs.

Impact of chosen cutoff on response rate differences between selective serotonin reuptake inhibitors and placebo

Response defined as a 50% reduction in the sum score of the Hamilton Depression Rating Scale (HDRS-17-sum) is often used to assess the efficacy of antidepressants. Critics have, however, argued that dichotomising ratings with a cutoff close to the median may lead to scores clustering on either side, the result being inflation of miniscule drug-placebo differences. Using pooled patient-level data sets from trials of three selective serotonin reuptake inhibitors (SSRIs) (citalopram, paroxetine and sertraline) (n = 7909), and from similar trials of duloxetine (n = 3478), we thus assessed the impact of different cutoffs on response rates. Response criteria were based on (i) HDRS-17-sum, (ii) the sum score of the HDRS-6 subscale (HDRS-6-sum) and (iii) the depressed mood item. The separation between SSRI and placebo with respect to response rates increased when HDRS-17-sum was replaced by HDRS-6-sum or depressed mood as effect parameter and was markedly dependent on SSRI dose. With the exception of extreme cutoff values, differences in response rates were largely similar regardless of where the cutoff was placed, and also not markedly changed by the exclusion of subjects close to the selected cutoff (e.g., ±10%). The observation of similar response rate differences between active drugs and placebo for different cutoffs was corroborated by the analysis of duloxetine data. In conclusion, the suggestion that using a cutoff close to the median when defining response has markedly overestimated the separation between antidepressants and placebo may be discarded.

Association of Selective Serotonin Reuptake Inhibitor Use With Abnormal Physical Movement Patterns as Detected Using a Piezoelectric Accelerometer and Deep Learning in a Nationally Representative Sample of Noninstitutionalized Persons in the US

Selective serotonin reuptake inhibitors (SSRIs) are a common first-line treatment for some psychiatric disorders, including depression and anxiety; although they are generally well tolerated, SSRIs have known adverse effects, including movement problems, sleep disruption, and gastrointestinal problems (eg, nausea and upset stomach). No large-scale studies using naturalistic, longitudinal, objective data have validated physical activity findings, and actigraphy data are well suited to address this task. To evaluate whether differences in physical movement exist among individuals treated with SSRIs compared with control participants and to identify the unique features of the movement of patients treated with SSRIs. This cross-sectional study examines longitudinally collected wearable movement data within a cross-sectional sample of 7162 participants from the 2005-2006 National Health and Nutrition Examination Survey (NHANES), a nationally representative population-based sample of noninstitutionalized persons in the US having both medication information and passive movement data. Statistical analysis was performed from April 1, 2021, to February 1, 2022. The use of SSRIs (sertraline hydrochloride, escitalopram oxalate, fluoxetine hydrochloride, paroxetine hydrochloride, and citalopram hydrobromide), as reported by participants interviewed by NNHANES personnel, was the primary exposure, measured as a binary variable (taking an SSRI vs not taking an SSRI). The primary outcome was the intensity of body movement as recorded by a piezoelectric accelerometer worn on the right hip for more than 1 week. Of the 7162 participants included in the study, the mean (SD) age was 33.7 (22.6) years, 266 (3.7%) were taking an SSRI, 3706 (51.7%) were female, 1934 (27.0%) were Black, 1823 (25.5%) were Mexican American, 210 (2.9%) were other Hispanic, 336 (4.7%) were other or multiracial, and 2859 (39.9%) were White (per the NHANES data collection protocol). A cross-validated, deep learning classifier was constructed that achieved fair performance predicting SSRI use (area under the curve, 0.67 [95% CI, 0.64-0.71] for the validation set and 0.66 [95% CI, 0.64-0.68] for the test set). To account for possible confounding by indication, we constructed a parallel model incorporating depression severity, finding only marginal performance improvement. When averaged across individuals and across 7 days, the results show less overall movement in the SSRI group (mean, 120.1 vertical acceleration counts/min [95% CI, 115.7-124.6 vertical acceleration counts/min]) compared with the non-SSRI control group (mean, 168.8 vertical acceleration counts/min [95% CI, 162.8-174.9 vertical acceleration counts/min]). This cross-sectional study found a moderate association between passive movement and SSRI use, as well as SSRI detection capacity of passive movement using time series deep learning models. The results support the use of passive sensors for exploration and characterization of psychotropic medication adverse effects.