Exploring adverse events of Vilazodone: evidence from the FAERS database

Abstract

Objective

This study aims to conduct an exhaustive evaluation of Vilazodone's safety in clinical application and to unearth the potential adverse event (AE) risks associated with its utilization based on FDA Adverse Event Reporting System (FAERS) database.

Methods

This research employed data spanning from the first quarter of 2011 to the third quarter of 2023 from the FAERS database. Various signal detection methodologies, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM), were utilized to ascertain the correlation between Vilazodone and specific AEs.

Results

The study compiled a total of 17,439,268 reports of drug AEs, out of which 5,375 were related to Vilazodone. Through signal mining, 125 Preferred Terms (PTs) encompassing 27 System Organ Classes (SOCs) were identified. The findings indicated a higher prevalence among females and patients within the 45 to 65 age bracket. The principal categories of AEs included Psychiatric disorders, Nervous system disorders, and Gastrointestinal disorders, with prevalent incidents of Diarrhoea, Nausea, and Insomnia. Moreover, the study identified robust signals of novel potential AEs, notably in areas such as sleep disturbances (Sleep paralysis, Hypnagogic hallucination, Rapid eye movements sleep abnormal, Sleep terror, Terminal insomnia, Tachyphrenia), sexual dysfunctions (Female orgasmic disorder, Orgasm abnormal, Disturbance in sexual arousal, Spontaneous penile erection, Anorgasmia, Sexual dysfunction, Ejaculation delayed), and other symptoms and injuries (Electric shock sensation, Violence-related symptom, Gun shot wound).

Conclusion

Although Vilazodone presents a positive prospect in the management of MDD, the discovery of AEs linked to its use, particularly the newly identified potential risks such as sleep and sexual dysfunctions, necessitates heightened vigilance among clinicians.

Introduction

Major Depressive Disorder (MDD) is a severe and prevalent psychological disorder with a high incidence rate of approximately 6.7%. This condition not only profoundly impacts the physical and mental health of individuals but also significantly impairs their quality of life. MDD severely affects the mental and physical well-being of about 10% of the global population. Patients often experience extreme mood fluctuations, cognitive impairments, behavioral abnormalities, and can even suffer brain function damage leading to social disorders and, in extreme cases, self-harm or suicide [1, 2].

Pharmacotherapy has been a critical component in treating MDD, with common drug categories including Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Norepinephrine Reuptake Inhibitors (SNRIs). These are often complemented by psychological and physical therapies as part of a comprehensive intervention strategy. International treatment guidelines currently recommend SSRIs as the first-line pharmacological treatment for most MDD patients, including sertraline, escitalopram, fluoxetine, paroxetine, etc. [3, 4]. Although SSRIs can enhance synaptic plasticity, there is significant individual variation in response to these medications [5].

Vilazodone is a drug that has garnered widespread attention in this domain. Developed by Merck KgaA in Germany, Vilazodone received FDA approval in January 2011 for the treatment of MDD in adults. It represents a novel class of antidepressants, functioning both as a SSRI and a partial agonist at the 5-HT1A receptor. Vilazodone rapidly enhances the extracellular concentration of 5-HT1A, thereby exerting its antidepressant effects promptly [6].

Despite the therapeutic efficacy demonstrated by Vilazodone in treating MDD, pharmacotherapy is always accompanied by the risk of potential adverse events (AEs). Hence, this study aims to systematically mine and analyze AE signals related to Vilazodone based on the FDA Adverse Event Reporting System (FAERS) [7,8,9,10], to comprehensively evaluate its potential risks in clinical use, providing a safety reference for clinical practice.

Methods

Data source

The data for this study was sourced from the FAERS database. The FAERS database compiles all information on AEs and medication errors reported to the FDA. For the purposes of this study, data packages from the first quarter of 2011 to the third quarter of 2023 were downloaded. The collected data encompassed individual records, AE reports, medication usage, treatment outcomes, and reporting sources, with a specific focus on the target drug “Vilazodone”. Following the FDA-recommended method for removing duplicate reports, we select the PRIMARYID, CASEID, and FDA_DT fields from the DEMO table. We sort by CASEID, FDA_DT, and then PRIMARYID. For reports with the same CASEID, we retain the one with the largest FDA_DT value. Secondly, for reports where both CASEID and FDA_DT are the same, we retain the one with the largest PRIMARYID value. Since the first quarter of 2019, each quarterly data package has included a list of deleted reports. After data deduplication, we remove reports based on the CASEID listed in the deleted reports list.

Data standardization

To standardize the AE data, this study utilized the terminology set of AEs from the Medical Dictionary for Regulatory Activities (MedDRA) [11]. AEs were categorized and described using the System Organ Class (SOC) and Preferred Terms (PT) from MedDRA. Additionally, the MedDRA version 26.0 software was employed for the mapping of PTs and SOCs of AEs. Moreover, this study also utilized the related terminology set from MedDRA version 26.0 for classifying and describing AEs.

Signal detection methods

To mine signals related to Vilazodone-associated drug AEs, this study employed various signal detection methods. The primary methods included Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) from the disproportionality methods, Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) [12,13,14,15]. The ROR helps mitigate biases in events with fewer reports. The PRR stands out for its greater specificity compared to ROR. BCPNN is adept at combining and cross-validating multi-source data. The MGPS is particularly effective in identifying signals from infrequent events. This study utilizes a blend of ROR, PRR, BCPNN, and MGPS to capitalize on their individual strengths, enhancing the scope of detection and validation from diverse angles. This integrated approach aids in more accurately identifying safety signals, reducing false positives through cross-validation and refining detection of rare adverse reactions by adjusting thresholds and variance. The core algorithms of these methods are based on a 2 × 2 contingency table, used to calculate signal strength (Tables 1 and 2). A higher signal value indicates a stronger AE signal associated with Vilazodone, signifying a higher statistical association with the target AE.

Table 1 Four grid table

Table 2 ROR, PRR, BCPNN, and EBGM methods, formulas, and thresholds

Results

Basic characteristics of AE reports

Within the FAERS database, from the first quarter of 2011 to the third quarter of 2023, a total of 17,439,268 AE reports were collected, of which 5,375 were related to Vilazodone (Table 3). Among the reports with known gender, females accounted for 65.40%, and males for 27.65%. In terms of age, the most reports were in the 45 to 65 age group, accounting for 19.81%, followed by the 18 to 45 age group, accounting for 17.49%. Reports from individuals aged 75 and above were relatively few, comprising only 3.03%. Looking at the report years, the peak was in 2013, accounting for 28.17% of the reports. Subsequently, there was a fluctuating decrease in report numbers, dropping to 3.33% by 2023. The majority of reports were submitted by consumers (59.78%), followed by physicians (22.55%). The reports were primarily from the United States, accounting for 98.36%. Reports without a specified country comprised 1.21%, with reports from Canada, India, and Germany being very low. In terms of the severity of AEs, Hospitalization—Initial or Prolonged was the most common outcome, accounting for 5.54%, followed by Death and Disability at 1.49% and 1.06%, respectively. The most common timing for AE occurrence was within 30 days of medication use, accounting for 18.81%, with a decrease in reports over time.

Table 3 Basic information on AEs related to vilazodone

Risk signal mining

Signal mining for AEs where Vilazodone was the primary suspected drug identified 125 PTs involving 27 SOCs. According to the number of reports, the top five SOC categories in Table 4 were Psychiatric disorders, Nervous system disorders, Gastrointestinal disorders, General disorders and administration site conditions, General disorders and administration site conditions, consistent with the drug’s label. Additionally, Reproductive system and breast disorders, Ear and labyrinth disorders had a higher incidence and signal strength, representing new potential AEs.

Table 4 The signal strength of AEs of vilazodone at the SOC level

Based on the frequency of occurrence and EBGM values of PTs, the top 30 are listed in Tables 5 and 6. Among these, Diarrhoea, Nausea, Insomnia, Anxiety, Dizziness, Agitation, Tremor, Weight increased had higher incidence rates, aligning with the label records. Simultaneously, strong signals for new potential AEs were identified, including sleep disorders like Sleep paralysis, Hypnagogic hallucination, Rapid eye movements sleep abnormal, Sleep terror, Terminal insomnia, Tachyphrenia; sexual dysfunctions such as Female orgasmic disorder, Orgasm abnormal, Disturbance in sexual arousal, Spontaneous penile erection, Anorgasmia, Sexual dysfunction, Ejaculation delayed; and other symptoms and injuries like Electric shock sensation, Violence-related symptom, Gun shot wound.

Table 5 Top 30 PTs by report numbers for vilazodone AEs

Table 6 The top signal strength of AEs of vilazodone ranked by EBGM at the PTs level

Discussion

Vilazodone, as a novel selective SSRI, has attracted attention for its prominent agonistic effects on the 5-HT1A receptor and a longer half-life, promising to further improve the clinical cure rates for MDD and enhance patient medication adherence. However, like all medications, Vilazodone's use is associated with the risk of AEs, a crucial factor for clinicians and patients to consider when contemplating pharmacotherapy [16]. Therefore, with the continuous development and iteration of antidepressants, a comprehensive assessment of their efficacy and safety becomes a key task in the treatment of depression.

The study revealed specific gender and age tendencies, with 65.40% of the reports coming from females [17]. This may reflect the prevalence of antidepressant use among women and their proactivity in reporting drug adverse reactions. In terms of age, the highest reports were in the 45 to 65 age group, indicating that middle-aged and older adults might be the primary users of Vilazodone. The fluctuating decrease in report numbers since the peak in 2013 might be related to the heightened initial attention following the drug's release and subsequent reduction in monitoring. The majority of reports were submitted by consumers, predominantly in the United States, highlighting the significant role of patients in drug safety monitoring and geographical usage differences. The most common severe AEs included hospitalization, death, and disability, underscoring the potential serious risks of Vilazodone. Most AEs occurred within 30 days of medication use, emphasizing the critical importance of monitoring during the initial treatment phase. These findings contribute to understanding Vilazodone's safety profile, hold significant implications for improving clinical practice and patient management, and underscore the necessity for ongoing drug safety monitoring and individualized treatment approaches.

In the process of risk signal mining for AEs associated with Vilazodone, this study identified a range of AEs related to the drug's use. These included both known AEs already documented in the drug's label and new, potential AEs. The most common AEs included Psychiatric disorders, Nervous system disorders, Gastrointestinal disorders, and General disorders and administration site conditions, aligning with Vilazodone’s label information. Events such as Diarrhoea, Nausea, and Insomnia were noted for their higher incidence rates.

New Potential AEs were also identified. Sleep Disorders: Including Sleep paralysis, Hypnagogic hallucination, Rapid eye movements sleep abnormal, Sleep terror, Terminal insomnia, Tachyphrenia, these could stem from Vilazodone’s modulation of neurotransmitters and the sleep cycle. As a selective serotonin reuptake inhibitor and 5-HT1A receptor agonist, Vilazodone impacts the levels of serotonin and other neurotransmitters like dopamine and norepinephrine [18, 19]. This influence might lead to sleep paralysis (due to an imbalance in REM sleep regulation), Hypnagogic hallucination, and Tachyphrenia (due to alterations in cognitive processes and perception). Furthermore, Vilazodone’s effect on sleep cycles may result in Rapid Eye Movements Sleep Abnormal, Sleep Terror, and Terminal Insomnia, potentially originating from the drug’s adjustment of sleep architecture and depth [20]. The interplay of these mechanisms, especially Vilazodone’s impact on various neurotransmitter systems, could lead to complex sleep disturbances, reflecting the drug’s extensive influence on brain function and sleep regulation.

Sexual Dysfunction: Including Female orgasmic disorder, Orgasm abnormal, Disturbance in sexual arousal, Spontaneous penile erection, Anorgasmia, Sexual dysfunction, Ejaculation delayed. The sexual dysfunctions caused by Vilazodone could primarily be attributed to two mechanisms: altered neurotransmitter balance and the drug’s physiological actions. Firstly, as a selective SSRI, Vilazodone increases brain serotonin levels, which may indirectly affect the release of sex hormones and sexual function [21, 22]. Elevated serotonin levels could lead to reduced libido, sexual arousal disorders, thereby causing Female orgasmic disorder, Orgasm abnormal, Disturbance in sexual arousal, and similar issues. Secondly, Vilazodone’s impact on physiological responses, such as affecting blood flow and neural responses [23], might lead to Spontaneous penile erection, Anorgasmia, Ejaculation delayed, and other symptoms. These effects reflect Vilazodone’s extensive action on sex hormones and the nervous system, potentially leading to complex changes in sexual function.

The Electric shock sensation, Violence-related symptom, and Gun shot wound possibly linked to Vilazodone may be attributed to the drug's impact on neurotransmitter balance and hypersensitivity of the nervous system [24]. These symptoms underscore the need for cautious monitoring of patient reactions when using Vilazodone, particularly during dose adjustments or withdrawal periods.

This study is subject to several limitations. Firstly, reliance on spontaneous reporting to the FAERS database may introduce reporting biases and underreporting of adverse events. The database does not provide comprehensive data on the genetic or ethnic backgrounds of individuals, which could significantly influence the pharmacodynamics and pharmacokinetics of vilazodone. Additionally, this study primarily focuses on adverse event reports submitted to the FAERS database, which predominantly includes data from the United States. Therefore, our findings may not fully represent the adverse event profile of vilazodone in other populations, including China. Without including other antidepressants as controls, it is difficult to determine whether the adverse reactions found also exist in existing drugs, or if they are novel risks specific to Vilazodone. Future research should aim to include control groups of commonly used antidepressants like SSRIs and SNRIs to perform comparative assessments across multiple drugs. By analyzing genetic, ethnic, and regional variations in future studies, and by calculating report ratios and assessing signal strength differences, it would be possible to more clearly differentiate Vilazodone's unique spectrum of adverse reactions and enhance the generalizability of these findings to other populations.

Conclusion

This study, through an in-depth analysis of data from the FAERS database, has revealed the safety characteristics and potential AE risks of Vilazodone in clinical use. As a novel antidepressant, Vilazodone has demonstrated efficacy in treating MDD, but our findings emphasize the importance of a thorough understanding of its safety profile. The analysis revealed that reports related to Vilazodone use predominantly involved women and patients in the 45 to 65 age group, which might reflect the sensitivity of these specific demographics to the drug. The main categories of AEs included Psychiatric disorders, Nervous system disorders, and Gastrointestinal disorders, aligning with the drug’s label information. Notably, this study also identified new potential AEs, such as sleep disorders and sexual dysfunctions, suggesting that clinicians should be vigilant in monitoring and managing these potential risks when prescribing Vilazodone.