Major depressive disorder (MDD) is a common mental disorder that affects approximately 185 million people worldwide (Marx et al., 2023). The symptoms of MDD include depressed mood, reduced interest or pleasure in previously enjoyable activities, and recurrent thoughts of death (Marx et al., 2023). MDD is characterized by recurrent episodes, imposing a heavy burden on individuals, families and society (Marwaha et al., 2023). In the United States, the economic burden of adults with MDD has significantly increased over time, rising from $236 billion in 2010 to $326 billion in 2018 (Greenberg et al., 2021). Agents that target monoamine neurotransmission (such as serotonin, noradrenaline, and dopamine) are the mainstay of drug treatment for MDD (Greenberg et al., 2021; Njenga et al., 2024). However, due to the multifaceted etiology of MDD, research has uncovered that only approximately one-third of patients achieve remission with the first antidepressant treatment (Mills et al., 2021), and treatment resistance is common (Njenga et al., 2024).

Vortioxetine is a novel antidepressant, approved by FDA in September 2013 for the treatment of adult patients with MDD (Tritschler et al., 2014). Compared with other drugs for MDD, vortioxetine has a unique mechanism of action. It acts as an inhibitor of the serotonin (5-HT) transporter, 5-HT_1A receptor agonist, 5-HT_1B receptor partial agonist, 5-HT₃, 5-HT₇, and 5-HT_1D receptor antagonist (Mills et al., 2021). Vortioxetine has a long half-life of approximately 57 h, which is thought to partly explain its low rate of discontinuation symptoms (DS) (Sanchez et al., 2015). Siwek et al. reported that 8 out of 263 patients (3%) who had taken vortioxetine developed discontinuation syndrome DS after drug withdrawal. Among the group of patients experiencing DS, vortioxetine was more frequently discontinued abruptly and without prior medical consultation (Siwek et al., 2021). Clinical trials have demonstrated the efficacy of vortioxetine in the treatment of MDD as well as in the prevention of relapse (Mills et al., 2021; Thase et al., 2022). Some studies have consistently confirmed the efficacy of vortioxetine in improving anhedonia in MDD patients (Cao et al., 2019; McIntyre et al., 2021; Serretti, 2025), as well as in treating elderly depression and bipolar disorder (Dai et al., 2025; Rodrigues Alessi et al., 2025). Vortioxetine is a first-line antidepressant recommended by Canadian Network for Mood and Anxiety Treatments (CANMAT) (Lam et al., 2024). Furthermore, vortioxetine has been recommended by National Institute for Health and Care Excellence (NICE) as an option when there has been no or limited response to at least two antidepressants (NICE, 2022). Vortioxetine has also been observed to improve the cognitive symptoms associated with MDD. The recent network meta-analysis has shown that vortioxetine is the only antidepressant that improves cognitive dysfunction compared to placebo in the digit symbol substitution test (Baune et al., 2018). In recent years, there has been an increasing number of studies on the clinical application of vortioxetine. There is a study documenting the use of vortioxetine in the treatment of nine patients with depressive symptoms accompanied by epilepsy, with all patients achieving relief from their depressive symptoms (Siwek et al., 2022). A pooled analysis of 13 randomized, placebo-controlled trials demonstrated that vortioxetine was also effective in the treatment of patients with MDD accompanied by common comorbid somatic diseases (Baldwin et al., 2022). Some studies have indicated that vortioxetine has the potential to become a therapeutic option for pain syndromes, such as burning mouth syndrome and neuropathic pain (Adamo et al., 2021a; Adamo et al., 2021b; Eliaçık and Erdogan Kaya, 2024; Adamo et al., 2025).

Although vortioxetine exhibits clear therapeutic effects and advantages, its safety remains an important aspect requiring continuous evaluation. In clinical studies, the most common adverse events (AEs) related to vortioxetine include nausea, vomiting, dry mouth, headache, and dizziness (Baldwin et al., 2016; Findling et al., 2022). Given the relatively small sample size and short observation period of clinical trials, the AEs reported in these trials cannot fully capture the safety profile of vortioxetine in a clinical setting. Consequently, it is essential to conduct comprehensive and large-scale monitoring studies. The FDA Adverse Event Reporting System (FAERS) boasts a vast database of AE reports, serving as an essential resource for post-marketing surveillance and early detection of drug safety issues (Jiang et al., 2024). In this study, we analyzed potential AEs of vortioxetine from the FAERS, and evaluated the potential correlation between vortioxetine and AEs through disproportionality analysis. The purpose of this study is to comprehensively investigate the safety of vortioxetine, providing valuable insights for clinical use and further research.

As vortioxetine is increasingly widely used in clinical practice, it is necessary to continuously monitor its safety. In this study, we utilized disproportionality analysis to identify potential AE signals associated with vortioxetine in the FAERS database, enabling the identification of AEs that have not yet been recorded in the package insert. Among the AEs of vortioxetine as the primary suspected drug, it was observed to be significantly higher among females (61.20%) compared to males (26.57%). This may be attributed to the higher prevalence of MDD among females than males (Marx et al., 2023), which subsequently leads to an increased opportunity for drug use. Among the reported age data, the majority of patients were within the age range of 18–64 years, which aligned with the epidemiological characteristics of MDD (Malhi and Mann, 2018). In addition, the small proportion of patients under 18 years old was associated with the fact that the safety and efficacy of vortioxetine in children under 18 years old were not well established. Serious outcomes encompassed death, disability, hospitalization, and life-threatening events. With the increasing concern about drug safety, patients are strongly encouraged to directly submit their AEs to the national pharmacovigilance authority, which can help to avoid underreporting and enables the collection of more detailed descriptions of AEs (Inácio et al., 2017). The AEs in our study were primarily derived from consumer self-reporting, accounting for 51.57%. Since vortioxetine is an oral medication typically self-administered at home, patients are often the first to recognize and report AEs, thereby accounting for the preponderance of consumer reports in our study. Most of the AEs originated from the United States, which may be related to factors such as earlier market availability of vortioxetine in the United States, a larger user base for the drug and a stronger willingness among users to report AEs.

The adverse events associated with vortioxetine, primarily concentrated in psychiatric disorders, gastrointestinal disorders, and nervous system disorders, were in concordance with the safety information presented in the package insert and previous studies (Baldwin et al., 2016; Findling et al., 2022; Wu et al., 2025). It was noteworthy that psychiatric disorders had the highest number of reports and were identified as significant signals through disproportionality analysis. Our study also identified the AEs specified in the drug’s package insert, such as nausea, suicidal ideation, anxiety, vomiting, feeling abnormal, pruritus, insomnia, asthenia, weight increased, irritability, anger, and constipation, demonstrating the credibility of our research methodology.

Among the AE signals of the psychiatric disorders, the top five most frequently reported AEs were suicidal ideation, anxiety, insomnia, irritability, and anger. It is well known that 5-HT is involved in the regulation of sleep, memory, attention, emotion, appetite, and anxiety (Pourhamzeh et al., 2022). These signals may reflect vortioxetine’s modulation of the serotonin system. MDD is a severe disease that itself is a strong predictor of suicide ideation. Antidepressants are crucial in the treatment of MDD, yet the debate persists regarding their potential association with an elevated risk of suicide ideation in some patients. The FDA mandated in 2004 that all antidepressants should carry warnings on increased suicidality risks for children and adolescents diagnosed with MDD, and expanded it in 2007 to cover young adults up to 24 years old (Friedman and Leon, 2007). A study analyzing data from 13 clinical trials found no increased risk of suicidal ideation and behavior in adult MDD patients treated with vortioxetine (Mahableshwarkar et al., 2020). Our study revealed that suicidal ideation was the most commonly reported AEs within the SOC of psychiatric disorders, suggesting the importance of monitoring the risks of suicidal ideation during the treatment of MDD patients with vortioxetine. In addition, some PTs that were not specified in the package insert were identified, such as apathy, feeling guilty, panic attack, eating disorder, and bruxism. Feeling guilty (n = 165) had the highest signal strength, with a ROR of 277.16 (95% CI: 234.21–327.98), a PRR of 275.64 (χ² = 37252.24), an IC of 7.83 (IC₀₂₅ = 6.34), and an EBGM of 227.59 (EBGM₀₅ = 192.32). Study has found that guilt is closely related to suicidal ideation (Feiten et al., 2021). Although suicidal ideation, feeling guilty and apathy were detected to be strong positive signals, they may not necessarily represent an adverse reaction to the medication. Instead, these symptoms might simply be part of the clinical presentation of depression and dynamically evolve until significant therapeutic effects are achieved and depressive symptoms are relieved. A post-marketing study using the world pharmacovigilance database has demonstrated an association between bruxism and vortioxetine, which is consistent with our findings (Revet et al., 2020). Bruxism has been related to disturbances in the central dopaminergic system (Bhattacharjee et al., 2022). On the one hand, vortioxetine can enhance the dopamine levels in certain regions of the brain (Gibb and Deeks, 2014). On the other hand, it may induce an elevation in the level of 5-HT (Gibb and Deeks, 2014), which in turn exerts an inhibitory effect on dopamine release. Therefore, it is necessary to conduct further research to clarify the specific role of the dopaminergic system in bruxism of vortioxetine, and to explore whether there are other mechanisms.

Regarding the nervous system, disturbance in attention was not recorded in the package insert, and there were no relevant clinical research reports. Hypersomnia and tremor have been reported in clinical study, with the incidence to be 2.6%–3.2% and 0.3%–1.3% respectively. Serotonin syndrome is a potentially life-threatening outcome associated with excessive serotonergic activity within both the peripheral and central nervous systems (Scotton et al., 2019). One case reported the serotonin syndrom in a 69-year-old female was related to the administration of vortioxetine, which was characterized by hypertension, rigidity in the upper extremities accompanied by intermittent tremors, brisk reflexes throughout the limbs, clonus in the limbs with upgoing plantar responses, and an elevated level of creatine kinase (Ong and Vasanwala, 2018). In addition, headache (n = 633) and dizziness (n = 486) were reported in relatively high numbers in our study and had also shown a high incidence rate in clinical trials (Mahableshwarkar et al., 2015; Baldwin et al., 2016). However, after conducting disproportionality analysis, we did not identify positive signals for these AEs. This could potentially be explained by the fact that, compared to vortioxetine, these AEs were also common among other drugs in the FAERS database, thereby influencing the signal values. The absence of signals did not imply the absence of relative AEs but rather signified that these AEs were not disproportionately common.

Sexual dysfunction is a common adverse reaction of antidepressants, which seriously affects the quality of life and medication compliance of patients (Montejo et al., 2015). We identified several AE signals related to sexual dysfunction, including libido decreased, erectile dysfunction, anorgasmia, loss of libido, orgasm abnormal, ejaculation delayed, and ejaculation failure. In a pooled analysis of seven studies, the incidence of sexual dysfunction were 25.7%–46.1% for vortioxetine 5–20 mg, with only 2.2% of these cases being spontaneously reported by patients (Jacobsen et al., 2016). Contrary to many other AEs, sexual dysfunction is seldom spontaneously reported (De Boer and Schoevers, 2017). Thus, physicians should remain vigilant and attentive to this aspect.

The most reported AE signals among gastrointestinal disorders included nausea, vomiting, constipation, and dry mouth, which aligned with the findings reported in clinical studies (Mahableshwarkar et al., 2015; Baldwin et al., 2016). A study reported that at the recommended therapeutic dose of 5–20 mg per day, the incidence rates of nausea, vomiting, constipation, and dry mouth were 20.9%–31.2%, 2.9%–6.5%, 3.3%–5.6% and 5.7%–7.0%, respectively (Baldwin et al., 2016). In terms of skin and subcutaneous tissue disorders, pruritus and hyperhidrosis were identified as positive signals, with the reported incidence rates being 6.6% for pruritus and 0.5%–2.4% for hyperhidrosis (Baldwin et al., 2016; Adair et al., 2024). The results of our analysis suggested that the potential AE signals of vortioxetine may also occurred in other organs or tissues. Notably, we identified unexpected significant signals including vision blurred, electrocardiogram QT prolonged, akathisia, dyskinesia, restless legs syndrome, and urinary retention. Among these, QT interval prolongation can potentially lead to fatal arrhythmias (Del Rosario et al., 2010). While one study suggested that once-daily vortioxetine (10 and 40 mg) for 14 days did not significantly affect the QT interval in healthy individuals (Wang et al., 2013), given the relatively short duration of this study, further validation was deemed necessary. Restless legs syndrome is characterized by an irresistible urge to move the legs, often accompanied by uncomfortable sensations in the legs, mainly occurring in the evening and at night, and disappearing with movement (Allen et al., 2014). A 54-year-old male reported unpleasant sensations in his legs and an urge to move them at night after 2–3 weeks of vortioxetine use, with significant improvement observed a week after discontinuing vortioxetine (Romigi et al., 2019). The causal relationship between vortioxetine and unexpected AEs is unclear, necessitating further clinical research to elucidate both the causality and the potential mechanisms.

Taking into account gender disparities in assessing drug safety enhances precise management of AEs. Our study provided gender-specific AE profiles. Specifically, we found that females were more likely to develop nausea, vomiting, crying, contusion, weight increased, pruritus, and pruritus generalised. While males were more prone to experience completed suicide, negative thoughts, anorgasmia, libido decreased, urinary retention, and sexual dysfunction. Baldwin et al. found that there was a dose effect of vortioxetine-related nausea and vomiting (Baldwin et al., 2016). The pharmacokinetic study of multiple dosing with vortioxetine showed that females had 27% higher AUC_0-24 (area under the plasma concentration-time curve from time 0–24 h) and 24% higher C_max (maximum plasma concentration) values compared to males (Chen et al., 2018). These findings indicate that females have a higher systemic exposure to vortioxetine after multiple doses, which may lead to a higher risk of nausea and vomiting. However, in addition to the biological factors associated with gender, gendered social factors play a predominant role in leading to this gender difference. Globally, males are more likely to commit suicide than females (Sher, 2020). It has been proposed that factors such as a lack of help-seeking behavior, work stress, impulsivity, alcohol and drug abuse, and the use of highly lethal means can contribute to male suicide (Sher, 2020). Compared with females, males tend to wait for symptoms to subside without intervention, which may lead to a higher likelihood of more serious adverse events in males (Zou et al., 2024). Despite requiring further validation, these findings offer a better reference for drug monitoring in both male and female patients to a certain extent.

A study found that vortioxetine-related nausea symptoms mainly occurred in the first 2 weeks after administration (Baldwin et al., 2016). Our analysis of TTO revealed that the median time for the potential AEs of vortioxetine was 7 days, with most AEs occurring within the first month following vortioxetine treatment (n = 1,309, 75.10%). Furthermore, we noticed a decreasing trend in the incidence of AEs over time. However, it is noteworthy that the TTO of the potential AEs of vortioxetine was missing from most of the reports in our study, which may limit the accurate reflection of the actual onset time. Therefore, patients and clinicians need to be vigilant about the onset time, actively identify adverse events, and promptly implement effective measures.

There are several inherent limitations worth discussing. First, the FAERS database is a spontaneous reporting system, which may lead to reporting biases, including underreporting, inaccurate reporting, and selective reporting. More than half of the reports in our research stemmed from consumers, potentially leading to a bias towards subjective or more dramatic incidents. Second, the absence of total number of patients treated with vortioxetine makes it impossible to calculate the incidence rate of each AE. Third, due to the lack of detailed clinical information, it difficult to control for confounding factors such as dose, treatment duration, concomitant medications, and comorbidities. For example, suicidal ideation may reflect the natural progression of underlying MDD rather than being directly attributable to vortioxetine use, thereby limiting the ability to establish a clear causal relationship between vortioxetine and AEs. Disproportionality analysis can only provide statistical associations rather than definitive causal links. In spite of these limitations, the FAERS database remains a valuable resource for identifying potential drug safety concerns. Our data offer a comprehensive list of case numbers and potential AE signal values of vortioxetine, helping the accumulation of knowledge on the safety profile of vortioxetine.

We conducted an assessment of the safety characteristics of vortioxetine, utilizing the AE reports submitted to the FAERS database spanning from the fourth quarter of 2013 to the fourth quarter of 2023. According to the disproportionality analysis results, potential AE signals of vortioxetine occurred in multiple organs and tissues, including psychiatric, nervous, gastrointestinal, cutaneous, ocular and reproductive system. The comprehensive and systematic analysis of the FAERS database has indeed identified some unexpected and significant potential AE signals of vortioxetine. However, due to most of the reports came from consumers and the inherent limitations of the FAERS database, it is essential to conduct prospective clinical trials to further validate these findings.