Allergic diseases are among the most prevalent chronic conditions globally. Second-generation antihistamines, the cornerstone of treatment, have raised safety concerns, particularly regarding neuropsychiatric adverse drug events (ADEs) (Nerush et al., 2024). Cetirizine, a selective H1 receptor antagonist, exhibits low lipid solubility and P-glycoprotein efflux, limiting central nervous system penetration and reducing neuropsychiatric risk compared to first-generation agents. Nonetheless, recent studies have reported drowsiness, anxiety, depression, and even hallucinations associated with cetirizine use (Li et al., 2022; Bian et al., 2021; Raju et al., 2022; Hu et al., 2024). Levocetirizine, the active enantiomer of cetirizine, was developed to improve tolerability by optimizing molecular configuration. However, neuropsychiatric ADEs have also been observed with levocetirizine (Li et al., 2022; Bian et al., 2021; Hu et al., 2024).

Clinical pharmacy emphasizes inter-individual pharmacokinetic variability, making precision dosing a key therapeutic goal. Notably, gender and age are the most readily accessible clinical variables. Research has shown that gender markedly affects absorption, distribution, metabolism, and excretion of drugs, making differences in ADEs between genders an important subject warranting in-depth investigation and scientific exploration (Miller, 2014). In pediatrics, distinct physiological characteristics—such as body fluid composition, plasma protein levels, gastric pH, gastric emptying, and immature renal function—affect ADE incidence and presentation (Lu and Rosenbaum, 2014). In the elderly, age-related pharmacokinetic and pharmacodynamic changes, along with comorbidities and polypharmacy, further alter ADE profiles (Drenth-van Maanen et al., 2020; Bellanca et al., 2023). Therefore, the ADE profiles of both cetirizine and levocetirizine—compounds with low metabolic liability and primary renal elimination—are likely modulated by age and sex (Chen, 2008).

Disproportionality analysis, a key pharmacovigilance tool, identifies drug-event associations that occur more frequently than expected by comparing observed and expected reporting rates across the database (Yoshimura et al., 2013). FDA Adverse Event Reporting System (FAERS) and EudraVigilance provide valuable real-world evidence for drug safety surveillance. Through quantitative methods, it facilitates early signal detection and risk assessment, thereby enhancing pharmacovigilance effectiveness (Sakaeda et al., 2013).

This study utilized the data of the FAERS and EudraVigilance databases to evaluate neuropsychiatric ADEs associated with cetirizine and levocetirizine, providing the first comprehensive comparison of their age- and gender-specific differences.

We conducted a systematic pharmacovigilance analysis of neuropsychiatric ADEs associated with cetirizine and levocetirizine using the FAERS and EudraVigilance databases. By evaluating data across the overall population and stratifying by sex and age, we provided quantitative evidence to support clinical risk-benefit assessments.

The most prominent ADE identified for both drugs was somnolence, a finding consistent with existing literature. A systematic review on the efficacy and safety of treatments for difficult-to-control chronic spontaneous urticaria noted that drowsiness is the main adverse reaction and that dose escalation of cetirizine may increase this risk (Iriarte Sotés et al., 2021). Another review on off-label high doses of second-generation antihistamines for spontaneous urticaria also cited drowsiness and headache as the main reactions for these drugs (Podder et al., 2023). A systematic review reported that levocetirizine carries a mild sedative risk (risk ratio 1.67), which is not significantly different from other second-generation antihistamines (Snidvongs et al., 2017). Furthermore, a randomized, double-blind, crossover, placebo-controlled trial in patients with perennial allergic rhinitis found that individuals with a history of mild to moderate sedation from cetirizine are unlikely to experience a different sedative response to levocetirizine (Tzanetos et al., 2011).

Disproportionality analyses conducted in this study consistently demonstrated that the signal strength for mood disorder-related adverse events (e.g., anxiety, depression) was predominantly lower with levocetirizine than with cetirizine across primary, sensitivity, and subgroup analyses. A potential mechanism involves the disruption of histamine metabolism. In the oxidative deamination metabolic pathway, histamine is converted to imidazoleacetic acid (IAA), which is then oxidized and ribosylated for transport. IAA-ribosylation may be involved in regulating synaptic transmission in the hippocampus, a crucial area of the brain for mood regulation (Bozdagi et al., 2011). As H1 receptor antagonists, cetirizine and levocetirizine may interfere with this process. Additionally, histamine promotes prostaglandin (PG) synthesis—particularly PGE2 and PGI2—via H1 receptors. Blocking H1 receptors may dysregulate PG production, which has been linked to neuropsychiatric symptoms, as PGE2 is known to reduce central dopamine levels (Van Kammen et al., 1989). Cetirizine’s racemic formulation may contribute to its higher neuropsychiatric risk. Only the R-enantiomer (levocetirizine) has significant H1 antagonistic activity. The S-enantiomer (dextrocetirizine) has much lower H1 affinity but may still interfere with neurotransmitter systems like GABA and 5-HT, potentially increasing the risk of mood disturbances (Tillement et al., 2003; Corsico et al., 2019). A controlled trial of 92 patients with chronic pruritus reported significantly higher rates of anxiety and depression in the cetirizine group than in the levocetirizine group (Ozdemir et al., 2014). Notably, while levocetirizine showed stronger disproportionality signals for serious psychiatric adverse events (e.g., suicide attempts, suicidal ideation) than cetirizine in primary and subgroup analyses, this trend reversed in the monotherapy sensitivity analysis. This discrepancy may be explained by concomitant medication use. Montelukast—a frequent co-prescribed drug with both cetirizine and levocetirizine—has itself been linked to neuropsychiatric effects such as mood changes and suicidal ideation (Sobczak and Pawliczak, 2025). Furthermore, since these antihistamines are mainly used for allergic diseases, and given that suicidal ideation/attempts represent a major fatal comorbidity in chronic spontaneous urticaria (CSU)—where second-generation H1-antihistamine monotherapy and omalizumab are associated with significantly lower mortality—the more common combination of levocetirizine with other antihistamines suggests possible suboptimal disease control, which could elevate the risk of serious psychiatric events (Kolkhir et al., 2025). Based on these findings, it remains unclear whether cetirizine or levocetirizine is more suitable for patients with psychiatric histories, and further studies are needed to clarify their comparative safety.

Our analysis revealed stronger pharmacovigilance signals for sleep-related ADEs with levocetirizine than with cetirizine. This may be explained by their effects on central histaminergic pathways. Histaminergic neurons, primarily located in the tuberomammillary nucleus (TMN) of the posterior hypothalamus, project broadly throughout the brain—including key sleep-regulating regions such as the ventrolateral preoptic nucleus (VLPO) (Brown et al., 2001). GABAergic neurons in these areas inhibit histaminergic activity by releasing GABA into the TMN, thereby reducing arousal and promoting sleep onset (Liu et al., 2010). Normally, histamine promotes wakefulness during the day, while decreased histamine activity at night facilitates sleep. As H1 receptor antagonists capable of crossing the blood–brain barrier in small amounts, both cetirizine and levocetirizine can disrupt this balance by impairing histaminergic signaling. Notably, levocetirizine has approximately twice the affinity for human H1 receptors compared to cetirizine, potentially leading to more pronounced effects on sleep architecture (Gillard et al., 2002). In some individuals, a drop in drug levels between doses—especially in the early morning hours—may cause rebound allergy symptoms or mild arousal, a phenomenon potentially more pronounced with levocetirizine. Although comparative studies are limited, both drugs have shown equivalent efficacy in improving sleep in patients with pruritus (Ozdemir et al., 2014). However, according to several studies, both can result in sleep difficulties. One study found an increased incidence of nightmares in pediatric patients when levocetirizine was used alongside montelukast (Altaş et al., 2023), while case reports have described exacerbation of pre-existing sleep terrors with cetirizine (Hussain and Aziz, 2021). Regarding insomnia, given that levocetirizine is frequently co-administered with other antihistamines, it is plausible that inadequate control of allergic pruritus in these patients contributes to sleep disturbances, thereby influencing the observed outcomes. In conclusion, patients at elevated risk of sleep disturbances may benefit more from cetirizine or alternative antihistamines with lower central nervous system activity.

Cetirizine is more frequently associated with reports of drug dependence and abuse than levocetirizine. Pharmacokinetic differences may underlie this observation. Levocetirizine exhibits a higher plasma protein binding rate (91.2% vs. 88%–90% for cetirizine), resulting in a significantly lower apparent volume of distribution (Bree et al., 2002). A lower volume of distribution allows therapeutic concentrations to be achieved with lower doses, thereby reducing interindividual variability in drug efficacy (Walsh et al., 2001). These pharmacokinetic advantages likely contribute to levocetirizine’s lower potential for dependence and abuse, supporting its consideration as a preferred option for long-term antihistamine therapy.

Elevated migraine signals associated with cetirizine were not sustained in the monotherapy sensitivity analysis, where migraine fell outside the top 30 PTs. This inconsistency may reflect confounding influences. Epidemiologic studies link migraine with allergic disorders, and histamine—via hypothalamic modulation—contributes to migraine pathophysiology and severity (Ferretti et al., 2023). Since cetirizine is primarily prescribed for allergic conditions, its use in patients with a higher baseline migraine risk may introduce confounding. Moreover, acetaminophen use frequently co-prescribed with cetirizine according to concomitant medication analysis, could further distort signal detection. Monotherapy analysis likely attenuated these confounders, yielding a more distinct signal profile. Similarly, after the monotherapy sensitivity analysis, cognition-related PTs did not rank within the top 30. Subsequent age subgroup analysis revealed that the elevated signals for cognitive impairment associated with cetirizine were primarily distributed among adult and elderly populations. This suggests that cognitive issues may themselves represent underlying comorbidities; to manage clinical symptoms, patients often require multiple concomitant medications beyond antihistamines alone, which likely explains the attenuation or disappearance of these signals in the monotherapy analysis. Nevertheless, existing studies still indicate that cetirizine can exert some degree of influence on cognitive function (van Ruitenbeek et al., 2010). However, studies have shown that levocetirizine did not demonstrate interference with objective measures of cognitive function after both single and repeated doses, and similarly, cetirizine showed no evidence of cognitive impairment after either acute or repeated administration (Hindmarch et al., 2001).

A population-based analysis revealed that neuropsychiatric ADEs related to cetirizine and levocetirizine were more frequently reported in women than in men. Gender-related physiological differences significantly influence drug pharmacokinetics (Lee et al., 2024). Women typically absorb drugs more slowly due to lower gastric acid secretion, delayed gastric emptying—especially during mid-menstruation—and reduced gastrointestinal blood flow. During pregnancy, gastric acid secretion decreases by 40%, while intestinal motility increases by 30%–50%, further altering absorption profiles (Fletcher et al., 1994). Additionally, women have a higher body fat percentage, lower total and plasma volumes, and fluctuating sex hormone levels, all of which affect drug distribution. Both cetirizine and levocetirizine are primarily eliminated via the kidneys. Since men generally have higher serum and urinary creatinine levels and greater creatinine clearance, they may excrete these drugs more efficiently than women. Lastly, consumer reports make up the majority of ADE data in FAERS, and sociocultural factors may drive higher reporting rates among women and adults (Lee et al., 2023).

Across gender subgroups, the pattern of differences between cetirizine and levocetirizine was generally consistent with the primary analysis, with the notable exception of febrile convulsions, which were specifically reported in males in association with levocetirizine. The observed differences between cetirizine and levocetirizine across genders may stem from sex-based distinctions in neural circuit function, hormone-receptor interactions, epigenetic regulation, evolutionary adaptations, and pathophysiological responses (Bangasser and Cuarenta, 2021). Additionally, this may reflect sex-specific modulation of the central histaminergic system, a key regulator of neural excitability (Kim et al., 2023). Cetirizine and levocetirizine may interfere with the central histaminergic neuronal system, causing epilepsy and tremors. Histamine lowers striatal dopamine levels in male mice, but increases striatal dopamine levels in some female mice, and this sex difference in neurotransmitter modulation provides an important foundation for understanding the neurological ADEs of antihistamine drugs (Van Zandt and Pittenger, 2025). Although the molecular mechanisms underlying these sex differences remain unclear and the findings may be influenced by imbalanced sample sizes, these observations still provide valuable insights for implementing sex-differentiated clinical practice.

Age-stratified analyses revealed weaker disproportionality signals in adults despite higher absolute reporting frequencies—a pattern warranting longitudinal surveillance due to potential data reporting artifacts. Special attention should be paid to pediatric and elderly populations due to their distinct physiology. In pediatric patients, levocetirizine demonstrated stronger pharmacovigilance signals for febrile convulsions and epilepsy—conditions with an elevated baseline prevalence in children (Gilsoul et al., 2019; Novorol et al., 2007; AlDaithan et al., 2024). While limited studies directly compare the safety profiles of cetirizine and levocetirizine in pediatric populations, existing evidence suggests that cetirizine is generally well-tolerated and does not significantly elevate systemic side effect risks beyond somnolence (Zhou et al., 2022). Hence, cetirizine is preferred over levocetirizine in pediatric patients. In the elderly, cetirizine was associated with severe organic neurological disorders, including subarachnoid hemorrhage—a finding of particular importance given its high fatality rate and poor prognosis (Tan et al., 2024) —as well as transient ischemic attack and carotid artery occlusion. Given that cognitive decline is a prominent feature of geriatric disorders, our finding that cetirizine was associated with reports of cognitive impairment warrants attention. Additionally, levocetirizine was linked to a higher risk of hepatic encephalopathy, a significant contributor to hospitalization, readmission, and death in patients with cirrhosis; the 1-year mortality rate for severe hepatic encephalopathy can be as high as 42% (Sahney and Wadhawan, 2022). These findings emphasize the need for vigilance regarding drug-induced subarachnoid hemorrhage, particularly with cetirizine in older adults, and suggest that levocetirizine should be avoided in patients with cirrhosis. Notably, as many adverse events may relate to age-related comorbidities not analyzed here, further studies are required to confirm these observations.

According to the TTO analysis, neuropsychiatric adverse events for both cetirizine and levocetirizine accumulated rapidly within 0–30 days post-initiation and plateaued by day 90, indicating that intensive early-phase monitoring, rather than long-term follow-up, may be more efficient for signal detection. Sex-stratified comparisons revealed a statistically significant difference in event-timing for cetirizine (P < 0.05) but not for levocetirizine, consistent with the more stable pharmacokinetics of the latter after structural optimization. In the elderly, cetirizine exhibited a “compressed” distribution (IQR 0.00–2.00 days), whereas levocetirizine showed a “dispersed-delayed” pattern (IQR 0.00–71.00 days); increased blood–brain barrier permeability and drug–drug interactions likely underlie this divergence. Therefore, the active surveillance window for levocetirizine in older adults should be extended to ≥90 days. Among adults aged 18–64 years, cetirizine demonstrated the greatest temporal dispersion (IQR 0.00–25.00 days), warranting individualized and prolonged follow-up in this population.

Although previous studies utilizing the FAERS database have investigated the neurological ADEs of antihistamines such as cetirizine and levocetirizine, they did not comprehensively examine psychiatric ADEs or provide detailed evaluations of gender and age differences (Hu et al., 2024). The current study systematically analyzed both drugs’ neuropsychiatric ADE profiles and, through gender-age stratified analyses, first revealed their population-specific safety differences, providing a comprehensive clinical medication guide. However, several limitations remain. In-depth analysis was impeded by concerns with underreporting and inadequate information in the FAERS database. Due to database deficiencies, it was also impossible to directly assess the relative risk differences between the two medicines. Additionally, the lack of detailed patient clinical information, including comorbidities, impeded the adjustment for potential confounders. Moreover, disproportionality analyses can only suggest potential signals and do not establish causality or measure true risk. The true incidence of ADEs could not be determined due to the absence of prescription population data. Given the high rate of missing data for key covariates such as age and gender in the FAERS database, performing multivariate regression would substantially reduce the sample size and introduce unreliable statistical assumptions. Therefore, multivariate logistic regression was considered not feasible in this study. Consequently, strong signals detected may reflect high reporting rates rather than true incidence, potentially biasing safety assessments. These limitations underscore the need for cautious interpretation of the findings and further research to validate the results.

This study employed pharmacovigilance analyses based on the FAERS and EudraVigilance databases to assess the neuropsychiatric safety profiles of cetirizine and levocetirizine. Somnolence, dizziness, headache, and insomnia were common ADEs with high signal strengths for both drugs, representing key shared central nervous system risks that require close attention in clinical practice. Cetirizine generally exhibited higher signal intensities for depression, anxiety, and drug abuse/dependence than levocetirizine, with unique associations with cognitive impairment and migraine. In contrast, levocetirizine showed a more concentrated signal for sleep-related ADEs, and its use warrants vigilance for serious psychiatric events such as suicide attempts and suicidal ideation. Subgroup analysis revealed population heterogeneity. Among levocetirizine users, febrile convulsions were more frequently reported in males, while pediatric patients presented with febrile convulsions and epilepsy. In the elderly, cetirizine was associated with subarachnoid hemorrhage, transient ischemic attack, and carotid artery occlusion, whereas levocetirizine was linked to hepatic encephalopathy. These findings indicate the necessity for individualized risk assessment in elderly patients based on their comorbidities.

In summary, this study has systematically identified distinct neuropsychiatric safety profiles for cetirizine and levocetirizine, thereby providing a crucial foundation for rational therapeutic decision-making.