Neuropsychiatric adverse events related to imipenem-cilastatin: a real-world pharmacovigilance study

Neuropsychiatric adverse events related to imipenem-cilastatin: a real-world pharmacovigilance study | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 23 May 2025 V1 Latest version Share on Neuropsychiatric adverse events related to imipenem-cilastatin: a real-world pharmacovigilance study Authors : Yang Yang 0009-0002-7909-5008 , Xinglan Lu , Feng Zhao , and Shiqiao Wang [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174800537.72807504/v1 367 views 171 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Imipenem-cilastatin is one of the commonly used antibacterial drugs for the treatment of severe infections in clinical practice. Since its launch, apart from seizures, other neuropsychiatric adverse events(AEs) have been rarely reported. This study comprehensively evaluates the neuropsychiatric AEs of imipenem-cilastatin in the real world through the FDA Adverse Event Reporting System (FAERS) database. Methods: This study searched the FAERS database for neuropsychiatric AEs related to imipenem-cilastatin from the first quarter of 2004 to the fourth quarter of 2024. We evaluated the association between imipenem-cilastatin and neuropsychiatric AEs through various disproportionality analysis methods. Results: We obtained a total of 1822 patients and 2899 reports of neuropsychiatric AEs related to imipenem-cilastatin from the data. The common AEs included epilepsy, seizure, delirium, dysphoria, and mental disorder. Additionally, we identified some unexpected signals such as uraemic encephalopathy, persecutory delusion, logorrhoea, and staring. The median age of patients with overall neuropsychiatric AEs with imipenem-cilastatin was 70 years, and the median time to onset of overall neuropsychiatric AEs with imipenem-cilastatin was 2 days, with median onset times of 2 days for seizures and 3 days for delirium-related AEs,no statistical differences in median onset times were found in gender and age subgroups. Conclusion: This study provides real-world insights into the use of imipenem-cilastatin, which is an important supplement to clinical application. Elderly patients should be closely monitored for neuropsychiatric AEs during early use of imipenem-cilastatin Neuropsychiatric adverse events related to imipenem-cilastatin: a real-world pharmacovigilance study Running Head: Neuropsychiatric adverse events related to imipenem-cilastatin Yang Yang a Xinglan Lu a Feng Zhao a Shiqiao Wang b* a Department of Pharmacy, Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, China b Department of Pharmacy, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China *Corresponding Author: Shiqiao Wang, E-mail: [email protected] Background : Imipenem-cilastatin is one of the commonly used antibacterial drugs for the treatment of severe infections in clinical practice. Since its launch, apart from seizures, other neuropsychiatric adverse events(AEs) have been rarely reported. This study comprehensively evaluates the neuropsychiatric AEs of imipenem-cilastatin in the real world through the FDA Adverse Event Reporting System (FAERS) database. Methods : This study searched the FAERS database for neuropsychiatric AEs related to imipenem-cilastatin from the first quarter of 2004 to the fourth quarter of 2024. We evaluated the association between imipenem-cilastatin and neuropsychiatric AEs through various disproportionality analysis methods. Results : We obtained a total of 1822 patients and 2899 reports of neuropsychiatric AEs related to imipenem-cilastatin from the data. The common AEs included epilepsy, seizure, delirium, dysphoria, and mental disorder. Additionally, we identified some unexpected signals such as uraemic encephalopathy, persecutory delusion, logorrhoea, and staring. The median age of patients with overall neuropsychiatric AEs with imipenem-cilastatin was 70 years, and the median time to onset of overall neuropsychiatric AEs with imipenem-cilastatin was 2 days, with median onset times of 2 days for seizures and 3 days for delirium-related AEs,no statistical differences in median onset times were found in gender and age subgroups. Conclusion : This study provides real-world insights into the use of imipenem-cilastatin, which is an important supplement to clinical application. Elderly patients should be closely monitored for neuropsychiatric AEs during early use of imipenem-cilastatin KEYWORDS：imipenem-cilastatin, carbapenem, seizure, epilepsy, delirium, neuropsychiatric, FAERS Word Count:3198 what is known about this subject: 1. The most common neuropsychiatric adverse event of imipenem-cilastatin is seizures， other neuropsychiatric adverse events are rarely reported. 2. Seizures caused by imipenem-cilastatin are usually associated with advanced age. 3. The timing of the occurrence of neuropsychiatric adverse events caused by imipenem-cilastatin is unclear what this study adds: 1. In addition to seizures, imipenem-cilastatin may cause various neuropsychiatric adverse events. 2. Elderly patients using imipenem-cilastatin are more prone to neurological and psychiatric adverse events such as seizures and delirium. 3. Neuropsychiatric adverse events related to imipenem-cilastatin mainly occur in the early stages of treatment, with no statistically significant difference in the median time to onset of neuropsychiatric events between different ages and genders. 1 Introduction Imipenem-cilastatin is the first carbapenem antibiotic applied in clinical practice. Its structure is derived from the semi-synthetic derivative (N- formimidoyl) of thienamycin developed in 1980, namely imipenem(Salmon-Rousseau et al., 2020). Imipenem is easily hydrolyzed and inactivated by renal dehydropeptidase in the body, so it is usually combined with the renal dehydropeptidase inhibitor cilastatin to delay metabolism and reduce drug toxicity. Since its launch, imipenem-cilastatin has shown good antibacterial activity against Gram-positive and Gram-negative bacteria and is widely used for lower respiratory tract infections, abdominal infections, skin and soft tissue infections, and endocarditis(Acar, 1985; Benfield and Chrisp, 1992; Fichtenbaum and Smith, 1992; Nichols et al., 1995). Carbapenem drugs represented by imipenem-cilastatin are the cornerstone of severe infection treatment and are important therapeutic agents for multidrug-resistant Gram-negative bacteria(Lee et al., 2023). Imipenem-cilastatin is a well-tolerated drug, with the most common symptoms being pain and induration at the injection site, rash, itching, nausea, and vomiting(Calandra et al., 1985). Neuropsychiatric adverse events(AEs) are rare and serious AEs associated with imipenem-cilastatin, with epilepsy being the most frequently reported neuropsychiatric adverse event in clinical cases(Aloui et al., 2024). Other AEs such as encephalopathy, hallucinations, and psychiatric disorders have been occasionally reported(Gschwind et al., 2016; Ninan and George, 2016). Imipenem-cilastatin was approved by the US FDA in 1985 and has been used clinically for 40 years, although some studies have reported neuropsychiatric adverse events of imipenem-cilastatin (Fink et al., 1994; Jaccard et al., 1998),due to the limited number of clinical trial participants and observation time,some potential neuropsychiatric AEs may not have been identified. Additionally, there has been no large-scale study on the differences in neuropsychiatric AEs of imipenem-cilastatin based on age and gender. In order to evaluate the relationship between imipenem-cilastatin and neuropsychiatric AEs, we conducted a comprehensive analysis of neuropsychiatric AEs related to imipenem-cilastatin from the first quarter to the fourth quarter of 2004 using the FDA Adverse Event Reporting System (FAERS) database and explored potential signals, aiming to provide safety references for the clinical use of imipenem-cilastatin and new compound formulations. 2 Materials and methods 2.1 Data sources The FAERS database is a publicly accessible data source (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html)，and it serves as a crucial database for monitoring adverse drug events and pharmacovigilance in the United States.The sources of FAERS reports include consumers, drug manufacturers, doctors, and pharmacists from around the world. The FAERS dataset consists of seven parts: demographic and administrative information (DEMO), adverse drug reaction information (REAC), drug information (DRUG), patient outcomes information (OUTC), reported sources (RPSR), drug therapy start and end dates (THER), and indications for drug administration (INDI)(Liu et al., 2025). There may be duplicate reports in the FAERS data submissions.We remove duplicate reports according to the guidance rules provided by the FDA(Zou et al., 2023b). After identifying the target drug, we include imipenem-cilastatin as the primary suspected(PS)drug report in the study. 2.2 Data Standardization and Signal Detection All AEs in the FAERS database are coded using the Medical Dictionary for Regulatory Activities (MedDRA), which is hierarchically organized from highest to lowest as follows: System Organ Class (SOC), High Level Group Term (HLGT), High Level Term (HLT), Preferred Terms (PTs), and Lowest Level Term (LLT)(Yang et al., 2025). In this study, neuropsychiatric adverse events include adverse events of the nervous system and psychiatric system. We use SOC, HLGT, and PTs in MedDRA version 27.1 to classify and code neuropsychiatric adverse events of imipenem-cilastatin. The screening flowchart of AEs of imipenem-cilastatin is shown in Figure 1. In this study, we used multiple asymmetric analysis methods to detect signals of neuropsychiatric AEs for imipenem-cilastatin,including the Reporting Odds Ratio (ROR) method, the proportional reporting ratio (PRR), the Bayesian Confidence Propagation Neural Network (BCPNN) method, and the Multi Item Gamma Poisson Shrinker (MGPS) method(Wen et al., 2024). To reduce bias from a single algorithm, we defined positive signals as those meeting the criteria of all four algorithms, thereby improving the reliability of the analysis results. All algorithms rely on 2×2 contingency tables (Supplementary Table 1), with specific formulas and thresholds shown in Supplementary Table 2. 2.3 Time to onset analysis We analyzed neuropsychiatric AEs of imipenem-cilastatin using the Weibull distribution test to determine the pattern of risk changes over time. When the shape parameter β of the Weibull distribution is less than 1, and its 95% confidence interval (CI) is less than 1, the risk is considered to decrease over time (early failure type); if the shape parameter β equals or is close to 1, and its 95% confidence interval includes 1, the risk occurs constantly over time (random failure type); if the shape parameter β is greater than 1, and its 95% confidence interval does not include 1, the risk is considered to increase over time (wear-out failure type)(Mazhar et al., 2021). 2.4 Statistical analysis The data were statistically analyzed using Microsoft EXCEL 2024, SAS 9.4, and R 4.4.3.The Wilcoxon rank-sum test and Kruskal-Wallis test were used to compare the median onset time of adverse events in different subgroups, the chi-square test was used to compare differences in adverse events between groups,and all the data were presented at P<0.05 defined as statistically different. 3 Results 3.1 Descriptive analyses We collected 4,155 patients and 10,550 imipenem-cilastatin adverse event reports from the FAERS database, among which neuropsychiatric adverse event reports involved 1,822 patients, including 2,899 adverse event reports. The demographic characteristics of imipenem-cilastatin are shown in Table 1, with more reports from males (n=1008, 55.32%) than females (n=761, 41.77%). Reports from those aged 65 and above accounted for the largest proportion (n=1026, 56.31%), followed by the 45-64 age group (n=426, 23.38%), and the fewest reports were from those under 18 years old (n=37, 2.03%). We identified PTs related to seizures and delirium through HLGT(Supplementary Table 3)and displayed the age distribution of adverse events using violin plots (Figure 2), where the median age for overall neuropsychiatric AEs was 70 years, and the median ages for seizure and delirium-related AEs were 69 and 73 years, respectively. The majority of reports came from pharmacists (60.59%), with China (71.73%) being the top reporting country, followed by the United States (8.84%) and France (5.65%). Figure 3A shows the distribution of reports of imipenem-cilastatin by year, with the highest number of reports in 2021. The number of reports in the past five years has increased significantly compared to previous years, among which neuropsychiatric AEs account for a large proportion of overall adverse events each year,most reports were serious adverse event reports (98.85%). Regarding treatment outcomes, hospitalization - initial or prolonged (28.65%)- was the most common event experienced by patients, followed by life-threatening events (9.55%), among which the number of reported death cases was 118 (6.48%).We visualize the top 10 adverse neuropsychiatric events experienced by patients who died as a treatment outcome through an alluvial diagram (Figure 3B), most of which are AEs related to seizures such as seizure (n=48), epilepsy (n=8), and generalised tonic-clonic seizure (n=7). The neuropsychiatric AEs experienced by deceased patients were mostly elderly patients over 65 years old. 3.2 Detection of signals at the PTs level A total of 241 PTs related to neuropsychiatric AEs of imipenem-cilastatin were involved(Supplementary Table 4). We displayed the top 50 PTs by number through a forest plot (Figure 4A), among which common AEs were epilepsy (n=601), seizure (n=300), delirium (n=298), dysphoria (n=80), and mental disorder (n=80). In addition, we used a heatmap to show the differences in the number of major neuropsychiatric adverse event reports by gender and age group (Figure 4B, Figure 4C), where males reported significantly more AEs such as epilepsy and delirium than females, and patients over 65 years old had significantly more AEs than the non-elderly group. Using four methods, we obtained 50 positive signals, among which disorganised speech, convulsions local, and epilepsy showed strong signal values(Table 2). We found some positive signals not mentioned in the instructions, such as uraemic encephalopathy, persecutory delusion, logorrhoea, and staring. 3.3 Differences in gender and age regarding the risk signals of imipenem-cilastatin We conducted a differential analysis of the top 10 neuropsychiatric AEs of imipenem-cilastatin(Supplement Table 5 and Table 6).Figure 5 shows the statistical differences in AEs among gender and age subgroups.In the gender subgroup, we found that males were more likely to experience delirium (P<0.05)( Figure 5A); in the age subgroup, we observed that elderly patients aged ≥65 were more likely to experience epilepsy (P<0.001), delirium (P<0.001), dysphoria (P<0.001), depressed level of consciousness ( P<0.001), seizure (P<0.05), hallucination ( P<0.05), and disorganised speech (P<0.05) ( Figure 5B). 3.4 TTO of neuropsychiatric events from imipenem-cilastatin A total of 1,419 onset times were recorded for neuropsychiatric AEs related to imipenem-cilastatin, with the vast majority of events occurring within one month of medication use (n=1419, 98.80%) (Figure 6A). The median onset time for neuropsychiatric AEs was 2 days, with an interquartile range(IQR)of 1-5 days. The Weibull distribution test indicated that the overall neuropsychiatric AEs decreased over time (Figure 6B). We also performed Weibull distribution tests on 789 seizure-related AEs and 321 delirium-related AEs. The median onset time for seizure-related AEs was 3 days, and the Weibull distribution test showed a constant occurrence of seizure-related AEs over time; the median onset time for delirium-related AEs was 2 days, with an increase in adverse events over time (Figure 6B). We conducted TTO analyses for gender and age subgroups within the overall neuropsychiatric AEs. There was no statistically significant difference in median onset time between females and males (P=0.175), nor among different age subgroups (P=0.473) (Figure 6C, Figure 6D). Additionally, separate TTO analyses for seizure and delirium-related AEs showed no statistically significant differences in event occurrence among gender and age subgroups (Supplementary Figure 1). 3.5 Combination drug analysis The FAERS database records some data on the combined use of imipenem-cilastatin, with the top six most frequent combination drugs being vancomycin, voriconazole, linezolid, amikacin, tigecycline, and ciprofloxacin. Among these, the combination of imipenem-cilastatin and voriconazole reported the most neuropsychiatric adverse events (n=85)(Supplementary Table 7). 4 Discussion We retrieved some clinical studies related to imipenem-cilastatin from the past ten years in the database(Chen et al., 2018; Portsmouth et al., 2018), but neuropsychiatric AEs were rarely mentioned in these studies. However, a large number of AEs have been reported in the FAERS database, suggesting that the incidence of neuropsychiatric AEs may be seriously underestimated in medical literature. We mined neuropsychiatric AEs signals of imipenem-cilastatin from the FAERS database and conducted subgroup analyses on the occurrence time of AEs as well as differences in gender and age.This is the first comprehensive and independent study on neuropsychiatric AEs since the launch of imipenem-cilastatin. Our research results provide valuable insights into the real-world application of imipenem-cilastatin. In baseline information, we found neuropsychiatric AE reports predominantly from China, probably because China is one of the world’s largest producers and consumers of antibiotics. A study on the trends of antimicrobial use in Chinese hospitals showed that the proportion of carbapenem use increased from 2.6% in 2015 to 3.6% in 2021(Wushouer et al., 2023). Data from the past five years indicate a significant increase in reports of neuropsychiatric AEs compared to previous years, which may be due to the global COVID-19 pandemic, where bacterial infections are common complications of viral respiratory infections, especially with a significant increase in mixed infections among critically ill patients(Seethalakshmi et al., 2022; Duan et al., 2024). From the reports of overall adverse events of imipenem-cilastatin over the years, neuropsychiatric events account for a large proportion, and the data show that 98% of the reports are serious adverse event reports. These statistics emphasize the necessity of monitoring neuropsychiatric AEs. AEs related to seizures are one of the main neuropsychiatric AEs of imipenem-cilastatin, with multiple seizure-related PTs such as epilepsy, seizure, and status epilepticus appearing in the data. A study based on 10 antibiotics associated with seizures found that imipenem-cilastatin showed the highest risk of seizures(Zou et al., 2023a). A meta-analysis indicated that among carbapenem drugs, imipenem-cilastatin has the highest risk of causing seizures, followed by ertapenem, meropenem, and doripenem, with no statistically significant difference found in head-to-head comparisons between imipenem and meropenem(Cannon et al., 2014). The incidence of seizures caused by imipenem-cilastatin varies greatly depending on the number of subjects in the trial and the study population.Literature reports the incidence of seizures caused by imipenem-cilastatin to be 3-33%(Wanleenuwat et al., 2020), but several large retrospective studies show a lower actual incidence. A retrospective analysis from the United States of 1,754 patients treated with imipenem-cilastatin showed that only 16 cases (0.9%) were judged to be seizures caused by imipenem-cilastatin(Calandra et al., 1988). Another study found that among 1,951 patients using imipenem-cilastatin, only 4 cases experienced seizures, all of whom had dosages exceeding the recommended dose for renal function(Pestotnik et al., 1993). Our data reported a large number of seizure-related AEs; however, we cannot obtain the actual number of patients using imipenem-cilastatin from the data, so we cannot infer the incidence of seizure-related events. There are multiple high-risk factors for imipenem-cilastatin-induced seizures,some recognized factors include advanced age, high-dose administration, renal insufficiency, and central nervous system diseases(Sutter et al., 2015; Neo et al., 2020). Therefore, patients with these high-risk factors should be monitored for seizure prevention. It is noteworthy that neurological AEs in deceased patients are not mostly related to seizure-related adverse events. Although the data do not indicate that seizures directly cause patient death, these events may further worsen symptoms in critically ill patients, thereby increasing the risk of death(Trinka et al., 2023). Delirium-related AEs are the main psychiatric AEs of imipenem-cilastatin, and delirium is not explicitly mentioned as a PTs in the package insert. In our study, delirium-related AEs included delirium, confusional state, disorientation, and delirium tremens. In clinical practice, delirium may also manifest as inattention, impaired level of consciousness, and cognitive impairment(Inouye et al., 2014). A statistical result shows that among various categories of antibacterial drugs, carbapenems have the highest risk of causing delirium, with ertapenem having the highest risk, followed by imipenem-cilastatin(Teng and Frei, 2022). The incidence of delirium usually increases with aging(Inouye et al., 1999), and in our data, most patients with delirium-related AEs were elderly. Studies show that delirium in critically ill patients prolongs hospital stay(Klein Klouwenberg et al., 2014), adds extra healthcare burden(Inouye et al., 1999), and may even increase the risk of patient mortality(Sanchez et al., 2020). In the study, we also identified some potential signals, such as uraemic encephalopathy, persecutory delusion, logorrhoea, and staring. Although the instructions mention encephalopathy, there may be various types of encephalopathy, so we retained the specific PT of uraemic encephalopathy in the data as a warning signal. In addition, some suspected false positive signals appeared in our data, such as cerebral softening, cerebral atrophy, and cerebral infarction, which can be observed as complications in patients with bacterial meningitis(Hsu et al., 2018; Wang et al., 2024). Of concern is that imipenem-cilastatin can cause neurotoxicity in clinical use, leading to brain lesions. We speculate that this may indirectly cause these AEs, but this hypothesis still needs further confirmation. Therefore, these potential signals should be fully monitored with caution. The neuropsychiatric AEs caused by imipenem-cilastatin may be due to the high affinity of its C2 side chain structure for gamma-aminobutyric acid (GABA). When imipenem-cilastatin competitively binds, it hinders GABA from binding to other receptors, thereby reducing the inhibitory discharge of neurons. When the balance between excitatory and inhibitory synaptic transmission is disrupted, it may increase central excitability, leading to agitation, involuntary limb movements, and seizures. The amino basicity strength, the spatial structure around the amino group, and the distance from the carboxyl group to the base in the imipenem-cilastatin structure all affect the action of central inhibitory neurotransmitters, ultimately causing neuropsychiatricAEs such as auditory hallucinations, visual hallucinations, and disorientation(Wanleenuwat et al., 2020; Zhan et al., 2024; Jia et al., 2025). In addition, the action of α-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptor complexes may also be one of the mechanisms inducing neuropsychiatric AEs(Koppel et al., 2001). There may be multiple factors contributing to neuropsychiatric AEs caused by imipenem-cilastatin. Due to the lack of detailed dosage records in the data and the unavailability of patient renal function status and primary disease-related data, we only conducted separate analyses for the two subgroups of age and gender. In the age subgroup, we observed that males had a higher risk of delirium than females. No statistical differences were observed in other common AEs. In the age subgroup, we found that elderly patients over 65 years old were more prone to multiple AEs such as epilepsy, delirium, and dysphoria. These data indicate that age is an important factor inducing epilepsy and other neuropsychiatric AEs. The reason may be that renal function declines with aging in elderly patients(Dutra et al., 2014), reducing the metabolism and excretion capacity of drugs, which easily leads to drug accumulation. Therefore, adjusting the appropriate dosage based on the renal function status of elderly patients is an essential step in drug therapy. The combined use of antimicrobial drugs is very common in the treatment of severe infections. This study did not show more reports of neuropsychiatric AEs caused by the combined use of imipenem-cilastatin. It is worth noting that the combination of imipenem-cilastatin with nephrotoxic drugs such as vancomycin and amikacin may further worsen the patient’s renal function. Compared with other drugs, the combination of imipenem-cilastatin and voriconazole showed more neuropsychiatric AEs, mainly because voriconazole itself may induce neuropsychiatric adverse events(Leveque et al., 2025). Additionally, this drug interacts with various other drugs(Theuretzbacher et al., 2006), which may indirectly lead to the occurrence of neuropsychiatric AEs. The TTO of adverse drug events is one of the important data for drug safety monitoring, which can help clinicians identify the safety risks of drugs in clinical application. Previous studies have reported that the average time to onset of seizures caused by imipenem-cilastatin is 7 days after the start of treatment(Calandra et al., 1988). This study shows that whether it is seizure-related AEs or delirium-related AEs, the median time to event occurrence is in the earlier stages of treatment. Similar results were observed in different gender and age subgroups. Therefore ，neuropsychiatric AEs should be monitored as early as possible, especially important in the first week after administration. Although this study analyzes the neuropsychiatric AEs of imipenem-cilastatin from multiple perspectives, there are still certain limitations. Firstly, FAERS is a spontaneous reporting database with issues such as duplicate data, missing data, and some other irregular entries, which may cause some bias in the statistical results. Secondly, the data reporting does not require providing a causal relationship between the drug and adverse events; positive signals only indicate a statistical association. Additionally, due to the lack of real-world population usage data, we are unable to estimate the incidence rate of adverse events. More prospective studies are needed in the future to further evaluate the neuropsychiatric AEs of imipenem-cilastatin. 5 Conclusion We mined and analyzed the real-world neuropsychiatric AEs of imipenem-cilastatin through the FAERS database. In the study, we identified common adverse events such as epilepsy, seizure, and delirium. Additionally, we discovered some unexpected signals. Subgroup analysis and related TTO data emphasized the necessity of monitoring and intervention in elderly patients and early neuropsychiatric AEs. This study provides important references for the clinical safe use of imipenem-cilastatin. Data availability statement The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author. Author contributions YY contributed to conception and study design, and performed the data analysis and drafted the manuscript. Xl L and FZ organize and reconcile data .Sq W collaborated in the study development and critically revised the manuscript. All authors drafted the manuscript, participated in data analyses and interpretation, and revisions of the manuscript and approved the final version. Funding This study did not receive any specific funding from public, commercial, or nonprofit sectors. Ethics statement The FAERS database contains anonymous patient information, so no ethical approval is required. Conflict of interest The authors declare no conflict of interest specific for this research. Consent to Participate Not applicable. Consent for Publication Not applicable. References Acar, J.F. (1985). Therapy for lower respiratory tract infections with imipenem/cilastatin: a review of worldwide experience. Rev Infect Dis 7 Suppl 3 , S513-517. doi: 10.1093/clinids/7.supplement_3.s513.Aloui, G., Houria, B.B., and Yousfi, M.A. (2024). Imipenem-Cilastatin-Induced Seizures: A Case Report. 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Figure 3 (A) Annual distribution of neuropsychiatric adverse events of imipenem-cilastatin.(B) Major neuropsychiatric adverse events experienced by patients who died using imipenem-cilastatin. Figure 4 (A) Forest plot of ROR for the top 50 PTs of neuropsychiatric adverse events associated with imipenem-cilastatin.(B) Heatmap of gender differences in the number of reports of neuropsychiatric adverse events of imipenem-cilastatin.(C) Heatmap of age differences in the number of reports of neuropsychiatric adverse events of imipenem-cilastatin. Figure 5 (A) Gender differences in neuropsychiatric adverse events of imipenem-cilastatin.(B) Age differences in neuropsychiatric adverse events of imipenem-cilastatin. Note:(A) ROR 1 indicates a higher risk in females, and the P value indicates the statistical significance of the event in gender subgroups.(B) Note: ROR 1 indicates a higher risk of adverse events in non-elderly patients under 65 years old.the P value indicates the statistical significance of the event in age subgroups. Figure 6(A) The occurrence time distribution of adverse neuropsychiatric events related to imipenem-cilastatin.(B) Table 5 Time to onset analysis of imipenem-cilastatin neuropsychiatric adverse events using the Weibull distribution test.(C) Gender differences in the timing of adverse neuropsychiatric events related to imipenem-cilastatin.(D) Age differences in the timing of adverse neuropsychiatric events related to imipenem-cilastatin. Note: IQR, interquartile range; TTO, Time to onset. Supplementary Material File (table 1 imipenem-cilastatin-.docx) Download 16.06 KB File (table2 imipenem cilastatin.docx) Download 28.81 KB Information & Authors Information Version history V1 Version 1 23 May 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords clinical pharmacology drug safety medication safety therapeutic drug monitoring Authors Affiliations Yang Yang 0009-0002-7909-5008 View all articles by this author Xinglan Lu Nanjing Brain Hospital View all articles by this author Feng Zhao View all articles by this author Shiqiao Wang [email protected] Jinan University Affiliated Guangdong Second Provincial General Hospital View all articles by this author Metrics & Citations Metrics Article Usage 367 views 171 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Yang Yang, Xinglan Lu, Feng Zhao, et al. Neuropsychiatric adverse events related to imipenem-cilastatin: a real-world pharmacovigilance study. 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