Pharmacological treatment is an important part of managing attention-deficit/hyperactivity disorder (ADHD), and its continuation is essential for maintaining therapeutic benefits; however, discontinuation is common in clinical practice. 1 While clinical guidelines suggest tapering stimulants and alpha-2 adrenergic agonists to reduce potential withdrawal effects, 2 the literature regarding drug withdrawal for non-stimulants remains limited. Therefore, we conducted a disproportionality analysis using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to explore safety signals of drug withdrawal across ADHD medications. The DEMO, DRUG, and REAC files from the FAERS database (2004 Q1–2025 Q3) were linked via “PRIMARYID” and analyzed. As previously described, 3 we deduplicated the reports using the “PRIMARYID, ” “CASEID, ” and “FDADT” variables from the DEMO files and excluded cases specified in the “Deleted Cases” list. We queried the DRUG files for reports involving six ADHD medications (amphetamine, methylphenidate, atomoxetine, guanfacine, clonidine, and viloxazine) identified by their generic and brand names, restricting the analysis to those designated with the role code “primary suspect. ” Based on the Medical Dictionary for Regulatory Activities (MedDRA) version 28. 1, drug withdrawal cases were identified in the REAC files using the 16 preferred terms within the broad scope of the Standardized MedDRA Query (SMQ) “Drug withdrawal” (code: 20000102). Disproportionality was assessed utilizing the reporting odds ratio (ROR). A significant signal was defined as the lower limit of the 95% confidence interval exceeding 1 (Figure S1). 4 All data preprocessing and statistical analyses were performed using R (version 4. 5. 1; R Foundation for Statistical Computing, Vienna, Austria; https: //www. r-project. org/). Following deduplication, a total of 19, 586, 624 unique cases were identified. Signals of drug withdrawal were detected for amphetamine, methylphenidate, guanfacine, clonidine, and viloxazine, but not for atomoxetine (Table 1). The RORs for the 16 individual preferred terms are listed in Table S1. Regarding alpha-2 adrenergic agonists, drug withdrawal signals were observed for both clonidine and guanfacine. Clonidine, a non-selective agonist with a short half-life, carries a known risk of rebound hypertension when stopped suddenly. 5 Consistent with this, our analysis of individual preferred terms revealed a signal for “Rebound effect” with clonidine but not with guanfacine (Table S1). Guanfacine is a selective alpha-2A agonist with a longer half-life, and a Phase 1 study failed to demonstrate rebound hypertension following its abrupt discontinuation. 5 However, the presence of a signal of drug withdrawal in this real-world dataset indicates that further research is needed to clarify the clinical relevance of this finding. Our study identified a withdrawal signal for viloxazine, in contrast to atomoxetine. While a recent FAERS analysis reported a signal for the preferred term “Withdrawal syndrome, ”6 our study extends this by confirming a signal at the broader SMQ level. Although both viloxazine and atomoxetine act as norepinephrine reuptake inhibitors, basic pharmacological studies indicate that they possess distinct profiles regarding serotonergic modulation. Atomoxetine is a selective norepinephrine transporter inhibitor that does not increase extracellular serotonin levels. 7 Conversely, viloxazine has been shown to increase extracellular serotonin concentrations in the prefrontal cortex. 8 We hypothesize that this serotonergic modulation might underlie withdrawal symptoms resembling those associated with serotonin-norepinephrine reuptake inhibitors. 9 However, clinical evidence supporting this inference is currently lacking. Further research into drug withdrawal is warranted for these norepinephrine reuptake inhibitors, alongside considerations regarding suicidal ideation and behavior. This study has several limitations. First, because the FAERS database is based on spontaneous reporting, reporting biases, such as those related to time on the market and reporting year, should be taken into account. Specifically, the signal for viloxazine, a recently approved medication for ADHD, may be influenced by its small number of total reports. Second, the database relies on reporters' judgment and does not detail clinical context, including treatment duration and the exact time of discontinuation. Consequently, it is challenging to rule out coding variability, misclassification, indication bias, and the influence of co-reported medications, or to distinguish true pharmacological withdrawal from the relapse of underlying ADHD symptoms or cessation following misuse. In particular, the detected signals regarding stimulants warrant interpretive caution, as the influence of misuse cannot be isolated. Additionally, because FAERS only contains cases where adverse events occurred, it is impossible to estimate the actual incidence. Lastly, research using the FAERS database cannot determine a causal relationship. In conclusion, our study explored pharmacovigilance signals of drug withdrawal for ADHD medications based on spontaneous reporting data. Given the inherent limitations of the FAERS database, further research is warranted to establish optimal discontinuation strategies and to assess the clinical need for monitoring drug withdrawal symptoms across both stimulants and non-stimulants. Takumi Ebina and Kunihiro Iwamoto were responsible for the study concept and design. Takumi Ebina analyzed the data and drafted the manuscript. All authors critically reviewed and approved the final article. This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant No. JP25K10859). T. E. has received speaker's honoraria from Otsuka Pharmaceutical and Sumitomo Pharma, outside the submitted work. K. I. has received speaker's honoraria from DAIICHI SANKYO, Eisai, Lundbeck Japan, Meiji Seika Pharma, MSD, Otsuka Pharmaceutical, Shionogi, Sumitomo Pharma, Takeda Pharmaceutical, and Viatris, outside the submitted work. M. I. has received speaker's honoraria from EA Pharma, Eisai, Janssen Pharmaceutical, Kyowa Pharma Chemical, Lundbeck Japan, Meiji Seika Pharma, Mochida Pharmaceutical, MSD, Otsuka Pharmaceutical, Sumitomo Pharma, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Towa Pharmaceutical, and Viatris, outside the submitted work. Institutional review board approval was not required because this study relied on publicly accessible, anonymized data from the FAERS database. N/A. N/A. The data that support the findings of this study are openly available in FDA Adverse Event Reporting System (FAERS) Database at https: //www. fda. gov/drugs/drug-approvals-and-databases/fda-adverse-event-reporting-system-faers-database. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Ebina et al. (Mon,) studied this question.