Possible Association Between Concomitant Use of SSRIs with NSAIDs and an Increased Risk of Adverse Events Among People with Depressive Disorders: Data Mining of FDA Adverse Event Reporting System.

: Depression, a major global health issue, is commonly treated with selective serotonin reuptake inhibitors (SSRIs). Given the link between depression and inflammation, nonsteroidal anti-inflammatory drugs (NSAIDs) may have adjunctive benefits. Clinically, SSRIs and NSAIDs are often co-prescribed for comorbid pain or inflammatory conditions. However, both drug classes pose risks of adverse effects, and their interaction may lead to clinically significant drug-drug interactions. : This study analyzed FDA Adverse Event Reporting System (FAERS) data (2004-2024) to assess gastrointestinal bleeding, thrombocytopenia, and acute kidney injury (AKI) potential risks linked to SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, and sertraline) and NSAIDs (propionic/acetic/enolic acid derivatives, COX-2 inhibitors) in depression patients, alone and combined. : Disproportionality analysis (crude reporting odds ratios, cROR) identified possible associations; drug interactions were evaluated using Ω shrinkage, additive, multiplicative, and combination risk ratio (CRR) models. : Gastrointestinal bleeding risk was potentially elevated with citalopram (cROR = 2.81), escitalopram (2.27), paroxetine (2.17), fluvoxamine (3.58), sertraline (1.69), and propionic acid NSAIDs (3.17). Thrombocytopenia showed a potential correlation with fluoxetine (2.11) and paroxetine (2.68). AKI risk may be increased with citalopram (1.39), escitalopram (1.36), fluvoxamine (3.24), and COX-2 inhibitors (2.24). DDI signal analysis suggested that citalopram in combination with propionic acid derivatives (additive model = 0.01, multiplicative model = 1.14, and CRR = 3.13) might increase the risk of bleeding. Paroxetine combined with NSAIDs (additive model = 0.014, multiplicative model = 2.65, and CRR = 2.99) could potentially increase the risk of thrombocytopenia. Sertraline combined with NSAIDs (Ω = 0.94, multiplicative model = 2.14) might be associated with an increasing risk of AKI. Citalopram combined with propionic acid derivatives (Ω = 1.08, multiplicative model = 2.17, and CRR = 2.42) could be associated with an increased risk of acute kidney injury. : Certain combinations of SSRIs and NSAIDs might further elevate these risks of gastrointestinal bleeding, thrombocytopenia, and acute kidney injury in patients with depression. Given the potential drug-drug interactions, heightened clinical vigilance is advised when prescribing SSRIs and NSAIDs in combination to patients with depression.