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Introduction: Pre-existing conditions relevant for adverse events (AE) and the potential for drug-drug interactions (DDIs) may limit safe pharmacotherapeutic augmentation options for patients with major depressive disorder (MDD). This concern may be heightened among patients with treatment-resistant depression (TRD), who often have comorbid medical disorders., Methods: Adults with MDD and ≥ 1 antidepressant claim within the first observed major depressive episode were identified in the MarketScan® Databases. Those initiating a new regimen after two regimens at adequate dose and duration were considered to have TRD. The index date was defined at TRD onset or on a random antidepressant claim among patients with non-TRD MDD. Pre-existing conditions 12 months pre-index and potential DDIs 3 months pre/post-index associated with specific non-antidepressant augmentation therapies, including atypical antipsychotics (APs), buspirone, psychostimulants, anticonvulsants, thyroid hormone, and lithium were compared between 1:1 matched TRD and non-TRD MDD cohorts., Results: Overall, 3414 patients with TRD and non-TRD MDD (mean age 39.7 years, 69% female) were matched. Relative to non-TRD MDD, patients with TRD had 33% higher likelihood of ≥ 1 pre-existing condition relevant for AEs listed in product labels of non-antidepressant augmentation therapies (p < 0.001). Patients with TRD vs. non-TRD MDD had 12.9 and 6.4 times higher likelihood of ≥ 2 and ≥ 3 DDIs, respectively, based on their medication regimen (all p < 0.001)., Conclusion: Pre-existing conditions relevant for listed AEs and potential DDIs limit safe augmentation options in MDD, particularly among patients with TRD. Payer prior authorization policies requiring several augmentation therapy trials to access novel treatments may complicate clinical management of this population., (© 2021. The Author(s).)