BACKGROUND: The economic burden of major depressive disorder (MDD) is substantial and increasing; however, the impact of key clinical events (eg, hospitalization, suicide attempt/ideation, and treatment changes) on health care resource use and costs are less established. OBJECTIVE: To evaluate the health care utilization and costs among patients with MDD, particularly for those with key clinical events. METHODS: In this retrospective analysis, administrative health care claims from the IBM MarketScan Commercial Claims and Encounters Database were used to identify adults with a new diagnosis of MDD (January 1, 2009, to December 31, 2017). Patients with 12 months or more of continuous health care coverage before and after the initial medical claim with an MDD diagnosis (index date) and 1 or more pharmacy claims for an antidepressant within 60 days of any qualifying medical claim were included. The effect of post-index date key clinical events (eg, treatment changes, moderate to severe MDD, MDD-related emergency department [ED] visits, MDD-related hospitalizations, suicide attempt/ideation, severe mental health disorder, use of brain stimulation therapies) on all-cause total costs was assessed. Actual allcause costs were summarized descriptively and reported per patient per year (PPPY). Multivariable analyses compared differences in all-cause costs during follow-up, depending on whether patients experienced a key clinical event. RESULTS: A total of 455,082 patients met eligibility criteria. The average age was 41 years and 64% of patients were female. Mean (SD) all-cause PPPY costs during the follow-up period were $10,074 ($25,694). The most common key clinical events were treatment changes, moderate to severe MDD diagnosis, and MDD-related ED visits. The majority of patients (90.1%) experienced at least 1 treatment change, which was most commonly treatment discontinuation. Generally, mean costs for up to 90 days following an event were higher than those preceding the event. In multivariable analyses, patients with any key clinical events had 51% higher PPPY allcause health care costs compared with those who did not have any key clinical events. Compared with patients without key clinical events, follow-up costs were more than 2 times higher among patients with severe mental health disorder, MDD-related hospitalization, and suicide attempt/ideation. The most impactful key clinical event was treatment with electroconvulsive therapy, vagal nerve stimulation, or transcranial magnetic stimulation, in which patients incurred 4.3 times higher follow-up costs than those who did not receive one of these treatments. CONCLUSIONS: Key clinical events exacerbate health care resource use and costs among patients with MDD. Effective therapeutic regimens initiated optimally in the course of treatment may mitigate costly clinical events associated with MDD. DISCLOSURES: This study was sponsored by Allergan plc (prior to its acquisition by AbbVie). The sponsor was involved in the study design, data collection, data analysis, manuscript preparation, and publication decisions. All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship. Dr Cutler is a consultant for AbbVie, Acadia Pharmaceuticals, Akili Interactive, Alfasigma, Alkermes, Allergan (now AbbVie), Avanir, BioXcel Therapeutics, BlackThorn Therapeutics, Intra-Cellular Therapies, Ironshore, Janssen, Karuna Therapeutics, Lundbeck, Neurocrine Biosciences, Noven, Otsuka, Sage Therapeutics, Sunovion, Supernus Pharmaceuticals, Takeda, Teva and Tris Pharma; has received speaker/promotional honoraria from AbbVie, Acadia Pharmaceuticals, Alfasigma, Alkermes, Allergan, Avanir, Intra-Cellular Therapies, Ironshore, Janssen, Lundbeck, Neurocrine Biosciences, Noven, Otsuka, Sunovion, Takeda, Teva, and Tris Pharma; and has received research grants from Aevi Genomics, Akili Interactive, Alkermes, Allergan (now AbbVie), Arbor Pharmaceuticals, Biohaven, Ironshore, KemPharm, Lilly, Lundbeck, Neos Therapeutics, Novartis, Otsuka, Purdue Canada, Sunovion, Supernus Pharmaceuticals, Takeda and Tris Pharma. Drs Keyloun and Gillard are AbbVie employees and may hold stock. Dr Higa was an employee of AbbVie at the time of the study and may hold stock. Ms Park is an employee of Merative, formerly IBM Watson Health, which received funding from Allergan (prior to its acquisition by AbbVie) to conduct this analysis. Dr Bonafede was an employee of IBM Watson Health, now Merative, which received funding from Allergan (prior to its acquisition by AbbVie) to conduct this analysis. Dr Jain has served as a consultant to Addrenex, Allergan (now AbbVie), Avanir, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Supernus, Takeda, and Teva; has been a paid speaker for Addrenex, Alkermes, Allergan (now AbbVie), Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Rhodes, Shionogi, Shire, Sunovion, Takeda, and Tris Pharmaceuticals; has received research support from Allergan (now AbbVie), AstraZeneca, Lilly, Lundbeck, Otsuka, Pfizer, Shire, and Takeda; and has served on the advisory boards for Addrenex, Alkermes, Avanir, Forum, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Supernus, Takeda, and Teva.