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Abstract Importance Antidepressant use is rising globally, with increasing duration of real-world prescribing. While the FDA considers 6-8 week trials adequate for regulatory approval, guidelines recommend prolonged treatment. This raises questions about the evidence supporting long-term prescribing practices. Objective To systematically compare the duration of placebo-controlled randomized trials of commonly prescribed antidepressants with real-world usage patterns. Design, Setting, and Participants: This descriptive review analyzed 52 eligible placebo-controlled randomized trials (n=10,116 participants) investigating the 10 most commonly prescribed antidepressants, selected based on 2022 United States prescription data. Trials were sampled at 5-year intervals from 1978 through 2023. Main Outcomes and Measures: The primary outcome was the comparison between trial duration and real-world antidepressant use duration based on National Health and Nutrition Examination Survey (NHANES) data. Secondary outcomes included methodological characteristics such as the use of standardized severity scales, withdrawal monitoring, taper protocols, and type of placebo used. Results The median duration of antidepressant use in the United States was approximately 5 years (260 weeks), while the median trial duration was 8 weeks (IQR: 6-12 weeks). Among trials, 88.5% (n=46) had a duration of 12 weeks or less, and only 11.5% (n=6) randomized participants beyond 12 weeks, with none exceeding 52 weeks. Although 94.2% of antidepressant users are prescribed medication for longer than 60 days, the median trial duration was 56 days. Few trials monitored for withdrawal symptoms (3.8%) or included taper protocols (18.9%), and only 1.9% reported depression or anxiety outcomes during the post-treatment period. No trials used active placebos to mitigate unblinding. Conclusions and Relevance A substantial discordance exists between the typical 8-week duration of clinical trials and the median 5-year real-world use of antidepressants. This gap, compounded by inadequate monitoring for withdrawal effects and post-treatment outcomes, raises important questions about the evidence supporting current long-term prescribing practices. Publicly funded trials of longer duration that monitor for withdrawal, sexual side effects, and relapse are necessary to determine optimal antidepressant therapy duration.