Antidepressant response onset is delayed in individuals with major depressive disorder (MDD). This study compared remission rates and time to remission onset for antidepressant medication delivered adjunctively to nightly time in bed (TIB) restriction of 6 hours or 8 hours for the initial 2 weeks. METHODS: Sixty-eight adults with DSM-IV-diagnosed MDD (mean +/- SD age = 25.4 +/- 6.6 years, 34 women) were recruited from September 2009 to December 2012 in an academic medical center. Participants received 8 weeks of open-label fluoxetine 20-40 mg and were randomized to 1 of 3 TIB conditions for the first 2 weeks: 8-hour TIB (n = 19); 6-hour TIB with a 2-hour bedtime delay (late bedtime, n = 24); or 6-hour TIB with a 2-hour rise time advance (early rise time, n = 25). Clinicians blinded to TIB condition rated symptom severity weekly. Symptom severity, remission rates, and remission onset as rated by the 17-item Hamilton Depression Rating Scale were the primary outcomes. RESULTS: Mixed effects models indicated lower depression severity for the 8-hour TIB compared to the 6-hour TIB group overall (F8, 226.9 = 2.1, P < .05), with 63.2% of 8-hour TIB compared to 32.6% of 6-hour TIB subjects remitting by week 8 (chi(2)(1) = 4.9, P < .05). Remission onset occurred earlier for the 8-hour TIB group (hazard ratio = 0.43; 95% CI, 0.20-0.91; P < .03), with no differences between 6-hour TIB conditions. CONCLUSIONS: Two consecutive weeks of nightly 6-hour TIB does not accelerate or improve antidepressant response. Further research is needed to determine whether adequate sleep opportunity is important to antidepressant treatment response. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01545843.