Add-on intravenous ketamine eliminates treatment lag period in severe non-treatment-resistant major depression: Rapid antidepressant and anti-suicidal effects – A randomized controlled trial

BACKGROUND: The 4-12 week lag period of conventional antidepressants creates critical vulnerability in severe depression, with peak suicide risk during the first month. While ketamine research has focused on treatment-resistant populations, its potential to eliminate this lag period in non-treatment-resistant severe depression remains unexplored. AIMS: To evaluate whether add-on intravenous ketamine eliminates the treatment lag period in severe non-treatment-resistant major depressive disorder and assess rapid antidepressant and anti-suicidal effects. METHODS: A randomized, double-blind, placebo-controlled trial was conducted at a tertiary care hospital from October 2020 to September 2022. Forty patients with severe MDD (HAM-D ≥19) received either ketamine (0.5 mg/kg IV, n = 19) or placebo (n = 21) as add-on therapy over 4 infusions on days 1, 3, 5, and 8. The primary outcome was ≥50% HAM-D reduction at day 12. Secondary outcomes included suicidal ideation using the Beck Scale for Suicidal Ideation (BSSI) and global functioning improvement. RESULTS: Primary response rate was 58% versus 29% in placebo (P < 0.05), yielding a number needed to treat of 3.4. Significant HAM-D improvement occurred from day 2 onwards (P < 0.05). Complete suicidal ideation resolution occurred by day 5 in the ketamine group versus persistent ideation in placebo (P < 0.001). Patients with anxiety features showed 0% treatment completion versus 93% in non-anxious patients. Effects were sustained at 4-week follow-up. CONCLUSIONS: This pilot randomized controlled trial provides preliminary evidence for rapid antidepressant and anti-suicidal effects of add-on intravenous ketamine in severe non-treatment-resistant major depression; findings require confirmation in an adequately powered trial.