Schmickl CN, Li Y, Orr JE, et al. - In this mechanistic, randomized, double-blind, placebo-controlled crossover trial, experts aspired to explore whether venlafaxine, a serotonin-norepinephrine reuptake inhibitor, would improve obstructive sleep apnea (OSA) severity. For this investigation, 20 OSA patients had two overnight polysomnograms ≥ 4 days apart receiving either 50 mg immediate-release venlafaxine or placebo before bedtime. There was no major difference overall with respect to apnea hypopnea index or SpO₂ nadir between venlafaxine vs placebo. Venlafaxine simultaneously worsened and improved different pathophysiological traits in unselected patients, resulting in a nil net-effect. A more robust response can be generated by careful patient selection based on pathophysiological traits or combination therapy with drugs that mitigate its warning effects.