Mirtazapine Reduces Susceptibility to Hypocapnic Central Sleep Apnea in Males with Sleep-disordered Breathing: a Pilot Study

Studies in humans and animal models with spinal cord injury (SCI) have demonstrated that medications targeting serotonin receptors may decrease the susceptibility to central sleep-disordered breathing (SDB). We hypothesized that mirtazapine would decrease the propensity to develop hypocapnic central sleep apnea (CSA) during sleep. We performed a single-blind pilot study on a total of 10 men with SDB (7 with chronic SCI and 3 noninjured) aged 52.0 ± 11.2 yr. Participants were randomly assigned to either mirtazapine (15 mg at bedtime) or a placebo for at least 1 wk, followed by a 7-day washout period before crossing over to the other intervention. Split-night studies included polysomnography and induction of hypocapnic CSA using a noninvasive ventilation (NIV) protocol. The primary outcome was CO reserve, defined as the difference between eupneic and end of NIV end-tidal CO ([Formula: see text]) preceding induced hypocapneic CSA. Secondary outcomes included controller gain (CG), other ventilatory parameters, and SDB severity. CG was defined as the ratio of change in minute ventilation (V̇e) between control and hypopnea to the change in CO during sleep. CO reserve was significantly widened on mirtazapine than placebo (-3.8 ± 1.2 vs. -2.0 ± 1.5 mmHg; = 0.015). CG was significantly decreased on mirtazapine compared with placebo [2.2 ± 0.7 vs. 3.5 ± 1.9 L/(mmHg × min); = 0.023]. There were no significant differences for other ventilatory parameters assessed or SDB severity between mirtazapine and placebo trials. These findings suggest that the administration of mirtazapine can decrease the susceptibility to central apnea by reducing chemosensitivity and increasing CO reserve; however, considering the lack of changes in apnea-hypopnea index (AHI), further research is required to understand the significance of this finding. To our knowledge, this research study is novel as it is the first study in humans assessing the effect of mirtazapine on CO reserve and chemosensitivity in individuals with severe sleep-disordered breathing. This is also the first study to determine the potential therapeutic effects of mirtazapine on sleep parameters in individuals with a spinal cord injury.