Mirtazapine reduces susceptibility to hypocapnic central sleep apnea in males with sleep-disordered breathing: a pilot study

Abstract

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 CO₂ reserve, defined as the difference between eupneic and end of NIV end-tidal CO₂ ([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 CO₂ during sleep. CO₂ reserve was significantly widened on mirtazapine than placebo (-3.8 ± 1.2 vs. -2.0 ± 1.5 mmHg; P = 0.015). CG was significantly decreased on mirtazapine compared with placebo [2.2 ± 0.7 vs. 3.5 ± 1.9 L/(mmHg × min); P = 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 CO₂ reserve; however, considering the lack of changes in apnea-hypopnea index (AHI), further research is required to understand the significance of this finding.NEW & NOTEWORTHY To our knowledge, this research study is novel as it is the first study in humans assessing the effect of mirtazapine on CO₂ 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.

Keywords: CO2 reserve; central sleep apnea; mirtazapine; sleep disordered-breathing; spinal cord injury.

Figure 1.

CONSORT flow diagram displaying the progress of all participants through each phase of the trial.

Figure 2.

Representative polygraphs from the NIV protocol depicting the difference in CO₂ reserve in an SCI subject between the placebo (A) and mirtazapine (B) arms. Eupneic PET_CO2 is represented by the upper dashed line of the bracket, and the AT PET_CO2 is represented by the lower dashed line of the bracket. The breaths used to calculate these values are denoted with asterisks. The CO₂ reserve was wider in the mirtazapine arm than the placebo arm. AT PET_CO2, end-tidal CO₂ partial pressure at apneic threshold; NIV, noninvasive ventilation; Pmask, mask pressure; SCI, spinal cord injury.

Figure 3.

Effect of mirtazapine on CO₂ reserve (n = 10) (A), PET_CO2 at apneic threshold (n = 9) (B), controller gain (n = 8) (C), and plant gain (n = 10) (D). *P < 0.05 vs. placebo using paired t test, presented as means ± SD. Solid symbols denote participants with cervical SCI, hollow symbols denote participants with thoracic SCI, x-marked symbols denote able-bodied participants. AT PET_CO2, end-tidal CO₂ partial pressure at apneic threshold; SCI, spinal cord injury.