Effect of Desipramine on Genioglossus Muscle Activity in Healthy Adults Study A (DESOSA)

Obstructive sleep apnea (OSA) is common and has major health implications but treatment options are limited. OSA patients show a marked reduction in upper airway (UA) dilator muscle activity at sleep onset and this phenomenon leads to increased collapsibility of UA compared to normal participants. Until recently, the search for medicines to activate pharyngeal muscles in sleeping humans has been discouraging. However, exciting new animal research has shown that drugs with noradrenergic and antimuscarinic effects can restore pharyngeal muscle activity to waking levels. In this protocol the investigators will test the effect of desipramine (a tricyclic antidepressant with strong noradrenergic and antimuscarinic effects) on genioglossus muscle activity (EMG GG) during sleep in healthy control participants.

Two overnight sleep studies, a placebo night and a drug night, will be performed approximately one week apart in random order. The placebo or drug will be administered 2 hours before lights out. At least 15 minutes of quiet wakefulness will be recorded to quantify the participant's awake EMG GG activity. Participants will then sleep in the lateral position to minimize pharyngeal resistance similar to previous studies of this kind. The same will be done for stable non-rapid eye movement (NREM) and rapid eye movement (REM) sleep (free of arousals and other artifacts). Both NREM and REM sleep will be analyzed, recognizing that REM is less frequent on these drugs. During the second part of the night, the participants will be connected to a modified continuous positive airway pressure (CPAP) machine (Pcrit3000, Respironics) which can provide a wide range of pressures between 20 and -20 cm H2O in order to modify upper airway pressure and measure change in EMG GG as a function of epiglottic pressure (muscle responsiveness).

Desipramine 200 mg administered 2 hours before normal sleep time on first study night, then a 1-week non-treatment period, then placebo-matching desipramine administered 2 hours before normal sleep time on second study night.

Placebo-matching desipramine administered 2 hours before normal sleep time on first study night, then a 1-week non-treatment period, then desipramine administered 2 hours before normal sleep time on second study night.

Genioglossus Activity During Non-rapid Eye Movement (NREM) Sleep Measured as Percent of Wakefulness Activity

Electromyography (EMG) was used to analyze genioglossus (GG) [EMG GG] muscle movement. EMG GG activity was recorded via standard needle electrodes inserted into the genioglossus (tongue) muscle. Activity of EMG GG was measured during wakefulness and sleep as % of maximum activation obtained pushing the tongue against closed teeth during wakefulness (GG%max). Sleep values were then expressed as %wakefulness value for tonic and phasic EMG GG activity. Tonic activity was defined as the lowest EMG GG value during expiration, phasic activity was calculated as the peak value during inspiration minus the tonic value.

Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility

Participants were connected to a modified continuous positive airway pressure (CPAP) machine (Pcrit3000, Respironics) which provided a wide range of pressures between 20 and -20 cm H2O in order to modify upper airway pressure. Following a baseline recording period of 5 minutes, the CPAP level was reduced to varying suboptimal pressures. Change in Pcrit was used to determine the collapsibility of the upper airway under both passive and active conditions, and is expressed as Passive Pcrit: ventilation at a nasal pressure of 0 cm H2O when pharyngeal muscles are passive; Active Pcrit: ventilation at a nasal pressure of 0 cm H2O when pharyngeal muscles are active. Improved=more negative Pcrit.

Inclusion Criteria: Healthy control subjects Exclusion Criteria: Cardiovascular disease other than well controlled hypertension Depression

Taranto-Montemurro L, Edwards BA, Sands SA, Marques M, Eckert DJ, White DP, Wellman A. Desipramine Increases Genioglossus Activity and Reduces Upper Airway Collapsibility during Non-REM Sleep in Healthy Subjects. Am J Respir Crit Care Med. 2016 Oct 1;194(7):878-885. doi: 10.1164/rccm.201511-2172OC.