Effect of Desipramine on Upper Airway Collapsibility and Genioglossus Muscle Activity in Patients With Obstructive Sleep Apnea - Study B

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 EMG GG activity while awake and at sleep onset (alpha-theta transition at the electroencephalogram).

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 cmH2O in order to modify upper airway pressure and measure pharyngeal critical collapsing pressure (Pcrit), ventilation at 0 cmH2O when UA muscle are passive and active as well as change in EMG GG as a function of epiglottic pressure (muscle responsiveness).

Apnea-hypopnea index (AHI) will be calculated in each night from the part of the study off CPAP.

• Desipramine (Drug), also known as Norpramine: 200 mg administered 2 hours before normal sleep time
• Placebo (Drug): Placebo-matching desipramine administered 2 hours before normal sleep time

Primary outcomes

• Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility [1 night]: 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.

Secondary outcomes

• Genioglossus Muscle Responsiveness to Progressively Greater Epiglottic Pressure Swings [1 night]: Electromyography (EMG) was used to analyze genioglossus (GG) \[EMG GG\] muscle activity. EMG GG activity was recorded via standard needle electrodes inserted into the genioglossus muscle (tongue). 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). 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 and measure change in EMG GG as a function of epiglottic pressure (muscle responsiveness) (%max/cmH2O).
• Number of Apnoea-Hypopnea Index (AHI) Events During Non-Random Eye Movement (NREM) Sleep [1 night]: The AHI is the number of apneas (pauses in breathing) or hypopneas (shallow breathing) recorded during the study per hour of sleep. Data for the calculation of the AHI was collected while the participant was in NREM sleep in the supine position and off CPAP (breathing spontaneously).

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* Diagnosed OSA (moderate-to-severe; apnea hypopnea index >15 events/hr)

Exclusion Criteria:

* Cardiovascular disease other than well controlled hypertension
* Depression

Participant flow

Outcome results

• Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility (Primary), Median, cm H2O: Desipramine -5.2 (-7 to -2.8); Placebo -1.9 (-3.3 to -0.7) (p 0.049)
• Genioglossus Muscle Responsiveness to Progressively Greater Epiglottic Pressure Swings (Secondary), Median, %max/cmH2O: Desipramine -0.24 (-0.5 to -0.2); Placebo -0.25 (-0.4 to -0.1)
• Number of Apnoea-Hypopnea Index (AHI) Events During Non-Random Eye Movement (NREM) Sleep (Secondary), Median, events per hour: Desipramine 34.3 (14.7 to 62); Placebo 42.0 (20.5 to 53.3)

Adverse events

Other adverse events by term

• Andrew Wellman, MD PhD, Principal investigator, Brigham and Women's Hospital