Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation

Abstract

We recently demonstrated that desipramine reduces the sleep-related loss of upper airway dilator muscle activity and reduces pharyngeal collapsibility in healthy humans without obstructive sleep apnoea (OSA). The aim of the present physiological study was to determine the effects of desipramine on upper airway collapsibility and apnoea–hypopnea index (AHI) in OSA patients. A placebo-controlled, double-blind, randomised crossover trial in 14 OSA patients was performed. Participants received treatment or placebo in randomised order before sleep. Pharyngeal collapsibility (critical collapsing pressure of the upper airway (Pcrit)) and ventilation under both passive (V′0,passive) and active (V′0,active) upper airway muscle conditions were evaluated with continuous positive airway pressure (CPAP) manipulation. AHI was quantified off CPAP. Desipramine reduced active Pcrit (median (interquartile range) −5.2 (4.3) cmH2O on desipramine versus −1.9 (2.7) cmH2O on placebo; p=0.049) but not passive Pcrit (−2.2 (3.4) versus −0.7 (2.1) cmH2O; p=0.135). A greater reduction in AHI occurred in those with minimal muscle compensation (defined as V′0,active−V′0, passive) on placebo (r=0.71, p=0.009). The reduction in AHI was driven by the improvement in muscle compensation (r=0.72, p=0.009). In OSA patients, noradrenergic stimulation with desipramine improves pharyngeal collapsibility and may be an effective treatment in patients with minimal upper airway muscle compensation.

Personalised medicine in sleep respiratory disorders: focus on obstructive sleep apnoea diagnosis and treatment

“…As the role of non-anatomical factors becomes more important than upper airway anatomy, one or more interventions for each physiological impairment can be chosen in order to target treatment to improve upper airway muscle function, i.e. upper airway muscle stimulation [75,76], drugs [77], reduction of loop gain using acetazolamide [78] or increase of the arousal threshold using hypnotics [79][80][81][82][83]. While interested readers are referred to extensive reviews on this topic [42,84,85], some critical points need to be highlighted.…”

Neural memory of the genioglossus muscle during sleep is stage‐dependent in healthy subjects and obstructive sleep apnoea patients

“…Epiglottic pressure was determined with a small, flexible pressure‐tipped catheter (Millar Instruments, Houston, TX, USA) as described previously (Taranto‐Montemurro et al . )…”

A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

“…This approach is necessary for this review because previous attempts at OSA pharmacotherapy have largely been ineffective (for reviews see 33–38 ) and in many ways this has been predictable based on the targets chosen, and because the trials were comprised of un-phenotyped OSA patients, only a subset of which would be expected to benefit even if the pharmacological target was rational and effectively manipulated (discussed in Section 3.2). More recent clinical studies, however, using agents targeting the significant mechanisms of state-dependent pharyngeal muscle control identified from basic science experiments 39–42 , have proved beneficial when administered to phenotyped patients 43, 44 , with other studies ongoing 45–47 .…”

“…Nevertheless, the number and selectivity of drugs associated with a given target is useful information, not least because it can be taken as an indicator of the relative druggability of that target. Moreover, initial studies have shown that desipramine has beneficial effects on genioglossus muscle tone, upper airway collapsibility and OSA severity 43, 44 . Desipramine is a tricyclic anti-depressant with strong noradrenergic and some anti-muscarinic effects.…”