Two Randomized Placebo-Controlled Trials to Evaluate the Efficacy and Tolerability of Mirtazapine for the Treatment of Obstructive Sleep Apnea

摘要: OBSTRUCTIVE SLEEP APNEA (OSA) IS A COMMON DISORDER1 THAT HAS BEEN PROSPECTIVELY ASSOCIATED WITH HYPERTENSION AND DEPRESSION in community-based cohorts2,3 and with mortality patient cohorts case-control studies.4–6 Continuous positive airway pressure is the most efficacious treatment for severe OSA.7,8 However, effectiveness limited mild to moderate end of OSA spectrum9 by poor compliance generally. Moreover, other nonpharmacologic methods (e.g., mandibular advancement splints upper surgery) can be unacceptable patients or have questionable efficacy.10,11 As a result, there strong interest development pharmacotherapy OSA, which might better balance efficacy tolerability, particularly certain subsets. Despite many attempts, has been general lack success pharmacotherapy.12,13 Strategies included drugs that putatively alter physiology sleep apnea increasing muscle tone during sleep, respiratory drive, altering architecture (either slow-wave decreasing REM sleep). Most trials these medications shown no benefit benefits clinical importance.11 some clinically relevant effects placebo-controlled studies. For example, 1 study, acetazolamide, weak diuretic carbonic anhydrase inhibitory activity, reduced apnea-hypopnea index (AHI) from about 50 25 events per hour 10 patients.14 as result related side effects, its posttrial use was reported only patient. There also remains potential via weight reduction.15 Recently it daily administration antidepressant mirtazapine, (Remeron US Avanza Australia) at doses 4.5 15 mg week, AHI mean 22 11 placebo-controlled, 3-way, crossover trial.16 This report stated “this represents largest consistent drug-treatment effect demonstrated date controlled trial.” Such data, if confirmed, would hold great promise providing new alternative OSA. easily available drug offer attractive option group established options are effectiveness. Therefore, 2 proof-of-concept were designed assess different higher mirtazapine associated superior risk-benefit profile than previously observed.16 purposes comparison, mg, highest dose tested previous typical starting indication. The goal present studies confirm extend results Study triple-arm, randomized, crossover, dose-finding study (mirtazapine 0, 7.5, 15, 30, 45mg/day) weeks dose. 3-arm parallel-group, 2:2:1, trial compared versus + another compound (CD0012, dopaminergic serotinergic agent undergoing evaluation apnea), placebo 4 weeks. run simultaneously.