Zonisamide reduces obstructive sleep apnea: A randomized placebo-controlled study

Background: Carbonic anhydrase inhibition is associated with reduction of apneic events in sleep disordered breathing. Zonisamide has carbonic anhydrase inhibitory properties, and induces weight loss in obese patients. Our aim was to determine the therapeutic effects of zonisamide in obstructive sleep apnea (OSA). Methods: Forty-seven patients with moderate to severe OSA and a body mass index 27 to 35 kg/m2 were randomized to zonisamide, placebo or continuous positive airway pressure (CPAP) treatment for 4 weeks. In the open extension phase, all participants except those on CPAP received zonisamide for 20 weeks. Polysomnography, biochemistry and symptoms were evaluated. Results: The placebo controlled effect of zonisamide at 4 weeks was a reduction of apnea hypopnea index (AHI) 33±39% and oxygen desaturation index 28±31% (p=0.02 and 0.014, respectively). At 24 weeks the mean reduction of AHI after zonisamide and CPAP (adjusted for compliance) was 14 and 61% (p=0.001 between groups). CPAP but not zonisamide reduced sleepiness. Body weight was marginally changed at 4 weeks but reduced after zonisamide and increased after CPAP at 24 weeks (-2.7±3.0 vs. 2.3±2.0 kg, p<0.001). Zonisamide treatment induc a reduction of bicarbonate at 4 and 24 weeks. Drop-out rate was similar in the zonisamide and CPAP groups. Conclusions: Zonisamide reduced OSA independent of body weight potentially by mechanisms related to carbonic anhydrase inhibition. Added weight loss after long term zonisamide treatment may generate a further therapeutic potential for this class of drugs in OSA. Clinical trials registration: EudraCT; No.: 2009-015859-24; URL: https://eudract.ema.europa.eu/.