The combination of pimavanserin and atomoxetine reduces obstructive sleep apnea severity: a randomized crossover trial

The combination of pimavanserin and atomoxetine reduces obstructive sleep apnea severity: a randomized crossover trial | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search The combination of pimavanserin and atomoxetine reduces obstructive sleep apnea severity: a randomized crossover trial Ludovico Messineo , Madison Preuss , Ali Azarbarzin , Daniel Vena , Laura Gell , Atqiya Aishah , Neda Esmaeili , Molly Kim , Isabel Burdick , Tom Chen , David White , Scott A Sands , Andrew Wellman doi: https://doi.org/10.1101/2025.01.15.25320565 Ludovico Messineo 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: ludovico.messineo{at}yahoo.it Madison Preuss 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ali Azarbarzin 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel Vena 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Laura Gell 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Atqiya Aishah 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Neda Esmaeili 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Molly Kim 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Isabel Burdick 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tom Chen 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site David White 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Scott A Sands 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrew Wellman 1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women’s Hospital & Harvard Medical School , Boston, Massachusetts Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Data/Code Preview PDF ABSTRACT Background Obstructive sleep apnea (OSA) pharmacological interventions like the noradrenergic muscle stimulant atomoxetine have wake-promoting properties. Pimavanserin, a promising serotonin 2 A receptor antagonist, may help counteract atomoxetine’s noradrenergic effects by increasing arousal threshold and possibly reduce OSA severity. Research question In a randomized, crossover, two-period, double-blind clinical trial, we tested the effect of this drug combination on apnea-hypopnea index (AHI; primary outcome), arousal index and nadir oxygen saturation (SpO 2 ; secondary outcomes). Study design and methods Following baseline polysomnography , 18 OSA participants (AHI>15events/h) took pimavanserin-plus-atomoxetine (34/80mg; 34/40mg for the first 3 days) or placebo for one-week; follow-up polysomnography was performed to provide study outcomes. Safety outcomes, subjective sleep quality, and flow-estimated endotypes (using oronasal pneumotachograph flow) were also explored. Results Eleven and seven participants were randomized to atomoxetine-plus-pimavanserin and placebo first, respectively. The combination reduced AHI by 42 [95%CI: 18, 60] % vs. placebo, meeting the primary outcome (P<0.001). Absolute AHI reduction was 16.9 [8.1, 23.6] events/h greater than placebo. Nadir SpO 2 and arousal index were also improved, by 5.0 [1, 8] % and 10.9 [2.4, 18.1] events/h vs. placebo. Overnight heart rate was increased (+4.8 [1.5, 8.1]), but no other change in subjective sleep quality or next-morning vital signs was evident. There was no increased risk for side effects on the combination vs. placebo. Treatment vs. placebo improved pharyngeal collapsibility (+7.9 [1.6, 14.1]%V EUPNEA ), reduced loop gain by 20% (0.15 [-0.23, -0.07]), and did not reduce the arousal threshold. Interpretation Pimavanserin with atomoxetine is a strong pharmacological therapy candidate for OSA. The advent of pharmacotherapy for obstructive sleep apnea (OSA) represents an important breakthrough in clinical practice, with promising developments on the horizon. Since the landmark discovery in 2018 of a drug combination that could reduce OSA severity 1 , substantial progress has been made, including a number of positive preliminary trials testing different combinations of a noradrenergic and an anti-muscarinic 2 – 6 , and a large phase II trial on atomoxetine and aroxybutynin, which showed a post-intervention apnea hypopnea index (AHI) reduction of about 50% at 4 weeks 7 . In the original rationale for combining a noradrenergic agent with an antimuscarinic, we considered preclinical work demonstrating an important role of active muscarinic inhibition of the hypoglossal motor pool 1 , 8 . In available human studies, however, data suggest that antimuscarinics primarily minimize the wake-promoting effects of atomoxetine 9 , 10 . For example, atomoxetine was observed to lower the respiratory arousal threshold, but the combination with oxybutynin protected against this reduction and facilitated increased greater muscle compensation 10 . Similarly, in the MARIPOSA study, atomoxetine reduced total sleep time, yet the atomoxetine-oxybutynin did not, findings which were consistent with changes in PROMIS scores 7 . Taken together, available data indicates that there is an opportunity for the use of a hypnotic with atomoxetine in the continued search for effective OSA pharmacotherapies. Pimavanserin is an antagonist of serotonin 5HT 2A receptors which—in contrast to benzodiazepines and z-drugs 11 , 12 —has been shown to selectively suppress CO 2 -mediated arousals 13 . Pimavanserin is FDA-approved for hallucinations associated with Parkinson’s disease psychosis. In OSA, pimavanserin could possibly block the respiratory-related arousals and leave the upper airway response to CO 2 intact, which could lead to reinstatement of airway patency. In a previous randomized, controlled trial, we tested the administration of pimavanserin for one night on 18 OSA participants 14 . Although the drug did not decrease arousability per se, it increased total sleep time by 40 minutes and had a safe profile, i.e., no adverse events were reported and vital signs with vs. without the intervention did not change. In addition, OSA severity decreased in those individuals whose arousal threshold was raised by the treatment, suggesting that pimavanserin might need longer administration times to be effective for everyone. Through its specific and selective mechanism of action, pimavanserin might be a potent hypnotic that, in combination with atomoxetine, could perhaps efficaciously alleviate atomoxetine’s wake-promoting side effects and be well tolerated, while atomoxetine improves upper airway patency. Based on this study, we sought to test the efficacy of pimavanserin administered over a longer period of time (one week) with atomoxetine (Ato-pima) to simultaneously stimulate the pharyngeal muscles. OSA severity (per AHI) was the primary outcome of this randomized, double-blind, controlled, crossover study. On the basis that pimavanserin could strengthen sleep continuity, while atomoxetine provides increased pharyngeal muscle activity, we also assessed the effect of the combination on arousal index and nadir oxygen saturation as secondary outcomes. Safety outcomes (blood pressure, heart rate, adverse events and drop-out rate) were also assessed. In exploratory analyses, we evaluated the effect of the Ato-pima on other objective measures of sleep quality, OSA endotypes, and predictors of treatment response. STUDY DESIGN AND METHODS Participants Participants aged 21 to 70 with an in-lab diagnosis of moderate-to-severe OSA (AHI≥15 events/h) were recruited. Individuals were excluded if they had any major organ system disease or unstable medical condition, other types of sleep-disordered breathing or respiratory disease, or if they were using medications that could affect breathing (such as opioids or acetazolamide). Other exclusion criteria included pregnancy, the use of serotonin/norepinephrine reuptake inhibitors, a long QT interval (>440 milliseconds) or medications that lengthen it, hypokalemia, hypomagnesemia, or severe claustrophobia. Protocol During a screening visit, medications and comorbidities were reviewed, and an electrocardiogram (EKG) to measure the QTc interval and blood tests to assess magnesium and potassium levels were conducted. Following this, participants underwent a baseline, in-laboratory PSG to assess OSA severity. Those eligible continued with a week-long administration of either pimavanserin 34 mg plus atomoxetine, or placebo, with a one month washout in between, according to a randomized, double-blind, crossover, two-period design (figure 1). The pimavanserin dosage was selected as it is the FDA-approved dose for clinical use, with a well-studied pharmacokinetic profile. The administration of atomoxetine included a 3-day run-in at 40 mg, followed by 4 days at 80 mg. The length of the washout period was dictated by the extended half-life of pimavanserin’s active metabolites, while the week-long drug administration ensured that adequate plasma concentrations of pimavanserin could be reached 15 . Pimavanserin and atomoxetine were taken 4 hours and 30 minutes before bedtime. At the end of each treatment period, participants repeated in-laboratory PSGs. For all PSGs, alongside standard polysomnography equipment, patients were provided with an oronasal mask attached to a pneumotachograph (Hans-Rudolph, Kansas City, MO, USA). A pill count was performed at the end of each treatment period to assess adherence. Epworth Sleepiness Scale was assessed before each study night, and a visual analog scale for sleep quality was administered in the morning after each overnight study. Potential side effects (e.g., confusion, nausea, etc.) were also investigated in the morning after each overnight visit. Vital signs (i.e., blood pressure and heart rate) were measured in triplicate before and after (30 minutes after awakening) each overnight study. Study medications were prepared by [removed] and were placed in identical capsules that could not be identified by study personnel or participants. Randomization of the order of active treatment versus placebo was performed by [removed] using a pseudorandom number generator with two randomly permuted blocks of two. Outcome definitions Full details of data analysis are included in the Online Supplement. All analyses were conducted in a blind fashion with respect to the study interventions. The overnight heart rate was averaged from all the sleep periods for each individual. Since atomoxetine and pimavanserin can both potentially prolong the QT interval, the overnight corrected QT interval (QTc) was calculated in all patients. OSA endotypes were also calculated from PSGs using calibrated ventilation (i.e., from the pneumotach) and estimated ventilatory drive (i.e., predicted from prior swings in ventilation) 16 , 17 . Statistical analysis The primary outcome was the reduction of AHI from baseline with Ato-pima vs. placebo. Secondary outcomes were the effect of the combination on arousal index and nadir oxygen saturation, assessed hierarchically against placebo. Exploratory outcomes included the effect of the intervention on OSA endotypes vs. placebo. As supported by prior research 1 , a sample size of 18 patients was determined to provide over 99% power to detect a clinically significant 50% reduction in AHI between treatments, assuming an SD of 19% and 𝛼 = 0.05 significance level. This sample size also ensured 80% power to detect a 5% absolute change in nadir oxygen saturation (SD of ∼6%, 𝛼 = 0.05) and 89% power to detect a 20% change in arousal index (SD of 21%, 𝛼 = 0.05). For the analyses of the endotypes, a physiologically meaningful change (e.g., high vs. low loop gain) of approximately 20% with an SD of 15% was assumed, giving 81% power to detect such a difference at the 𝛼 = 0.05 significance level. Analysis of primary and secondary outcomes The effect of Ato-pima vs. placebo on AHI, arousal index and nadir oxygen saturation were assessed using linear mixed effects models. These models included subject as a random effect adjusted for treatment period, sequence (AB versus BA), and lateral sleeping position (proportion of sleep spent lateral) as fixed effects. The primary analysis quantified the effect on AHI both in terms of percent reduction from baseline and absolute values. The intention-to-treat approach was used for the analysis, although all participants completed both treatment periods, ensuring no deviations from this approach. Sensitivity analyses re-examined treatment efficacy using AHI 4 , AHI during rapid eye movements (REM) or non REM (NREM) sleep. All AHI, ODI and arousal index data were square root transformed to meet model assumptions and back-transformed for presentation. Normality of model residuals was verified using the Shapiro-Wilk test. Analysis of safety outcomes A similar approach as above was used to quantify the effect of Ato-pima vs. placebo on blood pressure, heart rate, ESS, VAS and overnight QTc. Logistic mixed model analysis assessed the odds of key side effects on Ato-pima vs. placebo (e.g., insomnia, etc). Exploratory analyses Additional sleep parameters, such as hypoxic burden, oxygen desaturation index (ODI), total sleep time, sleep architecture, sleep efficiency, arousal intensity, arousal burden (i.e., the product of arousal intensity and arousal index), wake after sleep onset (WASO), and the endotypes were compared between Ato-pima and placebo using the same mixed-effects modeling approach described previously. Hypoxic burden and arousal burden were log-transformed and back-transformed for presentation. Given the exploratory nature of these analyses, adjustments for multiple comparisons were not conducted, as the primary purpose is to inform future research directions. To evaluate potential determinants of treatment response, endotypes recorded at baseline were modeled as independent variables (after adjustment for baseline AHI and baseline loop gain) and the AHI percent reduction from placebo as response variable. The effect of the drug combination on AHI was ultimately tested on two subgroups of participants: 1) those with a low baseline arousal threshold (≤166.25%V EUPNEA ) 18 , and 2) those who had an increase in arousal threshold of at least 10% on Ato-Pima vs. placebo. Analyses were performed using Matlab (Mathwork, Natick, MA) and Graph Pad Prism 6.0 (Graph Pad Software, La Jolla, CA). For all analyses, significance was accepted if P<0.05. RESULTS Thirty-two people were enrolled and completed the baseline visit and PSG, from June 2022 to April 2024. Of these, four withdrew for personal reasons, one began a medication listed in the exclusion criteria after the baseline visit, and three were lost to follow-up. In addition, six had mild OSA at the baseline PSG (i.e., AHI<15 events/h) and were excluded from the study. The trial ended because the target population successfully completed both periods (plus wash-out time) of the study. The baseline characteristics of the eighteen participants who were randomized and completed the study are shown in table 1 . Adherence to study medications was overall good, with only one participant being partly compliant to treatment: this participant did not take pimavanserin for one night and missed atomoxetine for four nights during the active treatment period. However, Ato-pima still appeared to be effective in this patient (AHI, arousal index, and nadir saturation changed from 24.5 events/h, 28.4 events/h, and 74% to 9.2 events/h, 18.4 events/h and 84%, respectively). View this table: View inline View popup Download powerpoint Table 1. Baseline characteristics and medications by sequence and by total. Effect of Ato-pima on primary and secondary outcomes PSG data are reported in Table 2 . Ato-pima reduced OSA severity by 42% compared to placebo (mean difference [95%CI]: 16.9 [8.1, 23.6] events/h, P<0.001). In sensitivity analysis, AHI 4 was also reduced (37% from placebo). Individual data are presented in Figure 2. The effect of the treatment arm was not influenced by a reduced REM duration, as both NREM and REM AHI fell with Ato-pima, with the size of the reduction of NREM AHI being greater than REM AHI. In 44% of the participants there was a 50% reduction in AHI from placebo and a treatment AHI of under 15 events/hr. View this table: View inline View popup Table 2. OSA parameters – primary and secondary outcomes, and exploratory comparisons. Ato-pima reduced the arousal index by 26% and increased the nadir oxygen saturation compared to placebo. These individual data are also illustrated in Figure 2. Notably, the arousal index was also reduced by a similar amount in NREM (−10.8 [−18.5, −2.1]) and REM sleep (−12.2 [−24.6, 4.0]). Safety of Ato-pima Ato-pima was well tolerated, with only one instance of a severe complaint (i.e., nausea). All investigated side effects are shown in Table 3 . Overall, Ato-pima did not significantly increase the odds of any reported side effect (Figure 3). View this table: View inline View popup Download powerpoint Table 3. Investigated side effects. Although there was no change in evening or next-morning blood pressure and heart rate between treatment nights, overnight heart rate increased on Ato-Pima (+ 4.8 bpm; Table 4 ). QTc was unchanged on Ato-pima vs. placebo (mean difference [95%CI] = −3.3 [−12.8, 6] ms). View this table: View inline View popup Download powerpoint Table 4. Safety parameters. Effect of Ato-pima on additional sleep parameters and OSA endotypes In comparison to placebo, Ato-pima improved overnight oxygen saturation, hypoxic burden, and the following objective measures of sleep quality: arousal burden, arousal intensity, and sleep efficiency. N2 duration was increased, along with a reduction in WASO ( Table 2 ). For the endotypes, ato-pima reduced loop gain and collapsibility (increasing V PASSIVE and V MIN ; Table 5 , Figure 4), and it did not lower the arousal threshold. We also found that individuals with less-severe collapsibility (greater V PASSIVE ) at baseline experienced a more favorable AHI reduction on Ato-pima compared to placebo (additional 25.0 [−11.5, 48.7] % for each 1SD increase in V PASSIVE ). The effect size of AHI reduction in participants with low baseline arousal threshold (N=14) was similar to that of the whole group (42%). Only 3 participants had an arousal threshold increase of at least 10%, and 1 had a 20% increase on ato-pima.. View this table: View inline View popup Download powerpoint Table 5. OSA endotypes. DISCUSSION This study shows that a combination of pimavanserin and atomoxetine significantly reduced OSA severity compared to placebo, and it also decreased overnight arousability and hypoxemia, thus meeting the pre-established primary and secondary outcomes. In addition, Ato-pima was well tolerated. Importantly, there was no prolongation of the QT interval, but there was a 4.8 bpm increase in overnight heart rate. Mechanistically, Ato-pima significantly improved OSA endotypes via reductions in estimates of pharyngeal collapsibility and ventilatory control instability, without a reduction in arousal threshold. Overall, pimavanserin appears to be a strong candidate to accompany noradrenergic stimulation of pharyngeal muscles in OSA pharmacotherapy. Clinical implications Although the effect of Ato-pima on the AHI was substantial, a similar result was observed with other drug combinations employing a noradrenergic and an anti-muscarinic 1 , 4 , 7 , 9 . However, here, atomoxetine was combined with pimavanserin, a drug with clear hypnotic properties which, in previous studies, was able to selectively suppress CO 2 -mediated arousals 13 , 14 . Investigators have often refrained from using hypnotics in OSA combination therapies due to their potential deleterious effect on next-day alertness and/or adverse patient-reported outcomes 11 , 19 . However, common hypnotics previously used in OSA are mainly GABAergic, with an overall inhibitory effect on brain functions (e.g., alertness, ventilatory response to arousals). This is the first study demonstrating that atomoxetine and a selective serotonergic hypnotic can achieve a dual effect on OSA, namely reduced OSA severity and improved sleep consolidation (i.e., reductions in arousal index, WASO, borderline increments in sleep efficiency and N2). In particular, the effect on arousal intensity and arousal burden was noteworthy. To date, no OSA pharmacotherapy, including hypnotics 11 , 20 , has been demonstrated to decrease arousal intensity, which may contribute to OSA severity 21 , increase sympathetic tone 22 , and is a potential marker of incident dementia 23 . Ato-Pima is also the first pharmacological treatment shown to decrease arousal burden (34% reduction), another predictor of future cardiovascular death 24 . In addition, the increase in sleep efficiency on the treatment night, though borderline significant, was clinically meaningful: on Ato-pima, sleep efficiency approached the average levels observed in a lab-setting (i.e., 78.8% 25 vs. 76.8% on this study’s treatment arm) and the average increase seen on a hypnotic (i.e., 9% 20 ). Taken together, these findings suggest that the hypnotic effects of pimavanserin can complement the effect of atomoxetine on upper airway physiology, i.e., preventing arousals, but without shutting down brain responses to respiratory stimuli. This may prove particularly useful in patients who are sensitive to the noradrenergic effects of atomoxetine, who have daytime sleepiness (due to fragmented sleep or comorbid insomnia) or are intolerant to the anti-muscarinic effects of oxybutynin. These populations might be the target of future studies. Importantly, no effect of the combination on ESS was recorded: although we do not have an explanation for why an improvement in objective sleep quality did not translate into observable better patient outcomes, we note that ESS has substantial test–retest variability 26 , especially, we argue, when testing during acute drug administration. When atomoxetine was combined with other agents with hypnotic activity in previous studies (i.e., trazodone, dronabinol), the effect on OSA severity was modest 27 and only evaluated in selected populations 28 , while objective sleep quality did not improve 28 or worsened 27 . In comparison to some 1 , 7 , but not all 9 , studies in which atomoxetine was combined with an antimuscarinic, the arousal index and WASO improved in the current study. Other noradrenergic-plus-antimuscarinic combinations, such as atomoxetine-fesoterodine and reboxetine-oxybutynin, have caused deterioration in sleep quality 3 , 4 . Likewise, Ato-pima, in contrast to other studies 1 , 5 , 7 , was not associated with noradrenergic-related side effects, including insomnia (Figure 3), suggesting that pimavanserin might also mitigate some of atomoxetine’s noradrenergic stimulation. However, Ato-pima did increase overnight heart rate by 4.8 bpm vs. placebo. Ato-pima’s impact on heart rate was similar to that observed in the MARIPOSA trial, which reported a 5.1 bpm increase with atomoxetine-aroxybutynin (75-2.5 mg). This effect largely appears of limited clinical relevance in potential long term usage, especially in the context of other drugs with tachycardic effect—and which are responsible for increases in heart rate from 5 to up to 30 bpm 29 – 31 —that are highly prescribed, also in populations with high cardiovascular risk. Physiological observations Similar to previous findings 3 , 9 , 10 , Ato-pima decreased upper airway collapsibility (through increments in V PASSIVE and V ACTIVE ) and had a stabilizing effect on breathing, i.e., loop gain was reduced by ⁓20%, a more robust result than elsewhere. Importantly, Ato-pima did not reduce the arousal threshold compared to placebo, which is considerable given that many other pharmacotherapies involving a noradrenergic yielded a reduction in this endotype 3 , 4 , 9 , 10 . The absence of a decrease in arousal threshold is particularly notable given that arousal threshold commonly falls with adaptation to a lower AHI (even with CPAP) 32 . The expectation that simultaneous administration of atomoxetine would decrease the arousal threshold supports this notion. This also aligns with the findings of improved objective sleep quality on Ato-pima. Of note, the participants with low arousal threshold at baseline whom one might expect to have a larger drop in AHI after the administration of hypnotics 33 had a similar AHI change to the overall group. There are a number of possible explanations, including an hypnotic-related increase in the arousal threshold with pimavanserin that was too small, methodological errors in quantifying the arousal threshold, or that OSA severity improvements may occur beyond modifications in arousal threshold 33 . For example, we calculate the arousal threshold only from the actual arousals, while not accounting the magnitude of arousal threshold “hidden” in periods of stable sleep (which could be much higher), thus overall skewing the results towards lower values. The absence of an effect of the combination on arousal threshold, which is a metric of sensitivity to respiratory stimuli, does not detract from the finding that Ato-pima reduced the frequency and the intensity of arousals, which can be the expression of reduced sympathetic traffic 22 . A higher V PASSIVE at baseline was predictive of better AHI reductions from placebo. Although apparently counter-intuitive, as one might expect that people with the most abnormal traits would be more sensitive to targeted treatments, this is in line with recent literature. Indeed, responders seem to be more often those with less severe anatomical deficits 3 , 9 , 34 . Methodological considerations This study has several limitations. First, both atomoxetine and pimavanserin can raise QT. Although we rigorously measured QTc at the time where the drugs have their maximum plasma concentration and found no difference between study nights, the study was not powered to detect differences in QTc. More focused studies will be needed to assess the actual risk of this combination on arrhythmogenesis. These will also be essential to confirm the effect of Ato-pima on exploratory variables such as sleep efficiency, arousal intensity and N2 time. Second, pimavanserin has long-lasting metabolites, which could limit feasibility of administration and be a potential concern for long term use should accumulation occur, with consequent increased risk of side effects. We note that pimavanserin is already on the market for long term use, however longer trials are warranted to evaluate any accumulation potential in OSA patients. Third, both drugs are metabolized by cytochrome P450 isoenzyme 2D6. Approximately seven percent of individuals have little activity of this cytochrome (varies with ancestry) and are therefore exposed to more side effects from the drugs 35 , 36 . However, pimavanserin is metabolized by other cytochromes and, in our study, the two drugs did not cause side effects of concern. Again, administration over longer periods in larger populations would address this concern. Fourth, we did not study atomoxetine and pimavanserin alone in separate arms to understand the physiological features of each drug, e.g., the role of pimavanserin in potentially decreasing arousability. However, the wake-promoting effect of atomoxetine alone has already been established in previous trials 7 , 37 , making the role of pimavanserin in improving sleep quality highly plausible in this context. Fifth, the endotypes were estimated and not directly measured, yet we employed calibrated means (i.e., pneumotachograph) to obtain a gold standard flow signal to maximize reliability. We note that, although reproducibility of endotypes from PSG is overall good 38 , 39 , some degree of instability, especially in some individuals, has been observed 40 , thus an effect of night-to-night variability on our observed outcomes cannot be completely ruled out. INTERPRETATION The combination of atomoxetine and pimavanserin significantly reduced OSA severity while simultaneously decreasing arousal index and overnight hypoxemia. Compared to placebo, Ato-pima did not increase the risk of many of the adverse effects observed with similar drug combinations tested in previous trials (e.g., insomnia, headache, perceived tachycardia), with the exception of a mild increment in heart rate. Reductions in pharyngeal collapsibility and loop gain were also observed, and there was no decrease in arousal threshold. Overall, pimavanserin appears to be an excellent candidate to pair with atomoxetine to treat OSA and warrants longer and larger trials. Data Availability All data produced in the present study are available upon reasonable request to the authors FIGURES Figure 1. CONSORT diagram. AHI, apnea-hypopnea index. Figure 2. Effect of atomoxetine and pimavanserin (Ato-pima) on primary (AHI) and secondary (arousal index, SpO 2 nadir) outcomes vs. placebo. The combination significantly decreased AHI and arousal index, while increasing SpO 2 nadir. AHI, apnea hypopnea index; SpO 2 , oxygen saturation. Bars illustrate mean ± SD for descriptive purposes. Figure 3. Odds of more common side effects on Ato-pima compared to placebo. Note that due to the low incidence of potential relevant side effects (i.e., insomnia), similar symptoms have been grouped together to evaluate the impact of the combination on specific domains of side effects. For example, the wake-promoting domain includes symptoms such as restlessness and insomnia, while the gastrointestinal domain encompasses nausea, diarrhea, indigestion, and abdominal pain. Bars are odds ratio [95%CI]. Figure 4. Endogram of placebo (blue) vs. atomoxetine-plus-pimavanserin (Ato-pima; red) nights illustrating breath-by-breath values of ventilation at different levels of estimated ventilatory drive (means). The purple solid dots illustrate ventilation at eupneic drive (i.e., V PASSIVE , higher values reflect reduced collapsibility). The red solid dots represent ventilation at maximal (or pre-arousal) drive (i.e., V ACTIVE ). V MIN is ventilation at the lowest deciles of drive. Ventilation and drive data are expressed as a percentage of eupneic ventilation during non-REM. Shading is 95%CI. Footnotes Author contributions: Study design: LM, AW. Data collection: LM, MP, MK, IB. Data analysis: LM. Interpretation of results: All authors. Initial draft: LM. Review of the manuscript for important intellectual content: All authors. All authors have seen and approved the manuscript Institutional review board : The study received approval from the Mass General Brigham Human Research Protection Program (2020P002760-2) and was prospectively registered on clinicaltrials.gov ( NCT05350215 ). All participants provided written informed consent prior to enrolment. The research was conducted at the Center for Clinical Investigation at Brigham and Women’s Hospital in accordance with the Declaration of Helsinki. Financial support: NHLBI P01 149630. Conflicts of interest : LM received grant support from Apnimed, Inc. and ProSomnus. AA receives grant support from Somnifix and serves as a consultant for Somnifix, Inspire, and Apnimed; SS receives personal fees as a consultant for Nox Medical, Apnimed, Merck, and Inspire outside the submitted work, and he has received grant support from Apnimed, Prosomnus, and Dynaflex; SS received grant support from Apnimed, Prosomnus, and Dynaflex, and has served as a consultant for Apnimed, Nox Medical, Inspire Medical Systems, Eli Lilly, Respicardia, LinguaFlex, and Forepont. He receives royalties for intellectual property pertaining to combination pharmacotherapy for sleep apnea via his Institution. He is also co-inventor of intellectual property pertaining to wearable sleep apnea phenotyping, also via his Institution. His industry interactions are actively managed by his Institution; AW works as a consultant for Apnimed, Nox, Inspire, Mosanna, and Takeda. He has received grants from Prosomnus. He also has a financial interest in Apnimed Corp., a company developing pharmacologic therapies and wearable oximetry devices for sleep apnea. Dr. Wellman’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. LG contributed to the current study under her ongoing academic role at the Brigham and Women’s Hospital, but her primary employment is currently as a consultant for Apnimed. DPW is a consultant for Apnimed, Philips-Respironics, Cryosa, Xtrodes, Cerebra Health, Bairitone, Mosanna, Onera, SleepRes and LinguaFlex. DV, AA, NE, MK, IB and TC have no conflicts of interest. ABBREVIATION LIST 5HT 2A 5-hydroxytryptamine receptor, type 2A. 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Share The combination of pimavanserin and atomoxetine reduces obstructive sleep apnea severity: a randomized crossover trial Ludovico Messineo , Madison Preuss , Ali Azarbarzin , Daniel Vena , Laura Gell , Atqiya Aishah , Neda Esmaeili , Molly Kim , Isabel Burdick , Tom Chen , David White , Scott A Sands , Andrew Wellman medRxiv 2025.01.15.25320565; doi: https://doi.org/10.1101/2025.01.15.25320565 Share This Article: Copy Citation Tools The combination of pimavanserin and atomoxetine reduces obstructive sleep apnea severity: a randomized crossover trial Ludovico Messineo , Madison Preuss , Ali Azarbarzin , Daniel Vena , Laura Gell , Atqiya Aishah , Neda Esmaeili , Molly Kim , Isabel Burdick , Tom Chen , David White , Scott A Sands , Andrew Wellman medRxiv 2025.01.15.25320565; doi: https://doi.org/10.1101/2025.01.15.25320565 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Respiratory Medicine Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (299) Cardiovascular Medicine (4422) Dentistry and Oral Medicine (443) Dermatology (382) Emergency Medicine (607) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1507) Epidemiology (15219) Forensic Medicine (30) Gastroenterology (1123) Genetic and Genomic Medicine (6587) Geriatric Medicine (667) Health Economics (997) Health Informatics (4524) Health Policy (1368) Health Systems and Quality Improvement (1611) Hematology (540) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15910) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (145) Nephrology (667) Neurology (6587) Nursing (345) Nutrition (998) Obstetrics and Gynecology (1143) Occupational and Environmental Health (956) Oncology (3331) Ophthalmology (970) Orthopedics (369) Otolaryngology (420) Pain Medicine (435) Palliative Medicine (129) Pathology (663) Pediatrics (1690) Pharmacology and Therapeutics (691) Primary Care Research (710) Psychiatry and Clinical Psychology (5438) Public and Global Health (9218) Radiology and Imaging (2195) Rehabilitation Medicine and Physical Therapy (1369) Respiratory Medicine (1195) Rheumatology (593) Sexual and Reproductive Health (709) Sports Medicine (529) Surgery (709) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9ff7deec59f60db4',t:'MTc3OTQxMTQ4OA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();