The article you requested is

A Double-Blind, Placebo-Controlled Study of Armodafinil for Excessive Sleepiness in Patients With Treated Obstructive Sleep Apnea and Comorbid Depression

J Clin Psychiatry 2010;71(1):32-40
10.4088/JCP.09m05536gry

Objective: Treatment of excessive sleepiness in the context of obstructive sleep apnea (OSA) may be particularly difficult in those with depression because depression and/or antidepressant medications may cause sleepiness and fatigue in addition to that due to the OSA. This study evaluating armodafinil, a nonamphetamine wakefulness-promoting medication, is the first trial for treatment of excessive sleepiness in patients with treated OSA and comorbid depression.

Method: Men and women with OSA diagnosed using International Classification of Sleep Disorders criteria being treated with continuous positive airway pressure and comorbid major depressive disorder or dysthymic disorder according to DSM-IV-TR criteria were enrolled into a 12-week, randomized, double-blind, parallel-group study between September 2007 and March 2009 at 60 outpatient sites. Patients maintained on stable monotherapy with a serotonergic antidepressant and with a 17-item Hamilton Depression Rating Scale score <17 received placebo or armodafinil (target dose: 200 mg once daily). Coprimary outcomes were the proportion of patients with at least minimal improvement on the Clinical Global Impression of Change (CGI-C) as related to excessive sleepiness and mean change from baseline in Maintenance of Wakefulness Test mean sleep latency at final visit; the key secondary outcome was mean change in the Epworth Sleepiness Scale score.

Results: 249 patients were enrolled: 125 in the armodafinil group and 124 in the placebo group. The proportion of patients with at least minimal improvement on the CGI-C was statistically significantly greater in the armodafinil group (69%) compared with the placebo group (53%, P=.012). Mean (SD) increase in Maintenance of Wakefulness Test sleep latency was numerically but not significantly greater following armodafinil (2.6 [7.1] min) versus placebo (1.1 [7.6] min, P=.30) treatment. Mean decrease in Epworth Sleepiness Scale score was greater in the armodafinil group (–6.3 [4.8]) than in the placebo group (–4.8 [4.9], nominal P=.003). Headache, dry mouth, and insomnia were the most common adverse events occurring with armodafinil treatment. There was no clinically significant effect on depression in either group as measured by the Quick Inventory of Depressive Symptomatology–Self-Report 16.

Conclusions: Armodafinil significantly improved overall clinical condition related to excessive sleepiness as rated by the CGI-C and was well tolerated in patients with treated OSA and comorbid depression.

Trial Registration: clinicaltrials.gov Identifier: NCT00518986


Submitted: July 16, 2009; accepted October 30, 2009.

Online ahead of print: December 29, 2009

Corresponding author: Andrew D. Krystal, MD, Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, Duke Clinic, 200 Trent Dr, 4th Fl, White Zone, Durham, NC 27710 (kryst001@mc.duke.edu).

A Double-Blind, Placebo-Controlled Study of Armodafinil for Excessive Sleepiness in Patients With Treated Obstructive Sleep Apnea and Comorbid Depression

Objective: Treatment of excessive sleepiness in the context of obstructive sleep apnea (OSA) may be particularly difficult in those with depression because depression and/or antidepressant medications may cause sleepiness and fatigue in addition to that due to the OSA. This study evaluating armodafinil, a nonamphetamine wakefulness-promoting medication, is the first trial for treatment of excessive sleepiness in patients with treated OSA and comorbid depression.

Method: Men and women with OSA diagnosed using International Classification of Sleep Disorders criteria being treated with continuous positive airway pressure and comorbid major depressive disorder or dysthymic disorder according to DSM-IV-TR criteria were enrolled into a 12-week, randomized, double-blind, parallel-group study between September 2007 and March 2009 at 60 outpatient sites. Patients maintained on stable monotherapy with a serotonergic antidepressant and with a 17-item Hamilton Depression Rating Scale score <17 received placebo or armodafinil (target dose: 200 mg once daily). Coprimary outcomes were the proportion of patients with at least minimal improvement on the Clinical Global Impression of Change (CGI-C) as related to excessive sleepiness and mean change from baseline in Maintenance of Wakefulness Test mean sleep latency at final visit; the key secondary outcome was mean change in the Epworth Sleepiness Scale score.

Results: 249 patients were enrolled: 125 in the armodafinil group and 124 in the placebo group. The proportion of patients with at least minimal improvement on the CGI-C was statistically significantly greater in the armodafinil group (69%) compared with the placebo group (53%, P=.012). Mean (SD) increase in Maintenance of Wakefulness Test sleep latency was numerically but not significantly greater following armodafinil (2.6 [7.1] min) versus placebo (1.1 [7.6] min, P=.30) treatment. Mean decrease in Epworth Sleepiness Scale score was greater in the armodafinil group (–6.3 [4.8]) than in the placebo group (–4.8 [4.9], nominal P=.003). Headache, dry mouth, and insomnia were the most common adverse events occurring with armodafinil treatment. There was no clinically significant effect on depression in either group as measured by the Quick Inventory of Depressive Symptomatology–Self-Report 16.

Conclusions: Armodafinil significantly improved overall clinical condition related to excessive sleepiness as rated by the CGI-C and was well tolerated in patients with treated OSA and comorbid depression.

Trial Registration: clinicaltrials.gov Identifier: NCT00518986

J Clin Psychiatry 2010;71(1):32–40

Submitted: July 16, 2009; accepted October 30, 2009.

Online ahead of print: December 29, 2009 (doi:10.4088/JCP.09m05536gry).

Corresponding author: Andrew D. Krystal, MD, Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, Duke Clinic, 200 Trent Dr, 4th Fl, White Zone, Durham, NC 27710 (kryst001@mc.duke.edu).

In patients with obstructive sleep apnea (OSA), partial or complete collapse of the upper airway during sleep results in frequent arousals and sleep fragmentation.1 Excessive sleepiness is the most common presenting symptom in patients with OSA.1 Although continuous positive airway pressure (CPAP) reduces apneic events and sleepiness,2,3 many patients experience residual excessive sleepiness despite treatment of the underlying obstruction.4

Mood disorders are common comorbidities in patients with OSA. Prevalence rates reported for mood disorder in patients with OSA are as high as 63%, with most studies reporting rates in the range of 30% to 50%.5 Patients with OSA and major depressive disorder (MDD) have shown an increased duration of apnea compared with those without MDD,6 and injuries to specific cortical and subcortical brain regions have been associated with higher levels of depressive symptoms in patients with OSA.7 Higher levels of sleepiness or fatigue are also associated with depression in patients with OSA.8–10

The presence of depression may complicate the treatment of excessive sleepiness in patients with OSA. Depression may contribute to sleepiness because sleepiness is a common symptom in depressed patients without OSA and may persist even after mood symptoms have responded to therapy.11 An added burden of sleepiness may also accompany depression because it may be a side effect of antidepressant treatment. Patients with depression are typically treated with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs),12,13 and while these are effective medications, they are commonly associated with daytime somnolence.14–17 In a large prospective survey of those patients prescribed an SSRI, “drowsiness/fatigue” was the most common adverse event leading to SSRI discontinuation.15 Comorbid depression may also influence clinical outcomes in general, as has been well documented by the increased risk for poor outcomes in patients with cardiovascular disease and depression.18,19

Armodafinil is a nonamphetamine, wakefulness-promoting medication. It is the R- and longer-lasting isomer of modafinil.20 Armodafinil significantly improved wakefulness in patients with excessive sleepiness associated with treated OSA in 2 placebo-controlled, double-blind studies,21,22 as well as in studies of shift work disorder (Roth et al23 and data on file, Cephalon, Inc, Frazer, Pennsylvania) and narcolepsy.24 Because treatment of excessive sleepiness in patients with OSA may be more challenging in the context of comorbid depression, it is important to evaluate the efficacy of armodafinil in this population. This study, evaluating the efficacy and tolerability of armodafinil in patients with CPAP-treated OSA and stable comorbid MDD or dysthymic disorder requiring antidepressant monotherapy, is the first study of a treatment for excessive sleepiness focused exclusively on this patient population.

METHOD

Study Design

This 12-week, randomized, double-blind, parallel-group, placebo-controlled study was conducted from September 2007 through March 2009 at 60 outpatient sites in the United States. Written informed consent was obtained from each participant before any study-specific procedures were performed and after procedures and potential adverse events of study drug were explained. The protocol was approved by the appropriate health authorities and the independent ethics committee/institutional review board at each site. The study was conducted in full accordance with the Good Clinical Practice: Consolidated Guidance approved by the International Conference on Harmonization25 and any applicable national and local laws and regulations.

Clinic visits occurred during a 1-week, single-blind, placebo run-in, screening period; at baseline; and at weeks 4, 8, and 12 of double-blind treatment with armodafinil or placebo. Patients were contacted by telephone at week 2 to review medication usage and adverse events and also were asked to complete an Epworth Sleepiness Scale (ESS) at week 2. Except for the screening period, all clinic visits included an overnight sleep study. Patients arrived for their sleep study between 7 pm and 8 pm, were in bed by 10 pm, and were awakened at 7 am the following morning. Recurring assessments were performed at the same time of day for all in clinic study visits.

Patients

Eligible patients were men and women aged 18 to 65 years who met International Classification of Sleep Disorders (ICSD)1 diagnostic criteria for OSA and had a complaint of excessive sleepiness despite regular use of CPAP therapy. Patients were required to have a stable regimen of CPAP for ≥4 weeks that was effective as evidenced by an apnea-hypopnea index of ≤1026–29 at the baseline visit and as judged by the investigator. Regular use of CPAP (≥4 hours/night on ≥70% of nights)30 was confirmed during a 1-week evaluation period by review of data from the CPAP device. A Clinical Global Impressions-Severity of Illness scale (CGI-S)31 score relative to excessive sleepiness of ≥4 (at least moderately ill) and an ESS32 score of ≥10 were also required.

Eligible patients were also required to have a diagnosis of MDD or dysthymic disorder, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria and a 17-item Hamilton Depression Rating Scale (HDRS-17)33 score of <17 at screening and baseline. If HDRS-17 scores changed by ≥6 points between screening and baseline, patients were not permitted to continue in the study. Stable monotherapy with study-approved SSRIs or SNRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram, venlafaxine, or duloxetine) was required for ≥8 weeks at the time of screening. During the 1-week, single-blind, placebo run-in screening period, all patients were administered the Mini International Neuropsychiatric Interview (MINI)34 and HDRS-17 by a psychiatrist or licensed clinical psychologist. On the basis of clinical assessment, the primary diagnosis of MDD or dysthymic disorder was confirmed by the psychiatrist or licensed clinical psychologist, who also evaluated patients to ascertain that the patient was stable in regard to depressed mood and had shown a clinical response to the SSRI or SNRI.

In general, patients were excluded for having conditions believed to significantly increase their risk for harm or interfere with study conduct or interpretation of results. Exclusion criteria included a confirmed or suspected diagnosis of any currently active sleep disorders other than OSA (including polysomnography [PSG] revealing periodic leg movements of >10/h, suggestive of periodic limb movement disorder), current treatment-resistant depression (defined as failing ≥2 adequate trials of an antidepressant), a diagnosis of an Axis I disorder (confirmed by the MINI: eating disorder, psychotic disorder, delirium, dementia, substance-related disorders, or moderate to severe hypochondriasis) or Axis II disorder (confirmed by the MINI, as applicable) that could interfere with the conduct of the study (eg, severe antisocial or borderline personality disorders, mental retardation), or any clinically significant uncontrolled psychiatric condition. Patients with any history of bipolar disorder, psychotic depression, schizophrenia, schizoaffective disorder, or any other psychotic disorders were also specifically excluded. Additionally, patients with a score ≥2 on the suicidality item of the HDRS-17, with any history of suicidal ideation, or who were believed to be at imminent risk of self-harm were excluded. A history of substance abuse or dependence in the past year or a positive urine drug screen without medical explanation were also considered reasons for exclusion.

Patients who had previously taken armodafinil at any time, had taken modafinil within 1 month of the study baseline visit, or had a history of hypersensitivity to modafinil were excluded. Patients were also excluded for taking monoamine oxidase inhibitors, psychotropics (except the study-approved SSRIs and SNRIs), anticoagulants, anticonvulsants, investigational drugs, and >800 mg/d of caffeine within 2 to 4 weeks of study entry. Current consumption of >600 mg/d of caffeine was not permitted. Psychotherapy was not allowed unless it was initiated >8 weeks before study entry.

Study Drug

Patients were randomly assigned to armodafinil or matching placebo in a 1:1 ratio, stratified by center. Patients took armodafinil or placebo once daily, before 8 am. Armodafinil was initiated at a dose of 50 mg (1 tablet) and titrated in 50-mg increments on days 2, 5, and 8 to a target dose of 200 mg (4 tablets) daily. After 3 days at the target dose, the dose could be further increased to 250 mg on the basis of the investigator’s and patient’s perception of efficacy. The dose could also be decreased after the target dose was reached, on the basis of tolerability; patients unable to tolerate 150 mg daily were discontinued. Once a dose was decreased, it could not be increased, and no adjustments were permitted after week 3.

Assessments

Efficacy. The primary efficacy outcomes were the proportion of patients with at least minimal improvement as rated by investigators on the Clinical Global Impression of Change (CGI-C)31 and the mean change from baseline in the Maintenance of Wakefulness Test (MWT)35 mean sleep latency at final visit (week 12 or last postbaseline visit). The CGI-C is the clinician’s rating of the patient’s condition, in this case as related to the severity of excessive sleepiness associated with OSA, compared with a baseline measure of severity (CGI-S). The CGI-C is scored on a 7-point scale ranging from very much improved to very much worse. The CGI-C was performed at weeks 4, 8, and 12. The MWT is an objective measure of sleepiness that measures the ability of the patient to stay awake.35 It was administered for 30 minutes at 9 am, 11 am, 1 pm, and 3 pm. Sleep latency was defined as the time to onset of the first of 3 consecutive epochs of stage 1 sleep or the time to onset of any epoch stages 2, 3, and 4 or rapid eye movement (REM) sleep. If a patient fell asleep, he or she was awakened immediately and then prevented from falling asleep again throughout the reminder of the 30-minute period. The MWT was performed at baseline and weeks 4, 8, and 12.

The key secondary efficacy outcome was the mean change from baseline to final visit in ESS score.32 The ESS is a self-assessed measure of the propensity to fall asleep in 8 everyday situations. Scores range from 0 to 24, with higher scores indicating greater sleepiness. A score ≥10 has been used to define excessive sleepiness.36 The ESS was performed at screening, during the telephone contact (week 2), and at weeks 4, 8, and 12. The proportion of responders on ESS at final visit (as defined by achieving an ESS score <10) was another secondary efficacy outcome.

Tolerability. Adverse events were recorded at all patient contacts. Use of CPAP was monitored throughout the study. Vital signs were measured at all clinic visits. Electrocardiography (ECG), clinical laboratory testing, and physical examinations were performed at screening and final visit.

Nocturnal PSG was performed at baseline and final visit. Additionally, a patient diary assessing sleep latency, sleep disturbance, duration of sleep, and sleep quality over the previous week was completed at baseline and weeks 4, 8, and 12.

To assess tolerability as related to the patient’s MDD or dysthymia diagnosis, the Quick Inventory of Depressive Symptomatology—Self-Report (QIDS-SR-16)37 was performed at baseline and at all follow-up patient contacts. The QIDS-SR-16 is a 16-item self-rated scale of the severity of depression symptoms based on the DSM-IV criteria symptom domains. Patients with a total score ≥21 (indicating severe depression) or a score of 2 or 3 on item 12 (suicidality item) were to be immediately withdrawn from the study per protocol.

Statistical Analysis

The sample size calculation was based on a mean difference of 3.0 minutes in MWT sleep latency with SD of 7.65 (Δ=0.392). On the basis of a 2-sided significance level of .05 and 80% power, a total of 232 patients (116 per group) were planned to be enrolled to assure that at least 104 patients per group had postbaseline assessments of MWT or CGI-C.

The safety analysis set included all patients who received at least 1 dose of study drug. The efficacy analysis set included all patients who received at least 1 dose of study drug and completed at least 1 postbaseline MWT or CGI-C assessment. For the efficacy analysis, a last-observation-carried-forward approach was used for the final visit.

The CGI-C response rate at final visit was analyzed using the Pearson χ2 test. Changes from baseline to final visit in MWT mean sleep latency (mean of 4 time points: 9 am, 11 am, 1 pm, and 3 pm) and ESS score were analyzed using analysis of covariance (ANCOVA) with study drug as a fixed factor and the baseline value as covariate. The Hochberg procedure38 was used to control the overall Type I error rate at the .05 level for the primary outcomes. According to the Hochberg procedure, if the P values for both primary outcomes are ≤.05, the treatment effect is considered significant for both outcomes. If 1 P value is >.05 and the other is ≤.025, the outcome with a P value ≤.025 is claimed to be significant. If both primary outcomes are significant and the P value for the key secondary outcome is ≤.05, it is considered significant. If only 1 of the primary outcomes is significant, the key secondary outcome cannot be considered significant. Other secondary outcomes are to be tested according to a predefined hierarchy procedure for a claim of statistically significant treatment difference. However, nominal P values are reported in this article even if statistical significance cannot be claimed. Summary statistics and P values are reported for all outcomes.

Tolerability outcomes were summarized using descriptive statistics for continuous variables and patient counts and percentages for categorical variables.

RESULTS

Patients

Two hundred forty-nine patients were randomly assigned to treatment: 125 to the armodafinil group and 124 to the placebo group. Twenty-one percent of both treatment groups discontinued the study prematurely (Figure 1). Thirty-nine patients (31%) were receiving 250 mg of armodafinil at their final visit.

Baseline demographics were comparable across groups (Table 1). The mean body mass index (BMI) was 37.3 kg/m2 in the armodafinil group and 36.2 kg/m2 in the placebo group. Escitalopram was the most commonly prescribed antidepressant, reported by 21% of patients receiving armodafinil and 26% of patients receiving placebo. The mean (SD) HDRS-17 scores at baseline were 6.7 (4.1) for those in the armodafinil group and 6.3 (4.0) for those in the placebo group. Mean (SD) baseline ESS scores were 14.3 (3.1) in the armodafinil group and 15.3 (3.4) in the placebo group.

Figure 1

Click figure to enlarge

Efficacy

The proportion of patients with at least minimal improvement on CGI-C at final visit was significantly greater in the armodafinil group than in the placebo group (69% vs 53%, P=.012); this proportion was also numerically higher for those in the armodafinil group at weeks 4, 8, and 12 (Figure 2).

Table 1

Click figure to enlarge

Figure 2

Click figure to enlarge

Table 2

Click figure to enlarge

Figure 3

Click figure to enlarge

Table 3

Click figure to enlarge

Table 4

Click figure to enlarge

For the coprimary outcome, change from baseline to final visit in MWT mean sleep latency, mean change was greater in the armodafinil group (2.6 [7.1] minutes) compared with placebo (1.1 [7.6] minutes), but the difference was not statistically significant (95% CI, –0.80 to 2.54; P=.304). Changes at weeks 4, 8, and 12 were also numerically greater for those in the armodafinil group than for those in the placebo group (Table 2).

In a subgroup analysis, CGI-C response and MWT mean sleep latency were analyzed by depression type. For patients with MDD, the proportion of patients rated as minimally improved, much improved, or very much improved on the CGI-C was 70% (73/105) following armodafinil versus 54% (56/103) following placebo at the final visit (nominal P=.024). In the much smaller subgroup with dysthymic disorder, 63% (5/8) were at least minimally improved on the CGI-C following armodafinil versus 33% (3/9) following placebo (nominal P=.229). Mean (SD) change from baseline to final visit in MWT following armodafinil versus placebo was 2.5 (7.1) versus 1.2 (7.8) minutes in patients with MDD (nominal P=.268) and 3.7 (7.9) versus 0.8 (5.5) minutes in patients with dysthymic disorder (nominal P=.811).

For the key secondary outcome, change from baseline to final visit in ESS score, the mean (SD) decrease in score was greater in the armodafinil group (–6.3 [4.8]) than in the placebo group (–4.8 [4.9]; 95% CI, –3.13 to –0.66; nominal P=.003; Figure 3). Mean changes in ESS score were also numerically greater in the armodafinil group at the earliest time point evaluated (week 2) and at all subsequent study visits (Figure 3). The proportion of ESS responders (ESS<10) at final visit was 66% in the armodafinil group and 48% in the placebo group (nominal P=.006).

Tolerability

The most commonly reported adverse events were headache, dry mouth, and insomnia (Table 3). Most events were rated by the investigator as mild or moderate in nature. The only psychiatric events reported by >1 patient in the armodafinil group were insomnia, anxiety, and worsening of MDD (Table 4). The worsening of depression was rated as mild or moderate in all cases, was rated by the investigator as related to treatment in 1 case (armodafinil), and did not lead to study discontinuation for any patients. Three of the 4 patients with worsening MDD as an adverse event showed a 1-point improvement on the QIDS-SR-16 at final visit, whereas 1 showed a 4-point worsening. Small decreases from baseline (improvements) in mean (SD) QIDS-SR-16 scores were reported at final visit in both treatment groups: –2.2 (4.6) following armodafinil and –1.8 (4.2) following placebo. No patients reported suicidal ideation, mania, or hypomania. Two patients in the armodafinil group discontinued because of psychiatric adverse events—1 due to nervousness and the other due to anxiety.

One patient (1%) in the armodafinil group reported a serious adverse event (atypical chest pain, considered by the investigator not to be related to study drug), and 3 patients (2%) in the placebo group reported serious adverse events (unstable angina, cholelithiasis, and cervical spinal stenosis with intravertebral disc protrusion). No deaths were reported. Adverse event–related discontinuations occurred in 12 patients (10%) in the armodafinil group and 7 patients (6%) in the placebo group. Adverse events leading to study discontinuation in >1 patient were headache (n=3), dyspnea (n=3), dry mouth (n=2), and disturbance of attention (n=2) in the armodafinil group; no events were associated with >1 discontinuation in the placebo group.

Mean changes from baseline to final visit in clinical laboratory values, ECG parameters, and body weight were not considered clinically meaningful. Small increases from baseline to final visit were noted for heart rate and systolic blood pressure but were also not considered clinically important. Use of CPAP throughout the study was high: mean use was 6.9 h/night for the armodafinil group and 7.0 h/night for the placebo group at baseline, and mean change from baseline to final visit was similar for those in the armodafinil group (–0.7 h/night) and placebo group (–0.5 h/night).

Mean changes from baseline to final visit for nocturnal PSG variables were small and comparable between treatment groups. Mean changes from baseline in subjective measures of sleep, as documented in the patient diaries, did not suggest any meaningful differences between the armodafinil and placebo groups.

DISCUSSION

In patients with OSA and comorbid mood disorders, the etiology of excessive sleepiness and depression may be multifactorial. Somnolence occurring as an adverse effect of antidepressants14–17 and the sleepiness that is commonly reported as a symptom of depression11 may contribute to the excessive sleepiness associated with OSA and negatively affect treatment outcomes. Conversely, some of the depressive symptoms reported in the study might have been associated with mild OSA. Regardless of the etiology of the depression, patients in this study had to have been diagnosed with both depression and OSA as defined by the DSM-IV-TR and ICSD, respectively. Because all patients were treated for both conditions and remained depressed, the complexity of treating these patients remains the same irrespective of the cause of depression. It is important to determine the effects of armodafinil in patients with OSA and mood disorders because of the high incidence of these comorbidities5 and the potential for treatment resistance in this group.

In this study, the proportion of patients with at least minimal improvement in overall clinical condition as related to excessive sleepiness (CGI-C) was significantly higher in the armodafinil group than in the placebo group (P=.012). Improvement in ESS mean score and ESS responder rate were also greater in the armodafinil group than in the placebo group (nominal P values=.003 and .006, respectively), but these differences could not be considered statistically significant because, as stipulated by the hierarchical testing procedure, the coprimary outcome (change from baseline in MWT mean sleep latency) did not achieve statistical significance.

In 2 previous, similarly designed studies in a general population of patients with treated OSA, significant improvements in MWT mean sleep latency were detected for armodafinil compared with placebo. In addition, improvements over placebo were also detected for ESS score changes and the proportion of patients with at least minimal improvement on CGI-C.21,22 The MWT mean increase in sleep latency with armodafinil compared with placebo was 2.6 minutes in the current study. Mean increases of 2.3 minutes following armodafinil 150 mg,22 1.7 minutes following armodafinil 150 mg,21 and 2.2 minutes following armodafinil 250 mg22 have been reported in previous studies in OSA compared with placebo. The placebo response on MWT was higher in the current study than in these previous studies and appeared to account for the inability to detect significant differences in this study. Placebo response was also higher for ESS mean changes in the current study than reported in the earlier studies21,22 and was high for CGI-C, as has been previously reported.21 High rates of placebo response are commonly reported in studies of antidepressant efficacy for MDD, and the placebo response rate has been increasing over recent years.39 The findings from our study suggest that the increase in placebo response seen on assessments of depressive symptoms in patients with MDD may extend to objective and subjective assessments of sleepiness.

No prior studies of modafinil for excessive sleepiness in OSA patients with comorbid depression have been reported. However, 3 placebo-controlled studies of modafinil in patients with sleepiness and MDD40–42 did not show consistent effects of modafinil on excessive sleepiness. In the 2 studies that required patients to have excessive sleepiness at baseline (ESS score ≥10),41,42 changes from baseline to final visit in ESS score did not differ significantly between groups. The percentage of patients with at least minimal improvement on CGI-C was significantly higher in the modafinil group at final visit in 1 of these studies (P=.02 versus placebo); however, CGI-C was a measure of overall clinical condition (not specific to sleepiness) in that study.42 For the 1 study in which excessive sleepiness was not an entry criterion, 51% of patients nonetheless had baseline ESS scores ≥10.40 In that study, ESS scores declined significantly in the modafinil group at week 1, but at weeks 2 and 6, no benefit of modafinil over placebo was shown. Examination of the ESS data from these 3 studies suggests that a high placebo response rate played a role in the inability to detect significant differences.40–42 MWT sleep latency was not assessed in any of these studies.40–42

The tolerability profile of armodafinil in this study was largely similar to its tolerability in the general populations of patients from previous studies in treated OSA, shift work disorder, and narcolepsy (references 21, 22, and 24 and data on file, Cephalon, Inc., Frazer, Pennsylvania). Headache, insomnia, and nausea were among the most commonly reported events. Armodafinil was generally well tolerated, as shown by the rate of adverse event–related discontinuations, which was not substantially different between armodafinil (10%) and placebo (6%) or as compared with previously published studies.21,22,24

Given the nature of the study population, a higher incidence of psychiatric adverse events might be expected. Insomnia (including middle insomnia, early morning awakening, and dyssomnia) and anxiety occurred in a higher proportion of the armodafinil group than the placebo group. The increase in incidence of insomnia following armodafinil compared with placebo (9% vs 2%) was slightly higher than that seen in the previously published studies (5% vs 1%), but the difference in incidence of anxiety (5% vs 1%) was similar to those studies (4% vs 1%).21,22,24 The incidence of depression (or worsening of depression in this study) was 2% in the armodafinil group versus 1% in the placebo group. In the previously published studies, the incidence of depression was similar to that reported here (2% for armodafinil and none for placebo).21,22,24

Objective measures of sleep from PSG studies did not show clinically meaningful differences between treatment groups, nor did subjective variables reported in the sleep diary. On the whole, PSG data, sleep diary data, and adverse event reports of insomnia suggest that significant sleep disturbance is likely to be relatively uncommon among patients with excessive sleepiness associated with OSA and comorbid depression treated with armodafinil, although a small proportion of patients may experience insomnia as an adverse effect.

The limitations of this study include its relatively short duration (12 weeks), which does not permit generalization of the findings to treatment over a longer time period. In addition, there were limited objective data on patients’ history of CPAP use, which was based on a 1-week assessment of data collected from the patient’s CPAP device as well as the patients’ self-reports on CPAP use for 4 weeks prior to the study. All patients, though, were educated on the use of CPAP at screening, and intervention efforts to encourage compliance were documented throughout the study. Findings are also not generalizable to patients who are not receiving adequate CPAP therapy, have not responded to antidepressant therapy, require multiple antidepressants, or have severely depressed mood. The ability of the study to detect significant differences in MWT sleep latency was limited by the overestimate of the mean difference in MWT sleep latency and underestimate of the necessary patient sample size in the setting of a greater than expected observed placebo effect. This estimate was based on previous studies21,22 of armodafinil in populations of patients with treated OSA, the majority of whom did not have a history of depression and were not taking antidepressants.

CONCLUSIONS

In this population of patients with CPAP-treated OSA and comorbid MDD or dysthymic disorder, armodafinil significantly improved overall clinical condition as related to excessive sleepiness compared with placebo. The improvement in objective wakefulness, as reflected by MWT mean sleep latency, did not achieve statistical significance when compared with placebo. Coadministration of armodafinil with stable SSRI or SNRI monotherapy in patients with depression appeared to be generally well tolerated. Psychiatric adverse event rates and adverse-event–related discontinuation rates were low and consistent with previous studies in nondepressed, sleep-disordered populations. The results of this study suggest that armodafinil provides a clinically important benefit for the treatment of residual excessive sleepiness in patients with treated OSA and comorbid depression.

Drug names: armodafinil (Nuvigil), citalopram (Celexa and others), duloxetine (Cymbalta), escitalopram (Lexapro and others), fluoxetine (Prozac and others), paroxetine (Paxil, Pexeva, and others), sertraline (Zoloft and others), venlafaxine (Effexor and others).

Author affiliations: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina (Dr Krystal); Department of Psychology, The University of Southern Mississippi, Hattiesburg (Dr Harsh); Biometrics Department (Dr Yang) and Medical Services and Clinical Research (Dr Rippon), Cephalon, Inc., Frazer, Pennsylvania; and Sleep Disorders Center of Georgia, Atlanta (Dr Lankford).

Potential conflicts of interest: Dr Krystal has received grant/research support from the National Institutes of Health, Sanofi-Aventis, Cephalon, GlaxoSmithKline, Merck, Neurocrine, Pfizer, Sepracor, Somaxon, Takeda, Transcept, Respironics, Neurogen, Evotec, Astellas, and Neuronetics and has been a consultant for Actelion, Arena, Astellas, Axiom, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Jazz, Johnson & Johnson, King, Merck, Neurocrine, Neurogen, Neuronetics, Novartis, Organon, Ortho-McNeil-Janssen, Pfizer, Respironics, Roche, Sanofi-Aventis, Sepracor, Somaxon, Takeda, Transcept, Astellas, Research Triangle Institute, Kingsdown Inc, and CHDI. Drs Yang and Rippon are employees of and stock shareholders in Cephalon. Dr Lankford has received research support from Actelion, Arena, Cephalon, Evotec, GlaxoSmithKline, Eli Lilly, Merck, Neurim, Neurocrine, Neurogen, Organon, Pfizer, Respironics, Sanofi-Aventis, Schering-Plough, Sepracor, Somaxon, Takeda, Transcept, and Vanda; has been a consultant/advisory board member for Actelion, Cephalon, Concert, GlaxoSmithKline, Neurocrine, Neurogen, Ovation, Pfizer, Somaxon, and Transcept; and has been on the speakers bureaus of Jazz, Somaxon, and Sanofi-Aventis. Dr Harsh reports no financial or other relationship relevant to the subject of this article.

Funding/support: This study was sponsored by Cephalon, Inc., Frazer, Pennsylvania. Funding for editorial support provided by Cephalon, Inc., to the Curry Rockefeller Group, LLC, Tarrytown, New York.

Previous presentation: Results were presented at the 19th Meeting of the European Neurological Society, June 20–24, 2009, Milan, Italy; and the 49th Annual New Research Approaches for Mental Health Interventions Meeting, June 29–July 2, 2009, Hollywood, Florida.

REFERENCES

1. American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

2. Patel SR, White DP, Malhotra A, et al. Continuous positive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a meta-analysis. Arch Intern Med. 2003;163(5):565–571. PubMed doi:10.1001/archinte.163.5.565

3. Giles TL, Lasserson TJ, Smith BJ, et al. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev. 2006;(1)CD001106.

4. Weaver TE, Maislin G, Dinges DF, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep. 2007;30(6):711–719. PubMed

5. Saunamäki T, Jehkonen M. Depression and anxiety in obstructive sleep apnea syndrome: a review. Acta Neurol Scand. 2007;116(5):277–288. PubMed doi:10.1111/j.1600-0404.2007.00901.x

6. Carney RM, Howells WB, Freedland KE, et al. Depression and obstructive sleep apnea in patients with coronary heart disease. Psychosom Med. 2006;68(3):443–448. PubMed doi:10.1097/01.psy.0000204632.91178.26

7. Cross RL, Kumar R, Macey PM, et al. Neural alterations and depressive symptoms in obstructive sleep apnea patients. Sleep. 2008;31(8): 1103–1109. PubMed

8. Bardwell WA, Ancoli-Israel S, Dimsdale JE. Comparison of the effects of depressive symptoms and apnea severity on fatigue in patients with obstructive sleep apnea: a replication study. J Affect Disord. 2007; 97(1–3):181–186. PubMed doi:10.1016/j.jad.2006.06.013

9. Yue W, Hao W, Liu P, et al. A case-control study on psychological symptoms in sleep apnea-hypopnea syndrome. Can J Psychiatry. 2003;48(5): 318–323. PubMed

10. Sforza E, de Saint Hilaire Z, Pelissolo A, et al. Personality, anxiety and mood traits in patients with sleep-related breathing disorders: effect of reduced daytime alertness. Sleep Med. 2002;3(2):139–145. PubMed doi:10.1016/S1389-9457(01)00128-9

11. Fava M. Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry. 2004;65(suppl 16):27–32. PubMed

12. Chen Y, Kelton CM, Jing Y, et al. Utilization, price, and spending trends for antidepressants in the US Medicaid Program. Res Social Adm Pharm. 2008;4(3):244–257. PubMed

13. Pirraglia PA, Stafford RS, Singer DE. Trends in prescribing of selective serotonin reuptake inhibitors and other newer antidepressant agents in adult primary care. Prim Care Companion J Clin Psychiatry. 2003;5(4): 153–157. PubMed doi:10.4088/PCC.v05n0402

14. Beasley CM Jr, Koke SC, Nilsson ME, et al. Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: an updated meta-analysis. Clin Ther. 2000;22(11):1319–1330. PubMed doi:10.1016/S0149-2918(00)83028-3

15. Bull SA, Hunkeler EM, Lee JY, et al. Discontinuing or switching selective serotonin-reuptake inhibitors. Ann Pharmacother. 2002;36(4):578–584. PubMed doi:10.1345/aph.1A254

16. Danjou P, Hackett D. Safety and tolerance profile of venlafaxine. Int Clin Psychopharmacol. 1995;10(suppl 2):15–20. PubMed doi:10.1097/00004850-199503002-00004

17. Papakostas GI, Homberger CH, Fava M. A meta-analysis of clinical trials comparing mirtazapine with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. J Psychopharmacol. 2008;22(8):843–848. PubMed doi:10.1177/0269881107083808

18. Rutledge T, Reis VA, Linke SE, et al. Depression in heart failure a meta-analytic review of prevalence, intervention effects, and associations with clinical outcomes. J Am Coll Cardiol. 2006;48(8):1527–1537. PubMed doi:10.1016/j.jacc.2006.06.055

19. van Melle JP, de Jonge P, Spijkerman TA, et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med. 2004;66(6):814–822. PubMed doi:10.1097/01.psy.0000146294.82810.9c

20. Robertson P Jr, Hellriegel ET. Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 2003;42(2):123–137. PubMed doi:10.2165/00003088-200342020-00002

21. Hirshkowitz M, Black JE, Wesnes K, et al. Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome. Respir Med. 2007;101(3):616–627. PubMed doi:10.1016/j.rmed.2006.06.007

22. Roth T, White D, Schmidt-Nowara W, et al. Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: a 12-week, multicenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults. Clin Ther. 2006;28(5):689–706. PubMed doi:10.1016/j.clinthera.2006.05.013

23. Roth T, Czeisler CA, Walsh JK, et al. Randomized, double-blind, placebo-controlled study of armodafinil for the treatment of excessive sleepiness associated with chronic shift work sleep disorder [abstract]. Neuropsychopharmacology. 2005;30:S140.

24. Harsh JR, Hayduk R, Rosenberg R, et al. The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin. 2006;22(4):761–774. PubMed doi:10.1185/030079906X100050

25. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) adopts consolidated guideline on good clinical practice in the conduct of clinical trials on medicinal products for human use. Int Dig Health Legis. 1997; 48(2):231–234. PubMed

26. Dickel MJ, Mosko SS. Morbidity cut-offs for sleep apnea and periodic leg movements in predicting subjective complaints in seniors. Sleep. 1990;13(2):155–166. PubMed

27. Kushida CA, Morgenthaler TI, Littner MR, et al; American Academy of Sleep. Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances: an update for 2005. Sleep. 2006;29(2): 240–243. PubMed

28. Lavie P. Incidence of sleep apnea in a presumably healthy working population: a significant relationship with excessive daytime sleepiness. Sleep. 1983;6(4):312–318. PubMed

29. Zammit G, Erman M, Wang-Weigand S, et al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med. 2007;3(5):495–504. PubMed

30. Kribbs NB, Pack AI, Kline LR, et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis. 1993;147(4):887–895. PubMed

31. Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education and Welfare publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health, 1976: 218–222.

32. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14(6):540–545. PubMed

33. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.

34. Sheehan DV, Lecrubier Y, Janavs J, et al. Mini-International Neuropsychiatric Interview (MINI). Tampa, FL: University of South Florida, Institute for Research in Psychiatry, and Paris, France: INSERM-Hôpital de la Salpêtrière; 1994.

35. Poceta JS, Timms RM, Jeong DU, et al. Maintenance of Wakefulness Test in obstructive sleep apnea syndrome. Chest. 1992;101(4):893–897. PubMed doi:10.1378/chest.101.4.893

36. Walsleben JA, Kapur VK, Newman AB, et al. Sleep and reported daytime sleepiness in normal subjects: the Sleep Heart Health Study. Sleep. 2004;27(2):293–298. PubMed

37. Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54(5):573–583. PubMed doi:10.1016/S0006-3223(02)01866-8

38. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57: 289–300.

39. Walsh BT, Seidman SN, Sysko R, et al. Placebo response in studies of major depression: variable, substantial, and growing. JAMA. 2002; 287(14):1840–1847. PubMed doi:10.1001/jama.287.14.1840

40. DeBattista C, Doghramji K, Menza MA, et al; Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry. 2003;64(9): 1057–1064. PubMed

41. Dunlop BW, Crits-Christoph P, Evans DL, et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2007;27(6):614–619. PubMed doi:10.1097/jcp.0b013e31815abefb

42. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66(1):85–93. PubMed