Modafinil reduces microsleep during partial sleep deprivation in depressed patients

Journal of Psychiatric Research 44 (2010) 853–864

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Journal of Psychiatric Research

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Modafinil reduces microsleep during partial sleep deprivation in depressed patients

J. Beck a,*, U. Hemmeter b, S. Brand a, F. Muheim a, M. Hatzinger c, E. Holsboer-Trachsler a

a Psychiatric Hospital of the University of Basel, Center of Affective Disorders and Depression and Center of Sleep Medicine, Basel/CH, Switzerlandb Psychiatric Service Center St. Gallen, Wil/CH, Switzerlandc Psychiatric Out-Patient Dept. of the University of Basel/CH, Switzerland

a r t i c l e i n f o

Article history:Received 16 October 2009Received in revised form 6 January 2010Accepted 12 January 2010

Keywords:ModafinilSleep deprivationPartial sleep deprivationDepressive disorders

0022-3956/$ - see front matter � 2010 Elsevier Ltd. Adoi:10.1016/j.jpsychires.2010.01.008

* Corresponding author. Address: Psychiatric UniveKlein-Strasse 27, CH-4025 Basel, Switzerland. Tel.: +4325 55 13.

E-mail address: [email protected] (J. Beck).

a b s t r a c t

Objective: Sleep deprivation (SD) can induce a prompt decrease in depressive symptoms within 24 h. Fol-lowing the recovery night, however, a relapse into depression occurs in most patients. Recovery sleep,naps and even very short episodes of sleep (microsleep; MS) during SD have been shown to provoke arapid relapse into depression. This study tested the hypothesis that modafinil reduces MS during SDand stabilizes the treatment response to PSD compared to placebo.Methods: A total of 28 patients (13 men, 15 women; age 45.1 ± 12.1 years) with a major depressive epi-sode and a cumulative daytime microsleep of five or more minutes were investigated using a double-blind placebo-controlled study design. All patients were treated with a stable mirtazapine monotherapy.A partial SD (PSD) was performed after one week. Additional morning treatment with modafinil vs. pla-cebo started during PSD and was maintained over two weeks. Sleep-EEG and MS episodes were recordedwith a portable EEG. Depression severity was assessed using the Hamilton Depression Rating Scalebefore, during and after PSD and at follow-ups after one and two weeks.Results: Patients treated with modafinil showed significantly reduced microsleep during PSD(11.63 ± 15.99 min) compared to the placebo group (47.77 ± 65.31 min). This suppression of MS wasnot associated with the antidepressive effect of PSD.Conclusions: Compared to placebo, modafinil was efficient in reducing daytime microsleep followingpartial sleep deprivation but did not enhance the antidepressive effects of PSD and did not stabilize anti-depressive effects over two weeks.

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1. Introduction

Sleep deprivation is an effective and fast acting antidepressanttherapy, leading to a marked improvement within hours in approx-imately 60% of patients (Germain and Kupfer, 2008; for review seeWu and Bunney, 1990). Beside SD of the total night, partial sleepdeprivation (PSD) in the second half of the night has also showncomparable antidepressant effects in patients with major depres-sion (Giedke and Schwärzler, 2002). The major drawback of SD,however, is the transient nature of the beneficial effect, as relapseinto depression often occurs on the second day after the recoverynight (Elsenga and van den Hoofdacker, 1980; Wu and Bunney,1990).

In addition to recovery sleep, also naps, predominantly morningnaps during SD provoke a rapid relapse into depression (Wiegandet al., 1989; Riemann et al., 1993). Even very short episodes ofsleep [termed, microsleep (MS)] during PSD have been shown to

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prevent the antidepressant effects of PSD (Hemmeter et al.,1998). In this study the accumulated amount of MS during PSD,predominantly until noon, was related to PSD-non-response. Anexplanation for the detrimental effect of sleep on the antidepres-sant response to SD is provided by the two process model ofBorbély (1982) suggesting a deficiency of the homeostatic processS component in depression, which may be corrected by SD. Thishas been shown also in depressed patients, as a high amount ofMS during SD was related to less slow wave sleep in the recoverynight (Hemmeter et al., 1998, 2007). Based on these findings it wasconcluded that increased sleep propensity – reflected by naps ormicrosleep – during PSD was related to non-response and thatpharmacological reduction of MS may lead to an augmentation ofthe response rate to PSD.

To achieve a reduction of sleep propensity, in a first study, thebenzodiazepine (BDZ) receptor antagonist flumazenil was applied.Flumazenil specifically antagonizes the effects of BDZ agonists atbehavioral, cellular and subcellular levels (Haefely et al., 1983).In healthy subjects flumazenil did suppress SWS, SWA (slow waveactivity) and growth hormone secretion in morning recovery sleep(between 5 am and 8 am), suggesting a specific effect on thestrength of process S (Seifritz et al., 1995). In a following clinical

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study 27 patients with major depression were subjected to a par-tial SD (PSD) and flumazenil was orally applied in a double blindrandomized placebo-controlled design. The results of this studyshowed that flumazenil suppressed MS during PSD. However, thissuppression of MS was not related to an augmentation of the anti-depressant response during PSD. A possible explanation of thisnegative result was that direct GABA-antagonistic effects of flu-mazenil on mood may have counteracted the beneficial effects ofMS suppression by flumazenil during PSD according to the GAB-Aergic hypothesis of depression (Petty et al., 1995). However, inour earlier MS studies (Hemmeter et al., 1998, 2007), depressed pa-tients without MS at baseline (before PSD) did not substantially in-crease with MS during PSD, while patients with a high amount ofMS already at baseline substantially increased with MS duringPSD under placebo conditions. Put in other words: In these earlierstudies results were biased due to different baseline conditions. Tocope with this issue, in the present study we thus included patientswith daytime sleepiness and a cumulative daytime microsleep offive or more minutes at baseline.

A different pharmacological approach to reduce sleep propen-sity during PSD is provided by the stimulant modafinil. Modafinilis able to reduce tiredness and increase vigilance in healthy sub-jects under normal 24 h sleep-wake conditions and during ex-tended wakefulness. Modafinil application is followed by anincrease of wakefulness and a reduction of SWA in sleep deprivedvolunteers (Chapotot et al., 2003; Caldwell et al., 2000). Anotherstudy in healthy volunteers showed that modafinil was able to re-duce microsleep and increase vigilance during a 60 h sleep depri-vation compared to placebo (Lagarde et al., 1995), In addition,healthy subjects treated with modafinil during sleep deprivationshowed less disturbance of sleep pattern in the recovery night thansubjects treated with amphetamine. Predominantly REM sleep wasless affected after modafinil, and SWS was intensified (Buguetet al., 1995). From these data we concluded that the homeostaticsleep regulation after modafinil-induced wakefulness remainedpreserved. In addition, one may claim that modafinil may increaseNonREM sleep pressure of the recovery night and suppress day-time microsleep.

The definitive action of modafinil on CNS-neurotransmitters isstill not completely clarified. Action on dopamine, serotonine, ace-tylcholine and also the orexin system have been reported (for re-view see Minzenberg and Carter (2008)). However, modafinildoes not directly act via the GABAergic system and therefore it isconceivable that compared to flumazenil, modafinil should havea different mechanism of action.

Based on these findings and considerations the present studytested the hypothesis that application of modafinil induces a sub-stantial reduction of microsleep during PSD. Four further hypothe-ses were tested as secondary study endpoints: (1) Modafinil-induced reduction of microsleep leads to an increased antidepres-sive response to partial sleep deprivation compared to placebo; (2)the application of modafinil over two additional weeks does stabi-lize the mood response to partial sleep deprivation compared toplacebo; (3) the homeostatic sleep response after modafinil-in-duced wakefulness is preserved; (4) the application of modafinilover two additional weeks augments the antidepressant responseto the ongoing treatment with mirtazapine.

2. Methods

In a combined within/between subjects design which includeda PSD in depressed patients (within subjects factor), half of the pa-tients received modafinil 200 mg by oral application, and half ofthe patients received placebo (between subjects factor) under dou-ble-blind conditions. During the whole study EEG was registered

continuously for 60 h by a portable device allowing the evaluationof sleep-EEG (before and after PSD) and MS episodes (at baselineand during PSD).

2.1. Study population

Twenty-eight in- and out-patients (13 men, 15 women, aged45.1 years (±12.1 standard deviation; range 19–65 years) withthe diagnosis of major depression (DSM-IV and ICD-10) andaccording to the SCID (Wittchen et al., 1987) participated in thestudy. The study protocol was approved by the local ethics com-mittee and all patients gave written informed consent after com-plete description of the study. All participants were naïve to aSD-therapy. Patients were randomly assigned to either additionalmodafinil or placebo treatment. For the purpose of randomization,the study medication (modafinil and placebo) was sealed in iden-tically looking capsules prepared by the pharmacy department ofthe university hospital of Basel. Modafinil and placebo were ran-domly assigned to subject numbers. Subject numbers were thenconsecutively assigned to patients enrolled in the study. Both thestudy staff and patients were unaware of the placebo/verum statusthroughout the study: The verum/placebo code was broken afterthe last patient had completed the study. The modafinil group con-sisted of eight men and six women, age 46.2 ± 12.2 years; the pla-cebo group consisted of five men and nine women, age43.9 ± 12.2 years. All patients were treated with a monotherapyof 30 mg mirtazapine daily at 9 pm throughout the study.

Severity of depression was evaluated by the 21 Item version ofHamilton depression rating scale (HDRS; Hamilton, 1967). Inclu-sion criteria comprised a HDRS-score of P15 and the presence ofsignificant daytime sleepiness, which was defined as a minimumscore of 12 points on the Epworth Sleepiness Scale (Jones, 1991).Furthermore, following previous findings (Hemmeter et al.,2007), a substantial amount of cumulative daytime microsleep atbaseline (>5 min) was required for the inclusion into the study.Therefore, daytime microsleep at baseline was immediately evalu-ated and quantified before further randomization. Exclusion crite-ria comprised somatic illness and psychiatric disorders other thandepression, chronic treatment with benzodiazepines and/or barbi-turates or anticonvulsants, as well as systemic hormonal therapy.In all patients a detailed history as well as clinical and laboratoryexaminations including clinical chemistry, blood count, electroen-cephalogram (EEG) and electrocardiogram (ECG) were performedto rule out exclusion criteria.

2.2. Study design

The study was designed as a placebo controlled double blindcombined within/between subjects design. All patients underwenta continuous 60-h EEG recording for the assessment of baselinesleep-EEG, a sleep-EEG immediately before PSD and a sleep-EEGof the recovery night. In addition, the EEG during the entire waketime before and during PSD was recorded in order to assess theamount of MS during wakefulness. Besides the continuous EEGregistration at day 1 (‘‘before PSD”), day 2 (‘‘during PSD”) andday 3 (‘‘after recovery night”), a Hamilton depression rating scale(Hamilton, 1967) was applied. Subjective psychopathology wasscored using a self-rating depression questionnaire (DS; Depres-sion rating scale; von Zerssen, 1976). During PSD, half of the pa-tients were additionally treated with 200 mg modafinil (oralapplication at 1.30 am). The time point of application was chosenaccording to the results of the previous studies on MS in depressedpatients. The studies of our workgroup demonstrated that MS inthe first part of the day of PSD and already at the beginning ofPSD was closely related to antidepressant response (Hemmeteret al., 1998). The second half of the patients received placebo at

J. Beck et al. / Journal of Psychiatric Research 44 (2010) 853–864 855

the respective time. After PSD, patients in the modafinil group re-ceived modafinil for additionally two weeks (200 mg/d at 8 am);patients of the placebo group received placebo for further twoweeks at the respective times. The antidepressant treatment withmirtazapine was maintained throughout the entire study (30 mg/d at 9 pm) After one week of ongoing treatment (named follow-up 1 [FU1]) psychopathological ratings and assessment of daytimemicrosleep were performed. After two weeks of ongoing treatment(named follow-up 2 [FU2]), psychopathological ratings, nightsleep-EEG and assessment of daytime microsleep were performed(see Fig. 1).

2.3. Outcome measures

PSD-response was assessed by 6 items of the Hamilton Depres-sion Rating Scale covering the items depressive mood, feelings ofguilt, working and leisure activities, depressive inhibition, psycho-logical symptoms of anxiety, somatic symptoms (Bech et al.,1975). An improvement of at least 30% from baseline was requiredto determine PSD response according to Leon et al. (2001). Changesin severity of depression were assessed by Hamilton Rating scale, 21items and by a depression self-rating scale (DS; von Zerssen, 1976).

2.4. Quantification of sleep and microsleep

Night sleep was allowed between 22.00 h and 7.00 h. Withinthis time patients could sleep according to their individual sleepneed. Sleep was recorded using standard procedures of polysom-nography (PSG): horizontal electrooculogram (EOG), submentalmyogram (EMG) and electroencephalogram (EEG: C3–A2, C4–A1,C3–C4). The sleep records were visually scored by two experiencedraters according to standardized criteria (Rechtschaffen and Kales,1968). Sleep-EEG was analyzed according to the definitions in thestandard program described by Lauer et al. (1991), which includesmain variables of sleep continuity, sleep architecture and REMsleep. Sleep data was analyzed for the whole night as well as forthe 1st and 2nd half of the night and the 1st, 2nd and 3rd thirdof the night.

To evaluate sleep episodes during the day, microsleep (MS) wasscored according to the criteria of Rechtschaffen and Kales (1968),with the exception of the length of the sleep sequences: For the

20h 8h 20h 8h 20h 8h

day 1 day 2 day 3

baseline night night of PSD recovery night

11h: HDRS1:30h 11h: HDR11h: HDRS

PSD

Additional trea

Start: EEG-registration End: EEG-registration

HDRS = Hamilton depression rating scale; PSD = partial sleep deprivation

Fig. 1. Study

purpose of this study, all sequences lasting 15 or more seconds(as opposed to 30 or more seconds) and fulfilling the criteria ofsleepiness (=stage 1), sleep (=stages 2, 3, 4 and REM-sleep) weredefined as microsleep. To assess sleepiness at follow-up’s occur-rence of stage 1 was rated. Both the total amount of MS in minutesand the number of MS episodes were assessed. All sequences wereevaluated by two experienced raters; ambiguous sequences havebeen printed on EEG paper, and additionally evaluated by an inde-pendent third rater.

2.5. Statistics

Analyses of variances (ANOVAs) with repeated measures with thebetween subjects factor Group (modafinil vs. placebo) and the with-in subjects factor Time (before and during/after PSD and the two fol-low up measurements, respectively) were performed. Dependentvariables were HAMD 21, HAMD 6, DS and microsleep parameters(amount in minutes and frequency). For sleep, outcome measureswere Total Sleep time (TST) [min], Total sleep (SPT) [min], Sleep on-set latency (SOL) [min], Time awake [%], Number of awakenings [n].Parameters of sleep architecture: Stage 1 [%], Stage 2 [%], Slow wavesleep (SWS) [%]. Parameters of REM sleep: REM sleep [%], REM time[min], REM latency [min], REM density [n/t].

In case of significant group, time or interaction effects, post hocanalyses by t-tests were performed. To counter the issue of multi-ple testing with 5 data points (baseline, during PSD, revovery night,FU1 and FU2) we set the level of significance at p < .01. Whereappropriate, effect sizes were calculated following Cohen (1988).For the statistical comparison of the response rates in the modafiniland placebo group, Chi-square tests were applied and odds ratioscalculated based on the HAMD-6 items response. In case of missingdata the number of patients included in the analyses was reportedin the results section and indicated in the footnote of the tables.

3. Results

3.1. Effects of modafinil on microsleep during partial sleep deprivation

With respect to the total microsleep during PSD, the ANOVAwith the factors Group (modafinil vs. placebo) and Time (baseline

20h

[FU1] day 7 [FU2] day 14

S

tment with modafinil versus placebo

microsleep Night sleep EEGmicrosleep

11h: HDRS 11h: HDRS

design.


vs. PSD) revealed a significant Time by Group interaction, that is: asignificant decrease of microsleep within the modafinil group wasobserved, but not within the placebo group (total amount of micro-sleep: F = 7.17, df = 1, 26, p < .05; Table 1; number of microsleepepisodes: F = 4.28, df = 1, 26, p < .05; Table 2). The reduction ofmicrosleep in the modafinil group compared to the placebo groupwas significant both over the entire PSD time (1.30–22.00 h) andthe time period between 12.00 h and 18.00 h (Table 1, Fig. 2). Notethat despite the randomization at the time of study inclusion, theamount of MS was descriptively, though not statistically, higherin the modafinil group compared to the placebo group. Moreover,the pattern of MS distribution between groups was opposed:whereas MS decreased in patients treated with modafinil, MS in-creased in patients treated with placebo.

3.2. Effects of modafinil vs. placebo on depressive mood during PSDand after the recovery night

For the experts and self-rating scores of depression, the ANOVAwith factors Group (modafinil vs. placebo) and Time (baseline vs.

Table 1Microsleep (MS) at baseline (cumulative amount. min.) before and during partial sleep de

Microsleep variables (min) Before PSD (Baseline) mean ± SD During PS

Microsleep totalPlacebo, N = 14 26.54 ± 44.26 47.77 ± 6Modafinil, N = 14 53.85 ± 46.22 11.63 ± 1

MS 1.30–6.00 hPlacebo 18.34 ± 3Modafinil

0.78 ± 1

MS 6.00–12.00 hPlacebo 14.23 ± 30.15 8.05 ± 1Modafinil 25.85 ± 46.60 2.16 ± 3



SD = standard deviation.a p < .01, t-test vs. baseline.

Table 2Frequency of microsleep at baseline and during partial sleep deprivation in patients with

Microsleep variables (frequency) Before PSD (Baseline) mean ± SD Durin

Microsleep totalPlacebo, N = 14 12.42 ± 15.94 19.85Modafinil, N = 14 18.14 ± 9.34 9.92

MS 1.30–6.00 hPlacebo 9.28

Modafinil 1.42

MS 6.00–12.00 hPlacebo 5.14 ± 6.99 4.28Modafinil 7.50 ± 7.91 3.71



SD = standard deviation.a p < .01, t-test vs. baseline.

during PSD vs. after PSD) revealed no significant main effects forthe factor Group (modafinil vs. placebo) (F0s < 1.42). Significant ef-fects for the factor Time (baseline vs. During PSD vs. After PSD)were detected for all depression ratings: HDRS-21 item-, HDRS-6item- and DS self-rating depression values decreased significantlyin both groups, compared to baseline (F0s (2, 52) > 4.23). No signif-icant main effects were found for the Time by Group interaction(F0s < 1.73; Table 3). In summary, HDRS-21 item-, HDRS-6 item-and self-rating depression values during and after PSD decreasedsignificantly in both groups from baseline to the recovery night,with no significant difference between patients treated with mod-afinil or placebo.

Based on the criterion of an at least 30% reduction of HDRS-6item values, seven patients (50.0%) of the modafinil group, andsix patients (42.9%) of the control group responded to sleep depri-vation. There was no significant difference of distribution betweenthe two groups (v2 (1) = 0.144, p > .10).

On the day after the recovery night, seven patients in the pla-cebo group and seven patients in the modafinil group showed animprovement of at least 30% compared to baseline (response rate

privation in patients with additional modafinil- or placebo-treatment.

D mean ± SD ANOVA reap. meas. df F p

Group 1, 26 0.116 .735.31 Time 1, 26 0.785 .3845.99a Int. act. 1, 26 7.172 .013

t-test6.14 t = �1.815, p = .081

u-test.76 z = �1.56, p = .118



Group 1, 26 0.592 .4490.98 Time 1, 26 2.821 .1055.18 Int. act. 1, 26 0.866 .361

additional modafinil or placebo treatment.

g PSD mean ± SD ANOVA reap. meas. df F p

Group 1, 26 0.251 .647± 23.68 Time 1, 26 0.011 .918± 8.73 Int. act. 1, 26 4.282 .049

t-test± 13.44 t = �2.123, p = .043

u-test± 3.29 z = �1.564, p = .118


Group 1, 26 0.016 .920± 4.28 Time 1, 26 7.23 .012± 2.94a Int. act. 1, 26 4.1 .053


0

500

1000

1500

2000

2500

1.30-2h 2-4h 4-6h 6-8h 8-10h 10-12h 12-14h 14-16h 16-18h 18-20h 20-22h

Microsleep, (sec.)

Placebo N=14

Modafinil N=14

Anova results for the time period between 12h and 18h

Group: F(1, 26) = 1.18, p = n.s.

Time: F(1, 26) = 7.11, p = .01

Group x Time interaction: F(1, 26) = 7.05, p = .01

Bars indicate means and standard deviations.

Fig. 2. Cumulative amount of microsleep (MS) in two hourly intervals during partial sleep deprivation (PSD) in patients with Major Depression and additional modafinil- orplacebo- treatment.

Table 3HDRS-21 and 6 Item, DS von Zerssen and self-rating of mood, before, during and after partial sleep deprivation (PSD) in patients additionally treated with modafinil or placebo.

Before PSD (day 0) mean ± SD During PSD (day 1) mean ± SD After PSD (day 2) mean ± SD ANOVA reap. meas. df F p

HDRS 21 Item Group 1, 26 0.352 .558Placebo, N = 14 21.79 ± 4.72 12.64 ± 8.38a Time 1, 26 40.063 .000Modafinil, N = 14 21.71 ± 6.56 15.71 ± 9.12a Int. act. 1, 26 1.726 .200

HDRS-6 Item Group 1, 26 0.503 .485Placebo, N = 14 8.71 ± 2.40 6.50 ± 2.56 5.07 ± 3.85a,b Time 1, 26 10.987 .000Modafinil, N = 14 9.43 ± 2.79 6.21 ± 3.84a 6.50 ± 3.69a Int. act. 1, 26 0.661 .521

DS von Zerssen Group 1, 26 1.423 .244Placebo, N = 14 19.07 ± 8.33 16.64 ± 8.14a 15.79 ± 10.26 Time 1, 26 4.226 .02Modafinil, N = 14 22.86 ± 7.98 20.21 ± 7.23 17.64 ± 6.51 Int. act. 1, 26 0.258 .773

Notes: SD = standard deviation.a p < .01, t-test vs. baseline.b p < .01, t-test vs. day 1.

Table 4Frequencies and percent of responders in HDRS-6 Item Rating scale for patients treated with modafinil or placebo during and after PSD and follow up’s.

Responders (frequencies and percent) During PSD After PSD FU 1 FU 2

Total sample, N = 28 13 (46,4%) 17 (60,7%) 11 (39,3%) 10 (35,7%)Placebo, N = 14 6 (42,9%) 7 (50,0%) 6 (42,9%) 3 (21,4%)Modafinil, N = 14 7 (50,0%) 7 (50,0%) 5 (35,7%) 7 (50,0%)

Notes: Frequencies = Number of patients, Percent of patients in the respective group.


each); the distribution of responders did not differ significantly be-tween groups (v2 (1) = 0.150, p = n.s.; see Table 4).

3.3. Effect of modafinil vs. placebo on parameters of sleep-EEG in therecovery night

With respect to sleep continuity measures, (Table 5a) therewere no significant main effects for the factor Group (modafinilvs. placebo) (F0s < 0.59).

Significant main effects for the factor Time were observed forTime awake% (F = 5.77, df = 1, 26, p < .05) and the number of awak-

enings (F = 9.02, df = 1, 26, p < .05). Moreover, a significant Time -Group interaction for Time awake after sleep onset (%) (F = 4.52,df = 1, 26, p < .05). Subsequent single comparisons showed thatTime awake after sleep onset (%) was reduced in the placebo group(t-test, p < .05, although not on the p < .01 level of significance),whereas for the modafinil group, the time awake after sleep onsetremained unaltered from baseline to recovery night (t-test,p = n.s.).

With respect to the sleep architecture measures, (Table 5b) nosignificant main effects were found for the factor Group(F0s < 0.48). A significant reduction of stage 1 (%) was found for fac-

Table 5Sleep-EEG variables at baseline- and recovery night.

Sleep-EEG variables Before PSD (baseline night) mean ± SD After PSD (recovery night) mean ± SD ANOVA reap. meas. df F p

(a) Sleep continuity

Total sleep (SPT) min Group 1, 26 0.59 0.450Placebo 475.29 ± 75.79 503.93 ± 65.80 Time 1, 26 2.04 0.170Modafinil 491.64 ± 77.13 517.35 ± 67.66 Int. act. 1, 26 0.00 0.940

Sleep onset latency (SOL) min Group 1, 26 0.19 0.660Placebo 26.50 ± 27.54 11.71 ± 7.42 Time 1, 26 3.26 0.083Modafinil 23.06 ± 18.93 20.28 ± 71.31 Int. act. 1, 26 1.52 0.230

Time awake Group 1, 26 0.13 0.720Placebo 12.40 ± 11.91 6.54 ± 6.39 Time 1, 26 5.77 0.024Modafinil 8.55 ± 5.78 8.19 ± 9.09 Int. act. 1, 26 4.52 0.043

Number of awakenings Group 1, 26 0.00 0.960Placebo 24.43 ± 14.73 15.93 ± 12.91a Time 1, 26 9.02 0.006Modafinil 21.21 ± 9.85 18.71 ± 12.10 Int. act. 1, 26 2.68 0.113

(b) Sleep architecture

Stage 1% total Group 1, 26 0.48 0.830Placebo 6.39 ± 2.64 4.27 ± 2.40a Time 1, 26 14.27 0.001Modafinil 6.02 ± 2.06 4.97 ± 2.28 Int. act. 1, 26 1.63 0.210

Stage 2% total Group 1, 26 0.12 0.910Placebo 52.34 ± 9.62 52.89 ± 11.58 Time 1, 26 0.00 0.970Modafinil 53.17 ± 7.62 53.74 ± 8.15 Int. act. 1, 26 0.10 0.760

Slow wave sleep (SWS)% total Group 1, 26 0.18 0.680Placebo 7.61 ± 8.54 10.51 ± 9.15 Time 1, 26 2.19 0.150Modafinil 7.78 ± 6.68 7.95 ± 6.93 Int. act. 1, 26 1.73 0.200

(c) REM sleep

REM sleep% total Group 1, 26 0.52 0.480Placebo 19.65 ± 7.87 24.58 ± 8.77 Time 1, 26 3.42 0.076Modafinil 23.72 ± 5.90 24.07 ± 7.38 Int. act. 1, 26 2.57 0.120

REM sleep%, 1st half Group 1, 26 0.07 0.790Placebo 18.41 ± 10.97 21.51 ± 10.80 Time 1, 26 2.12 0.157Modafinil 18.36 ± 7.90 19.89 ± 6.86 Int. act. 1, 26 0.25 0.625

REM sleep% 2nd half Group 1, 26 3.25 0.083Placebo 20.89 ± 6.74 27.62 ± 10.96 Time 1, 26 1.62 0.214Modafinil 29.06 ± 7.57 28.25 ± 9.74 Int. act. 1, 26 2.64 0.120

REM latency Group 1, 26 0.28 0.600Placebo 87.75 ± 48.42 65.07 ± 39.79 Time 1, 26 3.26 0.083Modafinil 93.42 ± 64.65 76.71 ± 52.36 Int. act. 1, 26 0.08 0.780

REM density, total Group 1, 26 0.11 0.750Placebo 7.96 ± 1.77 6.35 ± 2.05a Time 1, 26 13.27 0.001Modafinil 7.97 ± 1.70 6.09 ± 2.47 Int. act 1, 26 0.57 0.460

REM density 1st half Group 1, 26 0.15 0.700Placebo 3.85 ± 0.65 3.18 ± 1.34 Time 1, 26 5.18 0.031Modafinil 3.90 ± 1.48 3.48 ± 1.65 Int. act. 1, 26 0.26 0.610

REM density 2nd half Group 1, 26 0.61 0.810Placebo 4.12 ± 1.31 3.17 ± 1.00a Time 1, 26 16.07 0.000Modafinil 4.09 ± 1.90 3.46 ± 1.65 Int. act. 1, 26 0.62 0.440

REM density 1st third Group 1, 26 1.05 0.320Placebo 2.79 ± 1.71 2.55 ± 1.61 Time 1, 26 0.09 0.362Modafinil 3.50 ± 2.06 2.97 ± 1.87 Int. act. 1, 26 0.12 0.730

REM density 2nd third Group 1, 26 0.08 0.800Placebo 4.19 ± 1.27 3.26 ± 1.30a Time 1, 26 9.26 0.005Modafinil 4.09 ± 1.98 3.68 ± 1.80 Int. act. 1, 26 1.37 0.250

REM density 3rd third Group 1, 26 0.12 0.723Placebo 3.88 ± 1.74 3.16 ± 0.82 Time 1, 26 9.09 0.020Modafinil 3.99 ± 1.82 3.42 ± 1.60 Int. act. 1, 26 0.07 0.790

Notes: SD = standard deviation.a p < .01, t-test vs. baseline.


tor Time (F = 14.27, df = 1, 26, p < .05). Subsequent t-tests withinthe two groups showed that stage 1 (%) significantly decreasedfrom baseline to the recovery night only in the placebo group (t-test, p < .01, for both Total night and 1st half), but not in the mod-afinil group. No significant time effects were observed for sleepstage 2 and slow wave sleep (SWS). No significant effects werefound for the Group � Time interaction (F0s < 1.73).

With respect to the REM sleep measures, (Table 5c), there wasno significant main effect for the factor Group (modafinil vs. pla-cebo) (F0s < 3.25). Significant effects were observed for the factorTime (baseline night vs. recovery night), with a decrease of REMdensity in the total night (F = 13.27, df = 1, 26, p < .05) as well asfor the 1st half of the night (F = 5.18, df = 1, 26, p < .05) and the2nd half of the night (F = 16.07, df = 1, 26, p < .05). There were no


significant effects for the Time � Group interaction (F0s < .94).Thus, irrespective of the group, REM-density decreased from base-line to recovery night.

3.4. Effects of modafinil vs. placebo on microsleep at the two follow-up’s (FU1 and FU2)

For the factor Group (modafinil vs. placebo), no significant maineffects have been observed for both amount and frequency ofmicrosleep (F0s < 0.26). For the factor Time (baseline, FU1, FU2),microsleep total (min) decreased significantly (F = 5.03, df = 2, 44,p < .05). For the Group � Time interaction, no significant effectshave been observed (F0s < 1.72). Post hoc analyses showed a signif-icant reduction of microsleep at FU1, as well at FU2 compared tobaseline in the modafinil group, but not in the placebo group. Over-all, microsleep in minutes decreased continuously in the modafinilgroup, but not in the placebo group (Table 6).

For the frequency of microsleep, no significant effects for thefactor Group (modafinil vs. placebo), the factor Time (baseline,FU1, FU2) and the Group � Time interaction were found(F0s < 0.26).

3.5. Effects of modafinil vs. placebo on depression ratings at FU1 andFU2

With respect to expert rating scales (HDRS-21 and HDRS-6) nosignificant main effects were found for the factor Group (placebovs. modafinil) (F0s < 0.42). Significant Time effects for HDRS-21item (F = 11.07, df = 3, 75, p < .05) and HDRS-6 item-ratings(F = 6.70, df = 3, 75, p > .05) were detected: Compared to baseline,there was a significant reduction in HRDS-21 item score after therecovery night lasting until FU2. No significant effects were foundfor the Time � Group interaction (F0s < 0.80). With respect to theself-rating scores (DS) no significant effects were observed forGroup, Time, or Time � Group interaction (F0s < 2.10) (Table 7).

Table 7HDRS 21 and 6 Item, and DS van Zerssen before partial sleep deprivation (PSD), after PSD

Before PSD (day 0)mean ± SD

After PSD (day 2)mean ± SD

FU 1 (daymean ± SD

HDRS-21 ItemPlacebo, N = 13 21.92 ± 4.90 13.46 ± 8.12ª 16.85 ± 7.4Modafinil, N = 14 21.71 ± 6.56 15.71 ± 9.12ª 18.14 ± 6.8

HDRS-6 ItemPlacebo, N = 13 8.85 ± 2.44 5.46 ± 3.71ª 7.62 ± 4.1Modafinil, N = 14 9.43 ± 2.79 6.50 ± 3.69ª 8.14 ± 3.8

DS van ZerssenPlacebo, N = 13 18.92 ± 8.65 15.77 ± 10.67 17.38 ± 11Modafinil, N = 14 22.86 ± 7.98 17.64 ± 6.51 20.43 ± 8.5

SD = Standard deviation.a p < .01, t-test vs. baseline.

Table 6Microsleep (time and frequency) in depressed patients additionally treated with Modafini

Microsleep variables Before PSD (day -1/0) mean ± SD FU 1 (day 7/8) mean ± SD

Microsleep total (min)Placebo, N = 10 16.76 ± 15.68 9.40 ± 12.01Modafinil, N = 14 24.82 ± 16.68 12.31 ± 12.06

Microsleep total frequency (N)Placebo, N = 10 14.00 ± 13.40 10.50 ± 9.48Modafinil, N = 14 21.28 ± 11.27 13.85 ± 13.78

Notes: SD = Standard deviation.a p < .01, t-test vs. baseline.

With respect to the therapy response compared to baseline val-ues (at least 30% reduction of the HDRS-6 score, Table 4) in the pla-cebo group six patients (42.9%) responded at FU1 and threepatients (21.4%) at FU2. In the modafinil group five patients(35.7%) responded at FU1, whereas seven patients (50.0%) fulfilledthe response criterion at FU2. Chi-square test did not reveal signif-icant differences between groups (v2 = 2.09, df = 1, p = .148).

Odds ratio calculation revealed, that the chance to show anyimprovement in depressive symptoms scores on the HDRS-6 itemscale between baseline and FU2 was 6.4-fold higher in the modafi-nil group compared to the placebo group (OR = 6.42 CI = 1–41.21)with significant differences between groups v2 (1) = 4.25 p = .04).

3.6. Effects of modafinil vs. placebo on night sleep-EEG at FU2

Of the 28 patients in the study, 27 patients performed the sleep-EEG at FU2 (13 patients in the placebo and 14 patients in the mod-afinil group); one patient of the placebo group refused to performthe sleep eeg at FU2.

With respect to sleep continuity (Table 8a), no significant maineffects were observed for the factor Group (modafinil vs. placebo),Time (baseline vs. FU2), and for Group � Time interaction(F0s < 2.76).

With respect to sleep architecture (Table 8b), no significantmain effects have been observed for the factor Group (modafinilvs. placebo), the factor Time (baseline vs. FU2), and for the Group -Time interaction (F0s < 2.20).

With respect to REM-sleep (Table 8c), no significant main ef-fects were observed for the factor Group (modafinil vs. placebo)and the factor Time (F0s < 1.55). Significant Group � Time interac-tions were observed for REM sleep 2nd half (in min and %), withincreasing REM sleep for the placebo group and with decreasingREM sleep for the modafinil group (% and time, 2nd half)(F0s > 6.77, df = 1, 25, p < .05) with moderate effect sizes for bothREM% (d = 0.6) and REM time (d = 0.5) in the modafinil group.

, FU 1 and FU 2 in patients additionally treated with modafinil or placebo.

7) FU 2 (day 14)mean ± SD

ANOVAreap. meas.

df F p

Group 1, 25 0.155 .6979ª 16.54 ± 7.27ª Time 3, 75 11.068 .0009a 16.71 ± 5.53ª Int. act. 3, 75 0.372 .774

Group 1, 25 0.076 .7859 8.69 ± 3.94 Time 3, 75 6.706 .0008 7.64 ± 2.62 Int. act. 3, 75 0.798 .499

Group 1, 25 0.416 .525.31 20.54 ± 11.42 Time 3, 75 2.101 .1079 19.07 ± 8.08 Int. act. 3, 75 0.931 .430

l or placebo before partial sleep deprivation (PSD), FU 1 and FU 2.

FU 2 (day 14/15) mean ± SD ANOVA reap. meas. df F p

Group 1, 22 0.180 .67612.20 ± 18.56 Time 2, 44 5.033 .011

5.56 ± 7.21a Int. act. 2, 44 1.719 .194

Group 1, 22 0.295 .59312.40 ± 15.93 Time 2, 44 2.595 .086

6.71 ± 10.58a Int. act. 2, 44 1.687 .197

Table 8aSleep-EEG variables at baseline and FU 2 in patients with additional modafinil or placebo treatment.

Sleep-EEG variables Before PSD (baseline night) mean ± SD FU 2 (night 14/15) mean ± SD ANOVA reap. meas. df F p

Total Sleep time (TST) min Group 1, 25 0.025 .876Placebo, N = 13 428.50 ± 70.76 444.42 ± 79.95 Time 1, 25 0.033 .858Modafinil, N = 14 452.67 ± 74.29 428.50 ± 123.85 Int. act. 1, 25 0.770 .389

Total sleep (SPT) min Group 1, 25 0.017 .899Placebo, N = 13 491.15 ± 49.03 490.26 ± 74.14 Time 1, 25 0.014 .907Modafinil, N = 14 491.64 ± 77.13 495.21 ± 86.60 Int. act. 1, 25 0.005 .944

Sleep onset latency (SOL) min Group 1, 25 0.893 .354Placebo, N = 13 24.26 ± 27.30 13.69 ± 9.72 Time 1, 25 0.096 .76Modafinil, N = 14 23.06 ± 18.93 29.10 ± 41.52 Int. act. 1, 25 1.285 .268

Time awake% Group 1, 25 0.028 .869Placebo, N = 13 13.26 ± 11.92 9.53 ± 10.07 Time 1, 25 0.255 .618Modafinil, N = 14 8.55 ± 5.78 15.55 ± 20.22 Int. act. 1, 25 2.760 .109

Number of awakenings Group 1, 25 0.266 .611Placebo, N = 13 26.00 ± 14.05 22.46 ± 17.49 Time 1, 25 1.214 .281Mondafini, N = 14 21.21 ± 9.85 22.28 ± 9.85 Int. act. 1, 25 0.348 .561

N = 27 patients; 13 patients in the placebo and 14 patients in the modafinil group; SD = Standard deviation.

Table 8bSleep-EEG variables at baseline and FU 2 in patients with additional modafinil or placebo treatment, parameters of sleep architecture.


Stage 1% total Group 1, 25 0.832 .370Placebo, N = 13 6.63 ± 2.58 6.80 ± 3.31 Time 1, 25 0.005 .947Modafinil, N = 14 6.02 ± 2.06 5.80 ± 2.45 Int. act. 1, 25 0.154 .698

Stage 1%, 1st half Group 1,25 0.048 1, 25Placebo 5.67 ± 2.71 5.30 ± 2.94 Time 1, 25 0.733 .400Modafinil 5.65 ± 3.46 4.87 ± 3.48 Int. act. 1, 25 0.093 .763

Stage 1%, 2nd half Group 1,25 1.830 1, 25Placebo 7.62 ± 2.94 8.30 ± 4.57 Time 1, 25 0.377 .545Modafinil 6.40 ± 2.78 6.70 ± 3.10 Int. act. 1, 25 0.056 .815

Stage 2% total Group 1, 25 0.699 .411Placebo 54.23 ± 9.37 54.58 ± 9.63 Time 1, 25 0.144 .708Modafinil 53.17 ± 7.62 50.73 ± 14.03 Int. act. 1, 25 0.254 .619

Slow wave sleep (SWS)% total Group 1,25 0.161 1, 25Placebo 5.70 ± 4.94 6.79 ± 5.52 Time 1, 25 0.143 .837Modafinil 7.78 ± 6.68 6.28 ± 5.44 Int. act. 1, 25 1.680 .207

SWS%, 1st half Group 1,25 0.001 0979Placebo 8.50 ± 8.77 10.26 ± 7.73 Time 1, 25 0.057 .813Modafinil 10.68 ± 9.06 8.23 ± 7.54 Int. act. 1, 25 2.203 .150



Taken together, REM time (% and min) decreased over time inthe modafinil group, but increased in the placebo group.

For the REM-density, both the factor Group and the Time -Group interaction were not significant (F0s < 3.00). For the factorTime (baseline vs. FU2), REM-density decreased over time forREM-density total, 1st and 2nd half of the night as well as 2ndand 3rd third of the night (F0s > 5.04, df = 1, 25, p < .05). Descrip-tively, REM-density in the 1st third of the night decreased in themodafinil group and increased in the placebo group from baselineto FU2 (F = 3.06, df = 1, 25, p = .093).

4. Discussion

The present study assessed the effects of modafinil on daytimemicrosleep, sleep-EEG, response to partial sleep deprivation andmidterm antidepressant augmentation response under random-ized, placebo-controlled conditions.

The main finding of the present study was,

(1) That modafinil treated patients showed significantly lessmicrosleep during partial sleep deprivation, compared to patientsof the placebo group. Secondary study findings were that.

(2) The modafinil induced suppression of microsleep did notenhance the immediate antidepressive effect of partial sleep depri-vation within 24 h compared to placebo.

(3) While modafinil exhibited slightly arousing effects on sleepin the recovery night following the partial sleep deprivation, theseeffects were no longer present at follow-up after two weeks ofongoing modafinil treatment.

(4) After two weeks of treatment, the modafinil group showed asignificant reduction in REM sleep time in the 2nd half of the nightfor both relative (%) and absolute REM sleep time (minutes),whereas the placebo group showed an increase in these REM sleepparameters.

In accordance with our main hypothesis, we found that theapplication of modafinil significantly reduced microsleep in de-pressed patients during PSD, that is: In the modafinil group, therewas a reduction of MS for both the accumulative amount of MS andthe frequency of MS episodes, which were present also in the sec-ond part of the day until the evening. The significant Time � Groupinteraction showed a decrease within the modafinil group, but notwithin the placebo group. This pattern of results suggests an effectof modafinil on PSD induced daytime sleepiness even in the secondpart of the day following PSD. This finding is in line with earlier

Table 8cSleep-EEG variables at baseline and FU 2 in patients with additional modafinil or placebo treatment, parameters of REM sleep.


REM sleep% total Group 1, 25 0.242 .627Placebo, N = 13 19.60 ± 8.18 21.50 ± 6.27 Time 1, 25 0.284 .541Modafinil, N = 14 23.72 ± 5.90 19.92 ± 10.04 Int. act. 1, 25 3.460 .075

REM sleep%, 1st half Group 1, 25 0.034 .856Placebo, N = 13 18.03 ± 11.32 17.96 ± 7.68 Time 1, 25 0.240 .628Modafinil, N = 14 18.36 ± 7.90 16.48 ± 11.03 Int. act. 1, 25 0.211 .650

REM sleep% 2nd half Group 1, 25 1.551 .225Placebo, N = 13 21.18 ± 6.92 25.02 ± 6.00 Time 1, 25 0.253 .619Modafinil, N = 14 29.06 ± 7.57 23.38 ± 10.70c Int. act. 1, 25 6.768 .015

REM time total Group 1, 25 0.531 .473Placebo, N = 13 94.76 ± 34.38 96.46 ± 38.83 Time 1, 25 1.256 .273Modafinil, N = 14 116.46 ± 35.57 93.85 ± 54.40 Int. act. 1, 25 1.696 .205

REM time 1st half Group 1, 25 0.012 .913Placebo, N = 13 42.84 ± 22.67 43.15 ± 18.79 Time 1, 25 0.118 .734Modafinil, N = 14 45.64 ± 22.19 42.00 ± 27.27 Int. act. 1, 25 0.165 .688REM time 2nd half Group 1, 25 1.502 .232Placebo, N = 13 51.96 ± 17.17 61.00 ± 16.27 Time 1, 25 0.117 .735Modafinil, N = 14 70.82 ± 20.81 59.00 ± 26.58 Int. act. 1, 25 6.558 .017

REM latency Group 1, 25 0.017 .897Placebo, N = 13 90.92 ± 48.85 95.96 ± 39.56 Time 1, 25 0.173 .681Modafinil, N = 14 93.42 ± 64.65 98.71 ± 81.71 Int. act. 1, 25 0.000 .992

REM density, total Group 1, 25 0.226 .638Placebo, N = 13 8.15 ± 1.69 6.68 ± 1.67 Time 1, 25 11.082 .003Modafinil, N = 14 8.00 ± 3.25 5.92 ± 3.86 Int. act. 1, 25 0.318 .578

REM density 1st half Group 1, 25 0.426 .520Placebo, N = 13 3.91 ± 0.61 3.36 ± 1.01c Time 1, 25 6.525 .017Modafinil 3.90 ± 1.48 2.77 ± 2.21c Int. act. 1, 25 0.766 .390

REM density 2nd half Group 1, 25 0.078 .783Placebo, N = 13 4.23 ± 1.28 3.31 ± 1.09 Time 1, 25 7.889 .010Modafinil, N = 14 4.09 ± 1.90 3.15 ± 2.01 Int. act. 1, 25 0.001 .974

REM density 1st third Group 1, 25 0.000 .990Placebo, N = 13 2.80 ± 1.78 3.41 ± 1.16 Time 1, 25 0.039 .845Modafinil, N = 14 3.50 ± 2.06 2.72 ± 2.17 Int. act. 1, 25 3.059 .093

REM density 2nd third Group 1, 25 0.234 .633Placebo, N = 13 4.29 ± 1.25 3.41 ± 1.61 Time 1, 25 5.679 .025Modafinil, N = 14 4.09 ± 1.98 3.02 ± 2.46 Int. act. 1, 25 0.054 .818

REM density 3rd third Group 1, 25 0.028 .867Placebo, N = 13 3.97 ± 1.77 3.09 ± 1.11 Time 1, 25 5.042 .034Modafinil, N = 14 3.99 ± 1.82 3.26 ± 2.09 Int. act. 1, 25 0.041 .842



findings on modafinil application in healthy sleep deprived sub-jects (Lagarde et al., 1995; Wesensten et al., 2005). However, thepattern of microsleep suppression in the modafinil group over timewas slightly different from the pattern of the flumazenil inducedmicrosleep suppression of an earlier study (Hemmeter et al.,2007), that is to say: Hemmeter et al. (2007) found a reduced MSin depressed patients treated with flumazenil during PSD mainlyin the first part of the day following PSD. The differences betweenthe present pattern of microsleep suppression and the pattern ofmicrosleep suppression observed by Hemmeter et al. (2007) arelikely to be caused by differences of the biological half-life of mod-afinil and flumazenil: While flumazenil has a biological half-life of50–60 min, the biological half-life of modafinil is about ten timeslonger (10–12 h). Furthermore, the different patterns could alsobe caused by a difference in the basic antidepressant therapy usedin these studies (mirtazapine vs. trimipramine) due to the differentsedative potentials of these compounds.

In contrast to one of the secondary hypotheses (application ofmodafinil over two additional weeks does stabilize the mood re-sponse to partial sleep deprivation compared to placebo), resultsdid not show significant differences in mood response betweenthe modafinil and the placebo group throughout the study. Putin other words: While the partial sleep deprivation was effective

in reducing depressive symptoms in both the placebo and mod-afinil group, modafinil did not enhance this effect compared toplacebo. This was true with regard to experts’ ratings (HDRS-21and HDRS-6) and with regard to self ratings (DS). Interestingly,at the day following the recovery night, the response rates seenduring PSD (50% in the modafinil group, 42.9% in the placebogroup) remained virtually unchanged, being 50.0% after therecovery night in both groups. This finding is in contrast to theresults of an earlier study with flumazenil (Hemmeter et al.,2007): in the latter study, response rates deteriorated after therecovery night in both the flumazenil and the placebo group. Itis noteworthy that the response rates after recovery night re-mained relatively high in both groups (50.0%), which is higherthan the response rates after recovery night following sleepdeprivation reported in literature: in a meta-analysis on the effi-cacy of total sleep deprivation (TSD), 83% of unmedicated pa-tients who responded to TSD relapsed after the recovery night,i.e., only 17% of the patients retained the beneficial effect ofTSD after one night of recovery sleep (Wu and Bunney, 1990).A possible confounding factor in the present study is the basicantidepressant treatment with mirtazapine that was adminis-tered in both groups throughout the study, since combiningPSD with antidepressant therapy has been shown to have a sta-


bilizing effect on the antidepressant effects of sleep deprivationper se. This interpretation is supported by earlier studies, whichshowed that the antidepressant response to sleep deprivationwas successfully maintained with lithium salts (Szuba et al.,1994; Benedetti et al., 1999) and the 5-HT1a antagonist pindolol(Smeraldi et al., 1999). We thus hypothesized, that in our studymirtazapine already exerted a stabilizing effect on the PSD re-sponse. Additional modafinil treatment however did not furtherenhance this stabilization of the antidepressant response to PSDcompared to placebo. This finding is in contrast to earlier studieswhich showed a therapeutic efficacy of other strategies focusedon stabilizing the sleep wake cycle in order to maintain the anti-depressant effects of sleep deprivation. To name a few, suchstrategies are sleep phase advance therapy (Riemann et al.,1999; Voderholzer et al., 2003), bright light therapy, or the com-bination of both (Loving et al., 2002; Wu 2004). Another con-founding factor could be a difference in the distribution offunctionally relevant pharmacogenetic polymorphisms betweenthe groups, namely of the COMT and MDR1 genes: A recent phar-macogenetic study on modafinil found that the response to mod-afinil is modulated by the Val158Met polymorphism of COMT(Bodenmann et al., 2009). In Val/Val genotype subjects, modafinilpotently improved vigor and subjective well-being and main-tained stable performance with respect to executive functionand vigilant attention throughout 40 continuous hours of wake-fulness, whereas it was virtually ineffective in Met/Met genotypesubjects. Moreover, modafinil is a substrate of P-glycoprotein(Zhu et al., 2008), which is encoded by the multidrug resistancegene MDR1, while mirtazapine is not a substrate of P-glycopro-tein (Uhr et al., 2008). P-glycoprotein acts as an active effluxpump for a wide range of compounds at the blood–brain-barrierand thus regulates intracerebral concentrations of drugs. Whiletheoretically in carriers of the ABCB1 polymorphism bioavailabil-ity of modafinil in the CNS would be reduced, the CNS availabilityof mirtazapine would not be influenced.

Based on the widely equal response in both groups, we con-clude that while modafinil seemed to be efficient in reducing day-time microsleep following PSD, modafinil did not significantlyenhance the antidepressive effects of PSD. Again, this finding isin line with the results of a previous study (Hemmeter et al.,2007); flumazenil significantly reduced microsleep during PSD influmazenil treated patients without an increase in antidepressantresponse versus placebo. We therefore speculate that the occur-rence of microsleep and mood response during a PSD condition ismediated by different neurobiological mechanisms and that theremight be no direct association between microsleep and mood re-sponse. More specifically, the neurobiological mechanisms whichpromote wakefulness (e.g. orexinergic networks) do not seem todirectly interact with the neurobiology of mood regulation in aPSD condition.

In accordance with a further secondary hypothesis (the homeo-static sleep response after modafinil-induced wakefulness is pre-served), after two weeks of treatment modafinil treated patientsdid not show an impairment in their homeostatic sleep responsecompared to the placebo group. However, we observed slightlyarousing effects of modafinil on sleep in the recovery night afterPSD, that is to say: The only significant Group � Time interactioneffect which provided a proof for a different effect between the pla-cebo and the modafinil group was found for Time awake after sleeponset (%). We speculate that modafinil counteracted the effects ofPSD on sleep continuity in the recovery night. This was true forTime awake after sleep onset and for the number of awakeningsafter sleep onset. Therefore, these findings suggested that the in-take of modafinil did not only reduce sleepiness during the day,but modafinil seemed to exert arousing effects on subsequent sleepin the recovery night following PSD. Moreover, REM-sleep increase

in the placebo group after PSD was due to an increase all over thenight with a striking difference to modafinil in the second half ofthe night (increase in the placebo group). The more intense de-crease of REM-density in the placebo group may be related tothe slightly suppressing effects on Non-REM sleep pressure (noSWS increase, less stage 1 reduction in the recovery night, noimprovement of sleep continuity) of modafinil. Concerning the ef-fects of modafinil on the EEG sleep pattern at FU2, we did observethat the arousing effects of modafinil on sleep continuity (seen inthe recovery night following PSD) where no longer present atFU2. Then, REM time decreased over time in the modafinil, but in-creased in the placebo group. REM-density decreased in total andin both groups; however, in the first 3rd of the night REM densitydescriptively decreased in the modafinil and increased in the pla-cebo group. Note that elevated REM time and elevated REM densityare the most characteristic alterations in the sleep EEG duringdepression (Kupfer et al., 1990; Holsboer-Trachsler et al., 1994;Steiger and Holsboer, 1997; Hatzinger et al., 2004). Failure to nor-malize these elevated REM markers despite remission of affectivesymptoms was associated with an increased risk for relapse (Gileset al., 1987; Hatzinger et al., 2004). Therefore, we interpret theREM density and REM time decreasing effect of modafinil as a pos-sible indication that ongoing modafinil treatment over two weeksmay exert a favourable effect on the pathophysiologically alteredsleep regulation in depression.

In contrast to a further secondary hypothesis (the application ofmodafinil over two additional weeks augments the antidepressantresponse to the ongoing mirtazapine therapy), the results of thepresent study did not show different response rates between theplacebo and modafinil group at FU2.

However, it is noteworthy that odds ratio analysis revealed thatthe chance to show any improvement in depressive symptomsscores on the HDRS-6-item scale between baseline and FU2 was6.4-fold higher in the modafinil group compared to the placebogroup (OR = 6.42 CI = 1–41.21) with significant differences be-tween groups. Whereas this finding should not be over interpreted,on the other hand, this finding might suggest an antidepressiveaugmentation effect of modafinil on the combined mirtazapineplus PSD condition of this study. One might speculate that modafi-nil could have lead to a superior treatment outcome if the treat-ment with modafinil was further maintained. Such aninterpretation is in line with two earlier studies on modafinil asan add-on strategy in depressed patients with fatigue and sleepi-ness that showed only partial response to antidepressants. In thefirst study, a 4-week open-label adjunct modafinil treatment (withflexible dosing from 100 to 400 mg/day) was associated with sig-nificant improvements in the Beck Depression Inventory and Ham-ilton Depression Rating Scale, as well as measures of fatigue(DeBattista et al., 2003). The second study was a multicenter, ran-domized, placebo-controlled 8-week study of adjunct modafinil200 mg/day (added to concurrent treatment with selective seroto-nin reuptake inhibitors), which found significant improvements inHamD and sleepiness ratings compared to placebo (Fava et al.,2007). Further support for this interpretation is provided by thedata on the neurochemical mechanisms of modafinil, showing thatmodafinil modulates the activity of dopaminergic (de Saint Hilaireet al., 2001; Murillo-Rodriguez et al., 2007; Madras et al., 2006; Wi-sor et al., 2001), noradrenergic (Nishino et al., 1993; Stone et al.,2002; Madras et al., 2006), serotonergic (Ferraro et al., 2000; Ferr-aro et al., 2002; Ferraro et al., 2005), histaminergic (Scammell et al.,2000; Ishizuka et al., 2008) and orexinergic pathways (Nishino,2003; Chemelli et al., 1999; Scammell et al., 2000) (for reviewssee Kumar, 2008; and Minzenberg and Carter, 2008).

Taken together, we interpret our findings of decreased REMtime after two weeks of additional modafinil treatment as a possi-ble indication that modafinil may act as an antidepressant aug-


mentation compound that beneficially influences biological mark-ers of depression already after two weeks of add-on treatment.This interpretation is in line with results of earlier studies on ben-eficial effects of modafinil augmentation on antidepressant treat-ment after four (DeBattista et al., 2003) and eight weeks (Favaet al., 2007). Moreover, we hypothesize that modafinil exhibitsits beneficial effects on REM sleep markers of depression and onantidepressant treatment outcome via modulation of monoamin-ergic neurotransmission.

5. Limitations of the study

The interpretation of the study data on the pharmacological sta-bilization of the antidepressant effect of partial sleep deprivation islimited by the fact, that the basic antidepressant treatment withmirtazapine was administered in both the placebo and the modafi-nil group over the entire study time. Mirtazapine may have stabi-lized the antidepressant effect of PSD on its own and thus mayhave masked possible stabilizing effects of modafinil. From apurely academic point of view, a modafinil monotherapy vs. pla-cebo would have been a more clear-cut study design, however,ethical considerations prevented a monotherapy of depressed pa-tients with placebo over two weeks. Last, study results could beinfluenced by different distributions of functionally relevant phar-macogenetic polymorphisms, e.g. of the COMT and MDR1 geneswhich were not assessed in this study.

Acknowledgements

This project was supported by the Swiss National Science Foun-dation (SNF-Nr 3200B0-104022, E.H.) and Cephalon GmbH, Mar-tinsried, Germany.

References

Bech P, Gram LF, Dein E, Jacobsen O, Vitger J, Bolwig TG. Quantitative rating ofdepressive states. Acta Psychiatrica Scand. 1975;51:161–70.

Benedetti F, Colombo C, Barbini B, Campori E, Smeraldi E. Ongoing lithiumtreatment prevents relapse after total sleep deprivation. Journal of ClinicalPsychopharmacology 1999;19:240–5.

Bodenmann S, Xu S, Luhmann UFO, Arand M, Berger W, Jung HH, et al.Pharmacogenetics of modafinil after sleep loss: catechol-O-methyltransferasegenotype modulates waking functions but not recovery sleep. ClinicalPharmacology and Therapeutics 2009;85(3):296–303.

Borbély AA. A two process model of sleep regulation. Human Neurobiology1982;1:195–204.

Buguet A, Montmayeur A, Pigeau R, Naitoh P. Modafinil, d-amphetamine andplacebo during 64 hours of sustained mental work. II. Effects on two nights ofrecovery sleep. Journal of Sleep Research 1995;4(4):229–41.

Caldwell JA, Prazinko BF, Hall KK. The effects of body posture on restingelectroencephalographic activity in sleep-deprived subjects. ClinicalNeurophysiology 2000;111(3):464–70.

Chapotot F, Pigeau R, Canini F, Bourdon L, Buguet A. Distinctive effects of modafiniland d-amphetamine on the homeostatic and circadian modulation of thehuman waking EEG. Psychopharmacology 2003;166(2):127–38.

Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice.molecular genetics of sleep regulation. Cell 1999;98(4):437–51.

Cohen J. Statistical power analysis for the behavioral sciences. Hillsdale:Erlbaum; 1988.

de Saint Hilaire Z, Orosco M, Rouch C, et al. Variations in extracellular monoamines inthe prefrontal cortex and medial hypothalamus after modafinil administration: amicrodialysis study in rats. NeuroReport 2001;12(16):3533–7.

DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR. Modafinil indepression study group. Adjunct modafinil for the short-term treatment offatigue and sleepiness in patients with major depressive disorder: a preliminarydouble-blind, placebo-controlled study. Journal of Clinical Psychiatry2003;64(9):1057–64.

Elsenga S, van den Hoofdacker RH. Sleep deprivation and clomipramine inendogenous depression. In: Popvicu L, Asgian B, Badiu G , editors. Proceedingsof the fourth European congress on sleep research, Sleep 1978, Basel, Karger,Switzerland.

Fava M, Thase ME, DeBattista C, Doghramji K, Arora S, Hughes RJ. Modafinilaugmentation of selective serotonin reuptake inhibitor therapy in MDD partialresponders with persistent fatigue and sleepiness. Annals of Clinical Psychiatry2007;19(3):153–9.

Ferraro L, Fuxe K, Tanganelli S, et al. Amplification of cortical serotonin release: afurther neurochemical action of the vigilance-promoting drug modafinil.Neuropharmacology 2000;39(11):1974–83.

Ferraro L, Fuxe K, Tanganelli S, et al. Differential enhancement of dialysate serotoninlevels in distinct brain regions of the awake rat by modafinil: possible relevancefor wakefulness and depression. Journal of Neuroscience Research2002;68(1):107–12.

Ferraro L, Fuxe K, Agnati L, et al. Modafinil enhances the increase of extracellularserotonin levels induced by the antidepressant drugs fluoxetine andimipramine: a dual probe microdialysis study in awake rat. Synapse2005;55(4):230–41.

Germain A, Kupfer DJ. Circadian rhythm disturbances in depression. HumanPsychopharmacology 2008;23(7):571–85. Review.

Giedke H, Schwärzler F. Therapeutic use of sleep deprivation in depression. SleepMedical Review 2002;6(5):361–77. Review.

Giles DE, Jarrett RB, Roffwarg HP, Rush AJ. Reduced rapid eye movement latency. Apredictor of recurrence in depression. Neuropsychopharmacology 1987;1:33–9.

Haefely W, Bonetti EP, Burkhard WP, Cumin R, Laurent JP, Möhler H, Pieri L, Polc P,Richards JG, Schaffner R, Scherschlicht R, editors. BenzodiazepineantagonistsCosta E, editors. The benzodiazepines: from molecular biology toclinical practice. New York: Raven Press; 1983. p. 137–46.

Hamilton M. Development of a rating scale for primary depressive illness. BritishJournal of Clinical Pharmacology 1967;6:278–96.

Hatzinger M, Hemmeter UM, Brand S, Ising M, Holsboer-Trachsler E.Electroencephalographic sleep profiles in treatment course and long-termoutcome of major depression: association with DEX/CRH-test response. Journalof Psychiatric Research 2004;38:453–65.

Hemmeter U, Bischof R, Hatzinger M, Seifritz E, Holsboer-Trachsler E. Microsleepduring partial sleep deprivation in depression. Biological Psychiatry1998;43:829–39.

Hemmeter U, Hatzinger M, Brand S, Holsboer-Trachsler E. Effect of flumazenil-augmentation on microsleep and mood in depressed patients during partialsleep deprivation. Journal of Psychiatric Research 2007;41(10):876–84.

Holsboer-Trachsler E, Hemmeter U, Hatzinger M, Seifritz E, Gerhard U, Hobi V. Sleepdeprivation and bright light as potential augmenters of antidepressant drugtreatment–neurobiological and psychometric assessment of course. Journal ofPsychiatric Research 1994;28:381–99.

Ishizuka T, Murakami M, Yamatodani A. Involvement of central histaminergicsystems in modafinil-induced but not methylphenidate-induced increases inlocomotor activity in rats. European Journal of Pharmacology 2008;578(2–3):209–15.

Jones MW. A new method for measuring daytime sleepiness. The EpworthSleepiness Scale. Sleep 1991;14(6):540–5.

Kumar R. Approved and investigational uses of modafinil: an evidence-basedreview. Drugs 2008;68(13):1803–39.

Kupfer DJ, Frank E, McEachran AB, Grochocinski VJ. Delta sleep ratio. A biologicalcorrelate of early recurrence in unipolar affective disorder. Archives of GeneralPsychiatry 1990;47:1100–5.

Lagarde D, Batejat D, Van Beers P, et al. Interest of modafinil, a newpsychostimulant, during a 60-hour sleep deprivation experiment.Fundamental & Clinical Pharmacology 1995;9(3):271–9.

Lauer CJ, Riemann D, Wiegand M, Berger M. From early to late adulthood: changesin EEG sleep of depressed patients and healthy volunteers. Biological Psychiatry1991;29:979–93.

Leon AC, Blier P, Culpepper L, Gorman JM, Hirschfeld RM, Nierenberg AA, et al. Anideal trial to test differential onset of antidepressant effect. Journal of ClinicalPsychiatry 2001;62(Suppl. 4):34–40.

Loving RT, Kripke DF, Shuchter SR. Bright light augments antidepressant effects ofmedication and wake therapy. Depression and Anxiety 2002;16:1–3.

Madras BK, Xie Z, Lin Z, et al. Modafinil occupies dopamine and norepinephrinetransporters in vivo and modulates the transporters and trace amine activityin vitro. Journal of Pharmacology and Experimental Therapeutics2006;319(2):561–9.

Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effectson cognition. Neuropsychopharmacology 2008;33(7):1477–502. Review.

Murillo-Rodriguez E, Haro R, Palomero-Rivero M, et al. Modafinil enhancesextracellular levels of dopamine in the nucleus accumbens and increaseswakefulness in rats. Behavioural Brain Research 2007;176(2):353–7.

Nishino S. The hypocretin/orexin system in health and disease. Biological Psychiatry2003;54(2):87–95.

Nishino S, Fruhstorfer B, Arrigoni J, et al. Further characterization of the alpha-1receptor subtype involved in the control of cataplexy in canine narcolepsy.Journal of Pharmacology and Experimental Therapeutics 1993;264(3):1079–84.

Petty F, Kramer GL, Fulton M, Davis L, Ruch AJ. Stability of plasma GABA at four-yearfollow-up in patients with primary unipolar depression. Biological Psychiatry1995;37(11):806–10.

Rechtschaffen A, Kales A, editors. A manual of standardized terminology techniquesand scoring system for sleep stages of human subjects. Washington DC: PublicHealth Service, US Government Printing Office; 1968.

Riemann D, Wiegand M, Lauer CJ, Berger M. Naps after total sleep deprivation indepressed patients: are they depressiogenic? Psychiatry Research1993;49(2):109–20.

Riemann D, K}onig A, Hohagen F, Kiemen A, Voderholzer U, Backhaus J, et al. How topreserve the antidepressive effect of sleep deprivation: a comparison of sleepphase advance and sleep phase delay. European Archives of Psychiatry andClinical Neuroscience 1999;249:231–7.


Scammell TE, Estabrooke IV, McCarthy MT, et al. Hypothalamic arousal regions areactivated during modafinil-induced wakefulness. Journal of Neuroscience2000;20(22):8620–8.

Seifritz E, Hemmeter U, Traxel L, Lauer CJ, Hatzinger M, Emrich HM, et al. Effects offlumazenil on recovery sleep and hormonal secretion after sleep deprivation inmale controls. Psychopharmacology 1995;120:449–56.

Smeraldi E, Benedetti F, Barbini B, et al. Sustained antidepressant effect of sleepdeprivation combined with pindolol in bipolar depression: a placebo-controlledtrial. Neuropsychopharmacology 1999;20:380–5.

Steiger A, Holsboer F. Neuropeptides and human sleep. Sleep 1997;20:1038–52.Stone EA, Cotecchia S, Lin Y, et al. Role of brain alpha 1B-adrenoceptors in

modafinil-induced behavioral activity. Synapse 2002;46(4):269–70.Szuba MP, Baxter LRJ, Altshuler LL, Allen EM, Guze BH, Schwartz JM, Liston EH.

Lithium sustains the acute antidepressant effects of sleep deprivation:preliminary findings from a controlled study. Psychiatry Research 1994;51:283–95.

Uhr M, Tontsch A, Namendorf C, Ripke S, Lucae S, Ising M, et al. Polymorphisms inthe drug transporter gene ABCB1 predict antidepressant treatment response indepression. Neuron 2008;57(2):203–9.

Voderholzer U, Valerius G, Schaerer L, Riemann D, Giedke H, Schwarzler F, Berger M,Wiegand M. Is the antidepressive effect of sleep deprivation stabilized by athree day phase advance of the sleep period? A pilot study. European Archivesof Psychiatry and Clinical Neuroscience 2003;253:68–72.

Von Zerssen D. Depressivitäts-Skala [Depression scale]. Göttingen, German:Hogrefe; 1976.

Wesensten NJ, Killgore WD, Balkin TJ. Performance and alertness effects of caffeine,dextroamphetamine, and modafinil during sleep deprivation. Journal of SleepResearch 2005;14(3):255–66.

Wiegand M, Riemann D, Zulley J, editors. Effect of morning and afternoon naps onmood after sleep deprivation in depressivesHorne JA, editors. Sleep ’88. NewYork: Gustav Fischer; 1989. p. 227–9.

Wisor JP, Nishino S, Sora I, et al. Dopaminergic role in stimulant-inducedwakefulness. Journal of Neuroscience 2001;21:1787–94.

Wittchen U, Zaudig M, Schramm E, Spengler P, Mombour W, Klug J, Horn R.Strukturiertes klinisches Interview für DSM-III-R. Deutschsprachige erweiterteBearbeitung der amerikanischen Orginalversion des SCID von R.L. Spitzer, J.B.W.Williams, M. Gibbon, Weinheim: Beltz-Test; 1987.

Wu JC. Chronobiological augmentation of sleep deprivation as an antidepressantintervention. In The International Society for Affective Disorders (ISAD), 2ndBiennial Conference, Cancun, Mexico. Journal of Affective Disorders2004;78(Suppl. 1):S15.

Wu JC, Bunney WE. The biological basis of an antidepressant response to sleepdeprivation and relapse: review and hypothesis. American Journal of Psychiatry1990;147:1297–303.

Zhu HJ, Wang JS, Donovan JL, Jiang Y, Gibson BB, DeVane CL, Markowitz JS.Interactions of attention-deficit/hyperactivity disorder therapeutic agents withthe efflux transporter P-glycoprotein. European Journal of Pharmacology2008;578(2–3):148–58.

Modafinil reduces microsleep during partial sleep deprivation in depressed patients

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