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SLEEP, Vol. 31, No. 4, 2008
489
DIFFICULTY INITIATING AND/OR MAINTAINING SLEEP
IS COMMON IN MAJOR DEPRESSIVE DISORDER (MDD)
BUT IS OFTEN INADEQUATELY ADDRESSED. Subjec-
tive and objective (electroencephalographic) sleep disturbances
are associated with slower and lower rates of remission from
depression.
1-3
Depressed patients with abnormal sleep proles
have signicantly poorer clinical outcomes with respect to
symptom ratings, attrition and remission rates, and the stabil-
ity of response to treatment than those with more normal sleep
proles.
2,4
Patients with MDD who experience sleep continuity
disturbance and early morning awakening are also more likely
to have suicidal ideation than those without such disturbances.
5
Collectively, these ndings indicate that insomnia symptoms
hinder response to antidepressant treatment.
Sleep disturbance does not always resolve with antidepres-
sant treatment. Sleep difculties are also common residual
symptoms in individuals who have responded to depression
treatment.
6-10
Continued insomnia following the acute phase of
antidepressant therapy poses a signicant risk for relapse. For
example, two-thirds of patients with persistent insomnia at the
end of treatment with nortriptyline and interpersonal psycho-
therapy relapsed within one year after switching to pill placebo.
In contrast, 90% of patients with good sleep at the end of the
acute treatment remained well during the rst year after dis-
continuing antidepressants.
11
Additionally, there are indications
that insomnia may be a rst-occurring prodromal symptom in
previously depression-remitted persons.
12
Thus, insomnia is of-
ten more than merely a correlate or symptom of the depressive
illness; it also affects the course of the illness, response to treat-
ment, and when unresolved, it is a risk factor for relapse.
The prevailing model for the development of insomnia
is based on the diathesis-stress model whereby a “stressor”
precipitates insomnia in predisposed individuals. This model
posits that, with time, conditioned insomnia develops and per-
sists even after the stressor is removed. Specically, as anxiety
about not being able to sleep grows, it can lead to cognitive
and/or somatic arousal that further interferes with sleep and
perpetuates the sleep problem.
13
When these sleep difculties
become associated with signicant distress or impairment of
function in signicant domains, all criteria for a diagnosis of
insomnia are met and the individual experiences comorbid
MDD and insomnia. Thus, insomnia is no longer simply a
symptom of depression, but has become an independent dis-
ease process and a comorbid disorder that can subsequently
hinder antidepressant response.
INSOMNIA AND DEPRESSION
Cognitive Behavioral Therapy for Insomnia Enhances Depression Outcome in
Patients with Comorbid Major Depressive Disorder and Insomnia
Rachel Manber, PhD
1
; Jack D. Edinger, PhD
2
; Jenna L. Gress, BA
1
; Melanie G. San Pedro-Salcedo, MA
1
; Tracy F. Kuo, PhD
1
; Tasha Kalista, MA
1
1
Stanford University, Stanford, CA;
2
VA Medical Center and Duke University Medical Center, Durham, NC
Study Objective: Insomnia impacts the course of major depressive
disorder (MDD), hinders response to treatment, and increases risk for
depressive relapse. This study is an initial evaluation of adding cogni-
tive behavioral therapy for insomnia (CBTI) to the antidepressant medi-
cation escitalopram (EsCIT) in individuals with both disorders.
Design and setting: A randomized, controlled, pilot study in a single
academic medical center.
Participants: 30 individuals (61% female, mean age 35±18) with MDD
and insomnia.
Interventions: EsCIT and 7 individual therapy sessions of CBTI or
CTRL (quasi-desensitization).
Measurements and results: Depression was assessed with the
HRSD
17
and the depression portion of the SCID, administered by raters
masked to treatment assignment, at baseline and after 2, 4, 6, 8, and
12 weeks of treatment. The primary outcome was remission of MDD at
study exit, which required both an HRSD
17
score ≤ 7 and absence of
the 2 core symptoms of MDD. Sleep was assessed with the insomnia
severity index (ISI), daily sleep diaries, and actigraphy.
EsCIT + CBTI resulted in a higher rate of remission of depression
(61.5%) than EsCIT + CTRL (33.3%). EsCIT + CBTI was also associat-
ed with a greater remission from insomnia (50.0%) than EsCIT + CTRL
(7.7%) and larger improvement in all diary and actigraphy measures of
sleep, except for total sleep time.
Conclusion: This pilot study provides evidence that augmenting an
antidepressant medication with a brief, symptom focused, cognitive-
behavioral therapy for insomnia is promising for individuals with MDD
and comorbid insomnia in terms of alleviating both depression and in-
somnia.
Keywords: Major depressive disorder, Insomnia, Cognitive behavioral
therapy, Remission
Citation: Manber R; Edinger JD; Gress JL; San Pedro-Salcedo MG;
Kuo TF; Kalista T. Cognitive behavioral therapy for insomnia enhances
depression outcome in patients with comorbid major depressive disor-
der and insomnia. SLEEP 2008;31(4):489-495.
Disclosure Statement
This was not an industry supported study. Forest Laboratory provided
medication used in the study. Dr. Edinger has received research support
from Respironics; has consulted for Respironics/MiniMitter Division; has
participated in speaking engagements for Sleep Medicine Education Insti-
tute; and participated in a advisory panel meeting for Takeda. Dr. Kuo has
received research support from Jazz Pharmaceuticals. The other authors
have indicated no nancial conicts of interest.
Submitted for publication September, 2007
Accepted for publication January, 2008
Address correspondence to: Rachel Manber, PhD, Department of Psy-
chiatry and Behavioral Sciences, Stanford University, 401 Quarry Rd.,
Stanford, CA 94305; Tel: (650) 724-2377; Fax: (650) 725-8910; E-mail:
Rmanber@stanford.edu
Enhancing Depression Outcome in MDD and Insomnia—Manber et al
SLEEP, Vol. 31, No. 4, 2008
490
Cognitive-behavioral therapy for insomnia (CBTI) is a skill-
based, nonpharmacological intervention with many attributes
that make it appealing for addressing insomnia in the context of
MDD. Extensive research summarized in several meta-analy-
ses
14-17
has shown that CBTI produces improvements in primary
insomnia equivalent to those achieved during acute treatment with
hypnotic medications
18,19
in terms of reducing nocturnal wakeful-
ness, increasing sleep efciency, and improving subjective sleep
quality.
14,20
There is also some evidence that CBTI is effective for
insomnia that is comorbid with depression.
21-25
Most important,
sleep improvements achieved during CBTI endure up to 2 years
after the course of CBTI is completed.
26
This attribute of CBTI
is particularly important in the context of depression, as patients
who remain insomnia free are likely to remain depression free for
longer periods of time than those whose insomnia recurs.
12,27
The aim of the present randomized controlled pilot study
was to evaluate the feasibility, acceptability, and indications of
efcacy of combining an antidepressant medication (escitalo-
pram) with CBTI in people with MDD and insomnia. The main
outcome measure was remission from MDD, which is consid-
ered the ultimate goal of depression treatment.
28
METHOD
Participants
Participants were recruited through newspaper advertise-
ment, electronic bulletin boards, community postings, and bro-
chures in clinics. The advertisements invited participation in a
study on depression and insomnia and did not disclose the study
hypothesis. The advertising materials stated that “participants
will receive psychotherapy for insomnia and medication for de-
pression.” Recruitment took place between June 2004 and Au-
gust 2006. The study protocol was approved by the human sub-
jects committee at Stanford University School of Medicine, and
all participants provided a written consent for participation.
To be included participants had to: (1) be between the ages
of 18 and 75, (2) meet the Diagnostic and Statistical Manual
of Mental Disorders (DSM-IV-TR)
29
criteria for MDD (de-
termined by a Structured Clinical Interview for the DSM-IV
(SCID)
30
; (3) score at least 14 on the 17-item Hamilton Rating
Scale for Depression (HRSD
17
)
31
; (4) meet DSM-IV-TR criteria
for insomnia based on the Duke Structured Interview for Sleep
Disorders (available from coauthor JE); (5) meet the follow-
ing two quantitative criteria for insomnia, based on 2 weeks of
daily sleep diaries: a) sleep onset latency > 30 min and/or wake
after sleep onset > 30 min per night at least 3 nights per week;
b) total sleep time ≤ 6.5 h at least 3 times per week; (6) be free
of any psychotropic or hypnotic medication for at least 14 days
(45 days for uoxetine) prior to the screening visit.
Participants were excluded for the following reasons: (1)
current active suicidal potential, psychotic features, or having
received ECT or vagal nerve stimulation treatment during the
last year. (These presentations are not suitable to an experimen-
tal protocol unless it is specically designed to address such
severe presentations.); (2) seasonal pattern of MDD (to avoid
confounding the result with spontaneous remission due to sea-
sonal variations in mood); (3) history of treatment with the
study medication escitalopram or failing at least two SSRIs; (4)
conditions incompatible with the study medication escitalopram
(e.g., pregnancy or lactation, not using a reliable birth control
method, history of seizure disorder, presence of diseases, and
conditions that produce altered metabolism or hemodynamic
responses, and hepatic or renal dysfunction); (5) current ongo-
ing psychotherapy, pharmacotherapy, alternative therapy, or any
other treatment of claimed efcacy for depression or insomnia
including any over-the-counter medications or herbs (e.g., me-
latonin, valerian, kava, hop extract, St John wort, SAMe); (6)
Ten or more arousals per hour of sleep related to respiratory
events (apneas and hypopneas); (7) ten or more periodic limb
movement events per hour during sleep; (8) meeting The In-
ternational Classication Of Sleep Disorders, Second edition
(ICSD-2)
32
criteria for circadian rhythm disorder, parasomnia,
narcolepsy, or other primary sleep disorder; (9) uncontrolled
medical conditions; (10) comorbid psychiatric conditions other
than MDD (based on a SCID interview); (11) abnormal thyroid
function (based on laboratory testing) or abnormal urine drug
screen; (12) inadequate English language uency.
Treatments
Participants received 12 weeks of EsCIT, open label and
concomitantly 7 individual sessions of CBTI or CTRL therapy.
The frequency of CBTI and CTRL treatment was identical (5
weekly sessions followed by 2 biweekly sessions). EsCIT was
selected as a representative of the most commonly prescribed
class of antidepressant medications, the selective serotonin in-
hibitors (SSRIs). It has the added advantage that the proportion
of patients reporting daytime somnolence (6%) and insomnia
(9%) as side effects is equivalent (product insert: http://www.
frx.com/products/lexapro.aspx). The initial dose of EsCIT was
5 mg. It was increased to 10 mg during the second week, with
additional increases up to 20 mg based on clinical response and
tolerability. Medication management followed a standardized
protocol
33
and included biweekly visits for the rst 2 months
and a nal study visit at the end of treatment (end of week 12).
CBTI included the following components: (a) education
about normal sleep, sleep in depression, circadian rhythms,
and impact of substances (Session 1); (b) sleep restriction
34
and
stimulus control instructions
35
(introduced during Session 2 and
adjusted during subsequent sessions); (c) management of stress
and of cognitive and somatic arousals (Session 3); (d) cogni-
tive restructuring
36
(provided throughout the intervention); and
(e) instructions for continued schedule adjustment and relapse
prevention (Session 7).
The CTRL intervention consisted of a quasi-desensitization
procedure that has been used successfully as a control therapy
in a seminal insomnia outcome study.
37
The CTRL treatment
also included education about sleep and sleep hygiene (to in-
crease the credibility of the intervention to both therapists and
patients) but it did not include any other active components of
CBTI. The most recent practice parameters for the psychologi-
cal and behavioral treatments of insomnia concluded that there
is “insufcient evidence” for sleep hygiene education to be an
option as a single therapy.
38
Both CBTI and CTRL therapies focused only on sleep; neither
addressed mood, anhedonia, or other symptoms of depression.
All participants were instructed to limit caffeine intake to the
Enhancing Depression Outcome in MDD and Insomnia—Manber et al
SLEEP, Vol. 31, No. 4, 2008
491
equivalent of no more than 3 cups of coffee per day and avoid
all caffeine consumption in the late afternoon and evening hours.
They were also advised not to consume alcohol too close to bed-
time, to avoid eating large meals late at night, and to make the
bedroom environment adequately dark, temperate, and quiet.
Two licensed clinical psychologist provided both CBTI and
CTRL therapy, with equal case loads for each therapy. The thera-
pists, both naïve to CBTI, were trained in the delivery of CBTI
through reviewing the treatment manuals and role-playing. Ther-
apists received supervision initially weekly and later biweekly.
Training in CTRL followed the same procedures. To increase
the likelihood that the therapists will perceive the 2 therapies
as equally credible and expect them to be equally effective, the
therapists were told that although CBTI is the standard treatment
for insomnia, it has not been tested for insomnia comorbid with
depression and that issues of motivation might hinder compli-
ance with treatment recommendations. It was further stated that
the CTRL therapy, which is based on desensitization, might be
particularly relevant to treating insomnia in depressed patients as
depressed individuals are prone to rumination. Therapists were
told that the aim of the study was to compare 2 forms of psycho-
therapy for the treatment of insomnia in depression.
Measures
The main depression measures were the HRSD
17
and the de-
pression portion of the SCID, both administered at each study
visit (at baseline and after 2, 4, 6, 8, and 12 weeks of treatment)
by trained raters masked to participants’ treatment assignments.
The intraclass correlation based on 22 HRSD interviews was
0.96. When examined symptom-by-symptom, the median intra-
class correlation was 0.85. The main outcome measure was re-
mission of MDD at study exit, which required both an HRSD
17
-score ≤ 7 and absence of the 2 core symptoms of MDD.
Changes in sleep variables were measured with daily sleep
diaries and actigraphs. The daily sleep diary provides data on
bedtime, rise time, minutes to sleep onset latency, minutes
awake after sleep onset, minutes awake before planned (early
morning awakening), and subjective sleep quality. Actigraphs
provide objective minute-by-minute data on sleep-wake states.
An actigraph is a watch-size motion-recording apparatus that
contains an acceleration sensor, a processor, and memory. The
processor records physical motion and translates it to numeri-
cal digital data. Actigraphy provides an acceptable objective
longitudinal measure of sleep continuity in natural settings.
39
Each participant wore an Actiwatch™ by Minimitter daily on
the nondominant wrist for 2 weeks at baseline, between weeks
6 and 8 (midpoint of treatment), and between weeks 14 and 16
(end of treatment). To increase the accuracy of scoring, partici-
pants noted in the diary the times that the event marker for onset
and offset of the time in bed were pressed, and documented
when the unit was not worn. The following measures, recorded
and derived from the diary and actigraphy data, were analyzed:
total wake time (TWT; summation of sleep onset latency, wake
time after sleep onset, and early morning awakening), total
sleep time (TST), sleep efciency (SE; the ratio between TST
and time in bed); and subjective sleep quality (diary only).
The clinical signicance of the results was evaluated with
the Insomnia Severity Index (ISI).
36
This measure provides an
index of the global severity of insomnia, including perceived
daytime consequences and distress. It has good psychometric
properties.
40
The score range is between 0 and 28. Scores in
the range 0 to 7 represent “no clinically signicant insomnia”;
scores in the range of 8 to 14 represent “sub-threshold insom-
nia”; scores in the range of 15 to 21 represent “clinical insomnia
(moderate severity)”; and scores in the range 22 to 28 represent
“clinical insomnia (severe).” The ISI was administered at base-
line, treatment week 5, and at the end of treatment. Remission
of insomnia was dened by an ISI score ≤ 7.
Expectations of benet from treatment were completed in-
dependently by the therapists and patients after the second ses-
sion, when the 2 therapies diverged. Patients’ expectations were
measured with 4 items taken from the California Psychotherapy
Alliance Scales (CALPAS)
41,42
and the Session Evaluation Form
(SEF).
43
Since the items were not on the same scale, the average
z-scores of the 4 items constituted the patient expectation score.
Therapists’ expectations of benet for their client were com-
puted as the average of the following 2 items, both rated on a
5-point Likert scale: “Predict the likelihood that this patient will
benet from the particular treatment you are offering.” (1 = not
very likely and 5 = very likely) and “How much do you expect
this patient to improve by the end of the treatment?” (1 = not at
all and 5 = very much).
To assess compliance with the CBTI recommendations, ther-
apists rated each patient on a 5-point Likert scale as to how
much each instruction was followed. The Likert scale was an-
chored as follows: 0 = poor/no compliance; 1 = marginal; 2 =
fair; 3 = good; 4 = very good; 5 = excellent.
The instructions that were rated were as follows: (1) go to
bed only when sleepy; (2) get out of bed when unable to sleep
initially; (3) get out of bed when unable to sleep in the middle
of the night; (4) wake up at prescribed time; (5) get out of bed
shortly after waking up; (6) use bed and bedroom only for sleep.
An overall compliance score was computed as the mean score
of all items across all time points.
Procedures
Participants who expressed initial interest in the study
(N=763) were screened as follows: 1) a 15-min telephone
screening interview was used to ensure basic study criteria were
met; 2) in person interviews using the SCID, HRSD
17
, and the
Duke Structured Interview for Sleep Disorders; 3) in-home poly-
somnography to determine RDI and PLMS index; 4) laboratory
screens (thyroid and urine drug screen); 5) 2 weeks of sleep dia-
ries to verify that research criteria for insomnia were met; and
6) a meeting with the study physician to ensure that there were
no contra-indications for administering escitalopram. Qualied
participants (N = 30) entered a 2 week baseline period, dur-
ing which they completed sleep diaries and wore actigraphs.
Participants were then randomized to EsCIT+CBTI (N = 15)
or EsCIT + CTRL (N = 15). Randomization was performed in
blocks of 2 and separate randomization tables were created for
individuals with HRSD
17
scores above and below 20 to ensure
equal distribution of depression severity in the two conditions.
Treatment allocation was concealed from the principal investi-
gator and all other investigators and personnel, except for the
study coordinator, who assigned participants to their groups and
Enhancing Depression Outcome in MDD and Insomnia—Manber et al
SLEEP, Vol. 31, No. 4, 2008
492
large difference was not statistically signicant (P = 0.13 for a
one-tailed Fisher exact test). The mean baseline and endpoint
HRSD
17
scores and HRSD
17
scores after removing the 3 sleep
items, are depicted in Table 2 as are the Cohen’s-d effect sizes
for the differential change in HRSD scores.
Credibility
Participants’ expectations of sleep benet, measured at the
end of session 2 as the mean of the item z-scores, were -0.45
(0.64) for EsCIT + CBTI and -0.68 (0.70) for EsCIT + CTRL.
The difference did not reach statistical signicance (t = 0.88; P =
0.39; Cohen’s-d = 0.34). To test the impact of patients’ expecta-
tions on the main outcome we tested a logistic regression model
with remission status as the dependent variable. The predictors
included treatment group, patient expectations, both centered,
and their interaction. The overall model t was signicant (χ
2
=
9.4, P = 0.024). Of the variables in the model only the interac-
tion term was signicant (Wald = 4.5, P = 0.033). Follow up
examination of the 4 subgroups based on split median of all
patients’ expectations (CBTI-Low expectation, CBTI-High ex-
pectation, CTRL-Low expectation, CTRL-High Expectation)
revealed that expectations played a signicant role in the EsCIT
+ CTRL group, with 0% (0/9) of those with low expectation
attaining remission status and 83% (5/6) of those with high ex-
pectations attaining remission status. In contrast, in the EsCIT +
CBTI group, 80% (4/5) of those with low expectation remitted
and only 43% (3/7) of those with high expectation remitted.
Therapists’ expectations of benet were signicantly higher for
participants in the EsCIT + CBTI group, 4.5 (0.49), than for
those in the EsCIT + CTRL group, 3.5 (0.84) for CTRL (t = 3.5;
P = 0.002; Cohen’s-d = 1.31) and were signicantly correlated
with patients’ expectations (r = 0.40, P < 0.05).
Impact on Sleep
Table 3 summarizes the pre- and post-treatment values for
the ISI, sleep diary and actigraphy derived sleep parameters us-
ing the last available data. Participants in the CBTI group had
larger improvement than those in CTRL group in all measures,
indicated the assignment in the randomization table, and the
psychotherapists. The participants, the psychiatrist managing
the medications, and the clinical raters were masked to treat-
ment conditions. Seasonal variations in light were unlikely to
confound the results as CBTI and CTRL were both adminis-
tered equally at the different times of the year.
RESULTS
Baseline Characteristics
Participant ow from enrollment until the end of treatment
is depicted in Figure 1. The analyzable sample consisted of all
randomized participants who attended at least one post ran-
domization assessment visit (13 in EsCIT + CBTI and 15 in
EsCIT + CTRL). Demographic and baseline characteristics of
the sample with respect to depression and insomnia appear in
Table 1. There were no group differences in any of the baseline
variables depicted in Table 1.
Indication of Efficacy
EsCIT + CBTI resulted in a higher rate of remission from
depression (61.5%) than EsCIT + CTRL (33.3%), but this
98 enrolled and underwent screening
procedures to determine eligibility
30 Randomized
48 Excluded
Sleep apnea (17)
MDD criteria not met (10)
Insomnia criteria not met (5)
Comorbid psychiatric or
medical conditions (10)
Other (6)
3 Eligible but discontinued
before randomization
15 Assigned to receive EsCIT + CBTI
5 Discontinued
Medication side effects (1)
Time commitment (2)
Intolerance of sleep restriction (1)
Other (1)
15 Assigned to Receive EsCIT + CTRL
3 Discontinued
Medication side effects (2)
Time commitment (1)
13 included in analysis
(2 did not provide data
post randomization)
15 included in analysis
17 Did not complete screening
Time commitment (15)
Spontaneous remission (1)
Started sleep medication (1)
Figure 1—Patient ow in the study
Table 1—Baseline Characteristics
CBTI Mean (SD) CTRL Mean (SD) Total Mean (SD)
Age (years) 49.5 (13.6) 47.8 (13.4) 48.6 (13.3)
Female 54% 67% 61%
Hispanic 8% 7% 7%
Caucasian non-Hispanic 77% 67% 71%
Age of depression onset (years) 37 (16.6) 33 (19) 35 (18)
Duration of current MDE (months) 20.4 (22.9) 16.6 (15.7) 18.3 (19)
Number of past depressive episodes 2.3 (1.6) 2.9 (2.5) 2.6 (2.1)
Double depression (Dysthymia & MDD) 46% 47% 46%
Age of insomnia onset (years) 38 (15) 35 (14) 36 (14)
Duration of current insomnia episode (months) 27.9 (20.7) 32.6 (35.6) 30.4 (28.7)
BMI (Kg/m
2
) 26.3 (5.4) 25.5 (4.8) 25.9 (5.0)
PLM (events per hour) 0.4 (1.3) 0.2 (0.8) .03 (1.0)
Arousal RDI (events per hour) 2.5 (2.0) 2.1 (2.2) 2.3 (2.1)
Arousal RDI – average number of respiratory events associated with arousal per hour of sleep.
All P-values were ≥ 0.4.
Enhancing Depression Outcome in MDD and Insomnia—Manber et al
SLEEP, Vol. 31, No. 4, 2008
493
DISCUSSION
This pilot study provides evidence that the strategy of aug-
menting an antidepressant medication with a brief, symptom
focused cognitive-behavioral therapy for insomnia is promis-
ing for individuals with MDD and comorbid insomnia. With
respect to the primary aim of improving remission from de-
pression we found that the rate of remission from MDD was
markedly higher for those treated with EsCIT + CBTI (62%)
than in those treated with EsCIT + CTRL (33%). This is a clini-
cally meaningful nding as remission of depression is the ul-
timate goal of depression treatment.
28
With respect to treating
insomnia, we also found a clinically and statistically signicant
advantage for the augmentation strategy. Treatment with EsCIT
+ CBTI was associated with a higher rate of remission of in-
somnia (50%), dened by the ISI, than treatment with EsCIT +
CTRL (8%). The substantially higher remission rate of insom-
nia among those treated with EsCIT + CBTI suggests that CBTI
improves sleep above and beyond any improvement associated
with the antidepressant medication itself.
The mechanism by which augmentation of the SSRI escit-
alopram with a brief insomnia therapy enhances antidepressant
response cannot be discerned from this pilot study. The small
sample size precludes a meaningful test of the possibility that
the observed differential remission of MDD is mediated by the
differential improvement in sleep. Two ndings from this study
suggest that the magnitude of the difference in improvement
of depression exceeds what would be expected from the dif-
ferential improvement in sleep alone. The rst is the equivalent
effect sizes observed for the change in total HRSD scores and
except for TST. The largest effect sizes were observed for the
improvement in diary based sleep efciency (SE) and the in-
somnia severity index (ISI). The proportion of participants who
achieved insomnia remission (ISI score ≤ 7) at the last available
observation was 50.0% in the EsCIT + CBTI group and 7.7% in
the EsCIT + CTRL group (χ
2
= 5.7, P = 0.05). The correlation
between change in ISI scores and patients’ expectation of sleep
benets was signicant (r = 0.49, P = 0.015). Higher expecta-
tions of benet were associated greater reductions in ISI scores.
Although there is not sufcient power to conduct a meaningful
mediation analysis to determine if improvement in sleep me-
diated differential remission rates between the two insomnia
therapies, we describe the relationship between remission form
depression and remission from insomnia in the whole sample
(combining both groups). Among those whose insomnia remit-
ted 83% also experienced remission of depression, whereas
among those whose insomnia did not remit only 39% experi-
enced remission of depression (χ
2
= 3.6, P = 0.08).
Relationship between Remission of MDD and Compliance with
CBTI
For participants receiving EsCIT + CBTI, the correlation be-
tween the therapists’ ratings of patients’ compliance with CBTI
instructions and the change in HRSD
17
score from baseline to
the last available observation was 0.61 (P = 0.07). Compliance
with CBTI was not signicantly correlated with changes in
sleep (P = 0.13 for the diary rating of sleep quality and P-values
≥ 0.5 for changes in all other sleep diary variables and for the
change in ISI).
Table 2—Change in Depression Symptom Severity (Mean (SD))
CBTI (n=14) CTRL (n=14) Cohen’s-d
Baseline Endpoint Baseline Endpoint ES
HRSD
17
19.9 (3.8) 7.9 (6.6) 20.7 (5.8) 11.0 (8.7) 0.27
HRSD
17
minus sleep items 15.5 (3.8) 5.8 (5.6) 16.7 (5.2) 8.8 (7.3) 0.24
HRSD
17
= 17-item Hamilton Rating Scale for Depression; HRSD
17
minus sleep items = HRSD
17
scores after removing the three sleep items.
Endpoint values are based on the last available observation. ES – effect size.
Table 3—Sleep Measures Pre- and Post-Treatment (Mean [SD])
EsCIT + CBTI EsCIT + CTRL Cohen’s-d ES
Pre Post Pre Post
ISI 23.1 (2.4) 9.5 (6.3) 21.5 (5.0) 14.3 (5.1) 1.03
DIARY and ACTIGRAPHY
TWT (Min) Diary 150.5 (71.0) 72.0 (78.8) 149.0 (78.3) 90.7 (72.0) 0.31
Actigraph 88.2 (32.3) 72.0 (33.6) 79.2 (51.4) 82.2 (54.6) 1.1
TST (Min) Diary 329 (74) 371 (55) 330 (70) 349 (85) 0.36
Actigraph 377 (29) 371 (49) 374 (65) 393 (40) 0.61
SE (%) Diary 67.1 (15.9) 84.0 (13.0) 72.3 (15.0) 77.6 (15.0) 0.76
Actigraph 81.1 (6.1) 86.4 (5.9) 82.9 (9.8) 83.2 (9.1) 0.48
QUAL Diary 4.9 (1.6) 6.8 (1.7) 5.2 (2.1) 6.1 (2.5) 0.48
ISI = Insomnia Severity Index; TWT= total wake time from lights out to the time out of bed; TST = total sleep time; SE = sleep efciency;
QUAL = Sleep Quality, rated on a 10-point Likert scale; higher number indicates better subjective sleep quality. Cohen’s-d effect sizes were
computed for the group comparisons of the change from baseline to the last available data.
Enhancing Depression Outcome in MDD and Insomnia—Manber et al
SLEEP, Vol. 31, No. 4, 2008
494
There are many important unanswered questions related to
the treatment of comorbid insomnia and depression that the cur-
rent design cannot address. Although CBTI seems promising
for the treatment of individuals who experience depression and
insomnia at baseline, a different study design is needed to de-
termine if CBTI can improve sleep and depression in patients
with treatment emergent insomnia or in patients who experi-
ence residual symptoms of insomnia at the end of an adequate
antidepressant trial.
The experience in the pilot study suggests that CBTI is ac-
ceptable to patients, as evidenced by the fact that only one par-
ticipant did not tolerate treatment. We also found that CBTI
is relatively easy to disseminate. In 3 months we successfully
trained 2 general psychotherapists naive to sleep medicine and
insomnia therapy to deliver both CBTI and CTRL. This indi-
cates that the proposed intervention strategy, should it prove ef-
cacious in larger replication studies, will be relatively simple
to implement in the community utilizing licensed mental health
providers.
ABBREVIATIONS
MDD –major depressive disorder
CBTI – cognitive behavioral therapy for insomnia
CTRL – control therapy
EsCIT – escitalopram
HRSD
17
– Hamilton Rating Scale for Depression (17 items)
DSM-IV-TR – Diagnostic and Statistical Manual of Mental
Disorders
SCID – Structured Clinical Interview for the DSM-IV
ICSD-2 – The International Classication of Sleep Disorders,
Second edition
ISI - Insomnia Severity Index
TWT – total wake time
TST – total sleep time
SE – sleep efciency
BMI – Body Mass Index
RDI – Respiratory Disturbance Index
PLM – Periodic Limb Movement
QUAL – Sleep Quality
ACKNOWLEDGMENTS
The authors wish to thank the treatment providers, Drs Mag-
dolna Dunai, Brent Solvason, Kimberly Hill, and Kristin Luce,
and other research personnel, Chai-Yu Cardell and Viola Arias
for their contribution to the research presented in this manuscript.
This research was supported by a grant form the National Insti-
tute of Metal Health (NIMH), grant number MH066131. Medi-
cations for this study were provided by Forest Laboratory.
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