Efficacy of Trazodone vs. Cognitive Behavioral Therapy in Patients With Chronic Insomnia Associated With Objective Short Sleep Duration
Phase: NA
Conditions: Insomnia
Sponsor: Milton S. Hershey Medical Center

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Efficacy of Trazodone vs. Cognitive Behavioral Therapy in Patients with Chronic 
Insomnia associated with Objective Short Sleep Duration
Principal Investigator: Alexandros N. Vgontzas, M.D.
Department of Psychiatry
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Table of Contents
Sections
1.0
Introduction
2.0
Objectives
3.0
Study Design and Methods
4.0
Inclusion and Exclusion Criteria
5.0
Recruitment and Consent Process
6.0
Study Procedures
7.0
Risks and Discomforts
8.0
Benefits
9.0
Reporting of Adverse Events and Unanticipated Problems Involving Risks to 
Participants or Others
10.0
Study Withdrawal/Discontinuation
11.0
Statistical Analysis of the Study
12.0
Privacy and Confidentiality Considerations
13.0
Data and Safety Monitoring Plan
14.0
Compensation
15.0
Drugs, Biologics, or Devices
16.0
Records and Study Monitoring
17.0
Facilities
18.0
References
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1.0
Introduction
Insomnia is the most common sleep disorder and is associated with significant 
morbidity and mortality. Female gender, middle-age, physical and mental health 
problems, and heredity have been reported as risk factors for the development of 
insomnia. Despite the fact that over the past two decades insomnia has been the focus of 
extensive research, its pathophysiology remains obscure and most commonly available 
treatments for this disorder are associated with good outcomes in subjective sleep quality 
but poor outcomes in objective sleep duration. Furthermore, the criteria for diagnosing 
insomnia is only based on subjective reports, and the decision on how to treat it is 
frequently a challenge to the clinician.
A. Chronic insomnia is associated with emotional and physiological 
hyperarousal – Insomnia is considered to be the most common sleep disorder (NIH, 
2005).  Its prevalence varies considerably based on the definition used.  While one-fourth 
to one-third of the general population reports a complaint of difficulty falling and/or 
staying asleep (US Department of HEW, 1970; Karacan et al, 1976; Bixler et al, 1979; 
Mellinger et al, 1985; Klink and Quan, 1987; Klink et al, 1992; Dodge et al, 1995; Foley 
et al, 1995; US Department of DHHS, 1996), about ten percent present chronic 
complaints and seek medical help for insomnia (Ancoli-Israel and Roth, 1999; Ford and 
Kamerow, 1989).  Insomnia is more common among women, middle-aged and older 
adults, and patients with medical or psychiatric disorders.  Despite the evidence that 
insomnia has significant public health implications, including impaired occupational 
performance, increased absenteeism at work, higher health care costs, and quality of life 
(NIH, 2005; Basta et al, 2007; Buysse et al, 2006; Simon and Von Korff, 1997; Chevalier 
et al, 1999), the connection of insomnia to significant medical morbidity, i.e., 
cardiometabolic and neurocognitive risks, and mortality has been just recently reported 
(Vgontzas et al, 2009a; Vgontzas et al, 2009b; Vgontzas et al, 2010; Fernandez-Mendoza 
et al, 2010).
The diagnosis of insomnia, according to the Diagnostic and Statistical Manual of 
Mental Disorders, Fourth Edition, Text Revision (DSM-IV TR), is based solely on the 
subjective complaints of difficulty initiating or maintaining sleep, early awakening, and 
interrupted or non-restorative sleep, that are associated with clinically significant 
impairment in daytime function, for which no identifiable cause i.e. other sleep disorder, 
psychiatric disorder, medical condition, is attributed (American Psychiatric Association, 
2000.).  There are no objective measures that are useful in the diagnosis, differential 
diagnosis, severity assessment, or therapeutic response of insomnia (NIH, 2005; Basta et 
al, 2007; Buysse et al, 2006; Chesson et al, 2000).  Such a gap increases the uncertainty 
in terms of diagnostic priorities and treatment guidelines.
Insomnia is associated with both emotional and physiological hyperarousal (Kales 
and Kales, 1984; Kales et al, 1983; Bonnet and Arand, 2003; Bonnet and Arand, 1995; 
Bonnet and Arand, 2006). Insomniacs tend to be anxious, ruminative, and depressed 
while physiologically they have significantly increased rectal temperature, heart rate, 
vasoconstriction, increased skeletal muscle movement before and during sleep, increased 
metabolic rate and inability to fall asleep during the day despite the subjective feeling of 
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fatigue, extreme at times (Kales and Kales, 1984; Kales et al, 1983; Bonnet and Arand, 
2003; Bonnet and Arand, 1995; Bonnet and Arand, 2006; Stepanski et al, 1988; Edinger 
et al, 2001).  These characteristics are different than those found in healthy subjects after 
sleep deprivation, i.e., severe objective sleepiness, decreased metabolic rate, etc. (Bonnet 
and Arand, 2003; Bonnet and Arand, 1995; Vgontzas et al, 1999; Vgontzas et al, 2004; 
Vgontzas et al, 2007).  Furthermore, data from the quantitative EEG analysis, 
neuroimaging and neurocognitive function suggest that insomnia is a disorder of 
physiological hyperarousal and not a disorder of sleep loss (Merica et al, 1998; Perlis et 
al, 2001; Nofzinger et al, 2004; Fernandez-Mendoza et al, 2010; Fulda and Schulz, 2001).
Until several years ago, few studies had assessed the activity of the stress system 
(e.g., cortisol levels) in insomniacs and their results were inconsistent.  The majority of 
these studies reported no difference between “poor” sleepers and normal individuals in 
the levels of 24-h cortisol and 17-hydorxysteroid excretion (Frankel et al, 1973; Johns et 
al, 1971; Adam et al, 1986).  A preliminary study by our group investigated possible 
association between chronic insomnia and the activity of the stress system by measuring 
urinary free cortisol (UFC), catecholamines, and growth hormone (GH) and found that 
24-h UFC levels, norepinephrine, and catecholamine metabolites were positively 
correlated with polysomnographic indices of sleep disturbance, i.e., total wake time 
(TWT) or percent stage 1 sleep (Vgontzas et al, 1998).
In a subsequent controlled study 24-h serial adrenocorticotropic hormone (ACTH) 
and cortisol levels were significantly higher in insomniacs compared to normal sleepers 
(Vgontzas et al, 2001).  Within the 24-h period the greatest elevations were observed in 
the evening and during the first half of the night.  Furthermore, within the group of 
insomniacs, the sub-group with high degree of objective sleep disturbance (%TST <70) 
had higher amount of cortisol compared to the subgroup with low degree of sleep 
disturbance.  The group of insomniacs with high sleep efficiency was not different in 
terms of cortisol levels from normal controls.  Based on these two studies, we concluded 
that in chronic insomnia 1) the activity of the stress system is directly proportional to the 
degree of objective sleep disturbance, and 2) polysomnographic measures can provide a 
reliable index of the biological impact and severity of chronic insomnia (Vgontzas et al, 
2001).  
These findings were confirmed by several studies (Rodenbeck et al, 2003; 
Rodenbeck et al, 2002; Irwin et al, 2003) but not all (Riemann et al, 2002; Varkevisser et 
al, 2005). It appears that the difference between these two groups of studies is the degree 
of polysomnographically documented sleep disturbance.  For example, in the study by 
Rodenbeck et al. (2002), the correlation between area under the curve (AUC) of cortisol 
and % sleep efficiency was 0.91, suggesting that high cortisol levels are present in those 
insomniacs with an objective short sleep duration.   In contrast, in the study by Riemann 
in which no cortisol differences were observed between insomniacs and controls, the 
objective sleep of insomniacs was very similar to that of controls, i.e., sleep efficiency of 
88.2% vs. 88.6% (Riemann et al, 2002).  Furthermore, in a study that applied constant 
routine conditions, all indices of physiological arousal were increased but not to a 
significant degree due to lack of power and not careful selection of controls (Varkevisser 
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et al, 2005; Bonnet, 2005).  Interestingly, in this study a visual inspection of cortisol data 
suggested an elevation of cortisol values of 15% to 20% in the insomnia group, a 
difference which is similar to that reported in our study and is considered of clinical 
significance (Varkevisser et al, 2005).
Collectively, these findings suggest that chronic insomnia with concomitant 
objective sleep disturbance is a state of physiological hyperarousal which puts the 
individual into a high risk of significant medical morbidity.
B. Chronic insomnia is associated with significant medical morbidity– Many 
studies have established that insomnia is highly comorbid with psychiatric disorders and 
is a risk factor for the development of depression, anxiety, and suicide (NIH, 2005; Basta 
et al, 2007; Buysse et al, 2006; Ford and Kamerow, 1989; Breslau et al, 1996; Ohayon et 
al, 2002).  However, in contrast to the other most common sleep disorder, i.e., sleep 
apnea, chronic insomnia has not been linked with significant medical morbidity, e.g., 
cardiovascular disorders.  Few studies that have examined the association of chronic 
insomnia with hypertension have reported modest and inconsistent effects of little or no 
clinical significance (Phillips and Mannino, 2007; Suka et al, 2003; Janson et al, 2001; 
Bixler et al, 2002). As we discussed in the previous section, most, but not all, studies 
have reported that chronic insomnia is associated with an overall hypersecretion of 
ACTH and cortisol, suggesting an activation of the hypothalamic-pituitary-adrenal (HPA) 
axis in these patients (Vgontzas et al, 1998; Vgontzas et al, 2001; Rodenbeck et al, 2003; 
Rodenbeck et al, 2002; Riemann et al, 2002; Varkevisser et al, 2005).  This association is 
strong in those insomniacs with evidence of objective poor sleep.
 Given the well-established association of hypercortisolemia with significant 
medical morbidity, i.e., hypertension, diabetes, metabolic syndrome, osteoporosis, and 
others (80), we examined the joint effects of insomnia and short sleep duration on the risk 
of medical morbidity, i.e., hypertension, diabetes, and neurocognitive deficits, and 
mortality in a general population sample of 1,741 men and women randomly selected 
from Central Pennsylvania (Penn State Cohort) (Bixler et al, 1998; Bixler et al, 2001). In 
the first study, the highest risk of hypertension was in insomniacs with < 5 hour sleep 
duration group (OR = 5.0), and the second highest in insomniacs who slept 5-6 hours 
(OR = 3.5) when compared to the normal sleeping and ≥ 6 hour sleep duration group 
(Vgontzas et al, 2009a). In the second study, we examined the joint association of 
insomnia and objective short sleep duration on the risk for diabetes. A significantly 
increased risk for diabetes was observed in the group of the most severe insomniacs, i.e., 
insomnia with objective sleep duration < 5 hours (Vgontzas et al, 2009b). In the third 
study, significant neurocognitive deficits were observed only in insomniacs with < 6 
hours as compared to controls or insomniacs with ≥ 6 hours (Fernandez-Mendoza et al, 
2010). In our fourth study, we reported that objective short sleep duration (< 6 hours) in 
male insomniacs predicts mortality over a period of 14 years of follow-up (Vgontzas et 
al, 2010). Finally, in the same cohort, we examined the differential psychological profile 
of insomniacs with objective short and normal sleep duration (Fernandez-Mendoza et al, 
2011). This latter study revealed that insomniacs with normal seep duration present with 
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sleep misperception (i.e., the tendency to underestimate sleep duration) and anxious-
ruminative and poor coping resources personality traits. 
Based on these studies, we have recently suggested that objective sleep 
duration in chronic insomnia is a marker of the biological severity of the disorder.
C. Subtypes of chronic insomnia based on its biological severity – The field of 
sleep disorders medicine has attempted to define subgroups within insomnia based on 
etiology (i.e., primary vs. secondary), age of onset (i.e., childhood vs. adult), and 
objective sleep findings (American Academy of Sleep Medicine, 2005). Although for 
years sleep specialists suggested that the sleep lab was of no use in the evaluation of 
insomnia (NIH, 2005), the previously published data on the association of insomnia 
combined with objective short sleep duration with the stress system (Vgontzas et al, 
1998; Vgontzas et al, 2001; Rodenbeck et al, 2003; Backhaus et al, 2006; Shaver et al, 
2002; Irwin et al, 2003), the autonomic system (Bonnet and Arand, 1997; Stepanski et al, 
1994; Bonnet and Arand, 1995), and with medical morbidity (Vgontzas et al,  2009a; 
Vgontzas et al, 2009b; Fernandez-Mendoza et al, 2010) and mortality (Vgontzas et al, 
2010), have led us to suggest two subtypes of chronic insomnia.
The first subtype is associated with physiological hyperarousal, i.e., short sleep 
duration, activation of the stress system (Vgontzas et al, 1998; Vgontzas et al, 2001; 
Rodenbeck et al, 2003; Backhaus et al, 2006; Shaver et al, 2002), and significant medical 
sequelae, e.g., hypertension (Vgontzas et al, 2009a), type 2 diabetes (Vgontzas et al, 
2009b), neurocognitive deficits (Fernandez-Mendoza et al, 2010) and increased mortality 
(Vgontzas et al, 2010), whereas the second subtype is not associated with physiological 
hyperarousal, i.e., normal sleep duration, normal activity of the stress system (Vgontzas 
et al, 1998; Vgontzas et al, 2001; Shaver et al, 2002), and lack of significant medical 
sequelae (Vgontzas et al, 2009a; Vgontzas et al, 2009b; Vgontzas et al, 2010; Fernandez-
Mendoza et al, 2010), but with sleep misperception and an anxious-ruminative, poor 
coping skills profile (Fernandez-Mendoza et al, 2011).
Thus, our proposed subtyping of chronic insomnia suggests that physiological 
hyperarousal may play a primary role in the phathophysiology of insomnia with objective 
short sleep duration, whereas psychological factors might be primary in insomnia with 
normal sleep duration. Our findings on these proposed subtypes may have a significant 
impact on how we diagnose and treat insomnia. Currently, the diagnosis of insomnia is 
only based on subjective complaints (American Psychiatric Association, 2000). The 
introduction of objective measures of sleep in the evaluation of insomnia may be of 
relevance for the practicing physician in terms of prioritizing intervention based on 
severity. In fact, we have also proposed that these 2 subtypes may respond differentially 
to treatment approaches. Insomniacs with objective short sleep duration may respond 
better to treatments that primarily aim at decreasing physiological hyperarousal (e.g., 
hypercortisolemia) and increasing sleep duration, such as medication or other biological 
treatments (Rodenbeck et al, 2003), whereas insomniacs with normal sleep duration may 
respond better to treatments that primarily aim at decreasing cognitive-emotional 
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hyperarousal (e.g., rumination) and altering sleep misperception, such as psychological 
treatment (Morin and Espie, 2003).
However, whether insomnia with objective short sleep duration responds 
better to pharmacological rather than to psychological treatment has not yet been 
examined.
D. Treatment of chronic insomnia – Most sleep specialists advocate a 
multidimensional approach for the treatment of insomnia that includes education on sleep 
hygiene, psychotherapy including behavioral methods and cognitive behavioral therapy 
(CBT), and medication including hypnotics, sedative antidepressants, or over-the-counter 
medications.
The list of behavioral and cognitive techniques  is long, and the latest American 
Academy of Sleep Medicine (AASM) paper on “Practice Parameters for the 
Psychological and Behavioral Treatment of Insomnia” lists seven methods for which 
there is no evidence for the superiority or specificity of one method in comparison to 
another one (Morgenthaler et al, 2006; Morin et al, 2006). According to the AASM 
committee, it is well established that CBT improves subjective measures of sleep in 
insomnia (Morgenthaler et al, 2006; Morin et al, 2006). However, only 11 studies out of 
the 37 systematically reviewed by the AASM practice parameters committee used 
objective sleep data to study the effects of CBT and their results could not prove that 
CBT is effective in improving objective sleep duration (Morgenthaler et al, 2006; Morin 
et al, 2006). Moreover, the most recent published studies (2004-2010) do not provide 
evidence supporting a clinically significant effect of CBT on extending objective sleep 
duration, either measured with PSG (Siversten et al, 2006a; Siversten et al, 2006b; 
Krystal and Edinger, 2010) or with actigraphy (Siversten et al, 2006a; Espie et al, 2007; 
Edinger et al, 2007; Edinger et al, 2009), with just one uncontrolled study being the 
exception (Cervena et al, 2004).  Furthermore, these recent studies demonstrate once 
again (Morgenthaler et al, 2006; Morin et al, 2006) that most studies examining the effect 
of CBT for insomnia have been comprised of samples of chronic insomniacs with a rather 
“normal” (≥ 6 hours) objective sleep duration (Okajima et al, 2010).
Very little evidence currently guides practitioners in terms of selecting behavioral 
or pharmacologic treatments for a specific patient, much less the specific treatment 
within these broad categories. Sleep–wake regulation is complex, and the number of 
neurotransmitters and neuromodulators involved is large. This creates a number of viable 
targets for insomnia therapy. The long standing reliance on benzodiazepine receptor 
agonists is likely to give way to a greater variety of treatments, including those affecting 
targets such as histamine, orexin, and serotonin receptors (Buysse, 2010). Hypnotics 
appear to be effective but only short-term, while the administration of sedative 
antidepressants such as trazodone, although widely used by the practicing physician 
(Morlock et al, 2006), is not supported by systematic studies including efficacy, 
tolerance, and side effects (Mendelson, 2005). Trazodone is a sedative triazolopyridine 
antidepressant, which possesses antidepressant and also anxiolytic and hypnotic activities 
(Al-Yassiri et al, 1981; McCall, 2010).
More importantly, the effectiveness of the available treatment options has not 
been evaluated in terms of the severity of the disorder or biological indices of known 
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clinical significance (such as the degree of objective sleep disturbance). The data on the 
association of objective short sleep duration in insomnia with hypercortisolemia 
(Vgontzas et al, 1998; Vgontzas et al, 2001; Rodenbeck et al, 2003; Rodenbeck et al, 
2002; Riemann et al, 2002; Varkevisser et al, 2005) and high risk for medical morbidity 
(Vgontzas et al, 2009a; Vgontzas et al, 2009b; Vgontzas et al, 2010; Fernandez-Mendoza 
et al, 2010) provide the basis for a guided approach in the treatment of insomnia, which 
can be useful to the general practitioner.  Because insomnia associated with objective 
short sleep duration is associated with HPA axis activation, the use of medication that 
down regulates the HPA axis, such as trazodone, may be a promising tool in the 
pharmacological approach.  In support of this argument are the results of a small study 
from Germany that showed that a small dose of a sedative antidepressant (doxepin) was 
effective in improving sleep and normalizing plasma cortisol secretion in primary 
insomniacs (Rodenbeck et al, 2003). Recent studies have also shown that doxepin is 
effective in increasing objective sleep duration in chronic insomniacs (Rodenbeck et al, 
2003; Krystal et al, 2010; Roth et al, 2010; Scharf et al, 2008; Roth et al, 2007; Hajak et 
al, 2001). In contrast, insomnia associated with “normal” sleep duration, normal activity 
of the HPA axis, and lack of significant medical morbidity may respond better to 
psychotherapeutic interventions.  In support of this hypothesis are the several studies on 
CBT effectiveness that included insomniacs with an average objective sleep duration of 6 
hours or more and reported improved sleep efficiency (better consolidation of sleep) but 
no significant lengthening of sleep duration (Edinger et al, 2001; Jacobs et al, 2004; 
Morin et al, 2004; Sivertsen et al, 2006a; Edinger et al, 2007a;Sivertsen et al, 2006b; 
Espie et al, 2007; Edinger et al, 2009; Krystal and Edinger, 2010; Okajima et al, 2010).  
In this project, we will focus on the more severe group and we will test whether a 
sedative antidepressant (trazodone) is more effective in insomnia with objective short 
sleep duration than CBT.
Collectively, the above reviewed studies show that chronic insomnia with 
objective short sleep duration is a state of hyperarousal associated with 
hyperactivity of the stress system and significant medical sequelae and suggest that 
sedative antidepressants may have better beneficial effects than CBT in improving 
insomnia with objective short sleep duration.
2.0  Objectives
Little is known about the pathophysiology of chronic insomnia whereas the 
currently available treatments are either partially effective and/or associated with poor 
outcome in objective measures of nighttime sleep.
Accumulating evidence points to the possibility that chronic insomnia is a state of 
physiological and emotional hyperarousal.  In individuals with chronic insomnia, 
objective short sleep duration is associated with hyperactivity of the stress system (e.g., 
hypercortisolemia) and with increased risk of significant medical sequelae, such as 
cardiometabolic and neurocognitive disorders.  It appears that objective measures of sleep 
may be a reliable index of the biological severity of the disorder. Finally, CBT, the 
current recommended first-line treatment for chronic insomnia is associated with 
improvement of subjective sleep quality whereas it does not appear to significantly 
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improve objective sleep duration. Interestingly, most studies examining the efficacy 
and/or effectiveness of CBT have been conducted in chronic insomniacs with a rather 
“normal” (> 6 hours) sleep duration.
Sedative antidepressants, such as trazodone, are widely used by the practicing 
physician to treat chronic insomnia. However, there is a lack of studies that have 
examined their efficacy, tolerance, and side effects. Several studies have reported that 
sedative antidepressants may reduce cortisol levels and/or increase objective sleep 
duration in chronic insomniacs. As yet, there have not been controlled studies to examine 
the effects of trazodone versus CBT on severe chronic insomnia, i.e., those with objective 
short sleep duration.  
The primary hypothesis to be tested is that trazodone improves both subjectively 
and objectively chronic insomnia with objective short sleep duration.  Specifically, in this 
study, we will assess the following specific aim/hypothesis: to examine the effects of 
trazodone vs. CBT in chronic insomniacs with objective short sleep duration.  
Specifically, we hypothesize that trazodone will be more effective than CBT in 
improving both subjectively and objectively chronic insomnia.  To test this hypothesis, 
we propose a pilot, 3-month randomized trial of trazodone compared to CBT in 24 male 
and female patients with chronic insomnia with objective short sleep duration.  
A. Primary outcomes: we hypothesize that trazodone will result in a greater 
improvement of objective sleep duration (assessed by PSG and actigraphy) and 
subjective nighttime sleep than CBT in insomniacs with objective short sleep duration.
B. Secondary outcomes: we hypothesize that trazodone compared to CBT will 
result in a greater improvement of daytime fatigue, cortisol, inflammatory markers, and 
insulin sensitivity in insomniacs with objective short sleep duration.
The accomplishment of the above-described objectives will create the basis for 
the development of novel and specific treatments for chronic insomnia, and improve our 
understanding of the pathophysiology of this heterogeneous disorder.
3.0
Study Design and Methods
1. Rationale – Current treatments for chronic insomnia are either partially 
effective and/or associated with poor outcomes in objective measures of nighttime sleep.  
Specifically, CBT, the most widely used therapeutic modality, is not associated with a 
satisfactory and clinically significant increase in objective sleep duration (Okajima et al, 
2010). Furthermore, it is not known whether CBT can reverse the activation of the stress 
system, i.e., hypercortisolemia, associated with insomnia with objective short sleep 
duration. Sedative antidepressants, such as trazodone, have been shown in several studies 
to increase objective sleep duration and/or decrease cortisol levels (McCall, 2010). The 
goal of this interventional study is to assess the effect of trazodone vs. CBT in patients 
with chronic insomnia with objective short sleep duration. 
All subjects will be randomly assigned into either a trazodone or a CBT group. 
The group assignment will be decided by our statistician so that the investigators 
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involved with subject recruitment and screening remain blind to the randomization 
process. 
4.0
Inclusion and Exclusion Criteria
Study Population – A total of 70 men and women will be screened for inclusion in 
this study.  24 men and women with chronic insomnia will be enrolled to receive study 
therapy over a 3-month period. This study will focus on adult men and women (30- 60 
years old) with a chronic complaint of insomnia and concomitant objective short sleep 
duration, based on both clinical and polysomnographic criteria. All subjects will meet the 
Research Diagnostic Criteria (RDC) for insomnia (Edinger et al, 2004) and will 
demonstrate < 6 hours of sleep, as assessed by polysomnography (Table 1).  In addition, 
they should meet the criteria for duration for more than one year because this is the 
population that is associated with hypercortisolemia and medical morbidity as shown in 
our previous experimental and epidemiological studies.
Table 1. Research diagnostic criteria (RDC) for insomnia.
Insomnia disorder 
A. The individual reports one or more of the following sleep related complaints:
1.
difficulty initiating sleep,
2.
difficulty maintaining sleep,
3.
waking up too early, or
4.
sleep that is chronically non-restorative or poor in quality.
B. The above sleep difficulty occurs despite adequate opportunity and circumstances for 
sleep.
C. At least one of the following forms of daytime impairment related to the nighttime sleep 
difficulty is reported by the individual:
1.
fatigue/malaise;
2.
attention, concentration, or memory impairment;
3.
social/vocational dysfunction or poor school performance;
4.
mood disturbance/irritability;
5.
daytime sleepiness;
6.
motivation/energy/initiative reduction;
7.
proneness for errors/accidents at work or while driving;
8.
tension headaches, and/or GI symptoms in response to sleep loss; and
9.
concerns or worries about sleep.
Our participants will be middle-aged adults since objective sleep duration 
significantly correlates with age in an inverse manner.  We will not exclude insomniacs 
with minor forms of anxiety or depression, i.e., dysthymic disorder, since these 
conditions are highly comorbid in chronic insomniacs (Buysse et al, 1993; Kales and 
Kales, 1984; Buysse et al, 1994a; Buysse et al 1994b).  However, insomniacs with a 
current diagnosis of a major mental disorder, i.e., schizophrenia, major depression, will 
be excluded from the study because these conditions are associated with the primary 
outcome variables of this study.  In addition, we will exclude subjects with morbid 
obesity (BMI > 39) because, at this level, obesity is frequently associated with frequent 
sleep pathology, i.e., apnea, EDS, and significant medical morbidity (Vgontzas et al, 
1994; Vgontzas et al, 1998).
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Participants with an apnea/hypopnea index (A/HI) > 5 or periodic limb 
movements > 5 per hour of sleep will be excluded from the study.  Also, subjects with a 
primary disorder of EDS, e.g., narcolepsy, or subjects with a history of shift work or 
circadian disorder will be excluded from the study (Vgontzas and Kales, 1999; Roehrs et 
al, 2005; Boggild and Knutsson, 1999) (Table 2).
Table 2. Inclusion/exclusion criteria.
Inclusion 
Exclusion
Chronic insomnia (RDC) with a duration ≥ 1 
year
Objective short sleep duration (< 6h)
BMI < 39
Age range: 30-60
Equal number of men and women
Major mental illness
Substance abuse/dependence
Sleep apnea (apnea/hypopnea index ≥ 5)
PLMD (periodic limb movements ≥ 5)
Objective normal sleep duration (≥6h)
Primary disorders of EDS, i.e., narcolepsy
Shift work or circadian disorders
Diabetes, chronic renal failure, hepatic 
insufficiency, chronic heart failure
Current use of hypnotics or sleep inducing 
sedative antidepressants
RDC = research diagnostic criteria; PLMD = periodic limb movements disorder
  
Subjects treated for diabetes or suffering from chronic renal failure or hepatic 
insufficiency or chronic heart failure will be excluded from the study.  Also, because of 
the known effects of steroids on sleep, subjects on those medications will be excluded 
from the study.  A family history of diabetes will be recorded during the medical history 
and physical examination and controlled within our analyses. Also, the potential effects 
of other medications or substances, such as alcohol or smoking, will be controlled within 
our analyses.  Subjects with a diagnosis of substance abuse or dependence will be 
excluded from the study due to the potential effects of these substances on sleep and 
metabolism.  Patients should be free of hypnotic use or sedative antidepressants 
administered at bedtime to improve sleep for one month before entering the study. 
Finally, patients using psychotropic medications, i.e., SSRI, who do not meet the criteria 
for a current major psychiatric disorder, and have continuous complaints of insomnia, 
will be included in the study.  This is because a large portion of insomniacs consist of 
depressed individuals whose depression improved but still they have complaints of 
chronic insomnia.  Potential confounding effects of medication on some of the outcome 
measures, i.e., objective sleep duration, will be dealt with in the analysis
Women and Minority Inclusion – In this project, we will include middle-aged 
men and women 30- 60 because they represent the majority of patients with insomnia in 
the general and clinic population.  Women who are pregnant or breastfeeding will not be 
enrolled in the study.  We plan to recruit about 21% of subjects belonging in minority 
groups.  The racial and ethnic distribution shown in the Targeted/Planned Enrollment 
Table reflects the general demographics of our region.  Minorities will be recruited from 
our clinics as well as through advertisements in papers with large groups of minority 
readers, such as Harrisburg, PA and Lebanon, PA.  
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Inclusion of Children – The prevalence and clinical characteristics of insomnia in 
children is not well established. In fact, current literature indicates that the etiology, 
clinical and sleep laboratory characteristics of insomnia in children are different than that 
in adults, i.e., bed-resistance, family dynamics, absence of sleep-related worry, etc. Most 
importantly, there is not sufficient evidence to use pharmacologic treatment in childhood 
insomnia.
5.0 Recruitment and Consent Process
When potential participants respond to an advertisement, a structured phone script 
or online script and interview is used to explain study procedures and determine 
eligibility.  A member of the research team will then offer eligible participants the 
opportunity to participate in the study by scheduling a visit and sending a copy of the 
consent form for thorough review prior to the visit. At the time of the visit, the participant 
signs the consent form and is enrolled in the study.  Potential participants may also be 
identified by clinicians in the Sleep Disorders Clinic and offered information about the 
study. 
6.0 Study Procedures
Screening phase
The subjects’ diagnoses of insomnia and other sleep disorders will be established 
by a clinical sleep history conducted by a clinical psychiatrist or psychologist who 
practices sleep medicine. The subjects that meet the research diagnostic criteria (RDC) 
for insomnia will be included in the study (see Table 1).  The subjects’ sleep patterns will 
be assessed via a sleep diary and actigraphy (for two weeks) prior to their visit to the 
sleep lab. Each subject will be monitored continuously for eight hours for one night in the 
sleep unit of the GCRC according to standard techniques (Rechtschaffen and Kales, 
1986; Iber et al, 2007.).  The first night will serve as a screening night for the presence of 
sleep apnea or periodic limb movements, and an adaptation night to control for “first 
night” effects. Prior to or during their visit to the sleep unit, the participants will be 
assessed for psychiatric disorders using a Structured Clinical Interview for DSM-IV, the 
Mini International Neuropsychiatric Interview ( MINI ; Sheehan et al, 2006).
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Figure 1. Screening phase, randomization of patients with insomnia.
Screening phase
Patients with Chronic Insomnia
PSG sleep duration ≥ 6 hours
Exit Study
PSG sleep duration < 6 hours
3-monthsTrazodone treatment
Randomization
3-months CBT treatment
Complete assessment as in 
screening phase
Complete assessment as in 
screening phase
9-months follow-up
9-months follow-up
Randomized Clinical Trial of Trazodone vs. CBT
a. Baseline measures – Following the screening night, the subjects that will enter 
the randomized trial will be monitored in the sleep laboratory continuously for 8 hours 
for 2 consecutive nights according to standard techniques (Rechtschaffen A, Kales A, 
1968) (Table 3).  Following the first night in the sleep laboratory, the participants will be 
admitted to GCRC for a complete semi-structured medical history and physical 
examination. Blood, urine and saliva will be collected and an electrocardiogram (EKG) 
will be performed.   A pregnancy test will be performed on females of child bearing age.  
Following the second night in the sleep laboratory, daytime sleepiness and fatigue, 
nighttime sleep quality and quantity, and mood will be assessed subjectively with 
standardized self-reported questionnaires.  
b. Randomization Scheme for Intervention – Subjects will be randomly assigned 
by our statistician into either a trazodone or a CBT program. Between the two 
intervention groups, we will attempt to have similar BMI, gender, and age distributions.  
If a patient is randomized and enters the randomization trial, then the patient will be 
considered enrolled in the study.
c. Completion of Study Visit – After 3 months on trazodone or CBT, the patients 
will undergo a repeat of the baseline evaluation as noted below (Table 3).  This will 
include a complete physical examination, 2-night, 8-hour polysomnography, two-week 
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actigraphy & sleep diary, blood, urine, and saliva collection, and subjective measures of 
nighttime sleep and daytime functioning.  
d.  Once patients have completed 3 months of study, they will be followed-up 
again 6 months later.  The same procedures performed during the baseline and post 
treatment phase will be repeated.  
Table 3. Study design of randomized trial of trazodone vs. CBT
Screening
Baseline
CBT
Weekly 
Visits
Trazodone 
Monthly
Visits
3 
months
9 
months
Structured Clinical Interview (MINI)
X
Polysomnography & Video Recording
    1 night
X
    2 nights
X
X
X
Actigraphy
    2 weeks
X
X
X
X
Pregnancy Test
X
X
Biomarkers
    Urinalysis
X
X
X
    Urine Drug Screen
X
X
X
    Blood Count
X
X
X
    Blood Chemistries
X
X
X
    Lipid Panel
X
X
X
    Thyroid
X
X
X
    Saliva cortisol
X
X
X
    Blood Inflammation
X
X
X
    Blood Insulin sensitivity
X
X
X
Medical history & physical exam.
X
X
X
EKG
X
X
X
Subjective Measures
    Post Sleep Assessment
X
X
X
X
    Sleep diary
X
X
X
X
X
X
    PSQI
X
X
X
    ISI
X
X
X
X
X
    PSAS
X
X
X
    APS
X
X
X
    FIRST
X
X
X
    POMS-F
X
X
X
    MFI
X
X
X
    ESS
X
X
X
    SSS
X
X
X
X
    BDI-II
X
X
X
    BAI
X
X
X
    HAD-S
X
X
X
    DBAS
X
X
X
d. Intervention Design – The CBT protocol used in this project will include 
evidence-based, behavioral and cognitive techniques; it will consist of what is called a 
“multimodal CBT treatment” covering sleep hygiene, stimulus control, sleep restriction, 
and cognitive therapy (Perlis et al, 2005).
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A session-by-session schedule of the CBT treatment program is presented in 
Table 4. The 1st intervention session will present a conceptual cognitive-behavioral model 
of insomnia (Perlis et al, 2005) and the patient will receive sleep hygiene instructions. A 
brief presentation of the cognitive-behavioral model of insomnia proposed by Perlis et al 
(2005) will be explained to the patients and will serve as the basis to present all clinical 
procedures that will be used during treatment. The role of sleep-related behaviors and 
habits will be addressed, and a standard handout with sleep hygiene instructions will be 
given to the patient at the end of the session (Perlis et al, 2005). The 2nd session will 
introduce stimulus control and sleep restriction therapies, which have shown to be 
strongly efficacious in insomnia (Perlis et al, 2005). The goals of these therapies are: to 
reduce activities incompatible with sleep and develop positive associations of good sleep 
with the bedroom, increase sleep-wake specificity by avoiding napping in the day and 
getting up if wakeful at night, increase sleep efficiency by spending less time in bed and 
build up the natural sleep drive, and establish regular sleep habits and keep to a consistent 
pattern from night to night throughout the week. Because stimulus control and sleep 
restriction involves getting up from bed and going to other room, sessions 3rd and 4th will 
focus on addressing difficulties associated with these techniques. The 5th session will 
introduce the cognitive therapy component. Cognitive therapy is a psychotherapeutic 
method designed to change a person’s beliefs, expectations, appraisals, and attributions 
(Morin, 1993; Perlis et al, 2005). In the context of insomnia, cognitive therapy seeks to 
change sleep expectations, catastrophic beliefs about the causes and consequences of 
insomnia, and beliefs about sleep-promoting practices. This intervention is predominantly 
verbal in nature and is more time consuming to implement in-session than behavioral 
procedures described in previous sessions. In fact, the 6th session will focus on cognitive 
restructuring, i.e., changing the patient’s dysfunctional concerns and beliefs about sleep 
and insomnia. The 7th session will give end to the cognitive restructuring component but 
will also address difficulties associated with all clinical procedures described. The 8th 
session will integrate all clinical procedures as to improve long-term adherence, relapse 
prevention and will also include a post-treatment assessment, as presented in Table 3.
Table 4. A session-by-session schedule of the CBT program
Session
New/Review*
Content
Duration
1
N
Conceptual model and sleep hygiene
50 min
2
N
Setting up sleep restriction and stimulus control, 
Set prescription for sleep restriction
50 min
3
R
Sleep restriction and stimulus control treatment 
gains and compliance 
50 min
4
R
Sleep restriction and stimulus control treatment 
gains and compliance
50 min
5
N
Cognitive therapy
50 min
6
R
Cognitive therapy
50 min
7
R
Cognitive therapy, sleep  restriction, and stimulus 
control gains and compliance 
50 min
8
N
Discuss relapse prevention 
Post-treatment assessment
50 min
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* New/Review refers to the introduction of a new clinical component vs. a review of the outcomes and 
adherence of previously introduced components.
   
This CBT protocol is designed to be implemented over a period of 12 weeks, 
with consultation sessions held on a weekly basis (Perlis et al, 2005). There will be 2 
sessions devoted to baseline evaluation, along with a 2-week baseline sleep diary and 
actigraphy monitoring period, followed by 8 therapy sessions. This number of sessions is 
needed to present a conceptual behavioral model of insomnia, describe all clinical 
procedures and their rationale, provide enough time for patients to experiment with those 
procedures at home, and to problem-solve difficulties encountered during home practice. 
Clinical sessions will be held weekly, to ensure continuity between sessions. The 
treatment program described here has been validated according to specific parameters 
(Perlis et al, 2005). Individual therapy sessions will last approximately for 50 minutes. 
Each therapy session is highly structured and covers a different aspect of treatment. 
Although their specific content varies on the technique presented/used, most sessions are 
structured according to the agenda outlined in Table 5.
Table 5. CBT session agenda

Review sleep diary.

Evaluate compliance with clinical procedures and homework assignment.

Identify problems during home practice and strategies for promoting treatment adherence. 

Introduce new treatment component and its rationale.

Present didactic material supporting this component.

Review homework assignments for the upcoming week.
The very first item of the agenda is to review the sleep diary for the previous 
week. This provides a clear message to the patient that self-monitoring is expected and is 
an essential component of therapy.  The next step is to check the extent to which the 
patient has complied with previous recommendations. After problem solving adherence 
issues, a new treatment component is introduced. Each procedure is described along with 
its rationale and objectives. Handouts will always be provided to consolidate the new 
information presented during the session. The final item on the agenda is to review 
homework assignment for the upcoming week giving a written summary to the patient. 
The trazodone group will receive a standard handout on sleep hygiene 
instructions and subsequent biweekly and monthly visits to check treatment effectiveness, 
adherence and possible side-effects, if they occur, and also follow-up review of sleep 
hygiene practices. All patients will receive a standard dose of trazodone 50 mg. in their 
first visit and will be followed-up with 2 additional biweekly visits. During these 
biweekly visits, doses will be adjusted according to drug effectiveness and possible side-
effects. Consecutive visits will be scheduled monthly and will focus on assessing 
treatment effectiveness, adherence and possible side-effects and need to adjust 
medication doses.
Techniques
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1. Medical History and Physical Examination 
Each subject will have a complete medical history and physical examination using 
a semi-structured format and a battery of clinical tests, including complete blood count, 
liver function test, urinalysis, lipid panel, thyroid indexes, and electrocardiography.  Pre-
menopausal women will also have a pregnancy test performed.  Blood pressure will be 
measured in the morning and in the evening using a pneumoelectric microprocessor-
controlled instrument.  The recorded blood pressure will be the average of 3 consecutive 
readings during a 5-minute period following 10 minutes of rest in the supine position.  
Anthropometric measures will include height, weight, neck size, and waist and hip 
measurements according to standard procedures.  Specifically, neck size is measured at 
the superior border of the cricothyroid membrane with the subject in the upright position.  
Waist is measured at or 1 cm above the umbilical midline and hip at the widest area 
around the buttocks.
2. Objective assessment of Nighttime Sleep
a. Polysomnography – Each subject will be monitored continuously for eight 
hours for 2 consecutive nights (adaptation night and one baseline night) according to 
standard techniques (Rechtschaffen A, Kales A, 1968).  Also, to improve the accuracy 
and reliability of our nighttime sleep measures, the subjects’ typical sleep time at home 
will be assessed objectively via actigraphy for two weeks before the sleep laboratory 
recordings (see below) and during the sleep lab recordings. Respiration will be monitored 
throughout the night by thermocouples at the nose and mouth (Salter Labs) and nasal 
cannula/pressure and by thoracic strain gauges.  We will use both thermocouples and 
nasal cannula because it has been reported that the pressure signal identifies transient 
elevated upper airway resistance not detected conventionally (Iber et al, 2007). An 
apnea/hypopnea index ≥ 5 will be used to define the presence of sleep apnea.
b. Actigraphy – An actigraphy monitor (ActiGraph GT3X) will be placed on the 
wrist of the nondominant hand of subjects.  The subjects will be asked to keep an 
actigraphy log for two week periods in which they note daily time to bed, time out of bed, 
or times when the device is removed (e.g., taking a bath, swimming).
3. Subjective assessment of Nighttime Sleep and Arousal
a. Post-sleep Assessment – Throughout the study, subjects will complete a post-
sleep questionnaire upon awakening each morning in the sleep lab and will estimate time 
to fall asleep, number of nightly awakenings, total sleep time, soundness and quality of 
sleep, and morning sleepiness.
b. Sleep Diary – A 2-week sleep log or diary will be used for assessment of the 
subjects’ perceived sleep patterns at the screening phase, at the onset of the study, during 
the intervention period,  at the end of the intervention and at follow-up.
c. Sleep Quality – The Pittsburg Sleep Quality Index (PSQI) will be used for 
assessment of the subjects’ overall sleep quality at the onset of the study, at the end of the 
intervention and at follow-up (Buysse et al, 1989).
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d. Insomnia Severity – The Insomnia Severity Index (ISI) will be used for 
assessment of the subjects’ overall perceived insomnia severity at the onset of the study, 
during the intervention period, at the end of the intervention and at follow-up (Bastien et 
al, 2001).
e. Pre-sleep Arousal – The Pre-Sleep Arousal Scale (PSAS) will be used for 
assessment of the subjects’ perceived pre-sleep cognitive and somatic arousal at the onset 
of the study, at the end of the intervention and at follow-up (Nicassio et al, 1985).
f. Arousability – The Arousability Predisposition Scale (APS) will be used for 
assessment of the subjects’ perceived overall tendency to present high levels of cognitive 
and emotional arousal at the onset of the study, at the end of the intervention and at 
follow-up (Coren, 1988).
g. Stress-related Insomnia – The Ford Insomnia Response to Stress Test (FIRST) 
will be used for assessment of the subjects’ overall perceived likelihood of having sleep 
disturbances in association with specific and common stressful events at the onset of the 
study, at the end of the intervention and at follow-up (Drake et al, 2004).
4. Assessment of Daytime Functioning
a. Sleepiness and Fatigue – Subjects will estimate degree of sleepiness/alertness 
after awakening in the sleep lab with a 10-cm analog scale that ranges from "extremely 
sleepy" to "not sleepy" and the Stanford Sleepiness Scale (SSS) (MacLean et al, 1992).  
The Epworth Sleepiness Scale (ESS) will be used for assessment of the subjects’ overall 
sleepiness at the onset of the study, at the end of the intervention and at follow-up (Johns, 
1991). The Fatigue subscale of the Profile of Mood States (POMS-F) (McNair et al, 
1971.), and the Multidimensional Fatigue Inventory (MFI) (Smets et al, 1995) will be 
used for assessments of the subjects’ overall fatigue at the onset of the study, at the end of 
the intervention and at follow-up.
b. Mood – The Beck Depression Inventory-II (BDI-II) will be used for assessment 
of the subjects’ overall severity of depressive symptoms at the onset of the study and at 
the end of the intervention (Beck et al, 1996). The Beck Anxiety Inventory (BAI) will be 
used for assessment of the subjects’ overall severity of anxious symptoms (somatic 
component) at the onset of the study, at the end of the intervention and at follow-up 
(Osman et al 1997). The Anxiety subscale of the Hospital Anxiety and Depression Scale 
(HAD-S) will be used for assessment of the subjects’ overall severity of anxious 
symptoms (cognitive component) at the onset of the study, at the end of the intervention 
and at follow-up (Zigmond and Snaith, 1983).
c. Cognition – The Dysfunctional Beliefs and Attitudes about Sleep scale (DBAS) 
will be used for assessment of the subjects’ sleep cognitions (i.e., causal attributions of 
insomnia, perceived consequences of insomnia, sleep requirements expectations, control 
and predictability of sleep, and beliefs about sleep-promoting practices) at the onset of 
the study, at the end of the intervention and at follow-up (Espie et al 2000).
5. Assessment of the Stress System, Inflammation, and Insulin Resistance
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a. Stress System – We propose to sample saliva at five time points during the day, 
i.e. 8:00 before breakfast, 12:00 before lunch, 3:00 pm, 6:00 pm, and 9:00 pm. It has been 
demonstrated that five samples are adequate to examine circadian variation of cortisol 
secretion (Pervanidou et al, 2007a; Pervanidou et al, 2007b). No food or exercise would 
be allowed at least half an hour before sample collection. Each sample will be collected 
by having the participant place a cotton swab in his or her mouth for 2 minutes or chew it 
for 1 minute. These samples will be collected on Day 2 of the baseline and follow-up 
phases (3 and 9 months) of the study.  The cotton swab will then be placed inside a 
plastic tube and kept in the refrigerator at 0-4ºC. Salivary cortisol will be extracted from 
the cotton by centrifuging the plastic tubes and cotton at 100g for 8 minutes to separate 
the saliva into the outer tube. The cotton will be removed and all samples will be stored at 
-85ºC.
b. Inflammation Markers– TNFα, TNFr1 and IL-6 will be measured in two single 
serum samples on Day 2(evening and morning pre- and post-sleep recording) because 
their concentration varies during the 24-hour sleep-wake cycle. Blood will be collected 
during the baseline and follow-up phases (3 and 9 months) of the study.  Serum TNFα, 
TNFr1, and IL-6 will be measured by ELISA (R&D Systems, Minneapolis, MN) 
(Vgontzas et al, 2004; Vgontzas et al, 2007; Vgontzas et al, 1997; Vgontzas et al, 2004; 
Vgontzas et al, 2008).
c. Insulin Sensitivity – Whole-body insulin sensitivity can be measured with the 
euglycemic insulin clamp technique, which measures insulin resistance (IR) directly and 
is considered the “gold standard”. However, the intensity, complexity and risks of the 
method make it unsuitable for large studies such as ours. The use of a fasting glucose to 
insulin (G/I) ratio is the simplest and easiest way technically and appears to provide a 
reasonable estimate of tissue sensitivity to insulin in large samples. Many studies have 
shown that simple indices of insulin sensitivity derived from fasting glucose and insulin 
levels, such as homeostasis model assessment (HOMA) (Ip et al, 2002; Punjabi et al, 
2002) and Quantitative Insulin Sensitivity Check Index (QUICKI), are simple, accurate 
methods for assessing insulin sensitivity in large studies (Quon, 2001; Katz et al, 2000). 
The reliability of the G/I ratio is expected to be very good in our study given that 
overnight fasting is well-controlled within the sleep lab environment. Blood samples will 
be collected on day 2 (evening and morning pre-and post-sleep recording) during the 
baseline and follow-up phases (3 and 9 months) of the study.
  
7.0
Risks and Discomforts
Protection of Human Subjects
1. The data to be collected from each subject include: medical history and 
physical examination; sleep EEG and respiration; actigraphy; and self-reported 
questionnaires and scales.
2. The venous puncture is associated with minor discomfort and a risk of a bruise 
at the site of the venous puncture.  
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3. Potential risks include the risk of study-related procedures. There is a minimal 
risk associated with the discomfort of having standard clinical EEG past electrodes 
applied to the scalp.  Rarely, we have had an individual who has had a mild allergic 
reaction to the tape applied over electrodes. This risk is minimized by using 
hypoallergenic tape. 
4. There are a few potential risks associated with trazodone. Trazodone is a 
sedative triazolopyridine antidepressant, habitually used for the treatment of depression 
and insomnia because it possesses antidepressant and also anxiolytic and hypnotic 
activities (Al-Yassiri et al, 1981; McCall, 2010). Pharmacologically, it is a serotonin 
antagonist and reuptake inhibitor; it is a blocker of postsynaptic serotonin receptors 5-
HT1A, 5-HT1C, and 5-HT2, as well as postsynaptic α1-adrenergic receptors. It has a 
peak serum concentration of 1-2 hours and an elimination half-life of about 5-9 hours. 
When prescribed as an antidepressant, i.e., to alleviate major depression, the usual doses 
of trazodone are ≥ 150 mg daily. Daytime doses of trazodone at 100 mg have been found 
to impair critical flicker fusion and choice reaction time 1-4 hours later in only two 
studies (Burns et al, 1986; Warrington et al, 1984). Bedtime doses of trazodone at 100 mg 
have been found to lower blood pressure and impair critical flicker fusion the next 
morning in one study (Saletu-Zyhlarz et al, 2001). One study mentioned in a recent 
review found orthostatic hypotension and priapism as a side effect of bedtime trazodone 
administration (James and Mendelson, 2004). When prescribed as a hypnotic, it is 
habitually used at low-doses (i.e., 50 mg daily at bedtime). The vast majority of studies 
have shown that trazodone improves subjective sleep quality and increases objective total 
sleep time, percent of stages 3 and 4, and sleep efficiency, and decreases the percent of 
stage 1, number of awakenings, and stage shifts, as assessed by PSG (Burns et al, 1986; 
Saletu-Zyhlarz et al, 2001; James and Mendelson, 2004; Dording et al, 2002; Nierenberg 
et al, 1994; Haffmans, 1999; Walsh et al, 1998; Montgomery et al, 1983; Yamadera et al, 
1998; Ware and Pittard, 1990; Kaynak et al, 2004; Zavesicka et al, 2008). There are no 
controlled studies or clinical reports of major side-effects with low-dose trazodone when 
administered at bedtime in insomniacs. The most common side effect of low-dose 
trazodone when administered at bedtime may be minimal morning sedation, based on 
clinical experience.  Common risks of trazodone given at higher doses include headache, 
dry mouth, blurred vision, dizziness, fatigue, nausea and suicidal thoughts in children, 
adolescents and young adults with depression.
 5. There are a few potential risks associated with CBT. When individuals start the 
sleep scheduling component they are asked to restrict their time in bed and in some 
instances their sleep duration. This procedure may cause some residual daytime 
sleepiness that might interfere with daytime functioning. The patient will be warned of 
this possible effect and will be asked not to get into risky behaviors if feeling excessively 
sleepy (e.g., driving). Another possible side-effect of CBT may be the frustration felt by 
the patient due to a lack of achievement of expected goals. CBT is a goal-oriented, 
homework-based psychotherapy and in some cases the patient may be delayed to respect 
to the planned objectives which may cause some frustration. However, we do not 
anticipate any major side-effects to occur. 
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8.0
Benefits
Risk to Benefit Ratio Only – In our opinion, these studies will provide significant 
new information in regard to the underlying mechanism of chronic insomnia and will lay 
the foundation for new treatments for a disorder that affects a large proportion of the 
general population. In addition, trazodone may hold the benefit of improving sleep 
duration in chronic insomnia, and a long-term reduction in the risk of developing 
cardiometabolic and/or psychiatric problems.  The benefit to others may be validation of 
trazodone as the basis for treatment of a common sleep disorder with significant medical 
sequelae. Data obtained in this study can be used to design larger multi-center trials 
testing these findings.  We believe that overall, the risks of these experiments are small 
compared to the importance of the knowledge that will be obtained.
9.0 
Reporting of Adverse Events and Unanticipated Problems Involving Risks to 
Participants or Others
The PI will report all adverse events or unanticipated problems to the IRB/HSPO 
according to established guidelines.  
10.0
Study Withdrawal/Discontinuation
Taking part in this research study is voluntary. The participants do not have to 
participate in this research. If they choose to take part, they have the right to stop at any 
time. If they decide not to participate or if they decide to stop taking part in the research 
at a later date, there will be no penalty or loss of benefits to which they are entitled and 
just need to notify the primary investigator that they wish to discontinue. 
The research investigators may also discontinue any participant. Possible reasons 
for this are: continuing the research would be harmful, they did not follow the 
instructions of the study doctor, or they experience serious side effects. 
11.0
Statistical Analysis of the Study
Analysis
a. Sample Size Calculation – This is a pilot study to collect preliminary data using 
two interventions, i.e., trazodone or CBT, with unknown effects for chronic insomnia 
with objective short sleep duration. Based on our previous experience with interventional 
studies, we suggest that 10 subjects per group will be adequate to detect a difference of 
20 minutes in objective sleep duration between the two treatment interventions. To allow 
for an anticipated 20% attrition rate, 24 subjects will be assigned to a study intervention 
to ensure complete data from 20 participants. The results of this study will allow the 
establishment of sample size for any future studies.  Our statistical consultant in this 
study is Dr. Duanping Liao.
b. Analytic Plan
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Specific Aim 1: Examine the Effect of Trazodone vs. CBT for the Primary Outcome 
Variables (objective and subjective sleep duration) in Patients with Chronic 
Insomnia with Objective Short sleep Duration
Throughout the analysis, we will compare the differences (end of the 
interventional study baseline) between the two groups of the outcome of interest (e.g., 
total sleep time).  
Total Sleep Time, Polysomnography:  Both at baseline and the end of the 
intervention, polysomnography will be measured for 2 consecutive nights. We will 
calculate the time-specific difference from the baseline to the end of intervention.  Then, 
we will compare the two treatment conditions with respect to the overall mean change 
across all time points (“difference of difference”) using the two-sample t-test. 
Alternatively, repeated measures analysis of variance (ANOVA) will be used to compare 
treatment conditions with respect to polysomnographic total sleep time changes from 
baseline. The time and treatment condition main effects as well as interaction between 
time and treatment condition will be tested. Adjustments for multiple comparisons across 
different time points and between intervention groups will be performed. Potential 
confounders and interaction between treatment condition and confounder will also be 
examined. In the event that the distribution of polysomnographic total sleep time are not 
consistent with the assumptions of normality required for ANOVA, attempts will be 
made to find suitable transformation.
Total Sleep Time, Actigraphy:  Both at baseline and the end of the intervention, 
actigraphy will be measured for 2 weeks. We will calculate the time-specific difference 
from the baseline to the end of intervention.  Then, we will compare the two treatment 
conditions with respect to the overall mean change across all time points (“difference of 
difference”) using the two-sample t-test. Alternatively, repeated measures analysis of 
variance (ANOVA) will be used to compare treatment conditions with respect to 
actigraphic total sleep time changes from baseline. The time and treatment condition 
main effects as well as interaction between time and treatment condition will be tested. 
Adjustments for multiple comparisons across different time points and between 
intervention groups will be performed. Potential confounders and interaction between 
treatment condition and confounder will also be examined. In the event that the 
distribution of actigraphic total sleep time are not consistent with the assumptions of 
normality required for ANOVA, attempts will be made to find suitable transformation. 
Total Sleep Time, sleep diary:  Both at baseline and the end of the intervention, 
subjective sleep duration will be measured with a 2-week sleep log. We will calculate the 
time-specific difference from the baseline to the end of intervention.  Then, we will 
compare the two treatment conditions with respect to the overall mean change across all 
time points (“difference of difference”) using the two-sample t-test. Alternatively, 
repeated measures analysis of variance (ANOVA) will be used to compare treatment 
conditions with respect to subjective total sleep time changes from baseline. The time and 
treatment condition main effects as well as interaction between time and treatment 
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condition will be tested. Adjustments for multiple comparisons across different time 
points and between intervention groups will be performed. Potential confounders and 
interaction between treatment condition and confounder will also be examined. In the 
event that the distribution of subjective total sleep time are not consistent with the 
assumptions of normality required for ANOVA, attempts will be made to find suitable 
transformation. 
Specific Aim 2: Examine the Effect of Trazodone vs. CBT on the Secondary 
Outcome Variables (insomnia severity, daytime functioning, stress, inflammation 
and insulin sensitivity) in Patients with Chronic Insomnia with Objective Short 
sleep Duration 
Subjective sleep quality and insomnia severity: Both at baseline and the end of the 
intervention, self-reported sleep quality (PSQI) and insomnia severity (ISI) will be 
measured. We will calculate the time-specific difference from the baseline to the end of 
intervention.  Then, we will compare the two treatment conditions with respect to the 
overall mean change across all time points (“difference of difference”) using multivariate 
repeated measures analysis of variance (MANOVA) to compare treatment conditions 
with respect to all measures of subjective sleep quality and insomnia severity changes 
from baseline. The time and treatment condition main effects as well as interaction 
between time and treatment condition will be tested. Adjustments for multiple 
comparisons across different time points and between intervention groups will be 
performed. Potential confounders and interaction between treatment condition and 
confounder will also be examined. In the event that the distribution of subjective sleep 
quality and insomnia severity measures are not consistent with the assumptions of 
normality required for MANOVA, attempts will be made to find suitable transformation.
Sleepiness, fatigue, and mood: Both at baseline and the end of the intervention, 
self-reported sleepiness (ESS), fatigue (POMS-F and MFI) and mood (BDI-II, BAI, and 
HAD-S) will be measured. We will calculate the time-specific difference from the 
baseline to the end of intervention.  Then, we will compare the two treatment conditions 
with respect to the overall mean change across all time points (“difference of difference”) 
using multivariate repeated measures analysis of variance (MANOVA) to compare 
treatment conditions with respect to all measures of sleepiness, fatigue, and mood 
changes from baseline. The time and treatment condition main effects as well as 
interaction between time and treatment condition will be tested. Adjustments for multiple 
comparisons across different time points and between intervention groups will be 
performed. Potential confounders and interaction between treatment condition and 
confounder will also be examined. In the event that the distribution of sleepiness, fatigue, 
and mood measures are not consistent with the assumptions of normality required for 
MANOVA, attempts will be made to find suitable transformation.
Stress, inflammation, and insulin sensitivity: Both at baseline and the end of the 
intervention, saliva cortisol, TNFα, TNFr1, IL-6, and the fasting glucose to insulin ratio 
(G/I) will be measured. We will calculate the time-specific difference from the baseline 
to the end of intervention.  Then, we will compare the two treatment conditions with 
respect to the overall mean change across all time points (“difference of difference”) 
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using multivariate repeated measures analysis of variance (MANOVA) to compare 
treatment conditions with respect to all measures of stress, inflammation and insulin 
sensitivity changes from baseline. The time and treatment condition main effects as well 
as interaction between time and treatment condition will be tested. Adjustments for 
multiple comparisons across different time points and between intervention groups will 
be performed. Potential confounders and interaction between treatment condition and 
confounder will also be examined. In the event that the distribution of stress, 
inflammation and insulin sensitivity measures are not consistent with the assumptions of 
normality required for MANOVA, attempts will be made to find suitable transformation.
12.0
Privacy and Confidentiality Considerations
All research records that are reviewed, stored, and analyzed at The Milton S. 
Hershey Medical Center (HMC) and Penn State College of Medicine (PSU) will be 
labeled with a code number.  The list that matches the participant’s name with the code 
number will be kept in a locked file in the PI’s office. The research records will be kept 
in password-protected computer files and in file cabinets in locked rooms. In the event of 
any publication or presentation resulting from the research, no personally identifiable 
information will be shared.
13.0
Data and Safety Monitoring Plan
This study involves low risk to subjects as it involves a low-dose sedative 
antidepressant treatment, a CBT program, and polysomnography. 
Oversight for the conduct of the study will be provided by the PI, Alexandros 
Vgontzas, MD.  He will ensure that all eligibility criteria and consent requirements are 
met prior to a subject’s participation in the study and that all study procedures and 
adverse event reporting occur according to the IRB approved protocol.  
All data forms and study specific information will be kept in locked file cabinets 
and in a password protected computer database with access limited to the PI and clinical 
research team. Any presentation or publication of the data will be done in aggregate 
fashion without identifiers.
All adverse events will be documented and reported by the PI to the IRB 
according to HSPO policies and procedures.
The PI will review cumulative adverse events, early termination of study 
participation, and accrual every six months and report any issues requiring modification 
of the study or alteration of the risk: benefit ratio to the IRB immediately.  A summary of 
adverse events, study progress and protocol modifications will be included for IRB 
review in the continuing review report. 
14.0
Compensation
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Participants will be compensated in the amount of $400 upon completion of the 
study.  Partial compensation will be given ($25 for each night spent in the sleep 
laboratory, $10 for each visit of treatment session, each monthly visit including initial 
visit to obtain actigraphy watch and sleep log.
15.0
Drugs, Biologics, or Devices
Trazodone is a sedative triazolopyridine antidepressant, habitually used for the 
treatment of depression and insomnia because it possesses antidepressant and also 
anxiolytic and hypnotic activities (Al-Yassiri et al, 1981; McCall, 2010). 
Pharmacologically, it is a serotonin antagonist and reuptake inhibitor; it is a blocker of 
postsynaptic serotonin receptors 5-HT1A, 5-HT1C, and 5-HT2, as well as postsynaptic 
α1-adrenergic receptors. It has a peak serum concentration of 1-2 hours and an 
elimination half-life of about 5-9 hours. When prescribed as an antidepressant, i.e., to 
alleviate major depression, the usual doses of trazodone are ≥ 150 mg daily. When 
prescribed as a hypnotic, it is habitually used at low-doses (i.e., 50 mg daily at bedtime). 
The effects of trazodone on sleep have been evaluated in a variety of subjects, including 
patients with insomnia and depression and normal controls. In general, most studies have 
shown that trazodone improves subjective sleep quality and increases objective total 
sleep time, percent of stages 3 and 4, and sleep efficiency, and decreases the percent of 
stage 1, number of awakenings, and stage shifts, as assessed by PSG (Burns et al, 1986; 
Saletu-Zyhlarz et al, 2001; James and Mendelson, 2004; Dording et al, 2002; Nierenberg 
et al, 1994; Haffmans, 1999; Walsh et al, 1998; Montgomery et al, 1983; Yamadera et al, 
1998; Ware and Pittard, 1990; Kaynak et al, 2004; Zavesicka et al, 2008).
16.0
Records and Study Monitoring
Not Applicable.
17.0
Facilities
General Clinical Research Center & Sleep Lab
18.0
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