INSOMNIA, THE MOST COMMON SLEEP ... are treated by their primary care physicians, and a large...

The Diagnosis and Treatment of Chronic Insomnia in Adults
Alexandros N. Vgontzas, MD
Sleep Research and Treatment Center, Department of Psychiatry, Pennsylvania State University College of Medicine, Hershey, PA
the last 10-15 years. The National Institutes of Health State of the
Science Conference Statement is a major step towards recognizing
that gap. The following points are offered in the spirit of contributing to a dialogue that is at its very beginning, and I appreciate
the opportunity that was made possible by the Editor of SLEEP.
One of the proposals included in the Statement is the use of the
term “comorbid insomnia” in lieu of terms such as “secondary”
or “primary” insomnia. This proposal is based on the recognition
that chronic insomnia is usually comorbid with psychiatric and
physical conditions and that currently there is limited understanding of the nature of their association or direction of causality. The
term “comorbid” suggests the presence of 1 or more disorders (or
diseases) in addition to a primary disease or disorder. It does not
imply either causality or association. The strong association of insomnia with psychiatric conditions appears to be the single most
important association and the most consistent finding across almost all studies in the last 30 years. For example, in a multicenter
field trial sponsored by NIMH, insomnia was associated with another diagnosable psychiatric condition in 90-93% of the cases depending on the diagnostic system used (DSM-IV vs. International
Classification of Diseases (ICD-10)). 1 Also, in a recent study in
1741 men and women of a random general population sample,
depression was the single strongest variable, followed by female
gender.2 Physical disorders were also associated with insomnia
but to a much lesser degree, eg, odds ratio (OR) for depression of
5.5 vs. OR for colitis of 1.3. Sleep apnea, defined as an OHI ≥ 15,
was not associated with insomnia, which is consistent with earlier
findings from clinical samples.
Do these data support any causal link between insomnia and
psychiatric conditions? Certainly not, as correctly pointed out in
the Statement. Despite the clinical evidence that emotional stress
or depression precedes the onset of insomnia and that insomnia is
a risk factor for depression, there is a need for long-term prospective studies to understand the nature of the association between
insomnia and psychiatric conditions. In the meantime, physicians
and the public should be informed about the strong association of
insomnia with mental health and appropriate diagnostic evaluation
and treatment of insomnia should always include a mental health
assessment, even in a brief office visit of a busy practitioner. This
message is very important, particularly now that many insomniacs
are treated by their primary care physicians, and a large number
of sleep specialists have no psychiatric background.
The panel expressed a concern that an emphasis on the association of insomnia with psychiatric conditions may promote undertreatment of insomnia. Insomnia as a distinct disorder has been
part of the DSM classification system of the American Psychiatric
Association and the ICD for almost 20 years, securing and promoting the idea that insomnia must be the focus of independent
research and clinical efforts. Also, clinicians have long recognized
that insomnia many times is maintained despite the remission of
the accompanying depression and that it requires separate therapeutic interventions from depression, including pharmacological,
psychobehavioral, and sleep hygiene interventions. Furthermore,
there is evidence that a primary complaint of insomnia associated with depression, in terms of its pathophysiology, is different
from depression without a primary complaint of insomnia. For
example, in chronic insomnia: (a) sleep efficiency measures are
the primary variables that are affected3 whereas in depression, it
is both sleep efficiency measures and REM sleep variables;4 (b)
cortisol secretion is related to sleep disturbance indices, eg, total
wake time (TWT) and stage 1 sleep,5,6 whereas in depression hypercortisolemia is related to REM sleep variables;7 (c) degree of
psychological distress correlates with objective sleep disturbances,8 whereas in depression there is a dissociation between depth
of depression and sleep abnormalities;4 and (d) sleep deprivation
does not have a mood-elevating effect in contrast to depression.
Collectively, these observations suggest that insomnia is not
simply a by-product of depression and, as the panel noted, the
complex association of these two disorders must be the focus
of intense research effort. Such research can only benefit by acknowledging the strong association of insomnia and mental health
and not by de-emphasizing its importance. To draw an analogy
from another prevalent sleep disorder, ie, sleep apnea, research
on that disorder can only gain by recognizing the strong and complex association of sleep apnea with obesity.
Another issue that is not dealt with in the Statement is whether
insomnia is a nighttime disorder or a disorder present throughout
the 24-hour sleep-wake cycle. Daytime impairment, in its various
forms, is now considered to be essential in the diagnosis of insomnia.9 This approach is a departure from the traditional view in
sleep medicine that has focused its efforts to improve the quality
and quantity of nighttime sleep of insomniacs with pharmacotherapeutic and/or psychobehavioral techniques.
In clinical and psychometric studies of the 1970s, it was reported that insomnia is frequently associated with depression, anxiety, rumination, and inhibition of emotional expression.8 At about
the same time, other studies pointed to the presence of increased
physiologic activation, such as increased heart rate, peripheral
vasoconstriction, elevated rectal temperature, and increased body
movement before and during sleep. These findings led to the formulation of the hypothesis that insomnia is a disorder of emo-
Disclosure Statement
Dr. Vgontzas has indicated no financial conflict of interest
Address correspondence to: Alexandros N. Vgontzas, MD, Sleep Research
and Treatment Center Department of Psychiatry H073, Pennsylvania State
University College of Medicine, 500 University Drive, Hershey, PA 17033;
Tel: (717) 531-8515; Fax: (717) 531-6491; E-mail: [email protected]
SLEEP, Vol. 28, No. 9, 2005
tional and physiologic arousal.
These early studies were strengthened by findings that insomnia is associated with: (a) decreased sleepiness the next day as
measured by a multiple sleep latency test (MSLT) in contrast to
normal sleepers after sleep loss;10 (b) increased cortical activation as indicated by increased higher frequency (beta and gamma)
wave activity and decreased delta wave activity during sleep and
while awake;11,12 (c) increased 24-hour metabolic rate compared
to controls;13 (d) greater glucose metabolism during sleep and
while awake in the prefrontal cortex;14 (e) 24-hour activation of
the stress system and, particularly, the hypothalamic-pituitary-adrenal (HPA) axis,5,6 in contrast to the effects of nonstressful total
or partial sleep deprivation in young, normal sleepers.15,16 Furthermore, the sleep disturbance experienced by middle age men
compared to young healthy men secondary to the administration
of the arousal peptide corticotropin-releasing hormone (CRH)
supports the role of increased physiologic arousal/decreased sleep
homeostatic pressure in the increased prevalence of insomnia in
the older vs. young individuals.17 In summary, these consistent
data over a 30-year period suggest that insomnia and sleep loss
are 2 distinct states and that insomnia is a disorder of physiologic
and emotional hyperarousal present throughout the 24-hour sleepwake cycle. Such a model has obvious therapeutic implications,
and it is important that future research, both clinical and basic, is
encouraged to examine its validity and clinical usefulness.
The last section of the report is devoted to the evidence on the
safety and efficacy of treatments currently used for chronic insomnia. The panel notes that there has been a significant shift in
the pattern of prescribed medications to treat chronic insomnia associated with a substantial increase in the off-label use of antidepressants, particularly trazodone. The panel appears to be puzzled
by these trends given the lack of studies documenting the sleep efficacy of antidepressants. Further, the panel is concerned about the
risk-benefit ratio of antidepressants given that all antidepressants
have potentially significant adverse effects. Although not based
on “hard” evidence, it appears that the widespread prescription of
antidepressants may be related to the following factors: (1) benzodiazepine receptor agonists are recommended only for short-term
use (with the exception of the recently released eszopiclone) for a
disorder that is chronic and possibly nonremitting; (2) antidepressant use is not associated with tolerance-withdrawal phenomena
as is the case with most benzodiazepine agonists; (3) although
the old tricyclic antidepressants, eg, amitriptyline, are associated
with significant adverse effects, trazodone appears to be safe with
minimal side effects in the dose range commonly used for sleep
(50-150 mg); and (4) sedative antidepressants, alone or in combination with the newer antidepressants, eg, SSRIs, appear to have a
normalizing effect on measures, ie, cortisol 18, which may have an
ameliorating effect on mood and other daytime symptoms experienced by chronic insomniacs. The panel called on the pharmaceutical industry to “support comparisons of its medications, not only
with placebo, but also with other effective treatments, including
cognitive behavioral therapy (CBT).” Given the widespread use
of antidepressants, and the absence of studies on their hypnotic
effectiveness, such a call should also include antidepressants, eg,
trazodone, as a primary comparison group. Such information is
important to the public, to the practicing physician, and potentially useful to understand further the pathophysiology of chronic
SLEEP, Vol. 28, No. 9, 2005
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