Escolar Documentos
Profissional Documentos
Cultura Documentos
3, pp 253–262, 2000
doi:10.1053/smrv.1999.0075,
available online at http://www.idealibrary.com on
SLEEP
MEDICINE
reviews
REVIEW ARTICLE
Chronic insomnia is a risk factor for the development of psychiatric disorders, including depression, as
well as a prodrome of major depressive episodes, a consequence or complication of depression that often
persists beyond the clinical episode, and a prognostic indicator of long-term illness course and treatment
response. In addition, sleep is physiologically abnormal in persons at risk for depression; for example,
shortened REM sleep latency is present not only during clinical episodes of depression, but also before
the clinical episode in subjects at risk for depressive illness. Although insomnia usually disappears as
depression is treated, it may persist, indicating heightened vulnerability to depressive relapse or recurrence.
Physiological changes in sleep related to depression correlate with the likelihood of response to psychotherapy
alone and may also identify which patients are unlikely to do well with psychosocial treatment and,
therefore, to need somatic therapy in order to preserve recovery. Electroencephalographic (EEG) sleep
changes also correlate with the speed of response and with the brittleness or durability of response (i.e.,
probability of relapse or recurrence). These observations suggest a close relationship between the regulation
of sleep and the regulation of mood. The importance of this relationship is further underscored by recent
brain imaging studies of sleep and sleep deprivation in patients with major depression. For example,
therapeutic sleep deprivation (TSD) may serve as both a catalyst of rapid antidepressant activity and as
a probe of treatment resistance. TSD’s effects on brain metabolic rates, especially in limbic areas, may
correlate with a therapeutic response to a night of sleep loss and to antidepressant medication. Finally,
treating chronic insomnia with newer selective serotonin reuptake inhibitor (SSRI) antidepressant
medication may represent an opportunity for preventing complications of insomnia, including depressive
illness. 2000 Harcourt Publishers Ltd
Key words: chronic insomnia, depression, preventative treatment, therapeutic sleep deprivation.
Chronic insomnia is a common complaint and a risk factor for the development of
depression. The NIMH Epidemiologic Catchment Area (ECA) study of sleep dis-
turbances and psychiatric disorders identified sleep disturbance as a highly significant
risk factor (odds ratio 39.8) for the subsequent development of major depression [1].
Practice Point
Chronic insomnia is a risk factor for the development of clinical depression. Treating
chronic insomnia effectively may reduce the incidence of depression and other
mental disorders.
specific to depression more than any single marker of depression [11]. It is unclear
why some depressed patients fail to exhibit these characteristic sleep changes, or why
patients with other psychiatric disorders exhibit sleep manifestations linked with
depression. However, it is clear that the combination of changes, such as decrease in
slow-wave activity during the first NREM period and corresponding increases in the
rate of production of REMs in the first REM period, is more pronounced earlier in a
clinical episode of depression than later [16,17]. While patients with chronic primary
insomnia typically show sleep continuity disturbance, they lack these more specific
macro and micro-architectural features of depression [5].
Increased cholinergic activity relative to monoaminergic neurotransmission occurs
in depression and may be the basis for the observed alterations in EEG sleep [18].
Increased cholinergic activity is associated with sleep changes linked to depression
such as increases in REM sleep, early REM induction and frequent arousals. Many
effective antidepressants increase serotonergic and or noradrenergic neurotransmission.
Some have anticholinergic effects. Antidepressants follow different mechanisms with
varying effects on sleep. Some antidepressants inhibit serotonin reuptake into pre-
synaptic neurons, antagonize postsynaptic 5HT2 receptors, or function and 5HT1A
receptor agonists [8].
Functional neuroimaging techniques, such as positron emission tomography, are
beginning to enhance our understanding of the relationship between insomnia and
depression. Patients with major depressive disorder have higher rates of glucose
metabolism during the first NREM sleep period as compared with non-depressed
control subjects [19,20]. This activation is also associated with decreased slow wave
sleep. REM sleep is associated with metabolic rate similar to wakefulness and increased
metabolism in limbic and paralimbic structures whereas REM sleep in depressed
patients correlates with overactivity and decreased response in structures which
respond to physiologic challenge [21]. To date, we are not aware of any similar PET
studies on chronic primary insomnia.
Practice Point
Electroencephalographic (EEG) sleep measures are abnormal in those at risk for
depression.
Practice Point
• Subjective sleep quality can be reliably measured by the Pittsburgh Sleep Quality
Index [26], where scores above 5 suggest clinically significant insomnia, either
primary psychophysiological insomnia or insomnia secondary to mental disorders
such as depression.
• Clinicians should pay attention to self-reported sleep quality. Return of normal
sleep quality is a good indicator of continued recovery from depression in patients
treated with maintenance interpersonal psychotherapy on a once monthly basis.
258 L. Lustberg and C. F. Reynolds III
The goal of treating concomitant insomnia and depression is to resolve the underlying
depression and prevent the onset and perpetuation of insomnia. The clinical man-
agement of insomnia entails an awareness of the reciprocal relationship between
insomnia and depression. Treating depression usually, but not always, mitigates
the symptomatic sleep disturbances. Prevention of persistent sleep disturbance may
decrease the risk of relapse or recurrence of depression.
Coprescription of sedative hypnotic agents in the management of insomnia associated
with depression assumes that the patient has been instructed in rules of good sleep
hygiene and entails five main principles: (1) administrating the lowest effective dose;
(2) following an intermittent dosing schedule of 2–4 times per week; (3) prescribing
medication for short-term use; (4) making an effort to gradually discontinue medication;
and (5) preventing rebound insomnia. In addition, serotonin specific antidepressants
such as paroxetine and nefazodone may relieve both sleep disturbances and depression,
potentially obviating the need for coprescription sedatives. SSRIs have fewer side
effects than tertiary tricyclic amines. However, no systematic evaluation has been
performed regarding the benefit of serotonin specific treatment for chronic primary
insomnia. Unlike benzodiazepines and imidazopyridines, which work on GABA
receptors, they have the advantage of decreases in dependence, withdrawal, and
rebound insomnia. We have recently reviewed this literature elsewhere [27].
Physicians prescribe tricyclic antidepressants (TCAs) to treat major depressive dis-
orders. Advantages of TCAs include low cost and efficacy [28]. However, TCAs produce
significant adverse side effects. TCAs induce anticholinergic symptoms with autonomic
and cardiovascular manifestations. They also pose a high risk in overdose. Considering
the possibility of lethal effects of high doses, TCAs should not be considered for
patients who present with increased risk of suicide. Physicians have shifted to selective
serotonin re-uptake inhibitors (SSRIs), notably in the elderly, for the treatment of
depression. These agents have shared a similar degree of success as TCAs but have
fewer side effects and are much safer in overdose. SSRIs such as paroxetine, and 5-
HT2 antagonists like nefazodone relieve sleep disturbances and depression with
decreases in dependency, withdrawal and rebound. However, no systematic evaluation
has been performed regarding the benefit of serotonin specific treatment of chronic
primary insomnia. Some SSRIs are associated with negative side effects subsequent to
overstimulation of the serotonin system such as agitation, headaches, nervousness,
insomnia, GI distress and sexual dysfunction. To decrease the severity of the effects,
physicians may prescribe hypnotics with SSRIs. The hypnotic may improve the
insomnia as the antidepressant treats the underlying psychiatric condition. As a class,
SSRIs tend to be alerting to sleep and increase the amount of wakefulness or light
sleep in those with depression. Subjectively, however, patients and clinicians rate sleep
as improved on SSRIs. Recent studies have contributed on this issue: Trivedi et al. [29],
and Rush et al. [30]. Treatment-emergent sleep disturbances may be successfully
managed with coprescription of agents such as trazadone in low doses or zolpidem [27].
Benzodiazepine sedatives exhibit CNS depressant effects and induce sleep, but also
cause muscle relation and anxiolytic and anticonvulsant activity as well. Negative
effects of benzodiazepines include residual sedative effects, dependency and increased
withdrawal effects such as rebound insomnia. Zolpidem, a non-benzodiazepine hyp-
notic, exhibits sedative effects without associated properties inherent in treatment with
Depression and Insomnia 259
Practice Point
SSRI pharmacotherapy may be effective in the management of chronic primary
insomnia, when combined with basic behavioral intervention such as instruction in
good sleep hygiene.
Practice Point
Combining one night of sleep deprivation with the start of antidepressant medication
may accelerate antidepressant response and improve early recognition of treatment
resistance.
Summary
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