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Sleep Disturbance and Depression 9Part I) The Neuroscience Institute Medscape Elizabeth P. Goodale, PharmD, GlaxoSmithKline, Research Triangle Park, North Carolina, USA and J. Andrew Johnston, PharmD, Innovaa Research, LLC, Chapel Hill, North Carolina, USA Abstract Sleep disturbances such as insomnia, hypersomnia and excessive sleepiness are among the most common symptoms of depression. These changes in sleep and wakefulness are associated with diminished quality of life and impaired occupational functioning and are among the most important predictors of relapse and recurrence of depression. Recognition and treatment of sleep disturbances are important aspects of managing depression. Introduction Sleep disturbances are a central feature of depression and are included among the diagnostic criteria for major depressive disorder (MDD). Most patients with depression experience subjective sleep changes such as insomnia, hypersomnia, and excessive sleepiness, as well as subjective changes in sleep architecture.[2-8] All depressed patients should be assessed for sleep disturbances, and when needed, clinical intervention should be undertaken.The purpose of this review is to provide a general review of the relationship between sleep and depression. A summary of the characteristics of normal sleep physiology is included to provide context for discussion. Normal Sleep Behaviorally, sleep is defined as a reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment. Sleep is a brain process, but is not a unitary process, and some sleep processes are active, involving significant cortical activation. Sleep is primarily studied through the use of overnight continuous electroencephalogram (EEG) sleep recordings which is referred to as polysomnography (PSG). In addition, electrooculograms (EOG) are included to measure eye movements and electromylograms (EMG) are used to record muscle activity. Two separate sleep states have been identified, non-rapid eye movement (NREM) and rapid eye movement (REM). NREM sleep has been divided into Stages 1-4. Thus during sleep individual 30 second recording periods (one epoch) are categorized as wakefulness (W or Stage 0) or Stage 1, 2, 3, or 4, or REM.[9,10] It is also been found that W, NREM and REM sleep are not mutually exclusive with elements of one or more of these states appearing simultaneously. During NREM sleep the brain is relatively inactive. The 4 NREM stages roughly parallel a depth of sleep continuum, with arousal thresholds generally lowest in Stage 1 and highest in Stage 4 sleep. Stages 3 and 4 (referred to as slow wave sleep [SWS]) occur when there is 20-50% and greater than 50% delta wave activity, respectively.[9,10] In contrast to NREM sleep, REM sleep is defined by EEG activation, muscle atonia, and episodic bursts of rapid eye movements. The mental activity of REM sleep is associated with dreaming. Other physiologic activities may accompany REM sleep including middle ear muscle activity, periorbital integrated potentials, and in males, sleep-related erections. There are two phases of REM sleep referred to as "phasic REM sleep" and "tonic REM sleep". Phasic REM sleep occurs when REM and other phasic activity are high, and tonic REM sleep occurs when REM background activity is present but there is very little phasic activity. Onset of sleep is not easily defined but is considered to occur with EEG changes from W to Stage 1 with the presence of slow eye movements. With a normal pattern of sleep, humans progress through NREM sleep (stages 1-4) with some fluctuation before entering REM sleep. NREM and REM sleep alternate in a cyclical fashion. The normal pattern is 90 - 120 minute long cycles of NREM and REM sleep. Sleep patterns for young adults are similar for men and women. A young adult who is a good sleeper has 95% sleep efficiency which means that 5% or less of the total time in bed is spent awake. Sleep onset typically occurs in less than 15 minutes and nocturnal awakening are few and brief. Stage 1 represents a very small portion of the total sleep time, 1-5%, with Stage 2 accounting for the largest portion, approximately half the nights sleep. REM sleep is greatest in the latter third of the night usually making up 20% to 25% of total sleep. Generally, there are 4-6 episodes of REM sleep with the latter episodes becoming progressively longer.[9,10] The remaining sleep time is made up of SWS, i.e. Stages 3 and 4. SWS predominates in the first third of the night. Sleep patterns are driven by circadian rhythm. Anything that disrupts this rhythm can affect sleep. For example, REM sleep can occur earlier, essentially reversing the sleep pattern. This can be seen in shift workers or frequent flyers. Human sleep should be viewed as a component of the 24-hour sleep-wake cycle rather than a discrete entity. The precise neurophysiologic basis for the sleep-wake cycle is not known. Brain function is supported by activating and inhibitory processes. Brain activation is high during waking, decreases during NREM sleep, and increases again during REM sleep. This involves nearly all structures of the brain. Neurotransmitters involved include γ-aminobutyric acid (GABA), glutamate, acetylcholine, norepinephrine, serotonin, dopamine, histamine, hypocretin and others.[9,12-13] Sleep patterns can be different based on a number of factors. With increasing age, there is a gradual decline in total sleep associated with fragmentation or greater wakefulness intermixed with sleep. SWS is maximal in young children and decreases with age. SWS may not be present after age 60, particularly in men. Elderly people typically spend more time in bed but less time sleeping. Sleep patterns will also be different depending on prior sleep history. Following sleep loss on previous nights, recovery sleep occurs which is usually prolonged and deeper. Pharmacotherapy commonly affects the sleep state distribution. Taking advantage of this, pharmacologic treatments have been developed for the treatment of sleep disorders, e.g. benzodiazepines. Most pertinent to this review, many antidepressants are known to cause disruption of sleep and the sleep pattern.[2,14] Lastly, sleep is affected by pathology. There are a number of disorders which are specifically related to sleep such as narcolepsy, sleep apnea, restless leg syndrome and parasomnias (undesirable behavioral or experiential phenomena occurring during sleep). Many medical conditions can affect sleep and most psychiatric conditions affect sleep. Sleep Disturbances in Depression Between 50 and 90% of patients with depression complain of sleep changes. Sleep disturbances in depression can be divided into subjective symptoms, typically patient reports of insomnia, hypersomnia, and excessive sleepiness, and objective findings, PSG recordings. While insomnia is commonly thought of as the classical sleep disturbance in depression, approximately 16-20% of depressed patients report hypersomnia. Hypersomnia is more typically reported in the significant subset of depressed patients with atypical features.[1,2] Insomnia may consist of difficulty falling asleep, frequent awakenings, or, most commonly in depression, early morning awakening. In addition, patients may complain of non-restorative sleep, decreased total sleep and disturbing dreams. Insomnia in depressed patients often results in daytime sleepiness. In reference to other psychiatric disorders, patients with affective disorders differ more frequently and significantly on PSG findings from normal controls. However, not all patients with depression have abnormal PSGs. In one study 45% of outpatients and 83% of inpatients had abnormal sleep studies compared to 10% of healthy controls. Abnormal PSG findings can be divided into three categories: sleep continuity disturbances, NREM sleep deficits and REM sleep abnormalities. Total sleep time and sleep efficiency are decreased and sleep latency (time to sleep onset) is increased. NREM sleep deficits include decreased amount of NREM sleep and decreased NREM percentage of total sleep. With regard to REM sleep, decreased REM latency is the most consistently reported finding. Other REM sleep disturbances reported in depressed patients include prolongation of first REM period, increased REM activity, increased REM density and increased REM percentage of total sleep.[15,16,18] It is not clear if sleep abnormalities in depression are "state dependent" or "trait" markers. It has been reported that REM sleep abnormalities are state dependent and normalize in remission following treatment. However, treatment usually includes antidepressants, many of which affect sleep architecture. Studies using non-pharmacologic treatments also show improvement in sleep parameters, but suggest that continuing sleep abnormalities can predict relapse. Other studies have shown that PSG changes in depressed patients are not state dependent and persist during remission. Further research is needed in this area. Summary Normal human sleep and sleep changes associated with depression have been well characterized. Depressed patients exhibit characteristic changes in sleep architecture including impaired sleep continuity and disturbed REM sleep. Understanding normal sleep architecture and the changes associated with depression will allow for better patient assessment and treatment. References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000. Thase ME. Depression, sleep, and antidepressants. J Clin Psychiatry 1998;59(suppl 4):55–65. Tylee A, Gastpar M, Lepine JP et al. DEPRES II (Depression Research in European Society II): a patient survey of the symptoms, disability and current management of depression in the community. Int Clin Psychopharmacol 1999;14:139–151. Hublin C, Kaprio J, Partinen M et al. Daytime sleepiness in an adult, Finnish population. J Intern Med 1996;239:417–423. Fava M. Symptoms of fatigue and cognitive/executive dysfunction in major depressive disorder before and after antidepressant treatment. J Clin Psychiatry 2003;64(suppl 14):30–34. Doghramji K. Sleep disorders: a selective update. Hosp Community Psychiatry 1989;40:29–47. Menza M, Marin H, Opper RS. Residual symptoms in depression: can treatment be symptom-specific? J Clin Psychiatry 2003;64:516–523. Thase ME. Antidepressant treatment of the depressed patient with insomnia. J Clin Psychiatry 1999;60(suppl 17):28–31. Carscadon MA, Dement WC. Normal human sleep: an overview. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia: W B Saunders Company; 2000:15-25. Hirshkowitz M. Normal human sleep: an overview. Med Clin N Am 2004;88:551-565. Mahowald MW, Schenck CH. Insights from studying human sleep disorders. Nature 2005;437:1279-1285. Gottesmann C. Brain inhibitory mechanisms involved in basic and higher integrated sleep processes. Brain Research Reviews 2004;45:230-249. Siegel JM. The neurotransmitters of sleep. J Clin Psychiatry 2004;65(suppl 16):4-7. Mayers AG, Baldwin DA. Antidepressants and their effect on sleep. Hum Psychopharmacol. 2005 Oct 17 Epub. Tsuno N, Besset A, Ritchie K. Sleep and depression. J Clin Psychiatry 2005;66:1254-1269. Benca RM. Mood disorders. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia: W B Saunders Company; 2000:1140-1157. Fava M. Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry 2004;65(suppl 16):27-32. Benca RM, Obermeyer WH, Thisted RA et al. Sleep and psychiatric disorders, a meta-analysis. Arch Gen Psychiatry 1992;49:651-668. Thase ME, Kupfer DJ, Fasiczka AJ et al. Identifying an abnormal electroencephalographic sleep profile to characterize major depressive disorder. Biol Psychiatry 1997;41:964-973. Thase ME, Fasiczka AL, Berman SR et al. Electroencephalographic sleep profiles before and after cognitive behavior therapy of depression. Arch Gen Psychiatry 1998;55:138-144.
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