Familiarity with the interaction among sleep, depression, and antidepressant medications may assist clinicians in selecting agents to suit the needs of the individual patient.

f02a.jpg (8243 bytes)We spend about one third of our lives asleep, so the perceived quality of one’s sleep is one of the principal indicators of subjective well-being. More than 16% of the adult population of the United States report serious difficulties initiating or maintaining sleep in any year.1 Persistent insomnia is associated with increased risk of developing a major depressive episode during a 1-year prospective follow-up study.2 Fawcett et al considered insomnia to be one of the “modifiable risks” for suicide, and another study from Turkey demonstrated that both insomnia and hypersomnia were associated with suicidal tendency in patients with major depression.3,4 Sleep disturbances are frequent complications of depressive disorders and their treatment. There is clearly a strong association between sleep disturbances and depression—so much that disturbed sleep has been included as one of the diagnostic criteria in DSM-III, DSM-III-R, and DSM-IV for major depressive episodes. The sleep disturbances associated with depression have both reversible or state-dependent and more persistent traits. Clinical descriptions dating as far back as the ancient Greeks have included disturbed sleep as part of the syndrome of melancholia.5 About 90% of the patients suffering from a major depressive episode report complaints of initiating and maintaining sleep as well as early morning awakening and remaining awake.6 At times, insomnia of these patients is so profound that many experience the disturbance as primarily a sleep disorder.7 Rather than an epiphenomenon of affective disorder, sleep disturbances are an essential part of its pathogenesis. Issues are often raised about insomnia caused by the disorders or worsened by the treatment.

Current Models
Sleep disturbances in depression have been documented objectively by means of a sleep polygraph—that is, by means of electroencephalography (EEG), electrooculography (EOG), and electromyography (EMG). An understanding of sleep disturbances may be fundamental to an understanding of depressive illness. The phase advance hypothesis postulates that there is an underlying disturbance of the control of circadian rhythmicity in depressive patients resulting in a shift forward in time of a set of circadian rhythms, including that of core body temperature and the propensity of rapid eye movement (REM) sleep.8 Others, however, differ considering the slow-wave sleep (SWS) mechanism to be faulty, while REM regulation is thought to be intact. “S-deficiency hypothesis” is believed to reflect a deficit in the chemical substrate underlying the propensity for SWS and sleep.9 Another hypothesis is that the fundamental disturbance seen in depressed patients may relate not to a disturbance of the regulation of either REM or SWS, but rather the regulation of the sleep-wake cycle as a whole.10 A deficit of serotonergic neurotransmission, a relative increase in pontine cholinergic activity, and an excess of noradrenergic and corticotrophin-releasing hormone activity have been implicated in the pathogenesis of sleep disturbances of more severe depressive disorders by others.11

Clinical characteristics
Major characteristics of normal sleep architecture include the generalized slowing of EEG activity that characterizes the transition from drowsiness to light sleep (stage 1), the emergence of sleep spindles and K-complex waves that accompany the onset of deeper sleep (stage 2), and the looping, desynchronized slow (delta) waves (stages 3 and 4).1,12 Sleep normally progresses from stage 1 to stage 4 and each cycle of this non-REM (NREM) sleep ends with an episode of REM sleep.11 NREM constitutes about 75% to 85% of total sleep. REM sleep is defined by faster EEG activity, rapid horizontal eye movements seen on EOG, vital sign instability, and occurrence of skeletal muscle hypotonia.

A reliable constellation of polysomnographic abnormalities has been observed in depressed patients. Major depressive disorders can disrupt sleep continuity. In comparison with the sleep of normal subjects, depressives show reduced sleep efficiency due to an increase in sleep latency, waking after sleep onset, early morning awakenings, decreased SWS, a causative shift of REM sleep to earlier in the night, and increased REM density.13-16 Other frequent sleep complaints by depressive patients include restlessness and nonrestorative sleep type (sleep of normal duration but of subnormal quality).17 Although some bipolar patients may suffer from hypersomnolence, there is evidence that, as a group, these patients share this feature with unipolar patients.18 During depression, the polysomnogram shows low delta sleep in the first cycle and more delta sleep in the second cycle. Most of the registered sleep abnormalities in depression also occur in other psychiatric disorders. Only some types of REM sleep alterations—short REM latency, increased REM density (RD), and shortening of mean latency of eye movements (M-LEM)—were reported as more specific to affective disorders.19 The question then is whether they are present before the onset of depression or are an effect of the illness itself. Some studies of patients with a history of depression have shown that changes in sleep architecture persist into the remission phase,20 and some have shown continuing changes in sleep architecture in patients in clinical remission even after the withdrawal of antidepressant medications.21-23 Although it was initially thought that these sleep changes were related to their endogenous or primary depression, it has been shown that these findings correlate with the severity of illness and are not restricted to any specific subgroup.15,24 Various studies have shown that relapse25 and improvement in clinical state26 are frequently preceded by sleep changes. The therapeutic effects of several procedures that consist of altering the sleep-wake cycle suggest that a disorder of sleep is central to depressive illness. Among these are total and partial sleep deprivation, selective REM deprivation, and the phase advance of the sleep period.27 Depressed people do not report consistent changes in dreaming, although their dreams may be more dysphoric or frightening in nature.28

Hypersomnia, commonly seen in depressed people in their 20s and 30s, is often associated with weight gain and increased appetite.29 “Anergic depression” has been used to describe the syndrome characterized by fatigue, psychomotor slowing, and hypersomnolence.29 This is commonly seen in bipolar affective disorder and seasonal affective disorder (SAD).30,31 Many mildly depressed outpatients, including a majority of those with dysthymic disorder, have relatively normal EEG sleep profiles.32,33 There is an association between sleep disturbance and suicidal tendency in patients with major depressive disorders. A retrospective study found that individuals who attempted suicide had a lower delta wave count in the first NREM sleep period than the others.34

Several factors are known to influence the degree of sleep disturbance displayed by depressed patients including age, gender, medication status, diagnosis, and severity of illness. Age exerts a strong influence on sleep in healthy subjects.35 With an increase in age, sleep onset latency is prolonged, the frequency of nocturnal awakening increases, early morning awakenings may occur, and SWS decreases.

In most studies on the sleep of depressed patients, REM latency showed negative age dependence and became increasingly shortened with progressive age in depressed patients as compared to healthy controls. RD was unrelated to age and was heightened in depressed patients compared to that in healthy controls throughout the whole age range.36-38 Therefore, RD seems to be the most reliable marker for sleep in depression. Two additional parameters of REM sleep include latency of eye movements (LEM)—time between start of REM sleep period and the first eye movements in this REM period—and M-LEM—mean value of the latencies of the eye movements from all REM sleep periods—were found to be significantly shorter in bipolar depressed patients as compared to healthy subjects.39,40 It is suggested that M-LEM might be a more sensitive indicator of the phasic events of REM sleep than RD; however, a study by Wichniak et al19 disagreed with these suggestions. They found RD was more significantly altered in depressed patients than M-LEM and suggested that M-LEM should be considered as an additional parameter to RD for estimation of phasic activity in depressed patients. A reduction in SWS does not seem to be present in depression of younger patients.

It has been shown that SWS is reduced in healthy males as compared to healthy females.41 Similar results have been reported for depressed patients.42 Sleep continuity is impaired with an increase in severity of depression.43-45 REM latency showed an inverse relationship with severity of depression, and RD was found to increase with severity of depression.

It is well known that withdrawal from antidepressant medication is accompanied by REM sleep rebound.46-49 Therefore, drug washout periods ranging from 7 to 14 days prior to sleep studies in psychopathological groups are utilized.

Effects of antidepressants
Different classes of antidepressants have distinctly different effects on sleep. REM suppression is the best documented and most broadly applicable effect of antidepressants.50,51 REM suppression may be mediated by potentiation of either noradrenergic or serotonergic neurotransmission, and direct agonism of 5-HT1A may prolong REM latency52; however a number of effective antidepressants (nefazodone, trazodone, and bupropion) do not suppress REM sleep. A common feature of these medications is that they do not potently block the reuptake of serotonin.51 None of the currently approved antidepressants increase visually scored SWS.50,51 Computer-scored measures of delta wave activity do, however, suggest some enhancement during treatment with tricyclic antidepressants (TCA).53

Monoamine-oxidase inhibitors generally suppress REM sleep more than other antidepressants.54 TCAs have been the most rigorously studied with regard to their effect on sleep. In general, they promote initiation and continuity of sleep while suppressing REM sleep, which is a dose-related phenomenon, and an increase in REM latency.54-56 Clomipramine may be the greatest REM suppressor in this class.55 Patients may develop a tolerance to REM suppression after 1 to 3 weeks, with a marked rebound following drug withdrawal.

As a class, selective serotonin-reuptake inhibitors (SSRIs) tend to be REM suppressing and sleep fragmenting.54,56 Fluoxetine has been the most extensively studied SSRI. Its unique effect is increased eye movements in NREM sleep, referred to as “Prozac eyes.”57 SSRIs are currently the most commonly prescribed antidepressants used to treat depression and anxiety disorders. SSRIs may increase sleep latency, decrease REM sleep, and worsen sleep efficiency.

Atypical agents such as trazodone cause significant sedation. It rarely is used as an antidepressant. It improves sleep efficiency, increases delta sleep, decreases sleep latency, suppresses REM sleep, and lengthens REM latency.58,59 These features make it an attractive agent for insomnia and it is not addictive. Adding a bedtime dose of trazodone to a SSRI may be helpful in relieving the insomnia and sleep disturbance caused by the SSRI. Nefazodone also improves sleep efficiency, besides decreasing the number of awakenings and increasing REM sleep time. It may be a good choice for depressed patients with insomnia.60

Other antidepressants like bupropion may increase REM sleep percentage without any effect on sleep efficiency or latency..61 Venlafaxine strongly suppresses REM sleep time and worsens sleep continuity in both healthy volunteers and depressed inpatients.62 Studies have shown that mirtazapine decreases sleep latency, improves sleep efficiency, and has no effect on REM sleep,63,64 which make it an appropriate choice for monotherapy in patients with major depressive disorder and comorbid insomnia.

Light therapy
Exposure to bright light at strategic times of the sleep-wake cycle results in a change in the underlying circadian rhythm.65 Time and duration of light therapy depend on diagnosis and individual response (delayed sleep phase syndrome or advanced sleep phase syndrome).65 The individual sits at a distance from a bright light source (fluorescent lights) with an illumination of more than 2,500 lux. For SAD or winter blues, the light therapy provides 5,000 to 10,000 lux.65 The effect of light therapy on human circadian rhythms depends on the intensity, wavelength, timing, duration, and distance from the light source. Adverse effects of phototherapy include headaches, eyestrain, profound advance of sleep onset, exposure to ultraviolet rays, and photosensitization. Phototherapy may precipitate mania in bipolar patients, and psychiatric history must be obtained prior to initiating light therapy.66 Retinopathy, glaucoma, and cataracts are contraindications for light therapy.

The use of phototherapy for nonseasonal depression appears to be promising. Kripke67 compared several controlled trials in terms of the relative benefit of light versus placebo. Within 1 week of phototherapy, depression scale ratings were as much as 24% lower after light therapy than after dim light placebo treatment. This result compares favorably with drug therapy studies conducted over 4 to 16 weeks.68 Several studies have combined light therapy with antidepressants and found accelerated improvement over the use of antidepressants alone.69 A study70 showed improvement among hospitalized, medicated patients with unipolar and bipolar depression who were given 10,000 lux treatments in 30-minute morning sessions. This improvement was less at 2,500 lux.

In Europe, newly admitted hospitalized depressed patients are given adjuvant phototherapy to speed recovery.71 Current available data clearly support the use of adjuvant phototherapy for depression in outpatient and inpatient environments; however, controlled trials are needed to further document the benefits of light therapy.

Conclusion
Sleep disturbances are an integral feature of depressive disorders. Clinicians must always distinguish insomnia as a symptom from insomnia as a sleep disorder so they can choose the most appropriate intervention. Sleep disturbances may precede an episode of severe depression and may be a marker for predicting such future episodes, aside from trouble concentrating and feelings of worthlessness or guilt.

Familiarity with the interaction among sleep, depression, and antidepressant medications may assist clinicians in selecting agents to suit the needs of the individual patient. REM suppression does not seem to be necessary for antidepressant effectiveness.

Naseer Masoodi, MD, is a fellow in geriatric medicine, SUNY at Buffalo, NY; and Taj M. Jiva, MD, is a diplomate of the American Board of Sleep Medicine, and director of Sleep Medicine Clinics, Buffalo Medical Group, PC, NY.

References
1. Gillin JC, Inkwell-Israel S, Erman M. Sleep and sleep wake disorders. In: Tasman A, Kay J, Lieberman JC, eds. Psychiatry. Philadelphia: W.B. Saunders Company; 1996:1217-1248.
2. Ford DE, Kamerow DB. Epidemiological studies of sleep disturbances and psychiatric disorders: an opportunity for prevention? JAMA. 1989;262:1479-1484.
3. Fawcett J, Scheftner WA. Time related predictors of suicide in major affective disorder. Am J Psychiatry. 1990;147:1189-1194.
4. Agargun MY, Kara H, Solmaz M. Sleep disturbances and suicidal behavior in patients with major depression. J Clin Psychiatry. 1997;58:249-251.
5. Jackson SW. Melancholia and Depression: From Hippocratic Times to Modern Times. New Haven, Conn: Yale University Press; 1986.
6. Diagnostic Classification Steering Committee (Thorpy MJ, Chairman). International Classification of Sleep Disorders. Diagnostic and Coding Manual. Rochester, Minn: American Sleep Disorders Association; 1990.
7. Goodwin FK, Jamison KR. Manic-depressive Illness. Oxford, England: Oxford University Press; 1990.
8. Wehr T, Wirz-Justice A. Internal coincidence model for sleep and depression. In: Koella W, ed. Sleep. Amsterdam: Karger; 1981.
9. Borbely A, Wirz-Justice A. Sleep, sleep deprivation, and depression: a hypothesis derived from a model of sleep regulation. Human Neurobiol. 1982;1:205-210.
10. Southmayd SE, Cairns J, David MM. Sleep disturbance in depression reconsidered. Can J Psychiatry. 1991;36:366-373.
11. Thase ME. Depression, sleep, and antidepressants. J Clin Psychiatry. 1998;59:S55-S65.
12. Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques, and Scoring System for Sleep Stages of Human Subjects. Washington, DC: US Government Printing Office; 1968. National Institutes of Health Publications 204.
13. Winokur A, Reynolds CF. The effects of antidepressants on sleep physiology. Prim Psychiatry. 1994;1:2-27.
14. Gillins JC, Sitaram N. Sleep and affective illness. In: Post R, Ballenger J, eds. Neurobiology of Mood Disorders. Baltimore: Williams and Wilkins; 1984.
15. Kupfer DJ, Bulik CM, Grochocinski V. Relationship between EEG sleep measures and clinical ratings of depression: a revisit. J Affect Disord. 1984;6:43-52.
16. Reynold C, Kupfer D. Sleep research in affective illness: state of the art circa 1987. Sleep. 1987;10:199-215.
17. Van Moffaert MM. Sleep disorders and depression: the ‘chicken and egg’ situation. J Pychosom Res. 1994;38:S9-S13.
18. Duncan W, Pettigrew K, Gillin JC. REM architecture changes in unipolar and bipolar depression. Am J Psychiatry. 1979;136:1424-1427.
19. Wichniak A, Riemann D. Comparison between eye movement latency and REM sleep parameters in major depression. Eur Arch Psychiatry Clin Neurosci. 2000;250:48-52.
20. Schulz H, Trojan B. A comparison of eye movement density in normal subjects and in depressed patient before and after remission [abstract]. Sleep Res. 1979;8:49.
21. Kupfer DJ. EEG sleep as biological marker in depression. In: Usdin E, Hanin I, eds. Biological Markers in Psychiatry and Neurology. Oxford, England: Pergamon Press; 1982:387-396.
22. Rush AJ, Erman MK. Polysomnographic findings in recently drug-free and clinically remitted depressed patients. Arch Gen Psychiatry. 1986;43:878-884.
23. Hauri P, Chernik D. Sleep of depressed patients in remission. Arch Gen Psychiatry. 1974;31:386-391.
24. Thase M, Kupfer D, Spiker D. Electroencephalographic sleep in secondary depression: a revisit. Biol Psychiatry. 1984;19:805-814.
25. Cairns J, Waldron J. Sleep and depression: a case study of EEG sleep prior to relapse. Can J Psychiatry. 1980;25:259-263.
26. Kupfer D, Spiker D. Sleep and treatment prediction in endogenous depression. Am J Psychiatry. 1981;138:429-434.
27. Gillin JC. The sleep therapies of depression. Prog Neuropsychopharmacol Biol Psychiatry. 1983;7:351-364.
28. Cartwright RD. Sleeping problems. In: Cosatell CG, ed. Symptoms of Depression. New York: John Wiley and Sons; 1993:243-257.
29. Thase ME. Anergic major depression. In: Greden J, Pande AC, eds. Atypical Depression. Washington, DC: American Psychiatric Press. In Press.
30. Thase ME, Himmelhoch JM, Mallinger AG, et al. Sleep EEG and DST findings in anergic bipolar depression. Am J Psychiatry. 1991;148:1177-1181.
31. Rosenthal NE, Wehr TA. Towards understanding the mechanism of action of light in seasonal affective disorders. Pharmacopsychiatry. 1992;25:56-60.
32. Thase ME, Kupfer DJ. Identifying an abnormal electroencephalographic sleep profile to characterize major depressive disorder. Biol Psychiatry. 1997;41:964-973.
33. Rush AH, Giles DE. Dexamethasone response: thyrotropin releasing hormone stimulation; rapid eye movement, latency and subtypes of depression. Biol Psychiatry. 1997;41:915-928.
34. Sabo E, Reynolds CF III, Kupfer DJ, et al. Sleep, depression, and suicide. Psychiatry Res. 1991;36:265-277.
35. Reynolds CF, Buysse D. REM sleep in successful, usual and pathological aging: the Pittsburgh experience 1980-1993. J Sleep Res. 1993;2:203-210.
36. Gillin JC, Duncan WC, Murphy DL, et al. Age related changes in sleep in depressed and normal subjects. Psychiatry Res. 1981;4:73-78.
37. Lauer C, Riemann D, Wiegand M, Berger M. From early to late adulthood. Changes in EEG sleep of depressed patients and healthy volunteers. Biol Psychiatry. 1991;29:979-993.
38. Riemann D, Hohagen F, Bahro M, Berger M. Sleep in depression: the influence of age, gender and diagnostic subtype on baseline sleep and the cholinergic REM induction test with RS 86. Eur Arch Psychiatry Clin Neurosci. 1994;243:279-290.
39. Jernajczyk W. Latency of eye movement and other REM sleep parameters in bipolar depression. Biol Psychiatry. 1986;21:465-472.
40. Gillin C, Jernajczyk W, Valladares-Noto DC, Golshan S, Lardon M, Stahl SM. Inhibition of REM sleep by ipsapirone, a 5HT1A agonist, in normal volunteers. Psychopharmacology (Berl). 1994;116:433-436.
41. Williams HL, Karacan J, Harsch CJ. Electroencephalography (EEG) of Human Sleep. New York: John Wiley and Sons; 1974.
42. Reynolds CF, Kupfer DJ. Sleep, sex, and depression: an analysis of gender effects on the electroencephalographic sleep of 302 depressed outpatients. Biol Psychiatry. 1990;28:673-684.
43. Spiker DJ, Coble P, Cofsky J, Kupfer D. EEG sleep and severity of depression. Biol Psychiatry. 1978;4:485-488.
44. Thase ME, Kupfer DJ, Ulrich RF. Electroencephalographic sleep in psychotic depression. Arch Gen Psychiatry. 1986;43:886-893.
45. Kerkhofs M, Kempenares C. Multivariate study of sleep EEG in depression. Acta Psychiatr Scand. 1998;77:463-468.
46. Dunleavy DLF, Brezinova V. Changes during weeks in effects of tricyclic drugs on human sleeping brain. Br J Psychiatry. 1972;120:663-672.
47. Oswald I. Sleep studies with clomipramine and related drugs. J Int Med Res. 1973;1:296-298.
48. Thaker GK, Wagman AM, Tamminga CA. Sleep polygraph in schizophrenia: methodological issues. Biol Psychiatry. 1990;28:240-246.
49. Tandon R, Shipley JE, Greden JF. Electroencephalographic sleep abnormalities in schizophrenia: relationship to positive/negative symptoms and prior neuroleptic treatment. Arch Gen Psychiatry. 1992;49:185-194.
50. Thase ME, Kupfer DJ. Current status of EEG sleep in the assessment and treatment of depression. In: Borrows GD, Werry JS, eds. Advances in Human Psychopharmacology. Greenwich, Conn: JAI Press; 1987:93-148.
51. Sharpley AL, Cowen PJ. Effects of pharmacological treatment on the sleep of depressed patients. Biol Psychiatry. 1995;37:85-98.
52. Gillin JC, Sohn JW, Stahl SM, et al. Isapirone, a 5HT1A agonist, suppresses REM sleep equally in unmedicated depressed patients and normal controls. Neuropsychopharmacology. 1996;15:109-115.
53. Reynolds CF III, Hoch CC, Buysse DJ, et al. Sleep in late-life recurrent depression: changes during early continuation therapy with nortriptyline. Neuropsychopharmacology. 1991;5:85-96.
54. Sharpley AL, Cowen PJ. Effect of pharmacological treatments of depressed patients. Biol Psychiatry. 1995;37:85-98.
55. Armitage R. Effects of antidepressant treatment on sleep EEG in depression. J Psychopharmacol. 1996;10:S22-S25.
56. Kupfer DJ, Spiker DG. Nortriptyline and EEG sleep in depressed patients. Biol Psychiatry. 1982;17:535-546.
57. Armitage R, Trivedi M, Rush AJ. Fluoxetine and oculomotor activity during sleep in depressed patients. Neuropsychopharmacology. 1995;12:159-165.
58. Van Bemmel AL, Havermans RG, van Diest R.. Effects of trazodone on EEG sleep and clinical state in major depression. Psychopharmacology (Berl). 1992;107:569-574.
59. Scharf MB, Sachais BA. Sleep laboratory evaluation of the effects and efficacy of trazodone in depressed insomniac patients. J Clin Psychiatry. 1990;51:S13-S17.
60. Rush AJ, Armitage R, Gillin JC, et al. Comparative effect of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder. Biol Psychiatry. 1998;44:3-14.
61. Nofzinger EA, Reynolds CF III, et al. REM sleep enhancement by bupropion in depressed men. Am J Psychiatry. 1995;152:274-276.
62. Luthringer R. A double blind, placebo-controlled evaluation of the effects of orally administered venlafaxine on sleep in inpatients with major depression. Psychopharmacol Bull. 1996;32:637-646.
63. Ruigt GS, Kemp B. Effects of antidepressant Org 3770 on human sleep. Eur J Clin Pharmacol. 1990;38:551-554.
64. Winokur A, Sateia MJ. Effects of mirtazapine on sleep architecture in patients with major depression: a pilot study [abstract]. Biol Psychiatry. 1998;43:S106-S107.
65. Czwisler CA, Kronauer RE, Allen JS, et al. Bright light induction of strong (type O) resetting of the human pacemaker. Science. 1989;224:1328.
66. Kripke DF. Timing of phototherapy and occurrence of mania. Biol Psychiatry. 1991;29:1156.
67. Kripke DF. Light treatment for nonseasonal depression: speed, efficacy, and combined treatment. J Affect Disord. 1998;49:109-117.
68. Yamada N, Martin-Iverson MT. Clinical and chronobiological effects of light therapy on nonseasonal affective disorders. Biol Psychiatry. 1995;37:866-873.
69. Kasper S, Ruhrmann S, Schuchardt HM. The effects of light therapy in treatment indications other than seasonal affective disorder (SAD). In: Jung EG, Holick MF, eds. Biologic Effects of Light. Berlin/New York: de Gruyter; 1994:206-218.
70. Beauchemin KM, Hays P. Phototherapy is a useful adjunct in the treatment of depressed patients. Acta Psychiatr Scand. 1997;95:424-427.
71. Wirz-Justice A, Graw P, Roosli H, Glauser G, Fleishhauer J. An open trial of light therapy in hospitalised major depression. J Affect Disord. 1999;52:291-292.