Sleep and Depression

From 20th Annual Advances in Psychiatry: Gender Differences, presented by the University of Michigan Medical School

Roseanne Armitage, PhD, Professor of Psychiatry, and Adjunct Professor of Psychology, and Director, Sleep and Chronophysiology Laboratory, University of Michigan Medical School, Ann Arbor

Educational Objectives

The goal of this program is to improve understanding of the relationship between sleep and depression, and about the role of sex-based differences in that relationship. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the relationship between sleep and depression.

2.   Cite sex-based differences in sleep and depression.

3.   Compare normal sleep and sleep in depression.

4.   Discuss biologic factors that influence sleep regulation.

5.   Explain disturbances in biologic and circadian rhythms that occur in depressed patients.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and plan­ning committee reported nothing to disclose.

Acknowledgements

Dr. Armitage was recorded at 20th Annual Advances in Psychiatry: Gender Differences, held November 6, 2008, in Ann Arbor, MI, and sponsored by the University of Michigan Medical School. The Audio-Digest Foundation thanks Dr. Armit­age and the University of Michigan Medical School for their cooperation in the production of this program.

Sex-based differences in the brain and in depression: sex differences in brain regulation produce different mani­festations of diseases, especially depression, in men and women; biologic risk factors in men and women dis­tinct; for women of reproductive age, risk of developing depression twice that for men, but risk also present before menarche and after menopause

Sleep problems: major risk factor for development of depression in both sexes; other risk factors include having bi­polar parent (risk higher if afflicted parent is mother, but not zero if afflicted parent is father) and, in women, marriage and children

Sexual dimorphism in humans: seen in sex chromosomes, circadian-clock genes, growth hormones, respiratory control centers, stress response in hypothalamic-pituitary-adrenal (HPA) axis, sex steroid receptors and their lo­cation in brain, neurotransmitter receptors, and sleep regulation; corpus callosum and anterior commissure smaller in men than in women, resulting in dimorphism in ability to transfer information between cerebral hemi­spheres; functional differences  —  serial processing of information more common in men and parallel in women; women show larger brain asymmetry during performance of tasks and have higher cerebral metabolism during both wakefulness and sleep; hormonal differences  —  women have greater number of estrogen receptors in supra­chiasmatic nucleii and throughout hypothalamus; dimorphic distribution of estrogen receptors seen in other areas of brain and in other sex hormone receptors as well; has significant impact on sleep regulation

Genetic influence: >650 genes known to be sexually dimorphic in brain, with »50% more highly expressed in women; genes on X chromosome more likely to be expressed in both sexes; male-biased genes expressed on both X and Y chromosomes, although Y chromosome has genes not expressed in women

Maternal vs paternal influence on depression: recent data indicate children 4 to 6 times more likely to develop de­pression if mother depressed than if father depressed; controversial whether girls more vulnerable to expression of risk inherited from mother than boys

Normal sleep and sleep in depression: >80% of depressed patients report some degree of sleep disturbance, most commonly insomnia; disturbed sleep most frequent presenting symptom in clinic; studies show that sleep distur­bance that persists >2 wk increases risk of developing psychiatric illness, and depression in particular; in those who have already had first episode of depression, persistent sleep disturbance increases risk for relapse and recurrence; formerly, believed that if depression treated, sleep disturbance would resolve; however, recent data demonstrate that this holds true only for approximately half of depressed patients; some newer antidepressants not “sleep-friendly” and associated with exacerbation or emergence of sleep disturbance during treatment; if intervention not made to correct sleep problem, risk for relapse and recurrence of depression elevated

Sleep disturbances common to depression: prolonged sleep latency or sleep onset (ie, insomnia); short latency to first rapid eye movement (REM) sleep period (»25% of depressed patients show persistently short REM latency; healthy young adults enter REM sleep »90 min after sleep onset; depressed patients may start REM sleep in <65 min); increased arousals and wakefulness during night characteristic of 65% to 75% of depressed patients; in­creased stage 1 sleep (light sleep between sleep and wakefulness); decreased slow-wave (stage 3 and 4) sleep more characteristic of men than women; reduced total sleep time occurs in some depressed patients; however, large per­centage (especially women) have hypersomnia; may sleep for, eg, 12 hr, but not feel rested or refreshed on awaken­ing; sleep efficiency <85% cause for concern about sleep architecture

Sleep regulation: factors that influence sleep affect onset of sleep, where sleep occurs during 24-hr day, and aspects of metabolic output during wakefulness that influence sleep

Homeostatic sleep drive: drive for sleep that cannot be overcome; sleep may be postponed for prolonged period, but individual eventually succumbs to sleep; “the debt you accumulate during wakefulness or the cost of being awake”; debt accumulates throughout wakefulness and dissipates rapidly during non-REM (NREM) sleep; di­rectly proportional to amount of previous wakefulness; eg, individual who achieves deep slow-wave sleep during daytime nap  loses same amount from nighttime sleep

Circadian influence: largely on timing of REM sleep; circadian drive associated with wakefulness and high meta­bolic output; overactive circadian rhythm or abnormality in timing or phase of circadian rhythm may cause REM sleep to start at wrong biologic time; REM sleep not influenced by amount of previous wakefulness; interactions between homeostatic and circadian drives shape basic drive for sleep, likelihood of falling asleep, and recovery process once asleep

“Zones” for sleep: all animals sleep, but sleep consolidated to nocturnal period only in humans and higher primates (most animals polyphasic); “siesta time” (approximately midday) best known zone in humans and primates; when sun rises and individual awakens, alertness at heightened level; alertness dips in early afternoon (unrelated to eating), with decrease in metabolic output, decline in core body temperature, and occurrence of other signals that permit sleep; “forbidden zone for sleep” for healthy, nonsleep-deprived individuals at approximately 9:00 pm, and next sleep zone starts »2 hr later; sleep-deprived individuals fall asleep quickly; in general, when drive for alertness maximal, drive for sleep minimal; reparative and restorative work of body occurs during homeo­static period (being awakened during this period results in grogginess and confusion)

Hypothesized homeostatic deficiency in major depressive disorder: evidenced by short REM latency; due to either insufficient drive for slow-wave sleep or slow-wave recovery or  to active disinhibition of REM sleep; both possi­ble, but data supporting either hypothesis found only in depressed men; in study, challenge to sleep regulatory system resulted in overreaction among depressed women and underreaction among depressed men; speaker opines that difference in reactivity to challenge may reflect sex-dependent propensity; impaired homeostat in de­pressed men (leading to inability to adequately respond to challenge) may manifest clinically as increased risk for suicidal ideation, relative to that in depressed women

Biologic rhythm disturbances: rhythms other than those in sleep that are affected by depression include phase-shifted temperature and melatonin rhythms, cortisol rhythms, dysregulation of electroencephalographic (EEG) activity, chaotic brain rhythms (more common in women), and erratic or weak circadian rest-activity cycles; 80% of depressed men show impairment of slow-wave activity; in healthy controls, ultradian rhythm regulates fast-frequency waves during night;  coherence measures extent of synchrony of brain wave activity between right and left cerebral hemispheres; 70% of depressed women show low temporal coherence in sleep EEG, both between hemispheres and within each hemisphere; in study, healthy women had highest coherence, then healthy men; de­pressed boys showed no evidence of impaired coherence until adolescence; depressed girls as young as 7 yr of age had lower coherence than all other groups, with progressive worsening in adolescence

Blinded study: looked at EEGs  of adolescent girls who had just experienced menarche; those of girls with personal or family history of depression compared to those without personal or family history of depression; of those girls with extremely low coherence measures (³2 standard deviations below mean of healthy controls), 50% devel­oped “full-blown” episode of depression within 3 to 5 yr; demonstrated feasibility of identifying biologic abnor­mality predictive of depression

Circadian rhythm disturbances: speaker’s group measured rest-activity cycles across 7 consecutive 24-hr days in healthy controls and depressed children and adolescents of both sexes (4 groups); amplitude of circadian rhythm significantly lower in girls with depression compared to all other groups; no evidence of dysregulation in boys with depression until adolescence

Light exposure: light most potent entrainer for circadian rhythm; visual tract and retinal-hypothalamic tract help keep 24-hr cycles entrained to normal life cycle (in humans, consolidate sleep to nocturnal period and activity to daytime period); young girls with depression had lowest level of light exposure; by adolescence, exposure roughly equal to that of healthy control girls; speaker posits that early decrease in light exposure may predispose girls to permanent dysregulation of circadian rhythm

Maternal history of depression vs personal history: youth with personal history of depression symptomatic and un­medicated; no difference seen in circadian amplitude between these groups; circadian amplitude significantly lower in both groups than in age- and sex-matched healthy controls; suggests circadian rhythm dysregulation and sleep disturbances in depression have early developmental roots

Speaker’s study of mothers and infants: low-risk infants defined as those whose mothers had no personal or family history of depression or other psychopathology; high-risk infants had mothers with previous episode of depres­sion or elevated score on Edinburgh Postnatal Depression Scale, with or without family history of depression; use of actograph allowed mothers and infants to be monitored at home rather than in sleep laboratory; low-risk infants fell asleep within 20 to 30 min; high-risk infants required up to 2 hr at 2 wk of age, with little improve­ment by 30 wk; sleep efficiency improved in both groups as they aged, but was significantly significantly lower in high-risk group; high-risk infants slept less, woke more, took longer to settle at night, and had less consolida­tion of sleep to nocturnal period (took more daytime naps); speaker opines that findings in high-risk infants rep­resent risk factor for dysregulation of circadian rhythm that predisposes to depression

Summation: studies suggest dysregulation in sleep and circadian rhythm constitute biologic risk factors for develop­ment of depression; chaotic sleep rhythm and EEG organization more characteristic of depression in girls, and ab­normalities of sleep homeostasis seen in depression in boys; anecdotal evidence suggests relationship between low slow-wave activity in boys and suicidality, but no studies done yet

Suggested Reading

Armitage R et al: Delta sleep EEG in depressed adolescent females and healthy controls. J Affect Disord 63:139, 2001; Armitage R et al: Early developmental changes in sleep in infants: the impact of maternal depression. Sleep 32:693, 2009; Armitage R et al: Sleep microarchitecture as a predictor of recurrence in children and adolescents with depression. Int J Neuropsychopharmacol 5:217, 2002; Armitage R et al: Sleep microarchitecture in childhood and adolescent depression: temporal coherence. Clin EEG Neurosci 37:1, 2006; Armitage R et al: Slow-wave activ­ity in NREM sleep: sex and age effects in depressed outpatients and healthy controls. Psychiatry Res 95:201, 2000; Armitage R, Hoffmann RF: Sleep EEG, depression and gender. Sleep Med Rev 5:237, 2001; Armitage R: Sleep and circadian rhythms in mood disorders. Acta Psychiatr Scand Suppl (433):104, 2007; Armitage R: The effects of antidepressants on sleep in patients with depression. Can J Psychiatry 45:803, 2000; Emslie GJ et al: Sleep poly­somnography as a predictor of recurrence in children and adolescents with major depressive disorder. Int J Neuropsy­chopharmacol 4:159, 2001; Hoffmann R et al: Slow-wave activity during non-REM sleep in men with schizophrenia and major depressive disorders. Psychiatry Res 95:215, 2000; Le Bon O et al: Relationships between the number of ultradian cycles and key sleep variables in outpatients with major depressive disorder. Psychiatry Res 165:60, 2009; Morehouse RL et al: Temporal coherence in ultradian sleep EEG rhythms in a never-depressed, high-risk cohort of female adolescents. Biol Psychiatry 51:446, 2002; Robert JJ et al: Sex and age differences in sleep macroarchitecture in childhood and adolescent depression. Sleep 29:351, 2006; Tekell JL et al: High frequency EEG activity during sleep: characteristics in schizophrenia and depression. Clin EEG Neurosci 36:25, 2005.