Elsevier

Biological Psychiatry

Volume 73, Issue 12, 15 June 2013, Pages 1164-1171
Biological Psychiatry

Review
Mechanisms of Rapid Antidepressant Effects of Sleep Deprivation Therapy: Clock Genes and Circadian Rhythms

https://doi.org/10.1016/j.biopsych.2012.07.020Get rights and content

A significant subset of both major depressive disorder and bipolar disorder patients rapidly (within 24 hours) and robustly improves with the chronotherapeutic intervention of sleep deprivation therapy (SDT). Major mood disorder patients are reported to have abnormal circadian rhythms including temperature, hormonal secretion, mood, and particularly sleep. These rhythms are modulated by the clock gene machinery and its products. It is hypothesized that SDT resets abnormal clock gene machinery, that relapse of depressive symptoms during recovery night sleep reactivates abnormal clock gene machinery, and that supplemental chronotherapies and medications can block relapse and help stabilize circadian-related improvement. The central circadian clock genes, BMAL1/CLOCK (NPAS2), bind to Enhancer Boxes to initiate the transcription of circadian genes, including the period genes (per1, per2, per3). It is suggested that a defect in BMAL1/CLOCK (NPAS2) or in the Enhancer Box binding contributes to altered circadian function associated, in part, with the period genes. The fact that chronotherapies, including SDT and sleep phase advance, are dramatically effective suggests that altered clock gene machinery may represent a core pathophysiological defect in a subset of mood disorder patients.

Section snippets

Clinical Evidence for Rapid Antidepressant Actions of Sleep Deprivation Therapy

A large number of studies in over a thousand patients during the past four decades has confirmed the efficacy of SDT in significantly reducing depressive symptoms in 40–60% of patients (3, 4, 5). The use of SDT to treat mood disorders that are frequently associated with sleep disruptions appears to be counterintuitive. Normal individuals often, but not always, experience dysphoria following prolonged sleep loss. However, the evidence for the rapid efficacy of SDT in mood disorders is highly

Circadian Rhythm Disturbances in Mood Disorders

Depression may represent an inability of the circadian clock to maintain synchrony among internal and external 24-hour rhythmic functions. Accumulating evidence detailing the circadian machinery, including the core clock genes and their products, suggests that disruption in these rhythms due to genetic or epigenetic factors may affect daily patterns of mood, sleep, hormones, neurotransmitters, and temperature.

Clock Gene Machinery

In mammals, the suprachiasmatic nucleus (SCN), considered the master circadian clock, synchronizes rhythms throughout the body. The intracellular clock gene machinery involves complex multiple interlocking transcriptional-translational loops containing positive and negative transcription factors that adjust rhythms to an approximate 24-hour cycle (Figure 1). The core loop includes a BMAL1/CLOCK (or the paralog to CLOCK, NPAS2) heterodimer that binds to Enhancer Box (E-box) containing elements

Hypothesis

The clock gene machinery essentially regulates all body rhythms. It is hypothesized that a subset of patients with severe depression who experience circadian rhythm abnormalities, including mood, sleep, hormonal, and/or temperature regulation, have a state-related defect in clock gene machinery (Figure 2). This hypothesis is supported by the findings that chronotherapeutic treatments that alter clock gene processes, including SDT and sleep phase advance treatment, can rapidly and dramatically

Sleep Deprivation and Clock Gene Alterations in Animals

Due to the challenges associated with collecting clock gene data in humans, there is little data characterizing the effects of SDT on the circadian machinery in humans. Nonetheless, research in rodents documents the effects of sleep deprivation (SD) on circadian function in the brain. A limitation to interpreting the animal data is that these studies did not address the effects of sleep deprivation in animal models of depression. Therefore, it is important to differentiate the two bodies of

Sleep Deprivation: Effects on Other Systems

The molecular actions of sleep deprivation involve many systems in addition to clock genes. In animal studies, these include mitochondrial genes, which show significant decreases in the activity of complex I-III (44), as well as changes in chaperones, heat shock proteins, activity-dependent synaptic plasticity, immune response, and neurogenesis (45). Sleep triggers hippocampal cell neurogenesis. Sleep deprivation, in contrast, suppresses neurogenesis and neuronal progenitor cell generation (46,

Studies of the Effects of Sleep Deprivation and Sleep Deprivation Therapy on Serotonin in Animals and Man

Sleep deprivation differentially affects neurotransmitter systems, including serotoninergic, cholinergic, noradrenergic, and dopaminergic function (48, 49, 50). One of the most consistent findings comes from data showing that it enhances serotonergic function, similar to that of the actions of many antidepressant medications (51) in humans (52) and animals (53, 54). Functional polymorphisms within the promoter of the serotonin transport gene, serotonin transporter-linked polymorphic region, may

Evidence for the Role of Clock Genes in Sleep Homeostasis

Since SDT response and relapse (following recovery sleep) can rapidly decrease depressive symptoms, it is important to review evidence that sleep homeostasis and sleep timing have direct links to clock gene machinery. Clock gene rhythms and homeostasis are generated independently, but together they determine the duration, timing, and quality of wakefulness and sleep (57). Sleep deprivation therapy manipulates both homeostasis and the clock gene machinery.

Sleep homeostasis is a homeostatic

The Association of Mood Disorders with Clock Gene Variants

Accumulating evidence implicating abnormal clock gene machinery in mood disorders comes from studies documenting an association between single nucleotide polymorphisms (SNPs) in circadian genes and depression. Variants associated with MDD include RORB (rs2028122) and CRY1 (rs2287161), while variants in BPD include RORB (rs7022435, rs3750420, rs1157358, rs3903529, rs10869435) and NR1D1 (Rev-erbα) (rs2314339), DEC1 (rs1537720, rs10982664), and BMAL1 (ARNTL) (rs747601) (66, 67, 68).

SDT Provides Clues for Its Mechanisms of Action

Sleep deprivation therapy is an ideal experimental model to study mechanisms involved in rapid antidepressant actions. Although there are relatively few studies in humans, data from healthy subjects document rapid (within 24 hours) phase shifts in the core clock genes, per2 (69), cry2 (70), hormones (71), and temperature (72) in response to sleep deprivation.

We addressed the question whether sleep deprivation would affect clock genes and provide biomarkers for response. Preliminary results were

Rapid Relapse During Nap Studies in SDT Responders

In addition to relapse associated with the first night of sleep after SDT response, naps during the recovery day can produce dramatic relapses in depressive symptoms, particularly morning naps that can precipitate relapses significantly more frequently than afternoon naps (76, 77), suggesting a possible circadian component. A clinical example of the critical importance of sleep in producing a dramatic relapse after SDT is illustrated by a 49-year-old female who was severely depressed with

Sustaining Therapeutic Effects of SDT with Sleep Phase Advance, Bright Light Chronotherapies and Lithium

One of the challenges in SDT is to block relapse and sustain improvement. In 11 of 19 studies where repeated SDTs were administered in combination with lithium (79) and/or antidepressants and brief chronotherapeutic interventions, bright light and sleep phase advance successfully sustained antidepressant responses for 2 weeks up until 6 months (8). In these treatment approaches, sleep phase advance and morning bright light therapy were administered within 24 hours after SDT for a period of

Potential for Generalizing the Role of Clock Genes in SDT and Its Relevance to the Other Documented Rapid Antidepressant, Low-Dose Ketamine

In addition to SDT, only one other treatment approach, low-dose ketamine, has been shown to robustly and rapidly decrease depressive symptoms within 24 hours in 50% to 70% of patients (94, 95). We hypothesized that the rapid antidepressant effects of ketamine could also involve the modulation of clock genes and circadian rhythms similar to that proposed for SDT. Compatible with this, our recent study (96) in neuronal cell culture showed that ketamine influences BMAL1/CLOCK (NPAS2) function

Limitations

Clinical research into the mechanisms of action of SDT has been, theoretically, limited by the relative inability to blind subjects to treatment. Efforts to blind subjects have included comparisons in efficacy between the more effective late partial sleep deprivation with early partial sleep deprivation. It can be argued, however, that many mood disorder patients who have experienced severe depressive symptoms for many months rapidly and dramatically improve within 24 hours following SDT. The

Future Research

Future research is needed to identify similar and different mechanisms of the rapid antidepressant action of SDT and low-dose ketamine; investigate possible circadian rhythm or CLOCK gene abnormalities as biological risk factors for the development of depressive disorders; and determine which of the additive treatments (lithium, antidepressants, sleep phase advance therapy, and bright light therapy) are essential for blocking the first night recovery sleep relapse and sustaining the rapid

Summary

There is substantial evidence to implicate abnormal clock genes in depressive illness. This includes the rapid efficacy of SDT and consistently reported abnormal rhythms in mood disorders, which are all regulated by clock gene machinery. It is hypothesized that a mechanism of antidepressant action of SDT involves resetting abnormal circadian clock gene machinery and that the frequent severe relapse in symptoms following the recovery night sleep after improvement reactivates clock gene

References (100)

  • S. Elsenga et al.

    Body core temperature and depression during total sleep deprivation in depressives

    Biol Psychiatry

    (1988)
  • B.P. Hasler et al.

    Phase relationships between core body temperature, melatonin, and sleep are associated with depression severity: Further evidence for circadian misalignment in non-seasonal depression

    Psychiatry Res

    (2010)
  • S. Shi et al.

    Circadian clock gene Bmal1 is not essential; functional replacement with its paralog, Bmal2

    Curr Biol

    (2010)
  • M.K. Bunger et al.

    Mop3 is an essential component of the master circadian pacemaker in mammals

    Cell

    (2000)
  • A.C. Andreazza et al.

    Impairment of the mitochondrial electron transport chain due to sleep deprivation in mice

    J Psychiatr Res

    (2010)
  • C. Cirelli

    Cellular consequences of sleep deprivation in the brain

    Sleep Med Rev

    (2006)
  • A. Wirz-Justice et al.

    Sleep deprivation: Effects on circadian rhythms of rat brain neurotransmitter receptors

    Psychiatry Res

    (1981)
  • R.M. Salomon et al.

    Effects of sleep deprivation on serotonin function in depression

    Biol Psychiatry

    (1994)
  • J.C. Zant et al.

    Increases in extracellular serotonin and dopamine metabolite levels in the basal forebrain during sleep deprivation

    Brain Res

    (2011)
  • C.J. Davis et al.

    Sleep loss changes microRNA levels in the brain: A possible mechanism for state-dependent translational regulation

    Neurosci Lett

    (2007)
  • M. Wiegand et al.

    Effect of morning and afternoon naps on mood after total sleep deprivation in patients with major depression

    Biol Psychiatry

    (1993)
  • D. Riemann et al.

    Naps after total sleep deprivation in depressed patients: Are they depressiogenic?

    Psychiatry Res

    (1993)
  • C.A. Zarate et al.

    Cellular plasticity cascades: Targets for the development of novel therapeutics for bipolar disorder

    Biol Psychiatry

    (2006)
  • S.S. Campbell et al.

    Lithium delays circadian phase of temperature and REM sleep in a bipolar depressive: A case report

    Psychiatry Res

    (1989)
  • F. Benedetti et al.

    Sleep phase advance and lithium to sustain the antidepressant effect of total sleep deprivation in bipolar depression: New findings supporting the internal coincidence model?

    J Psychiatr Res

    (2001)
  • R.M. Berman et al.

    Antidepressant effects of ketamine in depressed patients

    Biol Psychiatry

    (2000)
  • A.J. Lewy

    Depressive disorders may more commonly be related to circadian phase delays rather than advances: Time will tell

    Sleep Med

    (2010)
  • W. Schulte

    Kombinierte psycho- und pharmalotherapie bei Melancholikern

  • B. Pflug et al.

    Disturbance of the 24-hour rhythm in endogenous depression and the treatment of endogenous depression by sleep deprivation

    Int Pharmacopsychiatry

    (1971)
  • J.C. Wu et al.

    The biological basis of an antidepressant response to sleep deprivation and relapse: Review and hypothesis

    Am J Psychiatry

    (1990)
  • A. Wirz-Justice et al.

    Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy

    (2009)
  • B.G. Bunney et al.

    Rapid-acting antidepressant strategies: Mechanisms of action

    Int J Neuropsychopharmacol

    (2012)
  • F. Benedetti et al.

    Sleep deprivation in mood disorders

    Neuropsychobiology

    (2011)
  • W.E. Bunney et al.

    The “switch process” in manic-depressive illness. I.A systematic study of sequential behavioral changes

    Arch Gen Psychiatry

    (1972)
  • N. Sitaram et al.

    Circadian variation in the time of “switch” of a patient with 48-hour manic-depressive cycles

    Biol Psychiatry

    (1978)
  • A. Wirz-Justice

    Diurnal variation of depressive symptoms

    Dialogues Clin Neurosci

    (2008)
  • T.A. Wehr et al.

    Circadian rhythm disturbances in manic-depressive illness

    Fed Proc

    (1983)
  • D.W. Morris et al.

    Diurnal mood variation in outpatients with major depressive disorder

    Depress Anxiety

    (2009)
  • J. Mendlewicz

    Sleep disturbances: Core symptoms of major depressive disorder rather than associated or comorbid disorders

    World J Biol Psychiatry

    (2009)
  • D.J. Kupfer

    REM latency: A psychobiologic marker for primary depressive disease

    Biol Psychiatry

    (1976)
  • W.M. Troxel et al.

    Insomnia and objectively measured sleep disturbances predict treatment outcome in depressed patients treated with psychotherapy or psychotherapy-pharmacotherapy combinations

    J Clin Psychiatry

    (2012)
  • R. Gupta et al.

    Insomnia associated with depressive disorder: Primary, secondary, or mixed?

    Indian J Psychol Med

    (2011)
  • W.T. Carpenter et al.

    Adrenal cortical activity in depressive illness

    Am J Psychiatry

    (1971)
  • C.B. Nemeroff

    The corticotropin-releasing factor (CRF) hypothesis of depression: New findings and new directions

    Mol Psychiatry

    (1996)
  • B. Scharnholz et al.

    Does night-time cortisol excretion normalize in the long-term course of depression?

    Pharmacopsychiatry

    (2010)
  • E. Souetre et al.

    Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects

    Am J Psychiatry

    (1988)
  • D.H. Avery et al.

    Nocturnal sweating and temperature in depression

    Acta Psychiatr Scand

    (1999)
  • W.C. Duncan et al.

    Relationship between EEG sleep patterns and clinical improvement in depressed patients treated with sleep deprivation

    Biol Psychiatry

    (1980)
  • J.A. Mohawk et al.

    Central and peripheral circadian clocks in mammals

    Annu Rev Neurosci

    (2012)
  • E.E. Zhang et al.

    Clocks not winding down: Unravelling circadian networks

    Nature Reviews Mol Cell Biol

    (2010)
  • Cited by (131)

    • The circadian component of mood disorders: the sleep-wake cycle, biological rhythms, and chronotherapeutics

      2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
    View all citing articles on Scopus
    View full text