Cases That Test Your Skills

The bedtime solution

Current Psychiatry. 2009 December;8(12):91-104

References

1. AHCPR Depression Guideline Panel. Clinical practice guideline number 5. Depression in primary care. Volume 2: Treatment of major depression. Rockville, MD: Agency for Health Care Policy and Research, Public Health Services, U.S. Department of Health and Human Services; 1993. AHCPR publication 93-0550.

2. Fava M, Rush JA, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163(7):1161-1172.

3. Wirz-Justice A, Benedetti F, Berger M. Chronotherapeutics (light and wake therapy) in affective disorders. Psychol Med. 2005;35(7):939-944.

4. Giedke H, Schwärzler F. Therapeutic use of sleep deprivation in depression. Sleep Med Rev. 2002;6(5):361-377.

5. Lam RW, Tam EM, Shiah IS, et al. Effects of light therapy on suicidal ideation in patients with winter depression. J Clin Psychiatry. 2000;61(1):30-32.

6. Oliwenstein L. Lifting moods by losing sleep: an adjunct therapy for treating depression. Alternative and Complementary Therapies. 2006;12(2):66-70.

7. Wehr TA, Wirz-Justice A, Goodwin FK, et al. Phase advance of the circadian sleep-wake cycle as an antidepressant. Science. 1979;206(4419):710-713.

8. Moscovici L, Kotler M. A multistage chronobiologic intervention for the treatment of depression: a pilot study. J Affect Disord. 2009;116(3):201-217.

9. Benedetti F, Colombo C, Barbini B, et al. Morning sunlight reduces length of hospitalization in bipolar depression. J Affect Disord. 2001;62(3):221-223.

10. Benedetti F, Barbini B, Colombo C, et al. Chronotherapeutics in a psychiatric ward. Sleep Med Rev. 2007;11(6):509-522.

11. Lopez-Rodriguez F, Wilson CL, Maidment NT, et al. Total sleep deprivation increases extracellular serotonin in the rat hippocampus. Neuroscience. 2003;121(2):523-530.

12. Mayberg HS. Defining the neural circuitry of depression: toward a new nosology with therapeutic implications. Biol Psychiatry. 2007;61(6):729-730.

13. Wu JC, Gillin JC, Buchsbaum MS, et al. Sleep deprivation PET correlations of Hamilton symptom improvement ratings with changes in relative glucose metabolism in patients with depression. J Affect Disord. 2008;107(1-3):181-186.

14. Bunney JN, Potkin SG. Circadian abnormalities, molecular clock genes and chronobiological treatments in depression. Br Med Bull. 2008;86:23-32.

15. Benedetti F, Barbini B, Lucca A, et al. Sleep deprivation hastens the antidepressant action of fluoxetine. Eur Arch Psychiatry Clin Neurosci. 1997;247(2):100-103.

16. Vogel GW, Thurmond A, Gibbons P, et al. REM sleep reduction effects on depression syndromes. Arch Gen Psychiatry. 1975;32(6):765-777.

17. King D, Dowdy S, Jack R, et al. The dexamethasone suppression test as a predictor of sleep deprivation antidepressant effect. Psychiatry Res. 1982;7(1):93-99.

Although she is sleepy the morning after partial sleep deprivation, Ms. W reports a marked improvement in her mood, decline in hopelessness, and absence of suicidal ideation. She continues the sleep-phase advance protocol for the next 3 nights and participates in cognitive-behavioral therapy groups and ward activities. Psychiatric unit staff support her continued wakefulness during sleep manipulation. Because Ms. W had previously responded to antidepressant augmentation with an atypical antipsychotic we add aripiprazole and titrate the dosage to 7.5 mg/d. We also continue fluoxetine, 80 mg/d, and add trazodone, 100 mg at bedtime, and hydroxyzine, 25 mg as needed.

Table 1

Ms. W’s chronotherapy protocol: Hours permitted for sleep*

Day number
	1	2	3	4	5
Sleep deprivation	9 PM to2 AM
Sleep-phase advance		5 PM to midnight	7 PM to 2 AM	9 PM to 4 AM	10 PM to 5 AM
*Treatment was implemented while Ms. W was hospitalized

The authors’ observations

Chronotherapy incorporates manipulations of the sleep/wake cycle such as sleep deprivation and dark or light therapy. It may use combinations of interventions to generate and sustain a response in patients with depression. In a 4-week pilot study, Moscovici et al⁸ employed a regimen of late partial sleep deprivation, light, and sleep-phase advance to generate and maintain an anti depressant response in 12 patients. Benedetti et al⁹ used a similar regimen plus lithium to successfully treat bipolar depression and sleep-phase advance to continue that response in 50% of patients for 3 months.

Circadian rhythms affect the function of serotonin (5-HT), norepinephrine, and dopamine.^9,10 In a manner similar to antidepressant medications, sleep deprivation may up-regulate or otherwise alter these neurotransmitters’ function. In animals, sleep deprivation increases serotonin function.¹¹ Several hypothetical mechanisms of action for sleep deprivation and other types of chronotherapies have been suggested (Table 2).^11-14

Clinical Point

Chronotherapies may work by altering the function of serotonin, norepinephrine, and dopamine

Chronotherapies may affect function in brain pathways, as demonstrated by neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Depression has been associated with increased or decreased brain activity measured by PET or fMRI in regions of the limbic cortex (cingulate and anterior cingulate) and frontal cortex.¹²

Wu et al¹³ examined patients treated for depression with medication and total sleep deprivation therapy. Response to treatment was associated with increased function in the cingulate, anterior cingulate, and medial prefrontal cortex as measured by PET. In contrast, mood improvement was associated with reduced baseline activity in the left medial prefrontal cortex, left frontal pole, and right lateral prefrontal cortex.

Researchers have noted the convergence of sleep-wake rhythms and abnormalities seen in depression and the subsequent link with improved sleep-wake cycles related to depression remission. Bunney and Potkin¹⁴ note the powerful effect of zeitgebers—environmental agents that reset the body’s internal clock. They suggested that sleep deprivation may affect the function of “master clock” genes involved in controlling the biological clock. These effects on the suprachiasmatic nucleus hypothalamic pacemaker may improve mood by altering control of genetic expression through chromatin remodeling of this master clock circuit.

Certain factors may increase the likelihood that a patient may respond to chronotherapy (Table 3).^9,15-17

Table 2

Sleep deprivation for depression: Possible mechanisms

Mechanism	Components
Alterations to neurotransmitter function	Serotonin, norepinephrine, dopamine¹¹
Alterations to endogenous circadian pacemaker function	Increased gene expression¹⁴
Changes in perfusion/activity of brain regions	Anterior cingulate, frontal cortex regions^12,13

Table 3

Factors that suggest a patient might respond to chronotherapy

Diurnal mood variation¹⁵
Endogenous depression including insomnia and anorexia¹⁶
Abnormal dexamethasone suppression¹⁷
High motivation for treatment
Bipolar depression (possibly)⁹

OUTCOME: Lasting improvement

Ms. W’s mood improvement is sustained during her week-long hospitalization. At discharge she is hopeful about the future and does not have thoughts of suicide.

At subsequent outpatient visits up to 4 months after discharge, her depressive symptoms remain improved. Patient Health Questionnaire scores indicate mild depression, but Ms. W is not suicidal. She maintains a sleep schedule of 10 PM to 6:30 AM and undergoes 10,000 lux bright light therapy, which she began shortly after discharge, for 30 minutes every morning. She works more productively in psychotherapy, focusing on her eating disorder and anxiety.

Related resource

Wu JC, Kelsoe JR, Schachat C, et al. Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder. Biol Psychiatry. 2009; 66(3): 298-301.

Drug brand names

Aripiprazole • Abilify
Atomoxetine • Strattera
Bupropion • Wellbutrin
Buspirone • BuSpar
Citalopram • Celexa
Clomipramine • Anafranil
Clonazepam • Klonopin
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Neurontin
Hydrocodone/APAP • Vicodin
Hydroxyzine • Atarax, Vistaril
Leuprolide • Lupron
Liothyronine • Cytomel
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Nortriptyline • Aventyl
Paroxetine • Paxil
Risperidone • Risperdal, Risperdal Consta
Trazodone • Desyrel
Venlafaxine XR • Effexor XR
Zolpidem • Ambien