Depression and Sleep Disturbances: Common Bedfellows

Sleep disturbances are core symptoms of major depressive disorder (MDD) and may be the first reason patients with MDD seek help.¹

The high incidence of sleep disturbances in people with depression has been demonstrated in numerous studies; for example, difficulties in initiating and/or maintaining sleep have been reported in approximately three-quarters of patients with depression.¹ One large population-based study found that 83% of patients with depression had at least 1 insomnia symptom compared with 36% of individuals without depression.²

A growing body of evidence suggests that problems with sleep regulation precede depressive episodes and persist even during remission.³ A longitudinal study of 591 young adults found that insomnia lasting ≥2 weeks predicted MDD at subsequent interviews.⁴

Sleep disturbances can adversely affect all people, including those who experience depression. Poor sleep typically causes next-day symptoms of morning tiredness, daytime fatigue, concentration and attention problems, and irritable mood, which can cause functional impairment, especially in patients with depression and anxiety.⁵ Sleep disturbances in patients with depression are associated with increased episode recurrences, persistent illness course, and poor outcomes.⁵ Depressed patients with accompanying sleep disturbances are also more likely to have suicidal ideation.³

Insomnia can increase the risk for several medical conditions, including heart disease, respiratory disorders, hypertension, chronic pain, and weight gain. ⁵ It can also increase the risk for inflammation, which recent research suggests may be connected with depression, as well.⁵

“There is a bidirectional relationship between sleep disturbances and depression,” observed Bei Bei, DPsych, PhD, lecturer at the Monash School of Psychological Sciences, in Clayton, Australia, in an email interview with Psychiatry Advisor.

“If a person does not currently have depression but goes through extended periods of time with sleep disturbances or insomnia, the sleep disturbance can potentially contribute to a mood disturbance or to even more severe depression,” she told Psychiatry Advisor. “The other way around is that people with depression and other mood disorders are more likely to report sleep disturbances,” said Dr Bei, who is also a clinical psychologist at the Monash University Healthy Sleep Clinic

Mechanisms of Sleep Disturbance in Depression

The circadian process regulates the daily rhythms of the body and brain, including the sleep-wake cycle.¹ “Even though we do not see it, the circadian process is a biological rhythm that governs our alertness throughout the day and night,” Dr Bei explained.

The control of circadian rhythms and sleep is “complex and involves the fine orchestration of multiple molecular, biochemical, physiological, and behavioral mechanisms.”⁶ Circadian rhythms involve synchronization of numerous endogenous processes, with orchestration of the multiple oscillator systems in mammals being managed by a “central pacemaker.”⁶ The circadian pacemaker is located in the suprachiasmatic nucleus of the hypothalamus, which drives rhythms such as sleep-wake activity.¹ Circadian dysfunction can have an impact on mood.⁶

Circadian rhythms are markedly affected by light, with bright light in the evening delaying the clock and bright light in the morning essential to synchronizing the clock to a 24-hour rhythm.¹ “People with depression might have an altered circadian rhythm, might not be getting enough bright light in the morning and during the day, or might be staying up later at night, which contribute to circadian disruptions and, in turn, to depression,” Dr Bei said.

Several additional putative mechanisms underlie the relationship between sleep disturbances and depression. One hypothesis suggests that the mechanisms that control sleep overlap with the mechanisms that regulate mood.³ The same monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) involved in MDD may also be responsible for REM sleep disturbances in people with MDD.³

Depression disrupts sleep efficiency, making it more difficult for patients to fall asleep (sleep-onset latency) as well as increasing wakefulness throughout the night, thereby reducing total sleep time.⁵ “Even if people are getting quantitatively enough sleep, frequent waking leads to less consolidated sleep and more sleep fragmentation, which can contribute to mood problems,” Dr Bei noted.

Depression also impairs slow-wave sleep (stages 3 and 4) and disrupts REM sleep, leading to shorter REM latency, increased duration of the first REM period, and increased REM density.⁵

Psychological Mechanisms

Certain psychological mechanisms may connect sleep disturbances to depression, Dr Bei suggested. “For example, someone who is vulnerable to insomnia and depression might have overall psychological vulnerability, such as holding more black-and-white beliefs about the world and themselves.” The impact of this type of thinking is that they have more “extreme thoughts and beliefs” if they have difficulty sleeping and interpret their sleep problems in “a more alarming way, which can lead to a sense of hopelessness that can further increase the depression,” she said. Their agitation and sleep disturbance therefore create a vicious cycle.

“If you are not sleeping well, you often spend a lot of time in bed trying to get more sleep. Not only do you have less physical activity, but you may be agitated and restless, which contributes to further sleeplessness,” she explained.

Psychotherapeutic Interventions

Sleep disturbances tend to increase with age, and there is a greater incidence of insomnia among older people. The insomnia can also become more entrenched.^2,4 It is therefore important for clinicians to address sleep disturbances as early as possible, since successful treatment of insomnia can also improve outcomes in patients with depression.⁵

“These days we think that both conditions should be treated in their own right, and typically, with either condition one treats, the other tends to improve,” Dr Bei commented.

Dr Bei noted that cognitive behavioral therapy (CBT) has been shown to be “an effective non-drug therapy for both conditions.” CBT for insomnia (CBT-I) has several components that improve sleep, including stimulus-control techniques, restrictions to spending too much time in bed, relaxation, and cognitive restructuring to address negative and counterproductive beliefs about sleep.³

A recent multicenter trial compared a CBT-I intervention to a control intervention in people experiencing both depression and insomnia and taking antidepressants. The investigators found CBT-I to be superior to the control intervention in reducing insomnia. Of note, there were 3 different trajectories of long-term depression outcome, and rapid improvements in insomnia early in the treatment predicted better long-term depression outcomes.⁷

Other studies have found CBT-I to be superior to antidepressants for treating both insomnia and depression. A study comparing antidepressant therapy plus CBT-I, placebo plus CBT-I, and antidepressant plus education in sleep hygiene found that all groups reported improvements in both depressive symptoms and sleep. However, only the CBT-I groups improved in measures of objective sleep (assessed via polysomnography), and participants in the sleep hygiene group actually experienced poorer sleep quality.⁸

Another study comparing CBT-I to antidepressant monotherapy found the combination to be superior to use of antidepressants alone in alleviating both depression and insomnia.⁹

Pharmacotherapy for Sleep Disturbances

Several pharmacologic agents and classes have been used in patients with insomnia. These include hypnotics, sedating agents, and antidepressants. Further details can be found in Table 1.

Circadian-Oriented Interventions

Melatonin, a hormone produced by the pineal gland, is involved with sleep regulation and improves insomnia caused by circadian schedules, such as shift work or jet lag.¹⁰ Melatonin may also have an independent effect in improving depression. A study of patients with breast cancer found that melatonin reduced depressive symptoms during the 3 months following surgery.¹¹ A recent literature review suggested that, since chronobiological disturbances play a role in depression, a chronobiological approach that includes timely use of light and melatonin agonists could complement the treatment of MDD.¹²

An increasing body of evidence supports light therapy for depression and circadian sleep disorders. A meta-analysis found that augmentation of antidepressant therapy with light therapy was superior to antidepressant monotherapy in alleviating symptoms of MDD and bipolar depression.¹³ A study of 122 patients found that bright light treatment, both as monotherapy and in combination with fluoxetine, was efficacious and well tolerated in the treatment of adults with nonseasonal MDD.¹⁴

Tips for Clinicians

Clinicians routinely ask patients, “How is your sleep?” and sleep difficulties are commonly reported by patients, especially those seeking support for mood problems. Beyond asking a general question, it is important for clinicians to obtain more details about sleep disturbances experienced by their patients. A list of assessment tools can be found in Table 2.

Dr Bei emphasized that for the treatment of insomnia, CBT-I as a nondrug approach should be tried first. CBT-I is an evidence-based approach that is comparable to sleep medication in the short-term and has more superior benefits in the longer-term.

The National Sleep Foundation and the Anxiety and Depression Association of America are useful resources to help patients find practitioners or reliable online CBT interventions.

References

1. Nutt D, Wilson S, Paterson L. Sleep disorders as core symptoms of depression. Dialogues Clin Neurosci. 2008;10(3):329-336.
2. Stewart R, Besset A, Bebbington P, et al. Insomnia comorbidity and impact and hypnotic use by age group in a national survey population aged 16 to 74 years. Sleep. 2006;29(11):1391-1397.
3. Murphy MJ, Peterson MJ. Sleep disturbances in depression. Sleep Med Clin. 2015;10(1):17-23.
4. Buysse DJ, Angst J, Gamma A, Ajdacic V, Eich D, Rössler W. Prevalence, course, and comorbidity of insomnia and depression in young adults. Sleep. 2008;31(4):473-480.
5. Cutler AJ. The role of insomnia in depression and anxiety: its impact on functioning, treatment, and outcomes. J Clin Psychiatry. 2016;77(8):e1010.
6. Germain A, Kupfer DJ. Circadian rhythm disturbances in depression. Hum Psychopharmacol. 2008;23(7):571-585. 
7. Bei B, Asarnow LD, Krystal A, Edinger JD, Buysse DJ, Manber R. Treating insomnia in depression: Insomnia related factors predict long-term depression trajectories. J Consult Clin Psychol. 2018;86(3):282-293.
8. Carney CE, Edinger JD, Kuchibhatia M, et al. Cognitive behavioral insomnia therapy for those with insomnia and depression: a randomized controlled clinical trial. Sleep. 2017;40(4):zsx019.
9. Manber R, Edinger JD, Gress JL, San Pedro-Salcedo M, Kuo TF, Kalista T. Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia. Sleep. 2008;31(4):489-495.
10. Ramakrishnan K, Scheid DC. Treatment options for insomnia. Am Fam Physician. 2007;76(4):517-526.
11. Hansen MV, Andersen LT, Madsen MT, et al. Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized, double-blind, placebo-controlled trial. Breast Cancer Res Treat. 2014;145(3):683-695.
12. Zaki NFW, Spence DW, BaHammam AS, Pandi-Perumal SR, Cardinali DP, Brown GM. Chronobiological theories of mood disorder. Eur Arch Psychiatry Clin Neurosci. 2018;268(2):107-118.
13. Penders TM, Stanciu CN, Schoemann AM, Ninan PT, Bloch R, Saeed SA. Bright light therapy as augmentation of pharmacotherapy for treatment of depression: a systematic review and meta-analysis. Prim Care Companion CNS Disord. 2016;18(5).
14. Lam RW, Levitt AJ, Levitan RD, et al. Efficacy of bright light treatment, fluoxetine, and the combination in patients with nonseasonal major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2016;73(1):56-63. 

Table 1: Pharmacotherapy for Insomnia and Depression

Class	Agent/Comments
Benzodiazepines (use lowest dose possible and monitor for potential overuse)	Triazolam Estazolam Temazepam
Moderate γ- aminobutyric acid agonist receptor potentiating agents	Zaleplon Zolpidem Eszopiclone
Tricyclic antidepressants (can lead to sedation or REM sleep suppression and increased stage 2 sleep)	Amitriptyline Doxepin Nortriptyline Anafranil
Monoamine oxidase inhibitors (can cause insomnia, potent REM suppression)	Phenelzine Tranylcypromine
Selective serotonin reuptake inhibitors (can cause insomnia, REM suppression, increased eye movements in non-REM sleep)	Fluoxetine Sertraline Paroxetine Citalopram Escitalopram
Serotonin-norepinephrine reuptake inhibitors (can cause insomnia, REM suppression, increased eye movements in non-REM sleep)	Venlafaxine Duloxetine
Other antidepressants	Trazodone (can cause sedation) Bupropion (can cause insomnia/activation) Mirtazapine (can cause sedation, REM sleep activation)
Melatonin	Melatonin
Herbal remedies	Valerian root Lavender Passiflora Kava kava

REM=rapid eye movement

From Murphy MJ et al³ and Ramakrishnan K et al.¹⁰ 

Table 2. Assessment Tools for Sleep Disorders

Pittsburgh Sleep Quality Index (PSQI)	Assesses subjective sleep quality and sleep habits
PROMIS Sleep Disturbance	Evaluates self-reported sleep quality, sleep depth, satisfaction with sleep
Epworth Sleepiness Scale (EPS)	Assesses subjective daytime sleepiness
Functional Outcomes of Sleep Questionnaire (FOSQ)	Assesses impact of excessive sleepiness on daily activities
Insomnia Severity Index	Assesses severity/impact of insomnia

From Luyster FS, Choi J, Yeh C-H, et al. Screening and evaluation tools for sleep disorders in older adults. Appl Nurs Res. 2015;28(4):334-340.