Psychiatric Annals


Insomnia and Depression: A Reciprocal Relationship

Daniel D. Herrick, MD; Michael J. Sateia, MD


Available data consistently confirm the close association between chronic insomnia and depression. This review examines the evidence supporting a reciprocal relationship between the two disorders. The epidemiology and subjective presentation of sleep disturbance in depression is discussed, in addition to objective findings on polysomnography and electroencephalography. The evidence for insomnia as a risk factor for future depression is reviewed, and encouraging results showing benefit of treating insomnia as a preventive measure are presented. Prominent hypotheses regarding the sleep-related etiology of depression, including cholinergic/aminergic imbalance and circadian dysregulation, are discussed. Important effects of antidepressant pharmacotherapy on sleep are outlined, with a focus on activating versus sedating and motoric activation properties. Finally, the relationship between depression and other sleep disorders (obstructive sleep apnea, hypersomnia, and restless legs syndrome) is briefly discussed. The data clearly show that insomnia and depression are interrelated, and effective treatment of one disorder must incorporate consideration and management of the other. [Psychiatr Ann. 2016;46(3):164–172.]


Available data consistently confirm the close association between chronic insomnia and depression. This review examines the evidence supporting a reciprocal relationship between the two disorders. The epidemiology and subjective presentation of sleep disturbance in depression is discussed, in addition to objective findings on polysomnography and electroencephalography. The evidence for insomnia as a risk factor for future depression is reviewed, and encouraging results showing benefit of treating insomnia as a preventive measure are presented. Prominent hypotheses regarding the sleep-related etiology of depression, including cholinergic/aminergic imbalance and circadian dysregulation, are discussed. Important effects of antidepressant pharmacotherapy on sleep are outlined, with a focus on activating versus sedating and motoric activation properties. Finally, the relationship between depression and other sleep disorders (obstructive sleep apnea, hypersomnia, and restless legs syndrome) is briefly discussed. The data clearly show that insomnia and depression are interrelated, and effective treatment of one disorder must incorporate consideration and management of the other. [Psychiatr Ann. 2016;46(3):164–172.]

Both major depressive disorder (MDD) and insomnia disorder are highly prevalent in the general population, and their bidirectional association has been well recognized. This review aims to address the complex relationship among the symptoms, objective findings, genetics, and treatment of insomnia and depression. It also highlights sleep-related hypotheses in the etiology of depression.


In US adults, the lifetime prevalence estimate for MDD is 16.2% (12-month prevalence of 6.6%), with an increased risk (odds ratio of 1.7) in women.1 Chronic insomnia disorder occurs in about 10% of the population and is also more common in women.2 There is a clear association between symptoms of sleep disturbance (difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening, and nonrestorative sleep) and MDD,3 with 85% of nonpsychotic patients with MDD reporting insomnia symptoms in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.4 Conversely, people with insomnia are 9.82 times as likely to have clinically significant depression.5 Indeed, sleep has been studied more extensively in patients with depression than with any other psychiatric disorder.

Subjective Reports of Insomnia in Depression

Sleep disturbance (insomnia or hypersomnia) is a core diagnostic criterion for MDD in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5).6 Insomnia typically presents as middle insomnia (ie, waking up during the night with difficulty returning to sleep) or terminal insomnia (ie, early-morning awakening with difficulty returning to sleep), but initial difficulty falling asleep may also occur. Increased frequency of insomnia symptoms and increased number of awakenings correlate with worse depression severity,5 underscoring the significant relationship between sleep quality and affective state. Sleep disturbance is one of the most common residual symptoms of depression, and has been estimated to occur in up to 44% of patients in remission from major depression.7

The DSM-5 provides specifiers for MDD that include criteria related to sleep patterns.6 “With mixed features” specifies a depressive episode with co-occurring symptoms of mania or hypomania, one of which may be a decreased need for sleep (feeling rested despite sleeping less than usual). “With melancholic features” specifies a depressive episode that may include symptoms of early-morning awakening (ie, at least 2 hours before usual awakening) or depression that is regularly worse in the morning. Depression “with atypical features” may include hypersomnia with at least 10 hours of sleep per day, or at least 2 hours more than when euthymic. Finally, and probably most familiar, is depression “with seasonal pattern,” which is often characterized by hypersomnia.

Objective Sleep Findings in Depression

Polysomnography (PSG) and electroencephalogram (EEG) spectral analysis have shown specific objective changes in sleep architecture in patients with depression, raising interest in their use to identify biologic markers of MDD.


In general, there are three categories of PSG changes associated with depression: disturbance of sleep continuity, deficits of slow-wave sleep, and abnormalities of rapid eye movement (REM) sleep.8 Sleep efficiency is typically reduced, with prolonged sleep latency and increased wakefulness after sleep onset. There is a characteristic decrease in the amount of slow-wave sleep, although this association may be less robust in women.9 Changes in REM sleep include shortened REM latency, increased REM density (ie, number of eye movements per minute of REM sleep), increased percentage of REM sleep, and longer duration of the first REM period. REM sleep dysregulation is hypothesized to contribute to the development of cognitive depressive symptoms (eg, cognitive distortions, negative self-esteem) via consolidation of negatively toned emotional memories.10

Shortened REM latency and decreased slow-wave sleep may be trait markers of MDD, whereas increased REM density and sleep disturbance appear to be state markers that are most evident during acute episodes of depression.8 Furthermore, the persistence of decreased REM latency and slow-wave sleep abnormalities during remission suggests that these changes might reflect a biologic susceptibility for depression, although it is also possible that sleep changes are caused by depression and remain after affective symptoms resolve.

Adolescents with a family history of depression show a significant increase in wake after sleep onset and decrease in sleep efficiency compared to controls,11 although studies in children and adolescents have not found consistent changes in sleep architecture paralleling those in adult depression.12 PSG in children and adolescents with MDD does show decreased sleep spindle activity compared to healthy controls.13

Spectral Analysis/Electroencephalogram

Depressed patients have reduced delta (1 to 4.5 Hz) EEG power and slow-wave counts throughout the night,14 and this finding persists from acute depression to remission.15 Another measure of slow-wave sleep activity is the delta sleep ratio, which is defined as the ratio of average slow wave counts per minute in the first nonrapid eye movement (NREM) period to the average counts per minute in the second NREM sleep period. Depressed patients tend to have a lower ratio (≤1.10) compared to controls (>1.6).15 Reduced slow wave activity (SWA) is thought to reflect an abnormal homeostatic regulation of slow-wave sleep (ie, impaired Process S). Delta sleep ratio also predicts treatment response and likelihood of recurrence: patients with higher ratios are more likely to respond to treatments,16 and those with lower ratios are more likely to experience recurrent depression.17 A higher delta sleep ratio may also be a protective factor associated with resilience, as shown in patients treated with interferon-alpha treatment.18

Both intra- and interhemispheric coherence in the delta (0.5 to 4 Hz) and beta (16 to 32 Hz) frequency ranges have been shown to be lower in patients with major depression compared to controls, and decreased coherence correlates with risk of recurrence.19 Interestingly, topographic reductions in SWA (parieto-occipital) may be associated with hypersomnolence in MDD.20

Sleep Findings as a Diagnostic Aid in Major Depressive Disorder

In the future, PSG and spectral analysis findings may have clinical utility in the diagnosis and, perhaps, management of MDD. Variables such as delta sleep ratio, total SWA, and coherence of sleep EEG rhythms may one day be helpful in identifying those susceptible to developing affective illnesses or relapses. Short REM latency and decreased slow-wave sleep have been reported in other conditions (schizophrenia, borderline personality disorder, eating disorders, and alcoholism), although findings for patients with affective disorders differed most frequently and significantly from those for normal controls.21

Incident depression risk increases (relative risk of 2.4–4.7) with baseline PSG markers of increased (uppermost quartile) sleep latency and wakefulness after sleep onset, and decreased (lowest quartile) sleep efficiency and total sleep time.22 Changes in SWA can also predict clinical outcomes: depressed patients who have an increase of SWA over the night after antidepressant administration are more likely to respond to treatment.15

Ellis et al.23 examined PSG data in patients with acute insomnia. Those with shorter REM latency and reduced N3 sleep were more likely to transition to chronic insomnia at the 3-month follow-up examination and were more likely to develop first-onset depression compared to those who remitted from insomnia or were normal sleepers. The authors suggest that the “sleep architecture stigmata” of depression may develop over the course of transitioning from acute to chronic insomnia.

A meta-analysis of 31 publications suggests that PSG changes (particularly REM sleep parameters and sleep efficiency) in major depression are replicable with moderate effect sizes, but there is limited information on sensitivity, specificity, or predictive values.24 Challenges include heterogeneity in patients with MDD and variability in scoring definitions used. The authors call for a systematized effort toward translating PSG abnormalities to a clinically meaningful diagnostic test.

Insomnia as a Risk Factor for Major Depressive Disorder

Although insomnia is a common symptom of depression, there is mounting evidence that isolated insomnia disorder is a risk factor for incident depression. There seems to be a bidirectional relationship between the two disorders, suggesting a common etiology. The effect of insomnia has been demonstrated for new-onset depression as well as relapse/recurrence.

New Onset

There is a preponderance of evidence linking insomnia symptoms with new-onset depression. Johnson et al.25 showed that among adolescents with comorbid insomnia and depression, insomnia occurred first in 69% of cases, and this association was not significant for prior insomnia and anxiety disorders. In 1996, Breslau et al.26 published a prospective study in which insomnia at baseline conferred a 4.0 relative risk for new-onset major depression over a 3-year period. Further evidence shows the risk extends over the long-term (median follow up of 34 years) in those reporting insomnia at baseline (relative risk of 2.0) and in those with difficulty sleeping under stress at baseline (relative risk of 1.8).27 Vulnerability to stress-related sleeping disturbance (sleep reactivity) is associated with greater depressive symptoms, and this effect is at least partially mediated by insomnia.28 A 2011 meta-analysis of 21 studies showed nondepressed people with insomnia have a 2-fold risk of developing depression compared to those with no sleep difficulties.29 The majority of evidence continues to confirm these findings,30–32 even in the preschool to first-grade population.33 The association also holds when polysomnographic markers of insomnia (increased sleep latency, decreased sleep continuity, and duration) are considered.22


The evidence relating insomnia with relapse or recurrence of depression is less robust. Okajima et al.34 showed an association between insomnia and persistent depression over the course of 2 years. A study of patients treated pharmacologically for major depression showed a vast majority experienced subjective sleep disturbance/insomnia prior to relapse or recurrence.35 There is some evidence that it is duration of sleep (both short ≤6 hours, and long ≥10 hours) that predicts recurrent depressive episodes36 or a persistent and chronic depression course, compared to insomnia per se.37 Even if insomnia persists after remission of depression, not all studies show this translates to a risk for relapse,38 and some authors suggest insomnia and short sleep duration may be trait markers of depression.39

Treatment of Insomnia as a Preventive Measure

If insomnia is a risk factor for developing depression, then it would stand to reason that treating insomnia in nondepressed people could be effective preventive therapy for depression. There is evidence of such benefit using both cognitive-behavioral therapy (CBT) and pharmacotherapy.

Cognitive-behavioral therapy. People with comorbid symptoms of insomnia and depression have more severe insomnia symptom-focused rumination and dysfunctional beliefs about sleep compared to those with insomnia alone,40 making these patients prime candidates for CBT for insomnia. CBT for insomnia is effective in improving sleep disturbances associated with mood disorders, often with concurrent improvements in the comorbid affective symptoms.41 Adding CBT for insomnia to treatment as usual results in significantly better scores on physical functioning, social functioning, and mental health subscales,42 and this benefit has been shown in the adolescent population as well.43 A study by Blom et al.44 compared Internet-delivered CBT for insomnia or depression in patients with both diagnoses and showed CBT for insomnia was actually more effective for depression symptoms. The GoodNight study45 intends to evaluate whether Internet-delivered CBT for insomnia will prevent the onset of a major depressive episode in adults with subclinical depressive symptoms and insomnia.

Pharmacotherapy. Khazaie et al.46 looked at the question of pharmacotherapy for insomnia in the perinatal population and showed insomnia treatment with trazodone or diphenhydramine during the third trimester of pregnancy may prevent postpartum depression. Most of the evidence for pharmacotherapy addresses the treatment of co-occurring depression and insomnia rather than preventing new-onset of depression, and the evidence is mixed. One study with fluoxetine and eszopiclone showed significant improvement in sleep quality compared to fluoxetine alone, in addition to a faster onset and greater magnitude of antidepressant effect.47 Another study with nortriptyline, psychotherapy, and lorazepam showed greater likelihood of antidepressant response when lorazepam was added for anxiety or insomnia symptoms.48 Adding extended-release quetiapine improves sleep disturbance in patients with MDD who have had an inadequate response to antidepressant therapy, and is effective against depressive symptoms in patients with sleep disturbance.49

Although the addition of a sedative hypnotic for insomnia may improve antidepressant efficacy, not all evidence suggests that the presence of insomnia symptoms necessarily portends a worse response to antidepressant pharmacotherapy.50 Fava et al.51 showed adding zolpidem extended-release to escitalopram improved insomnia and some sleep-related next-day symptoms but did not significantly augment the antidepressant response of escitalopram. Another small (17 cases) retrospective study showed little benefit of low-dose doxepin in this population.52

Genetics and Familial Risk for Major Depressive Disorder and Insomnia

Further evidence that depression and insomnia share a common etiology can be found in genetic studies. Persistent sleep abnormalities in major depression (short REM latency and slow-wave sleep deficits) have been shown to occur in both affected and unaffected first-degree relatives, and short REM latency appears to confer an increased risk of major depression beyond the familial risk associated with a depressed first-degree relative.53 This finding suggests that changes in sleep macroarchitecture may predate the clinical expression of depression.

It has been estimated that at least 33% of the risk for major depression can result from genetic factors, with several candidate genes identified.54 At least two of these genes have also been related to sleep parameters. A gene for monoamine oxidase-A (MAO-A) has been implicated in depression and correlates with insomnia scores; a serotonin transporter gene (5-HTTLPR) is implicated in depression and correlates with treatment response to sleep deprivation.55 There is additional evidence that particular gene polymorphisms are associated with individual depressive symptoms, including insomnia.56,57

Sleep-Related Hypotheses in the Etiology of Depression

How might the underlying neurobiology of depression relate to that of sleep? The neurobiology of depression is poorly understood, with the monoamine hypothesis (ie, deficits in monoamine transmission, including noradrenergic, serotonergic, and dopaminergic) remaining prominent.58 However, neural plasticity (brain-derived neurotrophic factor and other trophic factors), neuroanatomic (cortical, hippocampal regions), endocrine (eg, cortisol), and genetic factors (altered gene expression) are also at play.58


REM sleep is promoted by cholinergic activation and inhibited by aminergic (serotonin and norepinephrine) activation. Reduced aminergic activity, which is the prominent theory to explain the neurobiology of depression, and/or enhanced cholinergic activity could explain polysomnographic findings of short REM latency and increased REM density.59 Neuroanatomically, the habenula is an epithalamic structure in the brain that negatively regulates the monoaminergic systems in the central nervous system. It has been hypothesized that habenular hyperactivation may mediate both depressive symptoms and alterations in REM sleep.60 Increased cholinergic activity may explain changes in REM sleep, and recent interest has arisen in the antidepressant effect of scopolamine (a muscarinic acetylcholine receptor antagonist)61 and drugs targeting nicotinic acetylcholine receptors (such as varenicline).62

Interestingly, inducing “depressive” sleep patterns in people who are not depressed with cholinergic agents does not cause depression, suggesting an underlying mechanism that is more complex. The excitatory neurotransmitter glutamate may play a role—functioning in neuroplasticity, sleep, and mood regulation, and interacting with cholinergic neurons to increase activity of the reticular-activating system associated with REM sleep onset.63

Chronobiologic/Circadian Factors

Chronobiology and circadian factors represent another shared process between sleep and mood. The DSM-5 offers two specifiers for major depression that have a circadian component.6 “With melancholic features” is used to describe depression that is regularly worse in the morning. “With seasonal pattern” describes the relationship between onset of major depressive episodes and a particular time of year (usually fall or winter), which suggests a correlation with diurnal patterns of light exposure. Also, environmental disruptions to circadian rhythms (shift work, travel across time zones, irregular social schedules) tend to precipitate or exacerbate mood episodes,64 perhaps via the neuroimmune system.65

Underlying these associations are genetic and neurobiologic interactions. There are data showing significantly dysregulated expression of circadian clock genes in patients with MDD,66 and a CLOCK gene polymorphism (3111 T/C) has been linked to the presence of insomnia or decreased sleep time in patients with a mood disorder.67 The monoamine hypothesis of depression may also help explain the overlap of circadian dysregulation and depression, as reciprocal connections exist between the serotonin and circadian networks in the brain.68

An evening chronotype (ie, tendency for delayed sleep phase) may be a risk factor for insomnia and depression in adolescents69 and is also associated with nonremission of depression (odds ratio of 3.36) in adults.70 Patients with a stronger evening chronotype also show less improvement in depression symptoms with CBT for insomnia.71 Melatonin may play a role, as those with low endogenous melatonin secretion show alterations in REM sleep and a higher incidence of subsyndromal depressive symptoms compared to normal secretors.72 Phase-delayed dim light melatonin onset and midsleep time have been associated with increased appetite, hypersomnia, and body mass index (symptoms of atypical depression).73

Chronotherapeutic interventions in mood disorders. Antidepressant effects of shifting circadian secretion of melatonin using bright-light therapy, sleep deprivation, or agomelatine have been identified.74 Bright-light therapy has shown efficacy in treating seasonal affective disorder as well as nonseasonal depression, perhaps mediated by effects on the autonomic nervous system.75 It is hypothesized that sleep deprivation therapy mediates effects by resetting abnormal clock gene machinery.76

Agomelatine (not available in the United States) is a melatonin agonist and serotonin (5-HT2C) antagonist.77 Efficacy studies showed improvement in depressive symptoms, sleep efficiency, and resynchronization of disrupted circadian rhythms. In comparison to escitalopram, agomelatine reduced sleep latency, preserved sleep cycles, and reduced daytime sleepiness, with similar improvements in Hamilton depression scores.78

Sleep-Related Complications/Effects of Antidepressant Therapy

The close association between insomnia and depression is also evident when considering pharmacotherapy for depression. Antidepressants can be categorized according to the degree of sedation or activation they produce. Some selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, and bupropion can cause significant sleep disruption and worsen insomnia in some patients, whereas trazodone and mirtazapine are sedating and can improve sleep initiation and maintenance.79 Most tricyclic antidepressants are also sedating and may be helpful in treating depressed patients with insomnia. Paroxetine is unique in that it is an SSRI that is more associated with sedation. Objective differences have been shown on the Multiple Sleep Latency Test (MSLT) between evening doses of escitalopram (stimulating effect) and amitriptyline (reduced alertness/vigilance).80 Of clinical importance is that antidepressant-induced difficulty sleeping is associated with late response to therapy81 and more functional impairment.82

The insomnia that is associated with certain antidepressant treatment is believed to be mediated by 5HT2 receptor stimulation. 5HT2 receptor antagonists may be more effective at improving comorbid insomnia and depression.83 Another serotonin-mediated effect is the atypical eye movements during NREM sleep associated with SSRIs.84 These eye movements can still be present months to years after discontinuing the medication.

Increased motor activity is the other major sleep-related effect of some antidepressant medications. This effect produces increased risk of pharmacologically induced/exacerbated restless legs syndrome (RLS), periodic limb movements in sleep (PLMS), and REM behavior disorder/REM sleep without atonia.85 Tricyclic antidepressants (TCAs) and SSRIs have been implicated in precipitating or exacerbating RLS and periodic leg movements, which can be associated with insomnia and/or daytime fatigue.86 Mirtazapine has also been associated with PLMS and transient RLS.87 REM sleep behavior disorder (RBD) has been described with use of REM-suppressing medications (ie, most antidepressants). RBD is a prodromal marker of Parkinson's disease and other synuclein-mediated neurodegenerative syndromes, although it is unclear whether antidepressant-associated RBD portends a similar risk.88

Insomnia Comorbid with Other Sleep Disorders and Depression

The primary focus of this review has been the relationship between insomnia and depression, although both insomnia and depression may be associated with virtually every major category of sleep disorders,89 including sleep-related breathing disorders (eg, obstructive sleep apnea [OSA]), primary hypersomnolence conditions (eg, narcolepsy), and sleep-related movement disorders (eg, RLS).

Insomnia is a relatively common complaint among patients with OSA. This often takes the form of recurrent, brief awakenings but may transition to both difficulty initiating sleep and prolonged nocturnal waking. There are high rates of depressive symptoms in patients with OSA, and depression was the most common psychiatric comorbidity (21.8%) in a large cohort of patients diagnosed with OSA.90 It is as yet unclear whether OSA contributes to depression via its sleep fragmenting effect, hypoxemic burden, or both. Undetected OSA may be a contributing factor in treatment-refractory major depression. Studies have demonstrated a decrease in depression symptoms with institution of continuous positive airway pressure therapy,91 and conversely optimal management of depression is imperative to maximize the benefit of OSA therapy, in relation both to outcome92 and adherence.93

Regarding hypersomnia, epidemiologic studies have identified high rates of subjective sleepiness in patients with depression,94 although objective studies (using MSLT) generally fail to demonstrate significant pathologic sleepiness. Although overwhelmingly sleepy during waking hours, upwards of 50% of narcolepsy patients complain of nocturnal sleep disturbance. In treating depression comorbid with hypersomnolence, choice of antidepressant pharmacotherapy may have a significant impact on clinical outcome. The norepinephrine-dopamine reuptake inhibitor (NDRI) bupropion has been shown to provide greater resolution of sleepiness and fatigue compared to the SSRI class.95

RLS and PLMS disorder are not uncommonly associated with both insomnia and depression, as well as with certain antidepressant therapy. In one study,96 the odds ratio for a diagnosis of MDD in patients with RLS was 4.7, despite absence of association between antidepressant use and RLS (see above). Overlap between RLS-related and depression-related symptoms may be a confounding factor.97 The NDRI bupropion is less likely to exacerbate sleep-related movement disorders, and it may even be protective.98


The majority of patients presenting with a chief concern of depression will also experience co-occurring sleep disturbance. Likewise, high rates of insomnia are seen in patients diagnosed with chronic insomnia disorder. These linked disorders are common, present in characteristic manners, and are associated with consistent and replicable objective findings that one day may have clinical utility in diagnosis and management. Insomnia is a clear risk factor for new-onset depression and is associated with a persistent and chronic disease course. Early interventions, particularly CBT for insomnia, may improve both sleep disturbance and affective symptoms. Further study of the role of clock genes in both sleep disturbance and mood disorder may shed light on pathogenesis of both disorders. Attention to sleep-related effects of antidepressant pharmacotherapy is imperative for optimizing clinical outcomes. As the relationship between insomnia and depression continues to be elucidated, we will learn more about the etiology, diagnosis, and therapeutic management of both disorders.


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Daniel D. Herrick, MD, is an Assistant Professor of Psychiatry (Sleep Medicine), Geisel School of Medicine, Dartmouth-Hitchcock Sleep Disorders Center. Michael J. Sateia, MD, is an Emeritus Professor of Psychiatry (Sleep Medicine), Geisel School of Medicine, Dartmouth-Hitchcock Sleep Disorders Center.

Address correspondence to Michael J. Sateia, MD, Dartmouth-Hitchcock Sleep Disorders Center, One Medical Center Drive, Lebanon, NH 03756; email:

Disclosure: The authors have no relevant financial relationships to disclose.


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