The link between REM sleep and depression is well-known but not well understood.
While everyone experiences bad relationships, few are as mysterious and troubling as the relationship between rapid eye movement (REM) sleep and depression. While we know that REM sleep and depression are intimately linked, researchers are still trying to understand the intricacies of this troubled relationship.
REM sleep is a component of the sleep cycle characterised by random eye movements, reduced muscle tone, and an increased heart rate. This type of sleep is particularly important because it is associated with memory consolidation. Generally, 20% of total sleep per night should be comprised of REM sleep.
Depression is a chronic and disabling neuropsychiatric disorder associated with feelings of low mood, disinterest, fatigue, cognitive impairment, loss of appetite, low sex drive, and an inability to experience pleasure. This mood disorder is prevalent throughout the population, with 5% of people experiencing depression at a given moment and 20% of people experiencing depression throughout their lifetime. Among other symptoms, sleep disturbances are commonly reported in depressed individuals.
“Sleep recordings show that only REM sleep is altered in depressed patients, while other stages remain unaffected.”
Evidence provided by polysomnography, which measures brain waves, oxygen levels, and heart rate during sleep, show that dysregulation of REM sleep is common in individuals afflicted by depression. Interestingly, analyses of sleep recordings show that only REM sleep is altered in depressed patients, while other sleep stages remain unaffected.
Understanding how REM sleep dysfunction is associated with, and contributes to, the pathology of depression is the focus of much research today.
REM dysregulation in depression
The REM sleep stage is measured in two ways: REM latency and REM density. REM latency describes the time between the onset of sleep and the first REM stage, while REM density refers to the number of eye movements per 30-second epoch of REM sleep. A shortened REM latency, increased REM density, and increased total REM duration are regarded as biological markers of depression.
Not only is REM sleep affected in depression, but it is also a predictor of prognosis. Since patients present with sleep disturbances before displaying other symptoms of depression, these markers can predict the relapse and recurrence of depression. Studies show that patients experiencing a consistently shortened REM latency while in remission are more likely to relapse. Moreover, higher REM densities are associated with treatment-resistant depression.
“Almost all antidepressants selectively suppress REM sleep as an unintended side effect.”
The most convincing evidence to suggest that REM dysregulation is associated with the onset of depression is provided by the understanding of antidepressants. Almost all antidepressants, which have varying mechanisms of action, selectively suppress REM sleep as an unintended side effect. Furthermore, a rebound increase in REM sleep is seen after abrupt drug discontinuation.
The relationship between REM sleep and depression is further strengthened by studies that show an association between REM sleep and negative emotions. For example, REM density may be associated with depressive symptoms including self-harm, suicidal thoughts, and difficulties concentrating.
A study conducted by McNamara and colleagues shows that patients produced negative memories quicker after REM sleep awakenings compared to non-REM sleep awakenings. Moreover, dreams during REM sleep tend to be more negative and aggressive than those during non-REM sleep. The mechanisms underlying these findings are yet to be elucidated. Nonetheless, there are several existing models which aim to partially explain the apparent correlation between REM sleep and symptoms of depression.
Models of the relationship between REM sleep and depression
The two-process model
The two-process model of sleep was first proposed by Borbély and describes how sleep-wake regulation is controlled by two processes: process S and process C. Process C refers to the circadian control of the sleep-wake cycle. The circadian control of the sleep-wake cycle describes the internal mechanisms occurring during a 24-hour cycle responsible for the transitions between periods of wakefulness and sleep. Process S is the homeostatic process and describes how prolonged periods of wakefulness increases sleep pressure. This means the longer one is awake, the deeper their subsequent sleep. The propensity to sleep is controlled by the interaction between these two processes.
Borbély claims that depressed patients experience insufficient process S, which leads to their symptoms through disinhibition of REM sleep. Slow wave sleep (SWS) occurs during non-REM sleep and is a restorative and deep sleep associated with high sleep intensity and quality. Insufficient process S reduces the need for SWS, meaning REM occurs earlier, leading to a shortened REM latency. The mechanisms for how insufficient process S causes the onset of depressive symptoms remain to be elucidated, but changes to the prefrontal cortex may be involved.
One possible method for treating process S difficulties in patients with depression is wake therapy. Wake therapy involves 36-hour periods of sleep deprivation to treat depression. The two-process model suggests that this antidepressant effect is due to the prolonged wakefulness increasing the level of process S. It is estimated that 50% of depressed patients respond positively to wake therapy.
The phase-advance model
Contrastingly, the phase-advance model proposed by Papoušek in 1975 argues that REM dysregulation in depression occurs due to disturbances of the circadian rhythm. This model postulates that, in depressed patients, the pacemaker controlling REM sleep occurs too early. This is supported by symptoms such as early morning awakenings and shortened REM latencies seen in depressed patients. Moreover, it was found that depressed patients experience elevated moods when the onset of sleep is advanced to the afternoon, instead of sleeping at night. In doing this, the pacemakers controlling REM sleep and the time of sleep onset are in sync, ultimately eliminating the shortened REM latency.
These findings suggest that depressive symptoms could be caused by a mismatch between the onset of sleep and the onset of REM sleep. This notion is further supported by genetic analyses which show that variation in the four main genes responsible for the control of the circadian rhythm are associated with an increased susceptibility to depression.
Cholinergic-aminergic imbalance theory
Neurotransmitters, such as monoamines, are also implicated in REM sleep regulation and depression. The classical monoamine theory of depression postulates that depression is caused by the depletion of serotonin, dopamine, and noradrenaline in the central nervous system. The cholinergic-aminergic imbalance hypothesis improves this theory and suggests that the hypoactivity of monoamines is countered by hyperactive acetylcholine neurotransmission.
Acetylcholine is a neuromodulator which plays key roles in attention, arousal, motivation, and learning. Importantly, acetylcholine also plays a role in mediating the onset of REM sleep. In contrast, monoamines promote the onset of non-REM sleep. As a result, the depletion of monoamines, coupled with the hyperactivity of acetylcholine, in depression can have serious implications for REM sleep.
It has been shown that chronic administration of drugs that increase cholinergic activity induces depressive symptoms in healthy volunteers. These symptoms include a lack of energy and an inability to experience pleasure. In volunteers who are vulnerable to depression, these drugs were able to induce chronic symptoms of depression, including shortened REM latency. It is believed this disinhibition of REM sleep is caused by an imbalance of cholinergic and aminergic neurotransmission in the brainstem, the area of the brain which is responsible for many subconscious functions such as breathing. Furthermore, drugs blocking acetylcholine receptors, such as scopolamine, exert antidepressant effects.
Orexinergic theory
Another model postulates that abnormalities in sleep-wake regulation may be involved in the pathophysiology of depression. Orexin is a neurotransmitter responsible for the transition between periods of wakefulness and sleep. Narcolepsy is a disabling condition associated with the selective loss of orexin neurons. This condition involves the spontaneous transition from periods of wake to periods of REM sleep. This means narcolepsy patients experience a shortened REM latency, similarly to patients suffering from depression. Interestingly, 57% of narcolepsy patients experience depression independent of the debilitating nature of their condition.
Orexin interacts with the locus coeruleus and the dorsal raphe nucleus, the centres for the secretion of noradrenaline and serotonin, respectively. Since these two monoamines play a key role in the regulation of mood and sleep, alterations in the neurotransmission of orexin may result in both REM sleep dysregulation and mood dysfunction.
Allostatic load theory
A final theory outlining the relationship between REM and depression involves allostasis—the process of adapting to acute stress. The allostatic load theory attempts to describe how stress could be the link between REM sleep dysregulation and symptoms of depression. Receptor desensitisation is the decreased responsiveness of a receptor after repeated activation. It is well understood that monoamine receptor desensitisation is a consequence of chronic stress and can lead to the onset of depression.
“Sleep dysfunction might not only be a consequence of mental illness, but also an inciting force”
It has also been shown that chronic stress increases total REM sleep duration and REM sleep density, while reducing REM sleep latency. These observations, consistent with those seen in depression, appear to link the onset of depression with the beginning of REM sleep abnormalities. This suggests that stress may be the missing link connecting REM sleep dysregulation and the onset of depression. The amygdala is a part of the brain involved in the modulation of emotional responses such as stress, fear, and anxiety, and is particularly active during REM sleep. The effects of stress and allostatic load on mood and sleep are likely to be mediated by a hyperactive amygdala, but this remains to be elucidated.
Studies investigating the allostatic load theory also point the potential of a bilateral relationship between sleep and depression. Many studies use sleep deprivation as a stressor to investigate the onset of depression. Experiments in rats show that prolonged sleep deprivation leads to neurobiological changes reflective of those observed in depression. In other words, sleep dysfunction might not only be a consequence of mental illness, but also an inciting force in the pathogenesis of depression.
These observations demonstrate how intricately linked REM sleep and depression truly are. It is undebatable that the relationship between REM sleep and depression is present, but unclear. Several models attempt to explain the link between REM sleep and depression. Nonetheless, further investigation is required to uncover the full neuronal pathways linking dysregulation of REM sleep and mood disorders. Novel studies may try to combine several of these theories to determine if there are multiple pathways involved. Understanding this troubled relationship between REM sleep and depression is vital for improved prevention and treatment of mood disorders.
