REM Rebound Effect

Etiology

Researchers hypothesize that REM sleep provides an ideal environment for recontextualizing negative experiences and regulating emotional reactivity, as the typical stress response is subdued during this stage. In one study, participants showed reduced negative reactions to images of fearful faces and enhanced positive responses to happy faces after a 90-minute nap.[7] REM sleep deprivation and exposure to stress can alter hormone release via the hypothalamic-pituitary-adrenal (HPA) axis and affect neurotransmitter levels.[6] These alterations in signaling mechanisms lead to decreased sleep duration and quality and increased periods of wakefulness, which ultimately contribute to the development of insomnia.[3] 

Sleep research in rats exposed to various forms of physical stress reveals disruptions in the HPA axis and sympathetic response systems, particularly in the locus coeruleus and adrenal medulla. While rat models offer valuable insights into the effects of physical stress, the most significant stressors for humans tend to be social, including challenges related to family, work, and interpersonal relationships.[3]

In addition to sleep deprivation and stress, REM rebound can occur when individuals discontinue REM-inhibiting drugs. Patients who discontinue using benzodiazepines, barbiturates, certain antidepressants, some antipsychotic medications, and cannabis may experience REM rebound. Alcohol suppresses REM sleep during the early part of the night, often resulting in REM rebound later on. Cocaine is also known to suppress REM sleep.

In obstructive sleep apnea (OSA), recurring episodes of upper airway obstruction and oxygen desaturation lead to sleep fragmentation. Arousal is often required to restore breathing by reopening the obstructed airway. The sleep architecture of OSA is characterized by increased N1 and N2 sleep stages, with a reduction in slow-wave sleep (SWS) and REM sleep. Positive airway pressure (PAP) therapy is the standard treatment for OSA, maintaining the airway through positive pressure ventilation during sleep. Many patients experience REM rebound when starting PAP therapy, as both SWS and REM sleep increase following sleep fragmentation and deprivation.[8] 

Patients with major depression often show reduced SWS, shortened REM sleep latency, and increased REM sleep duration. Antidepressants, including tricyclics, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors, typically reduce the duration of REM sleep.[9] Given the benefits of REM sleep, REM rebound may act as an adaptive strategy to restore balance in the sleep cycle. The inability to initiate this compensatory response could result in potentially significant adverse consequences, affecting both physical and mental well-being.[3]

Epidemiology

Given the widespread prevalence of sleep deprivation and stress, REM sleep rebound is common both in the United States and globally. Data from the Centers for Disease Control and Prevention (CDC) indicate that over one-third of the US population experiences sleep deprivation, defined as receiving fewer than 7 hours of sleep per night.[10] According to the CDC, 37% of men, 39% of adults aged 45 to 64, and 49% of Native Hawaiian or Pacific Islander adults do not get adequate sleep.

Adequate sleep is essential for physical health and overall well-being, though the exact prevalence of chronic sleep deficiency within the population remains to be accurately quantified.[11] Recent studies show that average nightly sleep duration has decreased by about 1 hour globally over the past century, with the most significant reductions occurring in highly industrialized areas such as Europe, North America, and Asia.[12]

Inadequate sleep is associated with the onset of various health conditions, raising significant national and global concerns. These conditions and their associated comorbidities include obesity, metabolic disorders, hypertension, coronary artery disease, stroke, depression, anxiety, motor vehicle and workplace accidents, immunosuppression, declining renal function, medical errors, diminished quality of life, and reduced work productivity.[3][10]

Pathophysiology

Sleep is regulated by various neuropeptide and neurotransmitter systems located primarily in the brain stem and hypothalamus.[6] Bursts of pontine-geniculate-occipital (PGO) cortical waves, which are linked to theta activity in the hippocampus, form a key part of the EEG profile during REM sleep.

Circadian and Homeostatic Rhythms 

Sleep is regulated by 2 primary mechanisms—homeostatic and circadian. The homeostatic drive, known as "process S," pertains to the physiological urge for sleep, also called sleep pressure. Circadian rhythms, referred to as "process C," synchronize with the natural light/dark cycle to regulate sleep onset. They also function as a timing system that regulates alertness levels. Sleep is initiated through the interaction of 2 mechanisms—the accumulation of sleep pressure and alignment with the circadian rhythm cycle, which governs the natural timing of sleep. The suprachiasmatic nucleus collaborates with the pineal gland to release melatonin in response to the light-dark cycle. This synchronized process is key to inducing sleep.[6] 

Sleep homeostasis is influenced by the duration and quality of prior wakefulness.[6] The severity of sleep deprivation correlates with increasing compensatory changes in sleep architecture. Shorter periods of deprivation, up to 6 hours, result in increased non-REM sleep. In contrast, prolonged deprivation lasting 12 to 24 hours leads to increases in both non-REM and REM sleep. When sleep deprivation extends to around 96 hours, individuals primarily exhibit a marked increase in REM sleep and experience REM rebound.[6]

The Hypothalamus-Pituitary-Adrenal Axis and Sleep

The HPA axis and its associated hormones—including cortisol, adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), growth hormone-releasing hormone, and melatonin—play a key role in regulating sleep duration, onset, and the distribution of sleep stages throughout the night. Cortisol activity significantly decreases during the first half of the night, reflecting the inhibitory phase of the HPA axis. As the night advances and REM sleep becomes more prevalent, the inhibitory effects of the HPA axis diminish, resulting in a gradual increase in the levels of the adrenal hormone cortisol. In the latter part of the night, there is a rise in the secretion of cortisol, CRH, and ACTH, alongside increased sympathetic nervous system activity. Elevated cortisol levels and extended REM sleep characterize the final sleep cycle of the night.

Patients with Addison disease, a form of primary adrenal insufficiency, often show increased non-REM sleep and decreased REM sleep, which improves with glucocorticoid replacement therapy. Conversely, individuals with Cushing syndrome, characterized by excess cortisol, typically experience reduced non-REM sleep, increased REM sleep, and fragmented sleep cycles.[6] CRH, when administered intravenously, triggers REM rebound and increases non-REM sleep while simultaneously promoting wakefulness, thereby reducing the ability to recover from sleep deprivation.[3][13] ACTH also promotes wakefulness during both the light and dark phases of the circadian rhythm.[3] Corticotropin-like intermediate peptide, derived from proopiomelanocortin, is associated with the induction of prolonged REM sleep episodes.[6]

Prolactin

Prolactin, an essential neurotrophic hormone secreted by the pituitary gland, is vital in facilitating REM rebound and averting stress-induced reductions in neurogenesis. Several studies have elucidated the role of prolactin in inducing REM sleep and regulating the phenomenon of stress-induced REM sleep rebound. In these experiments, prolactin microinfusions into the dorsal raphe nucleus demonstrated the hormone's ability to induce REM sleep. Additionally, anti-prolactin antibodies have been shown to inhibit REM sleep in rats, further supporting the connection between prolactin and REM sleep.[4][6]

Neurotransmitters

Acetylcholine levels in the cortex peak during REM sleep. Compounds that enhance cholinergic transmission can induce REM sleep, as can the loss of cholinergic neurons. Some γ-aminobutyric acid (GABA)/galaninergic neurons also express c-Fos during REM sleep, indicating their activity during this phase. 

Serotonin, or 5-hydroxytryptamine (5-HT), plays a crucial role in regulating aspects of sleep, including REM sleep and wakefulness, which inhibits REM sleep and helps maintain alertness. Specific neurons in the brainstem produce serotonin and noradrenaline, which inhibit cholinergic neurons in the pons. These cholinergic neurons are essential for initiating REM sleep by activating the glutamatergic sublaterodorsal nucleus.

An abnormal increase in serotonin activity, induced by selective SSRIs, can lead to the loss of muscle atonia during REM sleep, a condition known as REM sleep without atonia.[14] Abrupt discontinuation of serotonergic antidepressants often results in REM rebound, which is frequently characterized by vivid dreams.[15] Empirical evidence suggests a correlation between the duration of REM rebound, elevated plasma prolactin levels, and serotonin levels in the hypothalamus. Serotonin stimulates prolactin release, and in turn, prolactin activates cholinergic neurons within the mesopontine tegmental region of the brain, a critical area for initiating REM sleep.[3]

History and Physical

A thorough clinical assessment is crucial for identifying sleep disturbances and pathologies that might lead to REM rebound. A comprehensive sleep history should be obtained, covering aspects such as sleep habits, snoring, restlessness, sleep duration, onset, dreaming, difficulties waking up, interruptions in sleep maintenance, issues with staying awake, and overall sleep quality. A significant symptom suggesting REM rebound is experiencing prolonged vivid dreams without any specific pharmacological causes. Patients might also report waking up feeling disoriented and confused and experiencing headaches.

Healthcare providers should consider factors such as the patient’s medical history, including past illnesses, neurological and psychiatric conditions, medications, substance use, and family history. This information is essential for identifying potential causes of sleep disturbances and determining if any comorbidities require further evaluation.

A thorough physical examination can uncover signs of respiratory, cardiac, gastrointestinal, endocrine, or neurological disorders that affect sleep. Relevant findings might include obesity, increased neck circumference, hypertension, enlarged tonsils and adenoids, and signs of respiratory or cardiac issues. Subjective sleepiness can be assessed using tools such as the Stanford Sleepiness Scale [16] or the Epworth Sleepiness Scale.[17]

Evaluation

Laboratory tests, including drug screening, may be necessary to evaluate medical, psychiatric, and neurological conditions that cause or contribute to sleep disturbances, as well as to assess the sleep disturbance itself.

In routine clinical settings, isolated evaluation for REM rebound is generally unnecessary. Additional evaluation is warranted if the patient's history or physical examination raises concerns for other sleep disorders. While REM rebound itself does not necessarily indicate an underlying sleep disorder, individuals with conditions such as parasomnias, narcolepsy, or OSA often experience disruptions in their sleep patterns, which can lead to REM rebound.

Assessment of contributing sleep disorders may involve a range of diagnostic tools, including overnight polysomnography (PSG), the Multiple Sleep Latency Test, the Maintenance of Wakefulness Test, actigraphy, and video-PSG. Additional studies may include upper airway imaging to detect potential obstructions, neuroimaging for suspected neurological conditions, pulmonary function tests for suspected respiratory issues, human leukocyte antigen testing for suspected narcolepsy, serum iron and ferritin levels for restless legs syndrome, and electromyography and nerve conduction studies for evaluating restless legs syndrome. An overnight PSG study is essential for evaluating patients with suspected sleep disorders. An overnight PSG is preferred over a single-day nap study, as it provides a complete assessment of sleep architecture, including REM sleep, which a nap study might miss.

Treatment / Management

REM rebound itself is not pathological but rather a homeostatic response to sleep deprivation or shift work, highlighting the importance of REM sleep. While REM rebound does not inherently signify an underlying sleep disorder, individuals with conditions like parasomnias, narcolepsy, or OSA often experience disrupted sleep patterns that lead to REM rebound. If an underlying sleep disorder is suspected, diagnosis and treatment should be pursued. Evidence suggests that addressing sleep disturbances can enhance REM sleep as long as high-quality sleep effectively alleviates REM pressure.

Implementing sleep hygiene techniques can improve overall sleep quality; however, evidence supporting their effectiveness in specifically addressing REM rebound—particularly in the absence of insomnia—is limited.[18] Sleep hygiene components may include behavioral modifications, adjustments to environmental factors, and stress reduction.[19]

Respiratory, cardiac, gastrointestinal, endocrine, psychiatric, and neurological disorders that affect sleep and potentially cause REM rebound should be diagnosed and treated. Medications or substances that might contribute to REM rebound should be adjusted as necessary to minimize their impact on REM sleep.

Differential Diagnosis

REM rebound is a clinical phenomenon associated with a broad spectrum of clinical conditions, including sleep deprivation, insomnia, psychosocial stress, medical disorders, psychiatric or neuropsychiatric disorders, parasomnias, OSA, narcolepsy, medication withdrawal, substance use, and shift work.

OSA leads to poor sleep quality in patients. The gold standard for diagnosing OSA is overnight PSG, and the most effective treatment is overnight CPAP.[20] A meta-analysis comparing OSA treatments shows no significant difference in outcomes between CPAP and bilevel-PAP. Nevertheless, treatment compliance remains a significant challenge for all OSA treatments, with the exception of surgical interventions. REM sleep rebound following initial OSA treatment is associated with improved sleep quality and elevated mood. Please see StatPearls' companion resource, "Obstructive Sleep Apnea," for more information.[21]

Patients with REM sleep behavior disorder (RBD) require additional assessment. Individuals with RBD seem to be acting out dreams due to a lack of muscle atonia during REM sleep. Dream reenactment may occur during periods of heightened emotional distress or withdrawal from medications or substances. Individuals with RBD are at risk of developing Parkinson disease or dementia with Lewy bodies later on. 

Toxicity and Adverse Effect Management

Various psychotropic medications can significantly impact sleep architecture, influencing the likelihood of experiencing REM rebound. For example, benzodiazepines suppress REM sleep, potentially leading to REM rebound upon discontinuation or withdrawal.[22] Barbiturates and alcohol have similar effects. In contrast, newer hypnotic sleep aids, such as zolpidem, do not typically cause REM rebound after discontinuation. After the sudden discontinuation of serotonergic antidepressants, patients may experience prolonged and intense dreams, along with symptoms indicative of REM rebound.[23]

Withdrawal from substances such as tetrahydrocannabinol, cocaine, heroin, and stimulants leads to significant REM rebound, indicating a compensatory adjustment toward sleep homeostasis following the discontinuation of these substances.[24]

Prognosis

The prognosis for resolving REM rebound is generally favorable, provided that any underlying medical, neurological, or psychiatric disorders, as well as sleep disorders, are effectively addressed. Restoring normal sleep architecture and managing contributing factors to sleep disturbances are key to resolving REM rebound phenomena.

The timeline for resolving REM rebound varies depending on the individual and the specifics of their sleep disorder. Maintaining good sleep hygiene and seeking appropriate medical, neurological, and psychiatric interventions can significantly aid recovery. If underlying issues are not effectively addressed, they may intermittently trigger REM rebound and its associated symptoms, potentially leading to recurrent cycles of poor sleep.

Complications

Sleep deprivation leads to increased sleepiness and impairs performance, vigilance, attention, and concentration, affecting both short- and long-term memory. Numerous studies highlight the significant adverse effects of poor sleep quality and deprivation on mental health. Insufficient sleep can have detrimental impacts on mood and emotional regulation. Research indicates that individuals who are sleep-deprived often show heightened irritability, anxiety, and depression.[3] Furthermore, they may experience increased emotional reactivity to negative stimuli and a diminished capacity to find pleasure in positive experiences.

Conversely, chronic sleep problems are often associated with mental health disorders. For instance, insomnia is highly prevalent among individuals with major depressive disorder, generalized anxiety disorder, and posttraumatic stress disorder (PTSD). A recent study has demonstrated a negative correlation between the duration of REM sleep episodes and the development of PTSD following traumatic events, suggesting that increased REM sleep may have a protective effect against the adverse impacts of stress.[25]

The relationship between sleep disturbances and mental health disorders is often bidirectional, meaning each can exacerbate the other, forming a vicious cycle that can be challenging to disrupt. Sleep is crucial for memory consolidation—a process where the brain stabilizes and integrates memories for long-term storage. As REM sleep is believed to have a key role in consolidating procedural and spatial memories, sleep deprivation can impair the ability to remember new information.

Inadequate sleep is linked to several physical health problems, increasing the risk of heart disease, diabetes, obesity, and weakened immune function. Maintaining good sleep hygiene and seeking appropriate treatment for sleep disorders are crucial for overall health and well-being.[3]

Nearly all antidepressants decrease REM sleep, and certain antipsychotic medications can almost completely suppress REM sleep. This raises questions about the complex relationship among psychiatric symptoms, REM sleep deprivation, and medication-induced weight gain.[26] Research indicates that regular REM sleep may help reduce the risk of obesity. The absence of the final REM period (fREMP) could increase appetite, potentially leading to excessive calorie intake and subsequent weight gain in individuals experiencing chronic sleep deprivation.[26]