A Quadruple Relationship: Sleep, Immune System, Inflammation and Psychiatric Disorders


Mesut Cetin, Feyza Aricioglu





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A Quadruple Relationship: Sleep, Immune System, Inflammation and Psychiatric Disorders


Mesut Cetina, Feyza Aricioglub


a Editor-In-Chief of Psychiatry & Clinical Psychopharmacology, Istanbul, Turkey;

b Academic Editor of Psychiatry & Clinical Psychopharmacology, Department of Pharmacology and Psychopharmacology Research Unit, School of Pharmacy, Marmara University, Istanbul, Turkey



Sleep is an important part of life and its quality is indispensable to a number of brain functions, including communication of neurons and therefore maintenance of brain health. Several studies have systematically demonstrated adverse effects when sleep behavior is compromised. Inadequate amount of sleep may cause: emotional and cognitive impairment. Sleep is regulated by the circadian system that times daily sleep which is driven by an internal timing system. Clock genes control rhythms in physiology and behavior which are associated with sleep and wakefulness and transcriptional level of them leads the gene networks that are released with a 24-hour cycle (1).  It has been accepted that disruption of circadian rhythms is associated with sleep disorders, and some chronic diseases including infectious diseases, autoimmune diseases, metabolic syndrome, neurodegenerative diseases. It is also highlighted that coordination between circadian clock of immune response through innate and adaptive immune cells and a regulatory layer relative to circadian clock. Inflammation based disorders such as infections can disrupt the circadian clock and reduce the amplitude of circadian rhythms significantly. Results obtained from autoimmune disease models neuroinflammation and demyelination may be due to an increase in pathogenic T lymphocytes showing the involvement of inflammation (2).  

Sleep is known to play an important role in immune function. However, the effects of sleep quality during hospitalization for COVID-19 remain unclear was investigated in a retrospective, single-center cohort study. It was conducted to investigate the effects of sleep quality on recovery from lymphopenia and clinical outcomes in hospitalized patients with laboratory-confirmed COVID-19. It has been found that poor sleep quality during hospitalization in COVID-19 patients with lymphopenia is associated with a slow recovery from lymphopenia and an increased need for ICU care (3).

It has been accepted that sleep problems are the most prominent symptom among with psychiatric disorders including major depressive disorder (MDD), bipolar disorder (BD), generalized anxiety disorder, post-traumatic stress disorder (PTSD), schizophrenia etc. In approximately 90% of depressive patients have some types of sleep disorder (sleep apnea syndrome, insomnia, parasomnias, restless legs syndrome etc.). Therefore, psychiatric disorders have an impact on sleep, sleep disorders have an impact on psychiatric conditions, treating sleep disorders.  MDD has been associated with the decreased REM sleep latency.   Transition into REM sleep is accompanied by a rapid decrease in monoamines such as serotonin [5‐HT], norepinephrine [NE] and dopamine and an increase in cholinergic activity. It is known that bi-directional interaction of cholinergic and monoaminergic neurons regulates the onset of REM sleep and main cause of depression is significant reduction of monoaminergic neurotransmitters (mainly 5‐HT and NE) (4-6).  

About 80 percent of depressive patients suffer from impaired sleep which show characteristic sleep-EEG changes such as impaired sleep continuity, disinhibition of REM sleep and changes in non-REM sleep. In the hypothalamus, the suprachiasmatic nucleus (SCN) which increases production of the hormone melatonin in order to trigger sleep is important for matching the body’s circadian rhythm to the external cycle of light and darkness through pineal gland. In communication with the brain stem, especially the pons and medulla, thalamus, cerebral cortex, basal forebrain and midbrain regulates sleep and wakefulness whereas the amygdala is involved in sleep more related with the mood (4). 

Recent accumulating data support a key role of gut microbiota, food intake and pathogen-associated molecular patterns (PAMPs) in triggering production of inflammatory mediators causing sleep changes. Environment, including stress, physical activity, and food intake can increase in endogenous danger/ damage-associated molecular patterns (DAMPs) production in brain, CSF and blood which can activate the immune system through pattern recognition receptors (PRRs).  PAMPs and DAMPs are involved in inflammatory response which may increase inflammatory mediators up to detectable level in the circulation and may lead low-grade inflammation. This kind of low-grade inflammation can be measured by various parameters lead two to three-fold elevation of C-reactive protein (CRP), IL-6, WBC, neutrophil and platelet counts. Low-grade inflammation is highly correlated with insulin resistance, endothelial dysfunction, atherosclerosis, and neuroinflammation and reflects to behavioral changes. Findings regarding role of PRRs in regulation of sleep is through Toll-like receptors (TLRs) and Nod-like receptors (NLRs). Activation of these receptors may lead increase of pro-inflammatory cytokines such as TNF and IL-1, causing changes in sleep regulation and especially increase in NREM sleep amount (7). 

On the other hand, in case of chronic inflammatory such as rheumatoid arthritis or infectious diseases  (eg,HIV)   the type of immunopathology frequently occurs in conjunction with comorbid conditions, highly related with sleep such as depression, anxiety, obesity, cardiovascular disease, and pain. The activation of the immune system is a response to acute or physical stressor which is a result of hypothalamus-pituitary-adrenal (HPA) axis activation which can be mediated by inflammatory mediators, including cytokines that signal to the brain. In this condition the response of CNS can be characterized with symptoms of sickness including fever, fatigue, sleepiness, social withdrawal, depressed mood, pain hypersensitivity, and decreased appetite (8). Lack of sleep in the form of short sleep duration or sleep disturbance appears to be a behavioral trigger of low-grade inflammation and related diseases (9). However, inflammatory balance is of great importance in evaluating the interaction between sleep and the immune system. Studies investigating the role of gender in the relationship between sleep and the immune system also show that insomnia complaints in women are more common and severe than men, and this dominance occurs after late adolescence. Autoimmune diseases such as rheumatoid arthritis, chronic pain such as fibromyalgia, and neurodegenerative diseases such as Alzheimer's disease are more common in women than men, and can also occur and progress differently between the sexes. With regard to infectious diseases, females have a higher influenza A infection mortality rate, a higher risk of developing AIDS, and stronger vaccine responses than males (10).   

Conversely, about 50% of patients with RA report sleep disturbances, including symptoms such as difficulties falling asleep and maintaining sleep, non-improvement sleep, and excessive daytime sleepiness (11). Also, the night and morning after complete sleep deprivation or restriction, NK cell activity is reduced in healthy humans. It is suggesting that sleep has a supportive effect on this functional immune parameter (12). Perhaps as evidence for this we can show a meta-analytical study of 40 prospective cohort studies involving more than 2 million participants. This study reported that shorter sleep times (<7 hours) in women and longer sleep times (> 8 hours) in both women and men were associated with increased all-cause mortality (13).  

Melatonin is widely used as an off-label drug to improve sleep. Although findings showed that exogenously given melatonin can reduce sleep onset time in insomnia patients, therapeutic value of melatonin for the treatment of primary insomnia or psychiatric comorbid conditions requires further research (4).

Most antidepressant drugs suppress REM sleep which is characterized by prolonged REM latency, reduced time spent in REM sleep, and decreased REM density. Antidepressant drugs differ in the potency of suppressing REM sleep. When an antidepressant drug withdrawn after two weeks of treatment REM rebound may occur. REM suppression occurs after almost all antidepressant drugs including tricyclics, tetracyclics, selective serotonin reuptake inhibitors (SSRIs), selective noradrenaline reuptake inhibitors (NRI), selective serotonin and noradrenaline reuptake inhibitors (SNRI), and monoamine oxidase inhibitors. Clomipramine and the irreversible monoamine oxidase inhibitors phenelzine and tranylcypromine can cause total REM suppression. Very limited number of antidepressants do not effect REM sleep such as imipramine, trazodone, bupropion, the serotonin reuptake enhancer tianeptine and the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine (4,6).

The pharmacological treatment of insomnia mainly based on both benzodiazepines [BZDs](lorazepam, triazolam, flurazepam, nitrazepam, diazepam, oxazepam) and nonbenzodiazepines/ Z‐drugs (zaleplon, eszopiclone and zolpidem) hypnotics besides antidepressants. BZDs has been gradually being replaced by Z-drugs due to their better effect and low negative consequences compared with BZDs. However, recent findings show a significant relationship between zolpidem use and suicide in people with or without comorbid mental disorders which was considered as alarm and usage of Z-drugs made to think that its use should be restricted. Further randomized controlled trials are required to verify its safety. The other issue with sedative‐hypnotic drugs are tolerance and exacerbating sleep disturbances and that’s why they mostly prescribed at possible lowest dose for insomnia patients (4,8).

Adequate and high quality sleep is a basic biological need which helps maintaining immune health. In case of chronic lack of sleep, the risk of immune dysfunction and several comorbidities such as cardiovascular, metabolic, autoimmune and neurodegenerative diseases and inflammation can increase significantly (6,8). During COVID-19 pandemic whole word learned once more how important the time and duration of sleep for strong immune system. Undoubtedly, in the treatment of sleep disorders, there is a need for new treatment algorithms / drugs that may have positive effects on the inflammation process and/or immune system while regulating sleep.




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