Introduction Title: Sleep-Wake Cycles in Major Depressive Disorder: A Literature Review

Literature Review 702

Introduction Title: Sleep-Wake Cycles in Major Depressive Disorder: A Literature Review

Background: A significant barrier to effectively preventing and intervening in depressive disorders among young people is the limited comprehension of their underlying causes. One promising area of investigation is the potential role of disruptions in the 24-hour sleep-wake cycle and the circadian system. Evidence shows that abnormalities in circadian rhythms are prevalent in adults with depressive disorders and are linked to key symptoms such as mood instability, chronic fatigue, non-restorative sleep, decreased physical activity, and fluctuations in appetite and weight https://pubmed.ncbi.nlm.nih.gov/34419186/

This Literature review aims to summarise four areas of research on sleep wake cycles in Major depressive disorder: 1) the Neurobiology of sleep-wake cycles and sleep stages. 2) Overview of sleep-wake cycle disorders in youth and how REM sleep disturbances are linked to the pathophysiology of Major depressive disorder (MDD)? 3) How Delayed sleep disturbances are related to the pathophysiology of MDD in Youth? 4) What treatments are available and what are the novel approaches to improve sleep-wake disturbances that would have potential to improve MDD symptoms.

Introduction: Changes in sleep neurophysiology are often observed in depressive patients, and impaired sleep is, in many cases, the chief complaint of depression. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433686/

Purpose of this research: In the past, sleep disturbances were always regarded as a concomitant of depression, and sleep problems were seldom a treatment target given the general assumption that sleep disturbances would resolve as an associated symptom with the treatment of depression. Recently, there has been a great deal of evidence suggesting that sleep disturbances precede depression.5,6Depressed patients with sleep disturbance are likely to present more severe symptoms and difficulties in treatment https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433686/

The findings of this research will underscore the stringent need to prioritise prevention by properly handling sleep disturbance before depression occurs.

Body:

Sleep- wake cycles

REM disturbance research

Major depressive disorder has been associated with the disruption of REMS.36,37The transition into REM sleep is accompanied by a rapid decrease in monoamines (eg serotonin [5HT], norepinephrine [NE] and dopamine) and a concomitant increase in cholinergic tone.38Thus, the mutual effect of cholinergic and monoaminergic neurons regulates the onset of REM sleep.39Regarding the pathophysiology of depression, the monoamine hypothesis is the most known hypothesis, which assumes that alterations in the levels of monoamines are the cause of depression. In patients diagnosed with MDD, levels of serotonin metabolites and NE are decreased, and abnormal genetic regulation of serotonergic transmission has been observed.40,41These monoamine neurotransmitters do not operate in isolation but are integrally interconnected.42INotably, the dysregulation of these same monoamine neurotransmitters that are responsible for the REM sleep abnormalities, is also related to the presentation of depression. However, some studies have found that there is no causal relation between REM sleep abnormalities and depression, which indicates that there may be two or more parallel pathways for the regulation of REM sleep and depression.44The role of monoamines and other related neurotransmitters should be better elucidated for understanding the association between sleep and depression.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433686/1

Pineal gland suprachiasmatic nucleus(SCN) and melatonin production: The pineal gland is located at the back of the brain and is an endocrine gland crucial for regulating the sleep-wake cycle. One of the important functions of SCN is also regulating sleep-wake cycles. Light information from the eyes is sent to SCN, which acts as the body's internal clock and its main function is to regulate the sleep-wake cycle. This information is then relayed to other parts of the hypothalamus.

When light is present, the SCN releases gamma-aminobutyric acid (GABA), inhibiting neurons in the hypothalamus's paraventricular nucleus (PVN). This inhibition stops the signal to the pineal gland, preventing melatonin production. Conversely, in darkness, the SCN releases glutamate, which activates the PVN and sends the signal to the pineal gland to produce melatonin.

https://pubmed.ncbi.nlm.nih.gov/31768006/

Melatonin levels in the blood are low during the day and increase at night, with the duration of melatonin production depending on the length of darkness. The enzyme serotonin N-acetyltransferase (NAT) is crucial for this process, as it converts serotonin into melatonin. NAT activity is low during the day and increases at night. Serotonin, derived from the amino acid tryptophan, is first converted into N-acetyl serotonin by NAT and then into melatonin. Melatonin then binds to G-protein coupled receptors found in the SCN, retina, pineal gland, and other tissues, helping regulate the sleep-wake cycle and other biological rhythms. https://www.ncbi.nlm.nih.gov/books/NBK550972/Sleep Stages

There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep (which has three different stages). Each is linked to specific brain waves and neuronal activity. You cycle through all stages of non-REM and REM sleep several times during a typical night, with increasingly longer, deeper REM periods occurring toward morning.

Stage 1non-REM sleep is the changeover from wakefulness to sleep. During this short period (lasting several minutes) of relatively light sleep, your heartbeat, breathing, and eye movements slow, and your muscles relax with occasional twitches. Your brain waves begin to slow from their daytime wakefulness patterns.Stage 2non-REM sleep is a period of light sleep before you enter deeper sleep. Your heartbeat and breathing slow, and muscles relax even further. Your body temperature drops and eye movements stop. Brain wave activity slows but is marked by brief bursts of electrical activity. You spend more of your repeated sleep cycles in stage 2 sleep than in other sleep stages

Stage 3non-REM sleep is the period of deep sleep that you need to feel refreshed in the morning. It occurs in longer periods during the first half of the night. Your heartbeat and breathing slow to their lowest levels during sleep. Your muscles are relaxed and it may be difficult to awaken you. Brain waves become even slower.

REM sleepfirst occurs about 90 minutes after falling asleep. Your eyes move rapidly from side to side behind closed eyelids. Mixed-frequency brain wave activity becomes closer to that seen in wakefulness. Your breathing becomes faster and more irregular, and your heart rate and blood pressure increase to near-waking levels. Most of your dreaming occurs during REM sleep, although some can also occur in non-REM sleep. Your arm and leg muscles become temporarily paralyzed, which prevents you from acting out your dreams. As you age, you sleep less of your time in REM sleep. Memory consolidation most likely requires both non-REM and REM sleep.

https://www.ninds.nih.gov/health-information/public-education/brain-basics/brain-basics-understanding-sleephttps://www.sciencedirect.com/science/article/abs/pii/S0165032724009157Jet Jag disorderYouve recently traveled to a different time zone, which takes you out of sync with the day/night schedule youre used to.

Shift work sleep disorder (SWSD You have trouble adjusting your circadian rhythm to your work schedule. Youre more prone to this if you work night shifts.

Delayed sleep-wake phase disorder(DSWPD).Your sleep/wake schedule is much later than the average person. Its more common in children and teenagers.

Advanced sleep-wake phase disorder (ASWPD).You go to bed earlier and wake earlier than the average person.

Irregular sleep-wake rhythm disorder (ISWRD).Your sleep and wake times happen at unpredictable, disorganized intervals. This usually happens to people withdementiaor otherdegenerative brain diseases.

Non-24-hour sleep-wake rhythm disorder (N24SWD).Your circadian rhythm is predictable, but it isnt 24 hours like most peoples. Its usually longer, but it could be shorter.

Sleep disturbances are common in major depressive disorder (MDD). More than 90% of patients with MDD have sleep disturbances (1). Previous polysomnography studies in MDD patients have observed shortened REM sleep latency, increased REM density, and decreased slow wave sleep (2). Sleep disturbances were reported to be associated with the severity of depressive symptoms (3) as well as increasing the risk of suicide (4) in patients with MDD.

Intervention Studies: There is a need for more intervention studies that specifically target sleep disturbances in patients with MDD to determine the effectiveness of different therapeutic approaches (e.g., CBT-I, pharmacological treatments) in reducing depressive symptoms and suicidal risk

Article: Report from a randomized control trial: improved alignment between circadian biology and sleepwake behavior as a mechanism of depression symptom improvement in evening-type adolescents with depressive symptoms

The randomized control trial titled "Improved Alignment Between Circadian Biology and SleepWake Behavior as a Mechanism of Depression Symptom Improvement in Evening-Type Adolescents with Depressive Symptoms" aimed to evaluate the effectiveness of a cognitive behavioral sleep intervention, known as the Transdiagnostic Sleep and Circadian Intervention (TranS-C). The study focused on adolescents with an evening circadian preference and significant depressive symptoms (ACAMH)

Key Findings

Intervention Effectiveness:

Adolescents who participated in the TranS-C intervention showed significant improvements in depression severity compared to those in the control group. This improvement was maintained at the 12-month follow-up

Mechanism of Improvement:

The study identified that the alignment between circadian biology and sleep-wake behavior was a crucial mechanism driving the reduction in depressive symptoms. Improved alignment led to better sleep quality and timing, which in turn contributed to the reduction in depression (ACAMH) (ScienceDaily).

Methodology:

Participants were randomly assigned to receive either the TranS-C intervention or a psychoeducation control condition. Measurements of circadian alignment, sleep patterns, and depression symptoms were taken before and after the treatment, as well as at 6- and 12-month follow-ups (HYPERLINK "https://www.scilit.net/publications/413d6515601b75a0061f0f42ea319119" t "_blank"Scilit).

Significance:

The findings suggest that targeting circadian misalignment can be an effective approach to treating depression in adolescents with an evening chronotype. This highlights the importance of considering circadian biology in the development of therapeutic interventions for depression (ScienceDaily) (Sleep Foundation).

Implications

The study's results provide valuable insights into the relationship between circadian rhythms and depression, particularly in adolescents. By improving circadian alignment, it may be possible to develop more effective treatments for depression that also address sleep issues. This research underscores the potential benefits of interventions that align sleep-wake behaviors with natural circadian rhythms, offering a promising avenue for improving mental health outcomes in adolescents.

For further reading, you can access the full study on the Journal of Child Psychology and Psychiatry's website or through relevant academic databases (ACAMH) (ScienceDaily) (Sleep Foundation).

Gaps

Causal Pathways: While the study suggests that improved circadian alignment mediates the reduction in depressive symptoms, the exact causal pathways and biological mechanisms remain unclear and require further investigation (Sleep Foundation).

Comparison with Other Treatments: There is a need for studies comparing TranS-C with other established treatments for depression, such as pharmacotherapy or other forms of cognitive-behavioral therapy, to better understand its relative efficacy (ScienceDaily).

Broader Age Range: Research including a broader age range of adolescents and young adults would help determine whether the findings are applicable across different developmental stages(Sleep Foundation).

Cultural Contexts: Additional research is needed to explore how cultural differences in sleep patterns, school schedules, and social norms affect the outcomes of circadian-based interventions for depression (Sleep Foundation).

In summary, while the study presents strong evidence for the benefits of aligning circadian biology with sleep-wake behavior in reducing depressive symptoms in evening-type adolescents, it also highlights areas that require further exploration to enhance understanding and applicability of these findings.

"The relationship between sleep disturbances and depression: A systematic review" (Journal of Affective Disorders, 2020)

"Circadian rhythm disturbances in major depressive disorder: A systematic review" (Journal of Affective Disorders, 2020)

"The impact of sleep and circadian rhythm disturbances on depression" (Nature Reviews Disease Primers, 2020)

"Sleep and circadian rhythm disturbances as predictors of depression: A systematic review" (Journal of Affective Disorders,2020)

- "The relationship between sleep, circadian rhythms, and depression: A systematic review and meta-analysis" (Sleep Medicine Reviews, 2020)

Dr. hermenes video. Schmaal, L., Pozzi, E., T, C. H., van Velzen, L. S., Veer, I. M., Opel, N., . . . Veltman, D. J. (2020). ENIGMA MDD: seven years of global neuroimaging studies of major

Lam et al. (2020). Sleep and depression: A systematic review. Journal of Affective Disorders, 268, 85-94.

Volkow et al. (2019). Dopamine and serotonin in depression: A review of the evidence. Journal of Psychopharmacology, 33(1), 13-24.

Jones et al. (2019). Cholinergic mechanisms in depression: A review of the evidence. Journal of Psychopharmacology, 33(1), 25-36.