Sleep, Mood & Mental Health

1. The Two-Process Model

Borbély’s 1982 two-process model remains the organising framework for sleep-wake regulation:

• Process S (homeostatic): sleep pressure accumulates monotonically during wake and dissipates during sleep. Its biomarker is adenosine — extracellular adenosine rises during wake, inhibiting wake-promoting neurones. Caffeine’s wake-promoting action: blocks adenosine A₁/A_2A receptors.
• Process C (circadian): the SCN-driven wake-promoting signal peaks in late afternoon and troughs in early morning, out of phase with Process S. This counteracts sleep pressure accumulating through the day, enabling sustained waking.

Sleep onset occurs when S − C exceeds a threshold. The model predicts why late afternoon is the “zone of alertness” despite high sleep pressure (the circadian wake signal is maximal), and why very early morning awakening is difficult (circadian wake signal at its nadir). Quantitative extensions (the SAFTE model, the Achermann two-process model) are used by NASA, armed forces, and airlines to predict alertness in operational settings.

2. Melatonin & Pharmacology

Melatonin is secreted by the pineal gland under SCN control (via a multisynaptic pathway through the paraventricular nucleus and superior cervical ganglion). Its evening rise (DLMO) is the gold-standard circadian phase marker in humans. Bright light at night suppresses melatonin by ~50% within minutes — a direct, measurable physiological disruption.

Pharmacological uses:

• Melatonin 0.3–3 mg evening doses advance the phase of the clock. Useful for DSPS, jet lag (eastward travel), shift workers. Higher doses do not produce better phase shift and cause side effects.
• Tasimelteon: MT1/MT2 agonist approved for non-24 sleep-wake disorder (common in totally blind individuals lacking ocular light input to the SCN).
• Ramelteon: MT1/MT2 agonist for insomnia.
• Agomelatine: MT1/MT2 agonist + 5-HT_2C antagonist; approved in Europe for depression. The only antidepressant with a circadian-based mechanism.

3. DSPS & FASPS

Delayed sleep phase syndrome (DSPS): chronic difficulty falling asleep before 2–4 am and waking before noon. Prevalence ~0.2–10% depending on age (peak in adolescence/young adulthood). Common causes: CRY1 c.1657+3A>C splice variant (Patke 2017); photosensitivity; adolescent biology; screen use. Treatment: bright morning light (first 30 min after waking), evening light avoidance, evening melatonin.

Familial advanced sleep phase (FASPS): sleep onset 19:00–21:30, wake 03:00–05:00. PER2 S662G mutation (Toh 2001), CK1δ T44A (Xu 2005). Extremely rare; clinical treatment usually unnecessary unless social impairment. Important as the clearest single-gene sleep phenotype.

4. Depression, Bipolar & Circadian Dysfunction

Circadian disruption is common in mood disorders:

• Major depression: blunted cortisol rhythm, altered sleep architecture (early REM onset, reduced slow-wave sleep), diurnal mood variation. Wake therapy (one night of sleep deprivation) produces rapid but transient antidepressant response in ~60% of responders.
• Seasonal affective disorder: winter depression responding to morning bright-light therapy (10 000 lux, 30 min). The best-established circadian treatment in psychiatry.
• Bipolar disorder: mania often preceded by sleep loss; circadian gene variants (CLOCK, BMAL1, PER3, NR1D1) are consistent bipolar-risk signals in GWAS. Lithium, the most effective mood-stabiliser, lengthens circadian period via GSK-3β inhibition.
• Schizophrenia: fragmented sleep, altered melatonin rhythms, clock-gene expression abnormalities in post-mortem prefrontal cortex (Seney 2019).

Social jetlag — the misalignment between social and biological time, quantifiable as MSF_sc (free-day sleep midpoint) vs work-day sleep midpoint — correlates with depression, obesity, and cardiovascular risk in population studies. Adolescents are especially affected because of chronotypic delay during puberty combined with early school start times — a modifiable public-health problem.

5. Cognition & the Clock

Attention, working memory, and executive function all vary over the 24-hour cycle, peaking in late afternoon for most tasks and troughing in the early morning. Surgical complication rates rise for procedures started after 16:00 (Arbous 2005). Chronic sleep deprivation (~6 h/night for 2 weeks) produces cognitive impairment equivalent to 2 nights of total sleep deprivation, but subjective alertness rapidly adapts — producing impaired function with preserved self-perception, a pattern characteristic of shift-work error risk.