Sleep is a cardinal biological process that backstops central nervous system function, which also plays a crucial role in regulating systemic homeostasis, including immune activities. Cytokines, particularly interleukin-1β and tumor necrosis factor-α, act as mediators bridging sleep and inflammation, also influencing both sleep architecture and sleep-wake cycle. Sleep deprivation and sleep disorders such as insomnia, narcolepsy, hypersomnia, or obstructive sleep apnoea may disrupt cytokine production, alter their circadian rhythm of release, and shift secretion peaks from night to day. These changes contribute to daytime fatigue, impaired cognitive and physical performance, increased susceptibility to infections and/or systemic inflammation. Molecular studies indicate that insufficient sleep primes immune cells to enhance pro-inflammatory responses, creating a feedback loop with neuroendocrine pathways that further exacerbates sleep patterns and inflammatory dysregulation. Understanding the bidirectional relationship between sleep and cytokines may highlight the role of sleep as an active component of immunity regulation and underscore the potential usefulness of multilevel interventions that include complementary and integrative health approaches restoring sleep, normalizing cytokine rhythms and mitigating inflammation.

The hypersomnolence disorder diagnostic criteria of the DSM-5-TR rely on the report of a 'hypersomnolence' syndrome, without defining the term or proposing any measuring tool to assess this. Among the vast diversity of tools to measure hypersomnolence, the Hypersomnia Severity Index (HSI) has been specifically designed to account for the multidimensionality of hypersomnolence. Showing good psychometric validity in two previous validation studies, the HSI has never been validated against the gold-standard Multiple Sleep Latency Test (MSLT).

Melancholic depression is characterized by loss of appetite, insomnia, psychomotor retardation, and a marked loss of responsiveness to their environments. Patients with melancholic depression typically experience diurnal variation with symptoms being worse in the morning. In contrast, atypical depression, as defined in the DSM-5, is associated with reactive mood (including the ability to respond emotionally to environmental cues), increased appetite, hypersomnia, leaden paralysis, and interpersonal rejection sensitivity, with symptoms often worse in the evening. Patients with atypical depressive episodes generally have a younger age of onset, are more often women, and frequently experience a chronic and persistent course. In addition, anxious depression represents a clinically relevant phenotype characterized by symptoms such as feeling keyed up or tense, unusual restlessness, and a sense of losing control, features that are associated with greater illness severity and treatment resistance.Considering the distinct biological mechanisms of these depressive subtypes, a better understanding of their pathophysiology can guide the prediction of treatment responses in major depressive disorder and support the development of more targeted therapeutic strategies.

Major depressive disorder (MDD) is a psychiatric condition that affects millions of individuals worldwide. Not only does it involve a persistent feeling of sadness and low mood, but it is also characterized by a lack of interest in pleasurable activities, by significant changes in weight, by insomnia or hypersomnia, by fatigue, and by feelings of worthlessness. MDD can last for long periods of time and, in severe cases, can significantly disrupt daily life, making everyday tasks increasingly challenging. In the worst-case scenario, MDD is associated with recurrent thoughts of death, suicidal ideation, or suicide attempts. There is a large body of literature indicating significant gender differences in the occurrence, clinical presentation, and comorbidities associated with MDD. A substantial gap in depression rates is observed, with females experiencing higher rates than males. This disparity is due to multiple factors, including biological, psychological, and sociocultural. MDD is often accompanied by various comorbidities, which also differ by gender. These differences are important for diagnosis, treatment, and prognosis. While researchers have gained valuable insights into the gender gap in MDD, many aspects still require further exploration. This chapter examines gender differences and comorbidities in MDD, including clinical characteristics and risk factors. By addressing these complexities, the chapter aims to improve clinical practice and support the development of gender-specific treatment programs to aid individuals suffering from MDD.

Daytime sleepiness and fatigue are common, yet hard to distinguish in depression. Sleepiness often reflects homeostatic sleep need caused by insufficient/disrupted sleep, and detection is critical for tailoring sleep-focused treatment in depression. However, misattributing fatigue to sleepiness is common on self-report, and terms like sleepy and tired are used interchangeably. The Pupillary Unrest Index (PUI) from the Pupil Sleepiness test (PST) is an objective measure of alertness that may help detect sleepiness due to insufficient/disrupted sleep. Currently, data linking the PUI to recent sleep behavior are limited and no study has examined these associations in depression. In a sample with varying levels of seasonal depression disorder (SAD) symptoms, we hypothesized that actigraphic sleep behaviors (duration, wake after sleep onset, sleep latency, efficiency, awakenings) would be associated with the PUI, and these associations would be stronger than those with self-reported sleepiness. We recruited 46 participants ranging from no history of depression through severe SAD. Assessments included the PUI, actigraphy 1-3 nights before the PUI, and self-reported sleepiness and fatigue. The PUI was not associated with SAD severity, fatigue, or self-reported sleepiness, whereas higher self-reported sleepiness was associated with higher SAD severity and fatigue. Longer sleep duration across 1-3 cumulative nights of sleep was associated with lower PUI. Shorter prior-night sleep latency was associated with higher next-day PUI. Both sleep duration and sleep latency were stronger predictors of the PUI than self-reported sleepiness. Results suggest the PUI can detect sleepiness associated with recent prior sleep behaviors, and diverges from SAD symptomology.