Insomnia pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Adnan Ezici, M.D[2]

It is thought that insomnia is caused by either molecular mechanism, hyperarousal model, sleep switch Model, cognitive and behavioural Model(3P model), and genetic factors. Genes involved in the pathogenesis of insomnia include apoE4, PER3, 5HTTLPR SNP (Single Nucleotide Polymorphism), CLOCK gene, HLA-DQB1*0602, CRY1.

The normal physiology of sleep can be understood as follows: The sleep-wake cycle is mediated by circadian rhythm and sleep-wake homeostasis, which is essential for sleeping at night and wakefulness during the day.^[1] Although sleep is influenced by a myriad of conditions, both physical and environmental, most sleep patterns follow a circadian rhythm which is in turn regulated by a number of compounds in the body.^[2]

• These compounds are broadly divided into either sleep-promoting or wake-promoting.^[3]
• Examples of sleep-promoting compounds are melatonin, adenosine, serotonin, etc.
• Wake-promoting compounds include catecholamines, histamine, etc.
• Although all cases of insomnia cannot be explained by an imbalance between sleep-promoting and wake-promoting compounds, an imbalance or an excess of either points to a sleep-wake disorder of some kind.
• Comorbid conditions like GERD, restless leg syndrome, anxiety disorder can result in chronic insomnia.
• Local sleep theory proposed by Krueger et al, defines sleep as a "fundamental emergent property of highly interconnected neurons"^[4]. This theory states that in insomnia, compounds which regulate sleep act locally at the site of neurons and influence sleep-wake regulation.

It is thought that insomnia is mediated by^[5]:

• Molecular Mechanism
  • Hormones causing wakefulness: Catecholamine, Histamine, Orexin
  • Hormones promoting sleep: Adenosine, serotonin, GABA, melatonin, Prostaglandin D2
• Hyperarousal model
  • Cognitive
  • Physiologic
  • Cortical
• Sleep switch Model (Orexin mediated)
  • Inhibition of sleep-promoting areas:Ventrolateral preoptic nucleus and median preoptic nucleus
  • Stimulation of wake-promoting areas:Tuberomammillary nucleus, dorsal raphe nucleus, locus coeruleus
• Cognitive and Behavioural Model(3P model): This model of insomnia helps to explain how acute insomnia becomes chronic and aids in assessing insomnia in individual patients
  • Precipitating factors
  • Predisposing factors
  • Perpetuating factors

Genes involved in the pathogenesis of insomnia include:^[5]

• ApoE4
• PER3
• 5HTTLPR SNP (Single Nucleotide Polymorphism)
• CLOCK gene
• HLA-DQB1*0602
• CRY1.^[6]