Pathophysiology

In the late 1980s, Spielman created a model of insomnia in terms of predisposing, precipitating, and perpetuating factors.

Predisposing factors

Genetic and neurobiologic factors likely determine a person’s risk of developing insomnia in the context of a precipitating factor (psychosocial, medical, or psychiatric). Many of these have not been identified. Sleep and wakefulness is an active, tightly regulated process that may differ between individuals who have different susceptibilities to exogenous influences.

Recent studies indicate differential genetic susceptibility to exogenous influences such as caffeine, light, and stress. For example, one study found that differences in the adenosine 2A receptor gene (ADORA2) determine differential sensitivity to caffeine’s effect on sleep. The ADORA2A 1083T>C genotype determined how closely the caffeine-induced changes in brain electrical activity (increased beta activity) during sleep resembled the alterations observed in patients with insomnia.

In addition, circadian clock genes (Clock, Per2) have been identified that regulate the circadian rhythm. For example, a mutation or functional polymorphism in the clock gene (Per2) can lead to circadian rhythm disorders such as advance sleep phase syndrome (sleep and morning awakening occur earlier than normal), and delayed sleep phase syndrome (sleep and morning awakening are delayed). Furthermore, a study examining the association between Clock gene polymorphisms and insomnia revealed a higher recurrence of initial, middle, and terminal insomnia in patients homozygous for the Clock genotype.

A missense mutation has been found in the gene encoding the GABA_A beta 3 subunit in a patient with chronic insomnia. Polymorphisms in the serotonin receptor transporter gene may modulate the ability of an individual to handle stress or may confer susceptibility to depression. In depression, serotonin is an important neurotransmitter for arousal mechanisms. Furthermore, antagonism of the 5-HT2 receptor promotes slow wave sleep. Therefore, preliminary basic science evidence indicates a possible genetic predisposition to hyperarousal and insomnia.

Clinical research has also shown that patients with chronic insomnia show evidence of increased brain arousal. For example, studies have indicated that patients with chronic primary insomnia demonstrate increased fast frequency activity during NREM sleep, an EEG sign of hyperarousal, and evidence of reduced deactivation in key sleep/wake regions during NREM sleep when compared with controls. Furthermore, patients with insomnia have higher day and night body temperatures, urinary cortisol and adrenaline secretion, and ACTH than patients with normal sleep. A study of normal sleepers demonstrated that these changes were not due to sleep deprivation. Only a fraction of patients with medical and psychiatric conditions develop insomnia, which suggests that some patients have an inherent susceptibility (whether psychosocial, medical, or psychiatric) to develop insomnia in the context of a stressful event.

Precipitating factors

In retrospective studies, a large proportion of patients with insomnia (78%) can identify a precipitating trigger for their insomnia. Morin and colleagues showed that these patients demonstrate an increased response to stress as compared with controls. A number of factors can trigger insomnia in vulnerable individuals. These factors include depression, anxiety, sleep-wake schedule changes, medications, other sleep disorders, and medical conditions. In addition, positive or negative family, work-related, and health events are common insomnia precipitants.

Perpetuating factors

Insomnia, regardless of how it is triggered, is generally accepted to be perpetuated by cognitive and behavioral mechanisms. Cognitive mechanisms include misconceptions about normal sleep requirements and excessive worry about the ramifications of the daytime effects of inadequate sleep. As a result, these patients often become obsessive about their sleep or try too hard to fall asleep. These dysfunctional beliefs often produce sleep disruptive behaviors such as trying to catch up on lost sleep with daytime naps or sleeping in late, which in turn reduces their natural homeostatic drive to sleep at their habitual bedtime. Learned sleep-preventing associations are characterized by overconcern about inability to fall asleep.

Consequently, these patients develop conditioned arousal to stimuli that would normally be associated with sleep (ie, heightened anxiety and ruminations about going to sleep in their bedroom). A cycle then develops in which the more the patients strive to sleep, the more agitated they become, and the less they are able to fall asleep. They also have ruminative thoughts or clock watching as they are trying to fall asleep in their bedroom. Thus, conditioned environmental cues causing insomnia develop from the continued association of sleeplessness with situations and behaviors that are typically related to sleep.

Theoretical model of the factors causing chronic insomnia. Chronic insomnia is believed to primarily occur in patients with predisposing or constitutional factors. These factors may cause the occasional night of poor sleep but not chronic insomnia. A precipitating factor, such as a major life event, causes the patient to have acute insomnia. If poor sleep habits or other perpetuating factors occur in the following weeks to months, chronic insomnia develops despite the removal of the precipitating factor. Adapted from Spielman AJ, Caruso LS, Glovinsky PB: A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987 Dec;10(4):541-53.