Recent Advances in the Understanding of Insomnia

Insomnia is the complaint of dissatisfaction with sleep quantity or quality associated with an inability to fall or stay asleep, or early morning awakening (1). Prior to a few decades ago, the medical profession had given little attention to this complaint, and insomnia had, traditionally, been regarded as a benign malady. Indeed, descriptions of insomnia were, in past years, relegated to lay articles and vignettes. The seeming lack of professional interest in this disorder was likely not a product of lack of need for relief on the part of insomnia sufferers. It was, more likely, due to the lack of awareness of the potential consequences of the disorder, and a deficiency in effective treatment modalities. Indeed, early accounts of treatment recommendations for the disorder were, by today’s standards, obviously ineffective and likely harmful, with some reputable sources recommending eating a large meal, taking a cold bath, and exercising just prior to bedtime (2). Medical interest in the disorder waxed, however, following technological advances, such as polysomnography, which made it possible to quantify sleep stages, as well as disturbances in sleep quality and quantity, with greater objectivity. Interest in the disorder was further augmented by the introduction of effective treatment modalities, such as cognitive behavioral therapy and hypnotic agents.

We now know, thanks to many large community-based demographic studies, that insomnia is one of the most commonly encountered maladies in clinical medicine; after pain, it represents the second most commonly expressed complaint (3). An astounding 35% of the adult population experience insomnia during the course of 1 year (4) and half experience the problem as severe. Studies also indicate that 20.1% of adults are dissatisfied with their sleep or take medication for sleeping difficulties (5). Insomnia is also an emerging problem in children and adolescents; an estimated 4% of children complain of insomnia at least three times per week over the course of a year (6). The risk of insomnia is greatest in certain populations, such as those who are affected by poor mental and physical health and those who use misuse recreational substances, potentially compounding the impairments associated with these conditions. Other at-risk populations include women, in whom the prevalence of insomnia peaks during pregnancy and the peri- and postmenopausal years; seniors, afflicting more than one-third of the population age 65 and older; individuals who engage in nontraditional occupational schedules, such as shift workers; individuals who fall in the lower socioeconomic range; divorced, widowed, or single individuals; and those who live in settings that are not conducive to sound sleep, such as noisy environments (7).

Emerging research also indicates that we can no longer regard insomnia as a benign condition, as it is now known to be associated with a variety of health risks and consequences. Compared with individuals without sleep complaints, insomniacs report greater difficulty with coping and accomplishing tasks, complain of greater impairment in mood, and experience greater breaches in interpersonal relationships and psychosocial upheaval. In community samples, people with insomnia, compared with those without sleep complaints, score lower on all subscales of the SF−36 questionnaire indicating impairments across multiple quality of life domains, including body pain, general health, mental health, emotional role, social and physical functioning, and vitality (8, 9). They also exhibit greater cognitive deficits, especially when responding to challenging reaction time tasks (10–12). Insomnia is also associated with heightened rates of work-related impairments and absenteeism (13). Emerging evidence links persistent insomnia to a heightened risk of development of new cardiovascular and metabolic abnormalities such as hypertension, heart failure, and glucose intolerance (14–17). Longitudinal studies have even linked insomnia to premature mortality; a community-based prospective cohort study of 3,430 adult subjects, following a median follow up period of nearly 16 years, noted that the relative risk for all-cause death in insomniacs was considerably elevated, and rose in proportion to the severity of the disorder; in severe insomnia, the relative risk was 1.70 (18).

There is also a strong association between insomnia and psychiatric disorders, particularly mood and anxiety disorders. Insomnia, in the form of difficulty falling asleep, frequent nocturnal awakenings, early morning awakening, nonrestorative sleep, decreased total sleep, or disturbing dreams, is reported by most patients with major depression (19). Conversely, 14%−20% of individuals with significant complaints of insomnia show evidence of major depression, whereas rates of depression are less than 1% in those without sleep complaints (4, 20). In the context of major depressive disorder, insomnia confers significant added morbidity, including suicidal behavior. In one study, suicidal depressive patients had higher scores of subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, and Pittsburgh Sleep Quality Index global scores than nonsuicidal patients (21). Whereas we had once believed that insomnia in the context of depression invariably follows the development of the mood disorder, recent longitudinal studies indicate that insomnia is more likely to emerge prior to the onset of the acute phase of a mood disorder (22). In addition, persistent insomnia, occurring in the absence of current mood or other disorders, also confers an increased future risk for the development of new psychiatric disorders over the course of the ensuing year, a risk that diminishes if the insomnia resolves (20, 23). Studies have also noted that the initial complaint of insomnia confers an enhanced risk for future mood disorders for a median of 34 years following the initial complaint (24). Persistent insomnia is also associated with the development of anxiety and substance use disorders (25, 26). The preponderance of longitudinal studies, therefore, raise the intriguing notion that there may be a bidirectional relationship between insomnia and various psychiatric disorders, one which is most robust in the case of depression. From a clinical standpoint, these data suggest that the presence of chronic insomnia should alert the clinician to the possibility of the future emergence of a mood, anxiety, or substance use disorder. In addition, the lack of sufficient response to the treatment of insomnia should alert the clinician to the possibility of an underlying, disguised, mood, substance use, or anxiety disorder that may warrant independent management.

The discussion above highlights the view that insomnia can exist as an autonomous clinical entity. Such a view would necessitate an understanding regarding pathophysiology. Some of the earliest attempts to explain the causes of insomnia can be ascribed to Sigmund Freud, who suggested that insomnia represents a failure of dream work (27). Dreams, according to Freud, are created by a combination of daily events (“residue”) and conflict-laden, anxiety-producing, unconscious wishes. These are, in turn, transformed into dreams through a series of mental processes, including displacement, condensation, symbolic representation, and secondary elaboration, which are collectively subsumed under the rubric of “dream work.” Freud further hypothesized that successful dream work is necessary for the preservation of sleep. However, in insomnia, unconscious wishes that are aversive and conflict-laden become activated. Dream work is unsuccessful because of the intensity of the anxiety caused by the underlying conflict, resulting in the awakening of the dreamer and the complaint of insomnia.

Later psychological formulations regarding insomnia focused on cognitive and behavioral principles. Insomniacs are theorized to have a predisposition for an exaggerated emotional reaction to everyday stressors, requiring less activation to achieve high levels of arousal, which, in turn leads to disturbed sleep. Insomniacs also harbor distorted beliefs about sleep itself, including the belief that poor sleep is inevitable, that the lack of a full night of sleep will inevitably lead to disastrous health consequences, and that a minimum of 8 hours of sleep per day is critical to maintain health; these, in turn, can induce further emotional and cognitive arousal. Such catastrophizing is encouraged by many nights of poor sleep, which can foment cognitive rumination and worry about not falling asleep and about the potential for disastrous next-day consequences of sleeplessness. Therefore, such a cycle of apprehension and worry can perpetuate insomnia and make future sleep even less likely. Insomniacs are prone to excessive cognitive monitoring at bedtime, which can further perpetuate insomnia; insomniacs carefully monitor mental and body sensations, as well as external cues such as the bedroom clock and environmental noises (28). The repeated experience of poor sleep also promotes an association between sleeplessness and both presleep activities and the sleep setting. Once these connections are established, the bedtime rituals and environment become contextual cues for arousal rather than for sleep.

More recently, paralleling technological refinements in the assessment of neurophysiologic function, research into sleep has focused on the state of hyperarousal or an overly active arousal system, both during sleep and during the waking state. When insomniacs are allowed the opportunity to nap during the course of their typical daytime, they display enhanced alertness or a decreased ability to fall asleep, compared with normal sleepers (29). This is consistent with the complaint of insomniacs that they have difficulty napping during the course of the day. Sleep electroencephalography now indicates that there is a reduction in low-frequency delta power (typical of deep, non-REM, sleep) across the night, particularly in the first part of the night, and increased high-frequency beta power across the entire night compared with healthy controls (30). Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) scans also reveal an increase in global glucose metabolic rates during both wakefulness and sleep compared with healthy control subjects, and note that the usual sleep-related decline in metabolism in brainstem arousal centers is attenuated (31). Studies also suggest that the changes noted in the central nervous system are paralleled throughout peripheral physiological and metabolic systems. Insomniacs exhibit an increase in heart rate, a decrease in heart beat-to-beat variability (32), and an increase in whole-body metabolic rate (33).

Research over the past decade has also implicated the circadian system in the genesis of insomnia, pointing to irregularities in the circadian control of sleep/wakefulness, melatonin, cortisol, core body temperature, and presumably other endogenous rhythms. A mutation in the human clock gene Per2 is associated with advanced sleep phase syndrome, and a functional polymorphism in Per3 is associated with delayed sleep phase syndrome, disorders of the circadian system, which are associated with terminal and initiation insomnia, respectively (34). The Per2 and Per3 genes are members of the Period family of genes and are expressed in a circadian pattern in the suprachiasmatic nucleus. Although genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior, the specific function of these genes is not yet known.

Our evolving views regarding insomnia were reflected in the recently introduced Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM−5) (Table 1). In its predecessor, the DSM-IV TR (35), insomnia appeared as a diagnostic entity in three separate forms: “Primary insomnia,” “insomnia related to an axis I or axis II disorder,” and “sleep disorder due to a general medical condition, insomnia type.” In general, therefore, insomnia was subdivided into two broad categories, primary insomnia and secondary insomnia. Insomnia was, therefore, presumed to represent either an independent disorder, as long as it meets certain duration criteria and is associated with daytime impairment, or one that is secondary to other medical or psychiatric disorders. Inherent in this view is the notion of one-way causality. Recently, however, in light of observations, a National Institutes of Health State of the Science Conference challenged the primary-secondary distinction, some of which are reviewed above, suggesting that psychiatric disorders and insomnia can assume potentially independent, yet mutually interactive, temporal courses (36). The Conference recommended, instead, the use of the term “comorbid insomnia” for those instances in which insomnia occurs in the context of other medical and psychiatric disorders. In addition, goodness-of-fit ratings with insomnia patients recently concluded that the category of primary insomnia has marginal reliability and validity (37). These views are reflected in the DSM−5, in which the diagnosis of “primary insomnia” is eliminated, in favor of “insomnia disorder,” and “secondary” insomnia conditions are eliminated altogether, in favor of “insomnia disorder” with concurrent specification of clinically comorbid medical and psychiatric conditions. In addition, the chief complaint is changed from “insomnia” in favor of “sleep dissatisfaction,” which is more strongly associated with daytime impairments than insomnia symptoms alone (38). “Early morning awakening” is added to core diagnostic criteria of “difficulty initiating sleep” and “difficulty maintaining sleep,” since all three complaints are common in insomniacs, yet the specification of early morning awakening may represent a distinctly unique complaint. A minimal insomnia frequency of three nights per week and duration of more than 3 months are also added as measures of the degree of impairment (39–41). Finally, the provision of an “adequate opportunity for sleep” is added to make the important distinction between insomnia and sleep deprivation or restriction; in the latter, sleep is curtailed due to externally induced or self-imposed reduction in the opportunity for sleep, whereas in insomnia, sleep is impaired in quality or quantity despite adequate opportunity to obtain it.

We now recognize that the complex nature of insomnia necessitates a systematic evaluation prior to proceeding with treatment. The last decade has seen the publication of a number of guidelines for the evaluation of insomnia (7, 42, 43). A variety of inventories have also been introduced, primarily to assist in the dimensional assessment or quantification of the severity of insomnia; although many are available, the Insomnia Severity Index (ISI) is one of the few that have been subjected to empirical validation (44). The ISI takes into account subjective symptoms and consequences of insomnia and the degree of concern or distress caused by the disturbance. It is a useful clinical and research tool for measuring treatment outcome. The age of digitization has also paved the way for the development of hand-held sleep diaries, which allow for data manipulation to display sleep/wake patterns over time with greater facility than paper-and-pencil sleep logs. Actigraphy is an even more accurate tool, and was recently granted a code that is nationally recognized by third-party payers. It utilizes small, wristwatch-like devices to record movement and ambient light levels. It assumes that lack of movement is equivalent to sleep and is not, therefore, an exact measure of sleep/wake times. However, it can be useful for the assessment of such patterns when this information is not reliably available by other means such as sleep logs. It can be appropriate for the documentation of changes in sleep patterns over prolonged periods and for the diagnostic phase. It can also be utilized in the treatment phase to understand the degree to which insomniacs follow sleep hygiene recommendations (e.g., to curtail time in bed or to regularize wake-up times) and the response to other behavioral or pharmacological treatments (45).

Decades of research in sleep disorders confirm that insomnia is a common condition with a host of associated risks and consequences. Although our understanding of the pathophysiology of the disorder is still in its infancy, neurophysiological studies point in the direction of a disturbance in the central arousal system, which has far-reaching effects throughout the body. In addition, our view of the relationship between co-occurring insomnia and medical/psychiatric disorders has undergone radical changes over the past decade, from a model of unidirectional causality to one of autonomous disorders interacting in a bidirectional fashion. These conceptual changes have served as the foundations of substantive changes in the diagnostic guidelines for insomnia in DSM−5. They have also opened the doors to important new directions in research, whose results promise to alter the nature of our clinical practice.