Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights r...

314KB Sizes 1 Downloads 5 Views

Recommend Documents

No documents
Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 45

Insomnia: nature, diagnosis, and treatment CHARLES M. MORIN 1 * AND RUTH M. BENCA 2 1 Universit Laval, Quebec, Canada 2

University of Wisconsin, Madison, WI, USA

INTRODUCTION Insomnia is a prevalent complaint both in the general population and in clinical practice. Chronic insomnia can present as the primary problem or as a coexisting condition with another medical or psychiatric disorder. Insomnia diagnosis and therapeutic approaches have evolved over the past two decades (National Institutes of Health, 2005). Whereas it used to be conceptualized exclusively as a symptom of other psychiatric or medical disorders, current diagnostic classifications of sleep disorders make a distinction between the symptom and the syndrome of insomnia (American Psychiatric Association, 2000; American Academy of Sleep Medicine, 2005). In addition, there have been significant advances in the treatment of insomnia, from a predominantly symptomatic approach to more focused interventions on perpetuating factors with cognitive– behavioral therapy (CBT) and on more targeted brain receptors with pharmacotherapy (National Institutes of Health, 2005).

SIGNIFICANCE OF INSOMNIA Population-based estimates indicate that about 30% of adults report insomnia symptoms, 9–12% experience additional daytime symptoms, and 6–10% meet diagnostic criteria for an insomnia syndrome (Ohayon, 2002). In primary care medicine, approximately 20% of patients report significant sleep disturbances (Simon and VonKorff, 1997). Insomnia is more prevalent among women, middle-aged and older adults, shiftworkers, and patients with medical or psychiatric disorders. Difficulties initiating sleep are more common among young adults, and problems maintaining sleep are more frequent among middle-aged and elderly adults. The incidence of insomnia is higher among

first-degree family members (daughter, mother) than in the general population (Dauvilliers et al., 2005), although it is unclear whether this link is inherited through a genetic predisposition, learned by observations of parental models, or simply a byproduct of another psychopathology. Persistent insomnia can produce an important burden for the individual and for society, as evidenced by increased rates of absenteeism, reduced productivity, increased risks of depression, and higher rates of healthcare utilization (Ford and Kamerow, 1989; Breslau et al., 1996; Simon and VonKorff, 1997; Sivertsen et al., 2006b; Ozminkowski et al., 2007; Daley et al., 2009).

NATURE OF INSOMNIA Presenting complaints Insomnia is characterized by a spectrum of complaints reflecting dissatisfaction with the quality, duration, or continuity of sleep. These complaints may involve problems with falling asleep initially at bedtime, waking up in the middle of the night and having difficulty going back to sleep, waking up too early in the morning with an inability to return to sleep, nonrestorative or unrefreshing sleep (American Psychiatric Association, 2000; American Academy of Sleep Medicine, 2005). In addition, daytime fatigue, cognitive impairments, and mood disturbances (e.g., irritability, dysphoria) are extremely frequent and often the primary concerns prompting patients with insomnia to seek treatment. In addition to clinical diagnostic criteria (Table 45.1), several quantitative indicators are useful to evaluate the severity and significance of insomnia. These include the intensity, frequency, and duration of sleep difficulties and their associated daytime consequences. For example, sleep-onset and sleep-maintenance insomnia

*Correspondence to: Charles M. Morin, Ph.D., Universite´ Laval, 2325 Rue des Bibliothe`ques, E´cole de Psychologie, Pavillon F.A.S., Quebec City, Quebec, Canada G1V 0A6. Tel: (418) 656-3275, Fax: (418) 656-5152, E-mail: [email protected]



Table 45.1 Diagnostic criteria for primary insomnia (adapted from DSM-IV-TR) ● ● ●

A subjective complaint of difficulty initiating or maintaining sleep, or of nonrestorative sleep Duration of insomnia longer than 1 month The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning The sleep disturbance does not occur exclusively in the context of another mental or sleep disorder, and is not the direct physiological effect of a substance or a general medical condition

are often defined by a latency to sleep onset and/or time awake after sleep onset greater than 30 or 45 minutes, with corresponding sleep time of less than 6.5 hours. Such criteria, while arbitrary, are useful to operationalize the definition of insomnia. Total sleep time alone is not a good index to define insomnia because there are individual differences in sleep needs. Some people may function well with as little as 5–6 hours of sleep and would not necessarily complain of insomnia, whereas others needing 9–10 hours may still complain of inadequate sleep. It is also important to distinguish the occasional insomnia that everyone experiences at one time or another in life from the more recurrent insomnia, usually defined by the presence of sleep difficulty for three or more nights per week. A distinction is also made between situational/acute insomnia, a condition lasting a few days and often associated with life events or jet lag, short-term insomnia (lasting between 1 and 4 weeks), and chronic insomnia, lasting more than a month. Finally, it is necessary to consider the impact of insomnia on a person’s psychosocial and occupational functioning to judge its clinical significance. As such, insomnia must be associated with marked distress or significant impairments of daytime functioning to make the diagnosis (American Psychiatric Association, 2000; Edinger et al., 2004; American Academy of Sleep Medicine, 2005).

Polysomnographic (PSG) findings PSG evaluation of self-defined insomniacs reveals more impairments of sleep continuity parameters (i.e., longer sleep latencies, more time awake after sleep onset, lower sleep efficiency) and reduced total sleep time compared with findings in self-defined good sleepers. Although sleep architecture is not always altered, a subset of individuals with chronic insomnia show increased amount of stage 1, reduced stages

3–4, and more frequent stage shifts through the night. Interestingly, sleep disturbances recorded in primary insomniacs are similar to those observed in patients with generalized anxiety disorder or some affective disorders such as dysthymia (Reynolds et al., 1984; Hauri and Fisher, 1986; Benca et al., 1992), perhaps suggesting a common underlying thread to these conditions. Investigations of the microstructure of sleep reveal increased beta activity in primary insomniacs relative to healthy controls, both around the sleep-onset period and during nonrapid eye movement (NREM) sleep (Lamarche and Ogilvie, 1997; Merica et al., 1998; Perlis et al., 2001b; Bastien et al., 2008). These data are consistent with the presumed role of attentional processes and information processing (Perlis et al., 2001a; Devoto et al., 2005; Jones et al., 2005), as well as with psychological findings of hypervigilance and a ruminative, worry-prone cognitive style among insomniacs. In general, there is a significant overlap in the sleep patterns of subjectively defined insomniacs and good sleepers, such that some insomniacs may show better objective sleep than good sleepers, and some good sleepers may show more sleep impairments than insomniacs.

Daytime complaints and findings Most patients with significant insomnia complaints also report impairments of daytime functioning, involving fatigue, mood disturbances, and difficulties with attention and concentration, memory, and completion of tasks (Buysse et al., 2007). Patients may initially report excessive daytime sleepiness, but a closer investigation usually reveals mental and physical fatigue rather than true physiological sleepiness, which is more likely among patients with insomnia comorbid with another medical (e.g., pain) or sleep disorders (e.g., sleep-related breathing disorders). Insomniacs have trouble sleeping at night, in part because of chronic state of hyperarousal, which may also interfere with the ability or propensity for sleep during the day. Despite significant subjective complaints, objective evaluation of daytime performance usually reveals fairly mild and selective deficits (e.g., attention) on various neurobehavioral measures (Riedel and Lichstein, 2000). In general, impairments on these measures are more strongly associated with subjective than with objective sleep disturbances. Individuals with insomnia tend to have lower expectations and to perceive their performance as more impaired relative to how they should perform, and as more impaired than that of normal controls. Discrepancies between subjective and objective performance are similar to those observed between subjective and objective

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT measures of sleep, which may reflect a generalized faulty appraisal of sleep and daytime functioning among individuals with insomnia (Vignola et al, 2000).

Subtypes of insomnia DSM-IV recognizes only one form of primary insomnia (American Psychiatric Association, 2000), whereas the International Classification of Sleep Disorders distinguishes different subtypes (Table 45.2), the most common being psychophysiological, paradoxical, and idiopathic insomnia (American Academy of Sleep Medicine, 2005). Psychophysiological insomnia is presumed to result from conditioned arousal, which is more likely to develop among individuals with an increased psychological (worry-prone) and biological predisposition (hyperarousability) to insomnia. The sleep of individuals with psychophysiological insomnia is more sensitive to daily stressors and is characterized by extensive night to night variability (Vallieres et al., 2005a). Table 45.2 Insomnia diagnostic subtypes Type of insomnia Primary insomnia Adjustment (< 3 months)

Psychophysiological (> 6 months) Paradoxical

Idiopathic insomnia

Inadequate sleep hygiene Behavioral insomnia of childhood Comorbid insomnia Associated with a mental disorder Associated with a drug or substance Associated with a medical condition Associated with another sleep disorder


Temporally linked with a stressor and expected to resolve with disappearance of initial precipitating factor Conditioned arousal, heightened anxiety about sleep Marked discrepancy between subjective complaints and PSG findings Insidious onset during childhood, unrelated to psychological trauma or medical disorders; persistent throughout adulthood


Paradoxical insomnia involves a genuine complaint of poor sleep that is not corroborated by objective findings. A patient may perceive very little sleep (e.g., 2–3 hours per night), whereas PSG recordings show normal or near-normal sleep duration and quality. This condition is not the result of an underlying psychiatric disorder or of malingering, but is likely to be mediated by psychological and cognitive (information processing) variables influencing the perception of sleep and wakefulness. To some degree, all insomniacs tend to overestimate the time it takes them to fall asleep and to underestimate the time they actually sleep. In paradoxical insomnia, however, the subjective complaint of poor sleep is disproportionate to objective findings. Thus, this condition may represent the far end of a continuum of individual differences in sleep perception. Idiopathic (childhood) insomnia presents an insidious onset during childhood, unrelated to psychological trauma or medical disorders, and is very persistent throughout the adult life. It does not present the variability observed with other forms of primary insomnia. A mild defect of the basic neurological sleep/wake mechanisms may be a predisposing factor, a hypothesis that comes from the observations that patients with this condition often have a history of learning disabilities, attention-deficit/hyperactivity disorder, or similar conditions associated with minimal brain dysfunction. Despite their heuristic value, these insomnia phenotypes and others remain to be validated empirically.

Course and prognosis The onset of Insomnia can occur at any time during life, but the first episode is more common in young adulthood. It is often precipitated by stressful life events, such as marital separation, occupational or family stress, and interpersonal conflicts (Bastien et al., 2004). In a small subset of cases (e.g., idiopathic insomnia), insomnia begins in childhood, in the absence of psychological or medical problems, and persists throughout adulthood (Hauri and Olmstead, 1980). Insomnia is a common problem among women during menopause and often persists even after other symptoms (e.g., hot flashes) have resolved with hormone replacement therapy. Insomnia may also have a latelife onset, which needs to be distinguished from normal (age-related) changes in sleep; such late-life onset is often associated with other health-related problems. Potential risk factors for insomnia include female sex, advancing age, a worry-prone cognitive style, hyperarousal, and a past history of insomnia (Klink et al., 1992; Morin and Espie, 2003). For most individuals, insomnia is transient in nature, lasting a few days, and resolving itself once the initial precipitating

726 C.M. MORIN AND R.M. BENCA event has subsided. For others, perhaps those more and increased cortisol and adrenocorticotropic horvulnerable to sleep disturbances, insomnia may persist mone levels during sleep and throughout the 24-hour long after the initial triggering event has disappeared; period (Vgontzas et al., 2001; Rodenbeck et al., other factors would then perpetuate sleep disturbances 2002). Reduced sleep efficiency was correlated with (Spielman and Glovinsky, 1991). The course of insomnia higher cortisol levels (Vgontzas et al., 2001; Rodenbeck may also be intermittent, with repeated brief episodes et al., 2002). A neuroimaging study revealed that, comof sleep difficulties following a close association with pared to healthy controls, insomniacs had increased the occurrence of stressful events (Vollrath et al., cerebral glucose metabolic rates during wakefulness 1989). Longitudinal studies have shown that chronicity and NREM sleep, and also exhibited smaller declines rates may range from 45% to 75% for follow-ups of in glucose metabolism from wakefulness to sleep in 1–7 years (Buysse et al., 2008; Morin et al., 2009). Even wake-promoting brain areas such as the ascending when insomnia has developed a chronic course, there is reticular activating system (Nofzinger et al., 2004). typically extensive night to night variability in sleep Positron emission tomography in patients with insompatterns, with an occasional restful night’s sleep internia demonstrated that increased wakefulness after twined with several nights of poor sleep (Vallieres sleep onset was correlated with increased activation in et al., 2005a). The subtype of insomnia (i.e., sleep onset the pontine region and in some thalamocortical netor maintenance insomnia) may also change over time. works during sleep (Nofzinger et al., 2006). Finally, a Although there is little information about its natural hisstudy of brain neurochemicals found that levels of tory, the prognosis for insomnia varies across indivigamma-aminobutyric acid (GABA) were nearly 30% duals and is probably mediated by a combination of lower in patients with primary insomnia than in conbiologically related predisposing factors and psychologtrols; GABA levels were negatively correlated with ical and behavioral perpetuating factors. It may also wake after sleep onset (Winkelman et al., 2008). be complicated by the presence of comorbid psychiatric or medical disorders. In fact, there is extensive comorPsychological basis. Psychological and behavioral bidity (40–50%) between insomnia and psychiatric factors also play an important role in the development disorders, most notably with major depression and and maintenance of insomnia, as evidenced by higher generalized anxiety disorder (Ford and Kamerow, levels of presleep cognitive arousal (e.g., intrusive 1989; Benca et al., 1992; Buysse et al., 1994; Breslau thoughts, worries) and general psychological reactivity et al., 1996; Ohayon and Roth, 2003). among individuals with insomnia relative to good sleepers. Although chronic exposure to stress may contribEtiology and pathophysiology ute to insomnia, it may be that sleep disturbance results from a reduced ability to cope with daily stresAlthough insomnia is likely multifactorial and the presors, combined with increased cognitive arousal at bedcise etiologies are not known, hyperarousal is considered time (Morin et al., 2003). to be a central feature of insomnia. A hyperarousal state Learning and conditioning are also involved in the can be conditioned to sleep-related stimuli or a more maintenance or exacerbation of sleep disturbances; enduring feature present throughout the 24-hour period. the discomfort associated with insomnia can lead to a It is likely that both biological and psychological factors negative association between temporal (bedtime) and contribute to increased arousal and interference with environmental (bed/bedroom) stimuli previously assonormal initiation and maintenance of sleep. ciated with sleep. Over time, the combination of Biological basis. In studies comparing patients with maladaptive sleep habits (e.g., napping, excessive insomnia to normal sleepers, a number of physiological amounts of time spent in bed) and sleep-related cognidifferences suggestive of increased arousal have been tions (e.g., unrealistic sleep expectations, worry about reported, including increases in body temperature, the consequences of insomnia, sleep-related monitorgalvanic skin response, heart rate, and metabolic rate, ing) may exacerbate or perpetuate what might otherboth near sleep onset and during sleep (Bonnet and wise have been a transient sleep problem (Espie, Arand, 1997). Patients with insomnia have also shown 2002; Morin and Espie, 2003; Morin et al., 2003). increased high-frequency (beta) EEG activity during Although it remains unclear whether hyperarousal is NREM sleep, and changes in patterns of event-related a direct cause, a byproduct, or even a consequence of potentials suggestive of increased arousal (Merica insomnia, it is a central feature in the pathophysiology et al., 1998; Perlis et al., 2001a, b; Devoto et al., 2005; of insomnia. Along with a reduced homeostatic sleep Bastien et al., 2008). Neuroendocrine studies have drive (Besset et al., 1998), it is likely to arise from the demonstrated increased levels of circulating catecholainteraction of biologically based predisposing factors mines and urinary free cortisol (Vgontzas et al., 1998), and psychologically based exacerbating factors.


EVALUATION AND DIFFERENTIAL DIAGNOSIS Clinical and laboratory evaluations The diagnosis of insomnia is derived primarily from a detailed clinical evaluation of the patient’s subjective complaint (Table 45.3). The sleep history should cover the type of complaint (initial, middle, late insomnia), its duration (acute vs. chronic), and course (recurrent, persistent); typical sleep schedule; functional analysis of precipitating, perpetuating, and alleviating factors; perceived consequences and functional impairments, and the presence of medical, psychiatric, or environmental contributing factors. A complete history of alcohol and drug use, and of prescribed and over-the-counter medications is also essential (Morin and Espie, 2003; Buysse et al., 2006; Schutte-Rodin et al., 2008). The use of a sleep diary is essential in the evaluation of insomnia (Table 45.4). The patient should keep a daily diary to document the nature and initial severity of insomnia, identify behavioral and scheduling factors that may perpetuate insomnia, and monitor treatment compliance and progress. The Insomnia Severity Index (Bastien et al., 2001) is a brief questionnaire that can also be helpful to measure the patient’s perception of insomnia severity and its impact on daytime functioning (Table 45.5). Several additional measures of insomnia symptoms, fatigue,


anxiety, and depressive symptomatology may also provide useful complementary information in the evaluation of insomnia (Buysse et al., 2006). A more comprehensive psychological evaluation may be necessary for patients with suspected psychiatric disorders. Although PSG is not indicated for the routine evaluation of insomnia, it is often necessary to rule out other sleep disorders that might contribute to the insomnia complaint (e.g., periodic movements during sleep, sleep apnea) (Littner et al., 2003). PSG can also be particularly useful in suspected case of paradoxical insomnia or when a patient is unresponsive to treatment. The role of actigraphy in insomnia evaluation and treatment monitoring is not well established. Although it may represent a useful adjunct, actigraphy is not clinically indicated for routine assessment, diagnosis, or management of insomnia (Ancoli-Israel et al., 2003; Buysse et al., 2006). In the research environment, actigraphy is useful for examining night to night variability and for identifying individuals with circadian rhythm disorders. It has also been used to document treatment adherence and outcome in clinical trials of behavioral therapy for insomnia (Morin et al., 2006). Although a potentially useful complement to selfreport and PSG measures, actigraphy devices and algorithms are not all equivalent and there may be significant variability in the reliability and validity of sleep–wake data derived from different devices.

Table 45.3 Evaluation of insomnia Nature of the complaint – difficulties falling or staying asleep, early morning awakening Daytime symptoms – fatigue, mood disturbances, attention/ concentration problems Clinical significance – frequency, severity, duration of sleep difficulties Onset and course of insomnia Typical sleep–wake schedule (weekdays, weekends) Sleeping environment (noise, light, temperature) Functional analysis – evening activities, pre-bedtime rituals, triggers of nocturnal and morning awakenings (pain, noise); behavioral responses to insomnia Perpetuating/exacerbating (worries about sleep loss, daytime napping, excessive amounts of time in bed) Beliefs about sleep requirement expectations and consequences of poor sleep Use of sleeping aids/substances (caffeine, alcohol, drugs) Other medical problems Recent life events contributing to insomnia Symptoms of other psychiatric disorders (anxiety, depression) Symptoms of other sleep disorders (restless legs syndrome, sleep apnea) Previous treatment for insomnia and outcome

Differential diagnosis The differential diagnosis of insomnia requires a distinction between primary insomnia and insomnia associated with a (comorbid) medical, psychiatric, or other sleep disorder. Although the essential clinical features of insomnia are similar for primary and comorbid insomnia, in primary insomnia the sleep disturbance does not occur exclusively during the course of another mental or sleep disorder and is not due to the direct physiological effects of a substance or general medical condition. Primary insomnia is a diagnosis essentially made by exclusion, after ruling out several other conditions such as psychiatric (depression and anxiety), medical (pain), circadian (phase-delay syndrome), or other sleep disorders (restless legs syndrome/periodic limb movements, sleep-breathing disorders) as the main contributing factor to sleep disturbances. A diagnosis of comorbid insomnia is made when the sleep disturbance is judged to be related temporally and causally to another psychiatric, medical, or sleep disorder (American Psychiatric Association, 2000; American Academy of Sleep Medicine, 2005). Such distinction is not always easily made, given the bidirectional relationship between insomnia and psychological symptoms



Table 45.4 Sleep diary Week: __________ to ___________ Example 1.

Yesterday, I napped from ___ to ___ (Note the times of all naps)


Yesterday, I took ___ mg of medication and/or ___ oz ___ of alcohol as sleep aid


Last night, I went to bed and turned the lights off at ___ o’clock

11:15 pm


After turning the lights off, I fell asleep in ___ minutes

40 min


My sleep was interrupted ___ times (Specify number of nighttime awakenings)



My sleep was interrupted for ___ minutes (Specify duration of each awakening)

10 min (45 min)


This morning, I woke up at ___ o’clock (Note time of last awakening)

6:15 am


This morning, I got out of bed at ___ o’clock (Specify the time)

6:40 am


When I got up this morning I felt ___ (1 ¼ Exhausted, 2 ¼ Fair, 3 ¼ Refreshed)



Overall, my sleep last night was ___ (1 ¼ Restless, 2 ¼ Fair, 3 ¼ Very Sound)









1:50 to 2:30 pm

Reproduced by permission of Guilford Press from Morin (1993).

and the difficulty in determining the relative onset and course of these different coexisting conditions. In clinical practice, the main differential diagnosis is usually between primary insomnia and insomnia comorbid with anxiety (generalized anxiety disorder; GAD) or depression (dysthymia or major depression). This distinction is not always clear as several symptoms (e.g., sleep disturbance, fatigue, mood and cognitive problems) overlap among those conditions. Excessive worrying is the predominant feature of GAD; this characteristic is also present in primary insomnia, but its main focus is limited to insomnia and its potential consequences, whereas in GAD worrying is about multiple sources (e.g., health, family, work). In depression, the predominant clinical feature is sadness and a significant loss of interest. In primary insomnia, the interest is present but there is a lack of energy or fatigue, presumably resulting from sleep disturbances, preventing the individual from

engaging in potentially pleasurable activities or social interactions. In addition to the nature of the symptoms, the history should also identify the relative onset and course of each condition in order to determine whether insomnia is primary or secondary in nature.

TREATMENT The first step in treating symptomatic insomnia is to identify and remove the contributing factors. General sleep hygiene recommendations are also useful as preventive strategies. Specific insomnia therapies include psychological and behavioral interventions, medications, and a variety of complementary and alternative therapies (e.g., acupuncture, yoga, herbal therapies). The rest of this chapter focuses on psychological/behavioral and pharmacological therapies; most of the alternative therapies have not been evaluated adequately with regard to their efficacy and safety in the management of insomnia.



Table 45.5 Insomnia Severity Index (ISI) For each question below, please circle the number corresponding most accurately to your sleep patterns in the LAST MONTH. For the first three questions, please rate the SEVERITY of your sleep difficulties. 1.

Difficulty falling asleep: None 0


Moderate 2

Severe 3

Very Severe 4

Mild 1

Moderate 2

Severe 3

Very Severe 4

Satisfied 1

Neutral 2

Dissatisfied 3

Very Dissatisfied 4

A Little Interfering 1

Somewhat Interfering 2

Much Interfering 3

Very Much Interfering 4

How NOTICEABLE to others do you think your sleeping problem is in terms of impairing the quality of your life? Not at all Noticeable 0


Mild 1

To what extent do you consider your sleep problem to INTERFERE with your daily functioning (e.g., daytime fatigue, ability to function at work/daily chores, concentration, memory, mood). Not at all Interfering 0


Very Severe 4

How SATISFIED/dissatisfied are you with your current sleep pattern? Very Satisfied 0


Severe 3

Problem waking up too early in the morning: None 0


Moderate 2

Difficulty staying asleep: None 0


Mild 1

A Little Noticeable 1

Somewhat Noticeable 2

Much Noticeable 3

Very Much Noticeable 4

How WORRIED/distressed are you about your current sleep problem? Not at all 0

A Little 1

Somewhat 2

Much 3

Very Much 4

Guidelines for Scoring/Interpretation: Add scores for all seven items ¼ _____ Total score ranges from 0–28 0–7 ¼ No clinically significant insomnia 8–14 ¼ Subthreshold insomnia 15–21 ¼ Clinical insomnia (moderate severity) 22–28 ¼ Clinical insomnia (severe) # Morin, C.M. (1993, 2006).

Psychological and behavioral therapies TREATMENT


Psychological and behavioral therapies for insomnia include sleep restriction, stimulus control therapy, relaxation-based interventions, cognitive strategies, sleep hygiene education, and combined cognitive and behavioral therapy. A summary of these interventions is provided below and in Table 45.6; more extensive descriptions are available in other sources (Morin and Espie, 2003). The main objectives of psychological and behavioral approaches are to alter the factors that

perpetuate or exacerbate sleep disturbances. Such features may include hyperarousal, sleep-scheduling factors, poor sleep habits, and misconceptions about sleep and the consequences of insomnia. Although numerous factors can precipitate insomnia, when it becomes a persistent problem, psychological and behavioral factors are almost always involved in perpetuating it over time, hence the need to target those factors directly in treatment (Spielman and Glovinsky, 1991). The primary indication for behavioral treatment is in the management of persistent insomnia, with evidence available for both primary and comorbid insomnia.



Table 45.6 Psychological and behavioral treatments for primary insomnias Therapy


Stimulus control therapy

A set of instructions designed to strengthen the association between the bed/bedroom with sleep and to re-establish a consistent sleep–wake schedule: (1) Go to bed only when sleepy; (2) get out of bed when unable to sleep; (3) use the bed/bedroom for sleep only (no reading, watching TV, etc.); (4) arise at the same time every morning; (5) no napping A method designed to restrict time spent in bed as close as possible to the actual sleep time, thereby producing mild sleep deprivation. Time in bed is then gradually increased over a period of few days/weeks until optimal sleep duration is achieved Clinical procedures aimed at reducing somatic tension (e.g., progressive muscle relaxation, autogenic training) or intrusive thoughts (e.g., imagery training, meditation) interfering with sleep. Most relaxation requires some professional guidance initially and daily practice over a period of a few weeks Psychotherapeutic method aimed at reducing worry and changing faulty beliefs and misconceptions about sleep, insomnia, and daytime consequences. Other cognitive strategies can also be used to control intrusive thoughts at bedtime and reduce excessive monitoring of the daytime consequences of insomnia General guidelines about health practices (e.g., diet, exercise, substance use) and environmental factors (e.g., light, noise, temperature) that may promote or interfere with sleep. This may also include some basic information about normal sleep and changes in sleep patterns with aging A combination of any of the above behavioral (e.g., stimulus control, sleep restriction, relaxation) and cognitive procedures

Sleep restriction therapy Relaxation training

Cognitive therapy

Sleep hygiene education Cognitive–behavioral therapy (CBT)



Poor sleepers often increase their time in bed in a misguided effort to provide more opportunity for sleep, a strategy that is more likely to result in fragmented and poor-quality sleep. Sleep restriction consists of curtailing the amount of time spent in bed to the actual amount of sleep (Spielman et al., 1987). For example, if a person reports sleeping an average of 6 hours per night out of 8 hours spent in bed, the initial sleep window (i.e., from initial bedtime to final arising time) would be set at 6 hours. Subsequent adjustments to this “sleep window” are based on sleep efficiency (SE) for a given period of time (usually the preceding week); time in bed is increased by about 20 minutes for a given week when SE exceeds 85%, decreased by the same amount of time when SE is lower than 80%, and kept stable when SE falls between 80% and 85%. Periodic (weekly) adjustments are made until optimal sleep duration is achieved. Changes to the prescribed sleep window can be made at the beginning of the night (i.e., postponing bedtime), at the end of the sleep period (i.e., advancing arising time), or at both ends. To prevent excessive daytime sleepiness, time in bed should not be reduced to fewer than 5 hours per night in bed. This procedure leads to improvements in sleep continuity through a mild sleep deprivation and reduction of sleep anticipatory anxiety. Caution is needed when using sleep restriction with patients operating heavy equipments or who are required to drive

long distances (e.g., truck drivers). Sleep restriction is contraindicated in patients with bipolar disorder, seizures, or with some parasomnias (sleep-walking, night terrors) (Smith and Perlis, 2006).



Individuals with insomnia may develop apprehension around bedtime and come to associate the bedroom with frustration and arousal rather than with sleep. Stimulus control therapy (Bootzin et al., 1991) consists of a set of instructions designed to strengthen the association between temporal (bedtime) and environmental (bed and bedroom) stimuli and rapid sleep onset, and to establish a regular circadian sleep–wake rhythm. These instructions are: ● ●

● ● ●

Go to bed only when sleepy. Get out of bed when unable to sleep (e.g., after 20 min), going to another room and returning to bed only when sleep is imminent. Curtail all sleep-incompatible activities (i.e., no TV watching, problem-solving in bed). Arise at a regular time every morning regardless of the amount of sleep the night before. Avoid daytime napping.

Despite the straightforward nature of these recommendations, the main challenge for most patients is to comply with all of them, which is essential to reverse

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT the conditioning processes perpetuating insomnia. Caution is advised in using some of these procedures (e.g., getting out of bed when unable to sleep) with the frail elderly, who may be at risk for falls.



Relaxation is probably the most commonly used nondrug therapy for insomnia. Some relaxation methods (e.g., progressive muscle relaxation) focus primarily on reducing somatic arousal (e.g., muscle tension), whereas attention-focusing procedures (e.g., imagery training, meditation) target mental arousal in the forms of worries or intrusive thoughts. Most of these methods are equally effective for treating insomnia. The most critical issue is to practice diligently and daily the selected method for at least 2–4 weeks. Professional guidance is often necessary in the initial phase of training.



This psychotherapeutic method seeks to alter dysfunctional sleep cognitions (e.g., beliefs, expectations, attributions) and maladaptive cognitive processes (e.g., excessive self-monitoring) through Socratic questioning and behavioral experiments. The basic premise of this approach is that appraisal of a given situation (sleeplessness) and excessive monitoring of sleeprelated cues (e.g., fatigue, time left for sleep) can trigger an emotional response (fear, anxiety) that is incompatible with sleep. For example, when a person is unable to sleep at night and worries about the possible consequences of sleep loss on the next day’s performance, this can set off a spiral reaction and feed into the vicious cycle of insomnia, emotional distress, and more sleep disturbances. Cognitive therapy is designed to identify dysfunctional cognitions and reframe them into more adaptive substitutes in order to short-circuit the self-fulfilling nature of this vicious cycle. Treatment targets may include unrealistic expectations (“I must get my 8 hours of sleep every night”) and amplification of the consequences of insomnia (“Insomnia may have serious consequences on my health”) (Morin and Espie, 2003). Cognitive therapy is particularly useful to modify these maladaptive cognitions and to teach patients more adaptive skills to cope with insomnia (Harvey et al., 2007).



Sleep hygiene education is intended to provide information about lifestyle (diet, exercise, substance use) and environmental factors (light, noise, temperature) that may either interfere with or promote better sleep. Sleep


hygiene guidelines include: (a) avoiding stimulants (e.g., caffeine) for several hours before bedtime; (b) avoiding alcohol around bedtime as it fragments sleep; (c) exercising regularly (especially in late afternoon or early evening) as it may deepen sleep; (d) allowing at least a 1-hour period to unwind before bedtime; (e) keeping the bedroom environment quiet, dark, and comfortable. In addition to these guidelines, it is useful to provide basic information about normal sleep, individual differences in sleep needs, and changes in sleep physiology over the course of the lifespan. This information is particularly useful to help some patients distinguish clinical insomnia from short sleep or from normal (age-related) sleep disturbances. Although inadequate sleep hygiene is rarely the primary cause of insomnia, it may potentiate sleep difficulties caused by other factors or interfere with treatment progress. Addressing these factors should be an integral part of insomnia management, even though it is rarely sufficient for more severe insomnia, which often requires more directive and potent behavioral interventions.



Despite some unique features, the interventions described above can be combined together effectively. There is a general preference among investigators and clinicians for combining multiple interventions, with CBT becoming the standard approach in the field (Morin et al., 2006). The most common combination involves a behavioral (stimulus control, sleep restriction, and, sometimes, relaxation), a cognitive, and an educational (sleep hygiene) component, usually referred to as CBT. Such a combination is often preferred to address the different components presumed to perpetuate insomnia.

Evidence for efficacy, durability, and generalizability EVIDENCE


Several meta-analyses (Morin et al., 1994a; Murtagh and Greenwood, 1995; Smith et al., 2002) and systematic reviews commissioned by the American Academy of Sleep Medicine (Morin et al., 1999b, 2006) have summarized the findings from clinical trials evaluating the efficacy of psychological and behavioral therapies for persistent insomnia. Evidence from these sources shows that treatment produces reliable changes in several sleep parameters, including sleep-onset latency (effect sizes ranging from 0.41 to 1.05), number of awakenings (0.25–0.83), duration of awakenings (0.61–1.03), total sleep time (0.15–0.49), and sleep quality ratings (0.94–1.14). Based on Cohen’s criteria, the

732 C.M. MORIN AND R.M. BENCA magnitude of those therapeutic effects is large (i.e., over time, with data available up to 24 and even 36 d > 0.8) for sleep latency and sleep quality, and modmonths after treatment completion. Although intervenerate (i.e., d > 0.5) for other sleep parameters. When tions that restrict the amount of time spent in bed may transformed into a percentile rank, these data indicate yield only modest increases (and even a reduction) of that approximately 70–80% of patients with insomnia sleep time during the initial treatment period, this achieve a therapeutic response with psychological and parameter is usually improved at follow-up, with total behavioral therapies. sleep time often exceeding 6.5 hours. Long-term outIn terms of absolute changes, treatment reduces come must be interpreted cautiously, however, as few subjective sleep-onset latency and time awake after studies report long-term follow-up and, among those sleep onset from averages of 60–70 min at baseline that do, attrition rates increase over time. In addition, to about 35 min following treatment, and total sleep a substantial proportion of patients with chronic time is increased by 30 min, from 6 to 6.5 h after treatinsomnia who benefit from short-term therapy may ment. Thus, for the average patient with insomnia, remain vulnerable to recurrent episodes of insomnia treatment effects may be expected to reduce sleep in the long term. As such, there is a need to develop latency and time awake after sleep onset by about and evaluate the effects of long-term, maintenance, 50% and to bring the absolute values of those sleep therapies to prevent or minimize the occurrence of parameters below or near the 30-min cutoff criterion those episodes. initially used to define insomnia. Treatment effects are similar for sleep-onset and sleep-maintenance proTREATMENT OF COMORBID INSOMNIA blems, although fewer studies have targeted the later Insomnia is often a pervasive problem among patients type and, particularly, early-morning awakening prosuffering from other medical and psychiatric condiblems. Overall, findings from meta-analyses represent tions (Taylor et al., 2007b). Although sleep may fairly conservative estimates of treatment effects as improve with appropriate treatment of the comorbid they are based on averages computed across all noncondition, sleep disturbances are also likely to persist. pharmacological interventions and insomnia diagnoses Thus, the presence of a comorbid medical or psychiat(i.e., primary and comorbid). On the other hand, ric disorder should not preclude using a behavioral although the majority of patients benefit from treatintervention concomitantly, as behavioral factors are ment, only 20–30% achieve clinical remission (Morin often involved in perpetuating or even exacerbating et al., 1999b, 2006). the sleep problem. Evidence from clinical case series Treatment outcome has been documented primarily (Morin et al., 1994b; Dashevsky and Kramer, 1998; with prospective daily sleep diaries, although several Taylor et al., 2007a) suggests that patients with medistudies have also complemented those findings with cal and psychiatric conditions can also benefit from data from PSG (Morin et al., 1999a; Edinger et al., insomnia-specific treatment (Smith et al., 2005). 2001) and wrist actigraphy (Edinger et al., 2007; Espie Controlled studies have also shown that behavioral et al., 2007). In general, the magnitude of improvetreatment is effective for insomnia associated with ments is smaller on PSG measures, but those changes chronic pain (Currie et al., 2000), fibromyalgia (Edinger tend to parallel sleep improvements reported in daily et al., 2005), cancer (Savard et al., 2005; Espie et al., sleep diaries. PSG findings indicate that treatment 2008), and various medical conditions in older adults does not only alter sleep perception, as measured by (Lichstein et al., 2000; Rybarczyk et al., 2005). In patient reported outcomes, but also produces objective general, insomnia symptoms are more severe among changes on EEG sleep continuity measures. Except for patients with comorbid disorders, but the absolute a modest increase in stages 3–4 following sleep restricchanges in those outcomes during treatment are tion, there is little evidence of changes in sleep archicomparable to those obtained with primary insomnia. tecture with psychological and behavioral treatment. Insomnia in older adults is more likely to be comorIn addition to improving sleep continuity parameters, bid with another medical or another sleep disorder than there is also some evidence showing improvements on to be primary in nature. Recent studies have shown several secondary endpoints, including measures of that older adults respond to insomnia treatment, particdaytime fatigue, quality of life, and psychological ularly when they are screened for other sleep disorders symptoms (Morin et al., 2006; Espie et al., 2007). that increase in incidence in older age (e.g., restless legs syndrome, sleep apnea). A meta-analysis (Irwin LONG-TERM OUTCOMES et al., 2006) suggested that effect sizes were comparaA fairly robust finding across behavioral treatment ble (moderate to large) for middle-aged and older studies is that sleep improvements are well maintained adults on subjective measures of sleep latency, wake

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT 733 after sleep onset, and sleep quality. Older adults with treatment is effective with all forms of insomnia or either comorbid medical or psychological conditions acceptable to all patients. Even among treatment can benefit from sleep-specific treatment (Lichstein responders, few patients achieve complete remission et al., 2000; Rybarczyk et al., 2002, 2005; Pallesen and some residual sleep disturbances often persist et al., 2003). Three clinical trials have shown that a after treatment. Thus, combined approaches should supervised and time-limited withdrawal program, with theoretically optimize outcome by capitalizing on the or without behavioral treatment for insomnia, can more immediate and potent effects of hypnotics and facilitate discontinuation of hypnotic medications the more sustained effects of behavioral interventions. among older adults with insomnia who are prolonged Only a few studies have directly compared the users (Morgan et al., 2003; Morin et al., 2004; Soeffing effects of behavioral and pharmacological therapies et al., 2008). for insomnia. Three studies compared triazolam with relaxation (McClusky et al., 1991; Milby et al., 1993) or sleep hygiene (Hauri, 1997), and four other investiWHICH INSOMNIA THERAPIES WORK BEST? gations compared CBT with temazepam (Morin et al., Although there has been no complete dismantling of 1999a), zolpidem (Jacobs et al., 2004), or zopiclone cognitive–behavioral therapies to isolate the relative (Vallieres et al., 2005b; Sivertsen et al., 2006a). Collecefficacy of each component, direct comparisons of tively, findings from these studies indicate that both some of those components indicate that sleep restrictherapies are effective in the short term, with medication, alone or combined with stimulus control therapy, tion producing faster results in the acute phase (first is more effective than relaxation, which, in turn, is week) of treatment, whereas both treatments are more effective than sleep hygiene education alone equally effective in the short-term interval (4–8 weeks). (Morin et al., 2006). Sleep restriction tends to produce Combined interventions appear to have a slight advana better outcome than stimulus control for improving tage over single treatment modality during the initial sleep efficiency and sleep continuity, but it also course of treatment, but it is unclear whether this decreases total sleep time during the initial intervenadvantage persists over time. Long-term effects are tion. Although some basic education about sleep consistent for the single treatment modalities; patients hygiene is incorporated to most insomnia treatments, treated with CBT maintain their improvement, whereas sleep hygiene education produces little impact on sleep therapeutic effects are typically lost after discontinuawhen used as the only intervention. A recent study tion of medication. Long-term effects of combined showed that cognitive therapy alone can be effective interventions are more equivocal. Some studies indiin the management of insomnia (Harvey et al., 2007). cate that a combined intervention (triazolam plus There is no strong evidence that a multicomponent relaxation) produces more sustained benefits than approach is more effective than any of its single compomedication alone (McClusky et al., 1991; Milby et al., nents. However, the appeal for this multimodal approach 1993), whereas others report more variable long-term may come from the fact that it addresses different facets outcomes (Hauri, 1997; Morin et al., 1999a). Some presumed to perpetuate sleep disturbances. Although litpatients retain their initial sleep improvement, but tle information is available about the active treatment others return to baseline values. As behavioral and attimechanisms of CBT, some evidence suggest that stimutudinal changes are often essential to sustain sleep lus control and sleep restriction are particularly effective improvements, patients’ attributions of the initial benefor improving sleep continuity, whereas changes in sleepfits may be critical in determining long-term outcomes. related cognitions are associated with better maintenance Attribution of therapeutic benefits to the hypnotic of sleep changes over time (Morin et al., 2002). With alone, without integration of self-management skills, increasing evidence that hyperarousal is implicated in may place a patient at greater risk for recurrence primary insomnia, there is a need for greater attention of insomnia once medication is discontinued. Thus, to identify the biological, as well as the psychological, despite the intuitive appeal of combining behavioral mechanisms responsible for sleep changes. and medication therapies, it is not entirely clear when, how, and for whom it is indicated to combine these treatment modalities for insomnia. Additional research Combined behavioral and pharmacological is needed to evaluate the effects of combined treatapproaches ments and to examine optimal methods for integrating Behavioral and pharmacological therapies can play a these therapies. complementary role in the management of insomnia. Comparisons of effect sizes from meta-analyses There are some practical and clinical reasons for con(Morin et al., 1994a; Nowell et al., 1997; Smith et al., sidering combining therapies. For example, no single 2002) on different sleep variables indicate that


Table 45.7 Drugs used to promote sleep


Dose range (mg) (dose range in the elderly)

Effects on sleep

Adverse effects

Increased total sleep time, stage 2%, REM latency Decreased sleep latency, WASO, stage 1%, SWS %, REM%

Dizziness, drowsiness, hypokinesia, dyskinesia, abnormal or impaired coordination, slurred speech, ataxia, amnesia, GI symptoms. Rebound/withdrawal effects more pronounced with shorter-acting agents


15–30 (15)

1.5–5.5 6–16 10–24 Quazepam and 2-oxoquazepam: 25–41 N-desakyl-1oxoquazepam: 70–75 47–100

Nonbenzodiazepines Zaleplon Zolpidem Zolpidem CR Eszopiclone

10–20 (5–10) 10 (5) 6.25–12.5 (6.25) 2–3 (1–2)

1 1.4–4.5 2.8 5–5.8

Dizziness, drowsiness, amnesia, GI symptoms. Zaleplon also can cause myalgia and headache Eszopiclone has an unpleasant taste and can cause dry mouth

Melatonin receptor agonist Ramelteon

Decreased sleep latency Eszopiclone, Indiplon (10–15-mg doses) : decreased WASO Zolpidem CR: decreased WASO during first 6 h

8 (8)


Sleep latency #

Antidepressants Amitriptyline

Drowsiness, dizziness, fatigue. Do not use with fluvoxamine, ketoconazole, or fluconazole

50–100* (20 mg)


75–100* (25–50)

10–28, including metabolite nortriptyline 8–24


15–45* (7.5–15)


Drowsiness, dizziness, confusion, blurred vision, dry mouth, constipation, urinary retention, arrhythmias, orthostatic hypotension, weight gain. Exacerbation of restless legs, periodic limb movements or REM sleep behavior disorder Drowsiness, dizziness, increased appetite, constipation, weight gain, agranulocytosis (rare)


150–400* (150)


Total sleep time " Sleep latency # Stage 2% " REM% # REM latency: " Total sleep time: " Sleep latency: # WASO: # Sleep latency # WASO # SWS% "

Drowsiness, dizziness, headache, blurred vision, dry mouth, arrhythmias, orthostatic hypotension, priapism


Benzodiazepine receptor agonists Benzodiazepines Triazolam 0.25–0.5 (0.125–0.25) Temazepam 7.5–30 (7.5) Estazolam 1–2 (0.5) Quazepam 7.5–15 (7.5)

Half-life (hours)

300–600* (300)


WASO $ to # SWS% "


4–8* (4)




50–100* (25–50)


Sleep latency # SWS% "

Antipsychotics Olanzapine

5–10* (5)


Sleep latency $ to # WASO # SWS% " REM% $ to #


25–200* (25)


Insufficient data

Diphenhydramine chloride: 50* Diphenhydramine citrate: 76* (25 mg) 2.5 mg evaluated in the elderly, but no standard dosage determined empirically


Sleep latency # WASO $ to # SWS% $ to " REM% # Sleep latency #

Over-the-counter agents Diphenhydramine



*Recommended maximum amounts for a single dose. $, no change; ", increase; #, decrease. GI, gastrointestinal; REM, rapid eye movement; SWS, slow-wave sleep; WASO, wake after sleep onset.

Drowsiness, dizziness, emotional lability, ataxia, tremor, blurred vision, diplopia, nystagmus, myalgia, peripheral edema Drowsiness, dizziness, ataxia, tremor, new-onset seizures in patients without epilepsy, difficulty with concentration or attention, nervousness, asthenia, abdominal pain, diarrhea, nausea Drowsiness, dizziness, ataxia, confusion, peripheral edema Drowsiness, dizziness, tremor, agitation, asthenia, extrapyramidal symptoms, dry mouth, dyspepsia, constipation, orthostatic hypotension, weight gain, new-onset diabetes mellitus, tardive dyskinesia and neuroleptic malignant syndrome

Drowsiness, dizziness, dyskinesias, dry mouth, epigastric distress, constipation. Tachycardia, risk of delirium and falls in elderly Concentration difficulty, dizziness, fatigue, headache, irritability


Anticonvulsants Gabapentin




behavioral therapy may have a slight advantage on measures of sleep-onset latency and sleep quality, and pharmacotherapy (benzodiazepine receptor agonists) a more favorable outcome on total sleep time. One recent study examined different sequences of CBT and medication therapies (Vallieres et al., 2005b). The best results were obtained when CBT was introduced first in the sequence, but medication was found helpful to improve total sleep time, which may be an important advantage given that one component of CBT (sleep restriction) reduces total sleep time during the initial course of therapy and could lead some patients to premature therapy discontinuation. Until more evidence-based treatment guidelines become available, several strategies can be considered for selecting the most appropriate treatment in the clinical management of insomnia. The use of hypnotic medication may be indicated particularly in the initial stage of therapy to break the vicious cycle of insomnia and to provide some rapid relief. On the other hand, CBT is essential to alter perpetuating factors and to teach coping skills. As such, it is an essential treatment component to maximize durability of sleep improvements. Ideally, hypnotic medications should be discontinued, under supervision, after an initial treatment course of a few weeks. However, given that insomnia may be a recurrent problem, even among those who benefit from treatment initially, it may be necessary to use medications intermittently after the initial acute treatment phase.

Pharmacotherapy A variety of medications are used for insomnia (Table 45.7), including both over-the-counter (OTC) and prescription agents; however, many of these are not approved by the US Food and Drug Administration (FDA) for the treatment of insomnia. Current FDA-approved insomnia medications include a group of benzodiazepine receptor agonists and one melatonin receptor agonist. Although not FDA-approved for treatment of insomnia, sedating antidepressants have been prescribed widely for insomnia; as recently as 2002, three of the top four most commonly prescribed medications for insomnia were sedating antidepressants (Walsh, 2004b). Other classes of prescription medication used for their potential sleep-inducing side-effects include atypical antipsychotics and anticonvulsants. According to population-based studies, almost twice as many individuals with insomnia self-medicate than take prescription medications (Johnson et al., 1998; Roehrs et al., 2002). Polls by the National Sleep Foundation have found that 16–28% of adults have used

alcohol and 22–29% have used OTC agents for sleep at some point during their life (National Sleep Foundation, 1991, 1995). In general, patients who self-medicate with alcohol or OTC agents tend to do so for shorter periods of time and have less severe insomnia than those who take prescription medications (Johnson et al., 1998).




The current FDA-approved BzRAs for insomnia include the older benzodiazepines (estazolam, flurazepam, quazepam, temazepam, triazolam) and the newer nonbenzodiazepines (eszopiclone, zaleplon, zolpidem) (see Table 45.7). These medications all bind to the GABA, type A, receptor complex. Benzodiazepines bind to all subtypes of GABAA receptor, whereas some of the newer nonbenzodiazepines, particularly zaleplon and zolpidem, bind preferentially to the type I GABAA receptor. The type I receptor is thought to mediate both the hypnotic and amnestic effects of BzRAs, but drugs acting selectively on this receptor may be less effective as muscle relaxants or anxiolytics. All BzRAs have the potential to produce amnesia. Benzodiazepines Benzodiazepine hypnotics, with the exception of triazolam, have relatively long half-lives. These agents (estazolam, flurazepam, quazepam, and temazepam) all reduce latency to sleep onset and tend to improve sleep maintenance, as indicated by decreased waking time after sleep onset, reduced number of awakenings, and/ or increased total sleep time (Aden and Thatcher, 1983; Hernandez Lara et al., 1983; Melo de Paula, 1984; Roehrs et al., 1986; Scharf et al., 1990; Cohn et al., 1991; Holbrook et al., 2000b). Triazolam also promotes sleep onset, but because of its short half-life does not appear to be as helpful for sleep maintenance (Ngen and Hassan, 1990; Kales et al., 1991). Benzodiazepines decrease time spent in stage 1 sleep and increase stage 2 sleep, but they also tend to suppress slow-wave sleep and, possibly, rapid eye movement (REM) sleep. Adverse effects of benzodiazepine hypnotics include daytime sedation, cognitive and psychomotor impairment, and memory impairment ( Ngen and Hassan, 1990; Holbrook et al., 2000b); such effects are more common with higher doses and longer-acting agents. Abrupt withdrawal may be associated with rebound insomnia (Kales et al., 1991; Mauri et al., 1993). As noted above, benzodiazepine hypnotics are indicated for the short-term treatment of insomnia. None has been studied in a randomized clinical trial for more than 12 weeks (Allen et al., 1987), so long-term efficacy data are not available.

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT 737 maintenance, and evidence of better next-day function, Nonbenzodiazepines as indicated by subjective reports of improved concenThe nonbenzodiazepine BzRAs include those with short tration and decreased morning sleepiness. half-lives (zaleplon and zolpidem) that are indicated priEszopiclone was the first hypnotic to be indicated for marily for promoting sleep onset, and those with either the treatment of insomnia without recommendations a longer half-life (eszopiclone) or controlled-release forfor restricted duration of use. It has a longer half-life mulations (zolpidem MR) that reduce sleep latency and than any of the other nonbenzodiazepines, which improve sleep maintenance. Zaleplon, with the shortest accounts for its effects on improving sleep maintehalf-life of currently available agents at about 1 hour, nance. In a 6-month placebo-controlled clinical trial, it may be dosed as long as the patient has at least 4 hours showed persistent efficacy in reducing latency to sleep remaining in bed; healthy volunteers did not demonstrate onset, decreasing wakefulness during sleep, and next-day impairment in driving ability, memory, or increasing total sleep time, as reported subjectively psychomotor function when tested 4–6 h after ingestion (Krystal et al., 2003). In another 6-month double-blind of 10–20 mg zaleplon (Verster et al., 2002). Although study, eszopiclone was shown not only to reduce insom5–10-mg doses of zaleplon primarily promote sleep nia, but also to enhance quality-of-life measures and onset, a dose of 20 mg increased subjective total reduce reported work limitations (Walsh et al., 2007). sleep time (Elie et al., 1999; Fry et al., 2000). It is also one of the first agents for which data suggest Zolpidem is currently the most commonly preimproved daytime function and/or decreased comorbidscribed sleep agent. It is effective in promoting sleep ity from other disorders. Elderly patients with insomnia onset, and also increases total sleep time at doses of taking 2 mg eszopiclone reported reduced daytime nap10 mg or above in both subjective and sleep laboratory ping (Scharf et al., 2005), and depressed patients given studies (Scharf et al., 1994). The increase in sleep effia combination of fluoxetine plus eszopiclone had ciency and/or total sleep is likely due to reduced sleep better sleep and higher rates of response and remission latency, as consistent effects on waking time after 8 weeks later in comparison with depressed patients sleep onset have not been observed. A 12-week, given fluoxetine plus placebo (Fava et al., 2006). placebo-controlled study demonstrated that intermittent use (three to five times per week) of zolpidem was associated with continued benefit on the night Efficacy of BzRAs the drug was taken and no obvious evidence of Several meta-analyses have assessed the efficacy of rebound insomnia on the nights it was not taken (Perlis BzRA hypnotics in comparison with placebo in the et al., 2004). Zolpidem has also been shown to be treatment of chronic insomnia. In a review of studies effective in subjects with depression treated with selecperformed on adults aged less than 65 years, benzodiative serotonin reuptake inhibitors (SSRIs), resulting in zepines and zolpidem were shown to produce signifisubjective increased total sleep, and improved sleep cant subjective improvement in sleep latency, total quality and daytime function (Asnis et al., 1999). Doses sleep, number of awakenings, and sleep quality, with of 10 mg zolpidem administered during the night did moderate effect sizes, ranging from 0.56 to 0.71 not lead to clinically significant effects on driving or (Nowell et al., 1997). A meta-analysis of studies performed psychomotor skills the next day, at least 4–6 h after on adults and elderly adults showed that benzodiazepines ingestion, in healthy subjects or insomnia patients produced significant improvements in both subjective (Verster et al., 2002; Staner et al., 2005), but higher and objective sleep parameters; sleep latency was reduced doses produced significant impairment (Verster et al., by 4.2 min objectively and 14.3 min subjectively, and 2002). The delayed-release zolpidem MR offers a lontotal sleep amount was increased by 61.8 min objectively ger duration of action with the same short half-life; and 48.4 min subjectively (Holbrook et al., 2000a, b). the dual-layer tablet consists of shell containing 7.5 mg Another analysis of drug effects in elderly insomnia immediate-release zolpidem and a core containing patients showed significant improvement in sleep qual5 mg delayed-release zolpidem for a total of 12.5 mg. ity (effect size 0.14), increased total sleep (25.2 min), A half-dose (6.25 mg) tablet contains 3.75 mg immediand decreased awakenings (effect size 0.63) with sedaate/2.5 mg delayed release. A recent double-blind, tive use compared with placebo (Glass et al., 2005). placebo-controlled, multicenter study showed clinical A comparison of benzodiazepine hypnotics with nonefficacy with zolpidem MR at a dose of 12.5 mg for benzodiazepines concluded that zolpidem may have up to 6 months when taken for 3–7 nights per week, benefits over temazepam in reducing sleep latency without significant rebound insomnia upon discontinuaand improving sleep quality, and over zaleplon in tion (Krystal et al., 2008). Subjects who took medication increasing sleep duration and improving sleep quality reported shorter sleep-onset latencies, improved sleep (Dundar et al., 2004). Zaleplon, however, may produce



less rebound insomnia than zolpidem. This analysis was limited, however, by the lack of directly comparative studies and short duration of the studies, which makes it difficult to assess longer-term effects. BzRA side-effects A number of adverse outcomes have been associated with drugs in this class. Sedation/daytime “hangover”, and impaired cognitive and psychomotor performance can be seen at peak blood levels, and may occur the following day with longer-acting agents (Verster et al., 2004). Anterograde amnesia, or loss of memory for events that occur after taking a hypnotic, is more common with higher doses and with drugs with rapidly increasing plasma levels, such as triazolam and the nonbenzodiazepines, or when combining BzRAs with alcohol. Confusional arousals or sleepwalking episodes may be a related phenomenon. BzRAs should therefore always be taken immediately prior to bedtime to minimize the risk of amnesia or parasomnias, and discontinued in patients who report these side-effects. All medications used for sleep, including BzRAs, but also antidepressants and anticonvulsants, can increase the risk of nighttime falls in elderly patients (Mendelson, 1992; Wang et al., 2001; Kelly et al., 2003). However, insomnia is an independent predictor of falls in the elderly (Brassington et al., 2000), and one study has suggested that insomnia, but not hypnotic use, was associated with a greater risk of falls (Avidan et al., 2005). Other side-effects associated with BzRAs include tolerance, rebound insomnia, abuse, and withdrawal. Rebound insomnia is generally seen for not more than 1–2 days, and not in all studies. Although concerns about tolerance may lead physicians and patients to limit use of these agents, the few longer-term studies that have been performed with eszopiclone, zolpidem, and zaleplon have, in fact, not shown evidence of obvious tolerance (Asnis et al., 1999; Walsh et al., 2000, 2007; Perlis et al., 2004). Abuse and dependence of BzRAs may occur in those with a history of substance abuse, and BzRAs should be avoided in those with a tendency to abuse substances. The risk is generally overestimated for those without such a history; patients with insomnia tend to show therapy-seeking, not drug-seeking, behavior (Mendelson et al., 2004). A recent attempt to assess risks and benefits for BzRAs in the treatment of insomnia concluded that, although these agents improved sleep, they also led to adverse effects in comparison to placebo (Holbrook et al., 2000a, b). These adverse effects, including increased daytime drowsiness (odds ratio 2.4) and dizziness or lightheadedness (odds ratio 2.6), did not, however, lead to increased rates of discontinuation of

hypnotics. A study of the use of BzRAs in elderly patients with insomnia, however, raised concerns that there were significant risks of both benzodiazepines and nonbenzodiazepines, including adverse cognitive events (4.78 times more common), adverse psychomotor events (2.61 times more common), and daytime fatigue (3.82 times more common) (Glass et al., 2005). The authors concluded that, in elderly patients, the risks of BzRAs might outweigh the benefits in some cases. Indications and limitations The benzodiazepines zolpidem and zaleplon are indicated for the “short-term treatment of insomnia”, whereas eszopiclone and zolpidem MR are indicated for the “treatment of insomnia”, without language-limiting duration of use. BzRAs should not be used during pregnancy (all are category C) or in those with a history of substance abuse. They should be used with caution in patients with pulmonary or liver disease, and in the elderly; dosage reductions at least are recommended in these populations. No hypnotics are approved for use in children under 18 years of age.



Melatonin, a hormone produced by the pineal gland, is available as an OTC preparation and has been used widely for insomnia and related sleep problems. Currently ramelteon is the only melatonin receptor agonist available for the treatment of insomnia and is available by prescription. These agents presumably act through their effects on melatonin receptors in the suprachiasmatic nucleus in the brain, although their exact mechanism has not been determined. Melatonin OTC melatonin preparations are absorbed rapidly and have a short half-life (up to 1 h). They are not regulated by the FDA. Melatonin’s hypnotic effects appear to be smaller than those of BzRAs; a recent meta-analysis showed an average decrease in sleep latency of 4 min (Brzezinski, 1997). Several studies have demonstrated that low doses of melatonin (300–500 mg) were effective in producing phase shifts in normal subjects and entraining circadian rhythms in blind individuals (Lewy et al., 1992, 2005; Sack et al., 2000). Melatonin does not appear to have obvious side-effects, other than sedation. Ramelteon Ramelteon, currently the only FDA-approved hypnotic that is not a BzRA, is an agonist of melatonin type 1 and 2 receptors and is structurally unrelated to melatonin; it does not show affinity for the GABA receptor

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT complex or for other receptors thought to be involved in sleep or wakefulness. It has a relatively short halflife (2.6 h) and its metabolite also acts as an melatonin receptor type 1 (MT1)/MT2 agonist. Ramelteon’s most robust sleep effects are the reduction of latency to sleep onset, and it is therefore indicated for the treatment of insomnia characterized by difficulty with sleep onset. It has also been reported to increase total sleep time in some studies (Erman et al., 2006), but it does not appear to decrease wakefulness after sleep onset. The main side-effects of ramelteon are somnolence, dizziness, and fatigue. Important distinctions from the BzRA class include no evidence of tolerance, withdrawal, rebound insomnia, cognitive or psychomotor impairment, or daytime sedation, and it is therefore not classified as a controlled substance by the FDA (Buysse et al., 2005). There are no data at present regarding its efficacy in treating circadian rhythm disorders. Ramelteon may not be as efficacious for insomnia as some of the BzRAs, but other factors make it an attractive alternative for many patients: its low toxicity and wide safety margin; few to no adverse effects; and its ability to be used in patients with a history of substance abuse and a variety of medical disorders, including mild to moderate pulmonary disease. It should not be used in combination with fluvoxamine or other potent inhibitors of cytochrome P450 1A2, because this leads to dramatically increased levels of ramelteon. It is not recommended for use in pregnant women.



In 2007, the FDA introduced a change in label for hypnotics, including benzodiazepines, BzRAs, and ramelteon, based on rare but potentially serious adverse events that had been reported following ingestion of hypnotics (US Food and Drug Administration, 2007). These included severe allergic reactions and complex sleep-related behaviors, such as sleep-driving, sleepeating, and sleep-sex, in which individuals engaged in these activities without awakening fully. Such reactions are more likely to occur when hypnotics are combined with other sedatives, including alcohol, or taken at higher than recommended doses.



Despite a relative lack of data and no FDA indication for insomnia, sedating antidepressants, such as the tricyclics, trazodone and mirtazapine, are some of the most commonly used agents for treating chronic insomnia. In general, there are relatively few efficacy data regarding the use of these agents in primary insomnia.


Tricyclic antidepressants (TCAs) Amitriptyline and doxepin are some of the more commonly used TCAs in the treatment of insomnia (Walsh, 2004a). Their therapeutic effects in depression are related to inhibition of serotonin and norepinephrine reuptake, whereas their effects on sleep are probably mediated by their antagonistic effects on histamine type 1 (H1), serotonin type 2 (5HT2) and a-adrenergic type 1 receptors. TCAs have long half-lives, which often leads to daytime sedation and other adverse effects. In general, when used to promote sleep they are prescribed at doses lower than those recommended for treating depression. The effects of TCAs on sleep have been studied more frequently in patients with major depressive disorder, where they have been shown to reduce latency to sleep onset and increase sleep efficiency (Roth et al., 1982; Shipley et al., 1985). PSG studies in adults and elderly adults with primary insomnia showed that low doses of doxepin (1, 3, or 6 mg) led to improvements in objective sleep and subjective sleep maintenance and duration in comparison with placebo, with no evidence of sideeffects such as anticholinergic effects, hangover, or memory impairment (Roth et al., 2007; Scharf et al., 2008). TCAs at higher doses have profound effects on sleep architecture, most notably suppression of REM sleep (Obermeyer and Benca, 1996; Mayers and Baldwin, 2005). REM sleep rebound and sleep disturbance may thus occur following abrupt discontinuation of TCAs, making them less attractive for intermittent dosing. TCAs can also have adverse effects on sleep, including the exacerbation of restless legs syndrome or periodic limb movements, or precipitation of REM behavior disorder (Wilson and Argyropoulos, 2005). They can also induce hypomania or mania in patients with underlying bipolar disorder, which is generally associated with severe insomnia. All tricyclics have significant anticholinergic effects, which leads to many of their side-effects, including dry mouth, constipation, urinary retention, and sweating, although amitriptyline has the strongest effects. Orthostatic hypotension can result from a1-receptor antagonism, increasing the risk of falls. The TCAs also have quinidine-like effects on cardiac conduction, which can result in prolongation of the QT interval; cardiotoxicity is a major concern and these drugs have a high risk of fatality in overdosage. Although there are relatively few studies documenting its effects on sleep, trazodone has been one of the most frequently prescribed drugs for insomnia, and is probably used almost exclusively for this purpose at present, usually in doses of up to 100 mg at bedtime. Its popularity is probably due to its low cost, low abuse potential, and lack of restrictions on long-term use.



Its effects on sleep are probably due to its antihistaminergic effects at the H1 receptor, a1-receptor antagonism, and 5HT2 receptor antagonism. In several studies in depressed patients, trazodone administration resulted in reduced sleep latency, and increased sleep efficiency and total sleep (Mendelson, 2005). In the one double-blind, placebo-controlled study that has been performed in primary insomnia, trazodone 50 mg and zolpidem 10 mg were compared with placebo over a 2-week period (Walsh et al., 1998). During the first week, trazodone and zolpidem led to subjective reductions in sleep latency, increases in total sleep and sleep quality, and decreased wakefulness after sleep onset, but zolpidem produced a greater reduction in sleep latency than trazodone. During the second week, trazodone did not differ from placebo, whereas zolpidem still produced a significantly shorter sleep latency and more total sleep. There are insufficient data to conclude that trazodone does not lead to tolerance or rebound insomnia. Trazodone is associated with a number of frequent adverse effects, including daytime sedation/drowsiness, dizziness, dry mouth, gastrointestintal upset, blurred vision, and headache; these have led to fairly high discontinuation rates in clinical trials (Mendelson, 2005). Although less common, significant cardiovascular effects, such as orthostatic hypotension, prolonged QT interval, and cardiac arrhythmias may occur. Priapism, although quite rare, is a medical emergency and can occur even with low doses. One of the major metabolites of trazodone, meta-chlorophenylpeperazine (m-CPP), has serotonergic effects and may contribute to serotonin syndrome (confusion/delirium, hyperreflexia, autonomic instability) when trazodone is used in combination with other serotonergic agents. These potential side-effects raise concerns about using trazodone in elderly or medically ill populations. Mirtazapine tends to be used at low doses (7.5–15 mg) as a sleep-inducing agent and probably affects sleep through antagonism of H1 receptors, 5HT2 receptors, and a1-adrenergic receptors. It is generally believed that lower doses of mirtazapine are more sedating than higher doses, but there are few objective clinical data to support this or other efficacy claims for mirtazapine. Common side-effects of mirtazapine include drowsiness, daytime sedation, dry mouth, increased appetite, and weight gain. Its low toxicity is an advantage over some of the other sedating antidepressants.



Atypical antipsychotics, particularly quetiapine and olanzapine, are also used with increasing frequency for insomnia. Like the older antipsychotics, these

agents act through blockade of dopamine type 2 (D2) receptors, but they also act through antagonism of 5HT2A and 5HT2C receptors, antihistaminergic effects, and antagonism of a1-adrenergic receptors. Although they may have a role in treating comorbid insomnia in patients with primary indications for their use (e.g., psychotic disorders, bipolar disorder, treatmentrefractory depression), their use in primary insomnia should be avoided if possible, because of their adverse side-effects. One controlled study on the effects of quetiapine at 25 or 100 mg performed in healthy male volunteers (Cohrs et al., 2004) resulted in shorter sleep latency, increased total sleep and sleep efficiency, and improved subjective sleep quality. The 100-mg dose, however, caused a significant increase in periodic leg movements. One night of administration of olanzapine to healthy male volunteers produced similar effects to quetiapine in comparison with placebo (Sharpley et al., 2000). In an open-label study in depressed patients, olanzapine added to SSRI treatment led to increased sleep efficiency and slow-wave sleep (Sharpley et al., 2005). In addition to the lack of efficacy data for insomnia, potentially serious adverse events are associated with atypical antipsychotics. As with the older antipsychotics, extrapyramidal effects may occur. Other concerns are the risk of weight gain, glucose intolerance, dyslipidemia, daytime sedation, and cognitive impairment. These agents carry a “black box warning” for increased risk of sudden death in elderly patients with dementia.

ANTICONVULSANTS Several anticonvulsants acting on the GABA system to increase GABA effects in the brain have been used in the treatment of insomnia. There are currently few data regarding their use in insomnia, but they appear to have some sedating and/or sleep-promoting effects. Their advantages include low toxicity and that they are not controlled substances. Gabapentin is thought to increase synaptic levels of GABA, but its mechanism of action is not clearly understood (Czapinski et al., 2005). There are no systematic studies on the efficacy of gabapentin for insomnia, but it has been reported to increase slowwave sleep in patients with epilepsy (Legros and Bazil, 2003), improve insomnia ratings in an open-label study of alcoholics with insomnia (Karam-Hage and Brower, 2003), and increase slow-wave sleep in normal adults (Foldvary-Schaefer et al., 2002). Gabapentin is generally well tolerated and has low toxicity, but it can cause daytime sedation, dizziness, and leukopenia. Tiagabine inhibits GABA reuptake through inhibition of the GABA transporter. It is one of the few

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT 741 anticonvulsants with data from placebo-controlled be useful for long-term treatment. Antihistamines can studies in insomnia. In a study of elderly subjects with cause adverse effects such as daytime sedation, cogniinsomnia, doses of 4–8 mg significantly increased tive impairment, increased risk of accidents, dizziness, slow-wave sleep, and doses of 6–8 mg led to decreased tinnitus, gastrointestinal symptoms, weight gain, and awakenings (Roth et al., 2006). At the 8-mg dose, howincreased intraocular pressure in narrow-angle glaucoma ever, subjects reported subjective decreases in total (Casale et al., 2003). sleep, less refreshing sleep, worse daytime functioning, and more adverse events. Similar effects were seen in Current status of pharmacotherapy a study of tiagabine in healthy elderly subjects (Walsh for insomnia et al., 2005). A study in nonelderly adults with primary The National Institutes of Health State of the Science insomnia using tiagabine doses of up to 16 mg also Conference on Manifestations and Management of showed that the drug produced increased slow-wave Chronic Insomnia in Adults was held in June 2005 sleep and decreased waking after sleep onset (at the ( 16-mg dose), but no significant effect on latency to htm). This nonpartisan review of currently available persistent sleep (Walsh et al., 2006). Higher doses were treatments came to several conclusions regarding associated with more adverse effects. Thus, although pharmacotherapy for insomnia: potentially helpful for insomnia, the side-effects of tiagabine may limit its utility. BzRAs. BzRAs, including benzodiazepines and nonPregabalin, like gabapentin, was designed as a GABA benzodiazepines, are effective in the short-term treatanalog and its mechanism of action is unclear. A comparment of insomnia and most have not been studied ison of alprazolam with pregabalin in healthy subjects long term using randomized clinical trials; eszopliclone showed that both drugs reduced sleep latency and has shown sustained efficacy for 6 months in patients decreased the amount of REM sleep (Hindmarch et al., with primary insomnia. Adverse effects of BzRAs 2005); however, pregabalin led to significant increases include residual daytime sedation, motor coordination in slow-wave sleep, whereas alprazolam decreased it. and cognitive impairment, dependence, and rebound The most common side-effects of pregabalin are insomnia. Side-effects are greater in elderly patients. dizziness and somnolence. Side-effects related to the newer benzodiazepine receptor agonists are lower, probably related to their shorter ANTIHISTAMINES half-lives. Abuse liability of BzRAs does not appear to be a major problem, but data relating to long-term use Antihistamines are the active ingredient in most OTC for insomnia require further study. medications and act through antagonism of H recep1

tors. Diphenhydramine and doxylamine are found in virtually all OTC sleeping medications, but it is important to note that doxepin, described above, is a more potent antihistamine than any of the OTCs. H1 antagonists cause sedation in most individuals, but can lead to paradoxical excitation in some individuals, particularly with higher doses and/or in children and the elderly. Despite the widespread use of these agents, there are almost no data regarding their effects on sleep, and there are no rigorous, placebo-controlled studies in insomnia. An outpatient study found that patients with mild to moderate insomnia in a family practice setting reported more restful sleep and shorter sleep latency with 50 mg diphenhydramine in comparison to those taking placebo (Rickels et al., 1983). An assessment of motor activity and subjective sleep parameters in normal adults showed minimal or no effects on sleep parameters, and a tendency for increased motor activity (Borbely and Youmbi-Balderer, 1988). Finally, a study in normal men showed that diphenhydramine led to rapid tolerance of its sedative effects (Richardson et al., 2002), suggesting that these agents may not

Sedating antidepressants. Trazodone is the most commonly prescribed medication for insomnia in the USA. It is sedating and improves several sleep parameters, but there are no studies of long-term use for chronic insomnia. Doxepin has beneficial effects for insomnia for up to 4 weeks, but there are insufficient data for other antidepressants, such as amitriptyline and mirtazapine, in the treatment of insomnia; all antidepressants have significant adverse effects. Other agents. There are no data regarding the use of antipsychotics for the treatment of insomnia; these agents have significant risks, and they are not recommended for use in insomnia. Antihistamines are commonly used, but there are no data regarding their efficacy for insomnia and they have significant adverse effects. Melatonin is not regulated by the FDA and there is significant variability in preparations. It appears to be effective for circadian rhythm disorders, but there is little evidence for efficacy in the treatment of insomnia. There are no data regarding safety in long-term use (National Institutes of Health, 2005).



SUMMARY AND CONCLUSIONS Insomnia is a prevalent health complaint that may present as a primary disorder or as a comorbid condition to a medical or psychiatric disorder. Persistent insomnia is associated with significant morbidity and healthcare costs. Progress has been made to standardize research diagnostic criteria, but there is still little information about the psychological and biological bases of insomnia, or about its natural history and long-term prognosis. Significant advances have also been made in developing and validating therapeutic approaches for the management of both acute and chronic insomnia. Despite these advances, insomnia remains underrecognized and undertreated in clinical practice. Additional research is needed to document further the etiology of insomnia and its natural history, and to optimize therapeutic outcomes, not only in terms of reducing insomnia symptoms but also in terms of impact on other indicators of morbidity and cost– effectiveness. A significant challenge for the future will be to disseminate validated therapies and practice guidelines more efficiently, and increase their use in practice.

ACKNOWLEDGEMENTS Preparation of this chapter was facilitated by research grants from the National Institute of Mental Health (MH60413) and the Canadian Institutes for Health Research (MT-42504).

REFERENCES Aden GC, Thatcher C (1983). Quazepam in the short-term treatment of insomnia in outpatients. J Clin Psychiatry 44: 454–456. Allen RP, Mendels J, Nevins J et al. (1987). Efficacy without tolerance or rebound insomnia for midazolam and temazepam after use for one to three months. J Clin Pharmacol 27: 768–775. American Academy of Sleep Medicine (2005). International Classification of Sleep Disorders: Diagnostic and Coding Manuel. 2nd edn. American Academy of Sleep Medicine, Westchester, IL. American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). American Psychiatric Association, Washington, DC. Ancoli-Israel S, Cole R, Alessi C et al. (2003). The role of actigraphy in the study of sleep and circadian rhythms. Sleep 26: 342–392. Asnis GM, Chakraburtty A, DuBoff EA et al. (1999). Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry 60: 668–676. Avidan AY, Fries BE, James ML et al. (2005). Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 53: 955–962.

Bastien CH, Vallie`res A, Morin CM (2001). Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2: 297–307. Bastien CH, Vallieres A, Morin CM (2004). Precipitating factors of insomnia. Behav Sleep Med 2: 50–62. Bastien CH, St-Jean G, Morin CM et al. (2008). Chronic psychophysiological insomnia: hyperarousal and/or inhibition deficits? An ERPs investigation. Sleep 31: 887–898. Benca RM, Obermeyer WH, Thisted RA et al. (1992). Sleep and psychiatric disorders. A meta-analysis. Arch Gen Psychiatry 49: 651–668. Besset A, Villemin E, Tafti M et al. (1998). Homeostatic process and sleep spindles in patients with sleepmaintenance insomnia: effect of partial (21 h) sleep deprivation. Electroencephalogr Clin Neurophysiol 107: 122–132. Bonnet MH, Arand DL (1997). Hyperarousal and insomnia. Sleep Med Rev 1: 97–108. Bootzin RR, Epstein D, Wood JM (1991). Stimulus control instructions. In: P Hauri (Ed.), Case Studies in Insomnia. Plenum Press, New York, pp. 19–28. Borbely AA, Youmbi-Balderer G (1988). Effect of diphenhydramine on subjective sleep parameters and on motor activity during bedtime. Int J Clin Pharmacol 26: 392–396. Brassington GS, King AC, Bliwise DL (2000). Sleep problems as a risk factor for falls in a sample of community-dwelling adults aged 64–99 years. J Am Geriatr Soc 48: 1234–1240. Breslau N, Roth T, Rosenthal L et al. (1996). Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 39: 411–418. Brzezinski A (1997). Melatonin in humans. N Engl J Med 336: 186–195. Buysse DJ, Reynolds CF3rd, Kupfer DJ et al. (1994). Clinical diagnoses in 216 insomnia patients using the International Classification of Sleep Disorders (ICSD), DSM-IV and ICD-10 categories: a report from the APA/NIMH DSMIV Field Trial. Sleep 17: 630–637. Buysse DJ, Bate G, Kirkpatrick P (2005). Fresh from the pipeline: ramelteon. Nat Rev Drug Discov 4: 881–882. Buysse DJ, Ancoli-Israel S, Edinger JD et al. (2006). Recommendations for a standard research assessment of insomnia. Sleep 29: 1155–1173. Buysse DJ, Thompson W, Scott J et al. (2007). Daytime symptoms in primary insomnia: a prospective analysis using ecological momentary assessment. Sleep Med 8: 198–208. Buysse DJ, Angst J, Gamma A et al. (2008). Prevalence, course, and comorbidity of insomnia and depression in young adults. Sleep 31: 473–480. Casale TB, Blaiss MS, Gelfand E et al. (2003). First do no harm: managing antihistamine impairment in patients with allergic rhinitis. J Allergy Clin Immunol 111: S835–S842. Cohn JB, Wilcox CS, Bremner J et al. (1991). Hypnotic efficacy of estazolam compared with flurazepam in outpatients with insomnia. J Clin Pharmacol 31: 747–750. Cohrs S, Rodenbeck A, Guan Z et al. (2004). Sleeppromoting properties of quetiapine in healthy subjects. Psychopharmacology 174: 421–429.

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT Currie SR, Wilson KG, Pontefract AJ et al. (2000). Cognitive-behavioral treatment of insomnia secondary to chronic pain. J Consult Clin Psychol 68: 407–416. Czapinski P, Blaszczyk B, Czuczwar SJ (2005). Mechanisms of action of antiepileptic drugs. Curr Top Med Chem 5: 3–14. Daley M, Morin CM, Leblanc M et al. (2009). The economic burden of insomnia: direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms and good sleepers. Sleep 32: 55–64. Dashevsky BA, Kramer M (1998). Behavioral treatment of chronic insomnia in psychiatrically ill patients. J Clin Psychiatry 59: 693–699. Dauvilliers Y, Morin CM, Cervena K et al. (2005). Family studies in insomnia. J Psychosom Res 58: 271–278. Devoto A, Manganelli S, Lucidi F et al. (2005). Quality of sleep and P300 amplitude in primary insomnia: a preliminary study. Sleep 28: 859–863. Dundar Y, Boland A, Strobl J et al. (2004). Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation. Health Technol Assess 8: iii–x, 1–125. Edinger JD, Wohlgemuth WK, Radtke RA et al. (2001). Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial. JAMA 285: 1856–1864. Edinger JD, Bonnet MH, Bootzin RR et al. (2004). Derivation of research diagnostic criteria for insomnia: report of an American Academy of Sleep Medicine Work Group. Sleep 27: 1567–1596. Edinger JD, Wohlgemuth WK, Krystal AD et al. (2005). Behavioral insomnia therapy for fibromyalgia patients: a randomized clinical trial. Arch Intern Med 165: 2527–2535. Edinger JD, Wohlgemuth WK, Radtke RA et al. (2007). Dose–response effects of cognitive-behavioral insomnia therapy: a randomized clinical trial. Sleep 30: 203–212. Elie R, Ruther E, Farr I et al. (1999). Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. Zaleplon Clinical Study Group. J Clin Psychiatry 60: 536–544. Erman M, Seiden D, Zammit G et al. (2006). An efficacy, safety, and dose–response study of ramelteon in patients with chronic primary insomnia. Sleep Med 7: 17–24. Espie CA (2002). Insomnia: conceptual issues in the development, persistence, and treatment of sleep disorder in adults. Annu Rev Psychol 53: 215–243. Espie CA, MacMahon KM, Kelly HL et al. (2007). Randomized clinical effectiveness trial of nurse-administered small-group cognitive behavior therapy for persistent insomnia in general practice. Sleep 30: 574–584. Espie CA, Fleming L, Cassidy J et al. (2008). Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer. J Clin Oncol 26: 4651–4658. Fava M, McCall WV, Krystal A et al. (2006). Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry 59: 1052–1060.


Foldvary-Schaefer N, De Leon Sanchez I, Karafa M et al. (2002). Gabapentin increases slow-wave sleep in normal adults. Epilepsia 43: 1493–1497. Ford DE, Kamerow DB (1989). Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention. JAMA 262: 1479–1484. Fry J, Scharf M, Mangano R et al. (2000). Zaleplon improves sleep without producing rebound effects in outpatients with insomnia. Zaleplon Clinical Study Group. Int Clin Psychopharmacol 15: 141–152. Glass J, Lanctot KL, Herrmann N et al. (2005). Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 331: 1169. Harvey AG, Sharpley AL, Ree MJ et al. (2007). An open trial of cognitive therapy for chronic insomnia. Behav Res Ther 45: 2491–2501. Hauri PJ (1997). Can we mix behavioral therapy with hypnotics when treating insomniacs? Sleep 20: 1111–1118. Hauri PJ, Fisher J (1986). Persistent psychophysiologic (learned) insomnia. Sleep 9: 38–53. Hauri PJ, Olmstead E (1980). Childhood-onset insomnia. Sleep 3: 59–65. Hernandez Lara R, Del Rosal PL, Ponce MC (1983). Shortterm study of quazepam 15 milligrams in the treatment of insomnia. J Int Med Res 11: 162–166. Hindmarch I, Dawson J, Stanley N (2005). A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep 28: 187–193. Holbrook AM, Crowther R, Lotter A et al. (2000a). The diagnosis and management of insomnia in clinical practice: a practical evidence-based approach. Can Med Assoc J 162: 216–220. Holbrook AM, Crowther R, Lotter A et al. (2000b). Metaanalysis of benzodiazepine use in the treatment of insomnia. Can Med Assoc J 162: 225–233. Irwin MR, Cole JC, Nicassio PM (2006). Comparative metaanalysis of behavioral interventions for insomnia and their efficacy in middle-aged adults and in older adults 55þ years of age. Health Psychol 25: 3–14. Jacobs GD, Pace-Schott EF, Stickgold R et al. (2004). Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern Med 164: 1888–1896. Johnson EO, Roehrs T, Roth T et al. (1998). Epidemiology of alcohol and medication as aids to sleep in early adulthood. Sleep 21: 178–186. Jones BT, Macphee LM, Broomfield NM et al. (2005). Sleep-related attentional bias in good, moderate, and poor (primary insomnia) sleepers. J Abnorm Psychol 114: 249–258. Kales A, Manfredi RL, Vgontzas AN et al. (1991). Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines. Clin Pharmacol Ther 49: 468–476. Karam-Hage M, Brower KJ (2003). Open pilot study of gabapentin versus trazodone to treat insomnia in alcoholic outpatients. Psychiatry Clin Neurosci 57: 542–544.



Kelly KD, Pickett W, Yiannakoulias N et al. (2003). Medication use and falls in community-dwelling older persons. Age Ageing 32: 503–509. Klink ME, Quan SF, Kaltenborn WT et al. (1992). Risk factors associated with complaints of insomnia in a general adult population. Influence of previous complaints of insomnia. Arch Intern Med 152: 1634–1637. Krystal AD, Walsh JK, Laska E et al. (2003). Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 26: 793–799. Krystal AD, Erman M, Zammit GK et al. (2008). Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Sleep 31: 79–90. Lamarche CH, Ogilvie RD (1997). Electrophysiological changes during the sleep onset period of psychophysiological insomniacs, psychiatric insomniacs, and normal sleepers. Sleep 20: 724–733. Legros B, Bazil CW (2003). Effects of antiepileptic drugs on sleep architecture: a pilot study. Sleep Med 4: 51–55. Lewy AJ, Ahmed S, Jackson JM et al. (1992). Melatonin shifts human circadian rhythms according to a phaseresponse curve. Chronobiol Int 9: 380–392. Lewy AJ, Emens JS, Lefler BJ et al. (2005). Melatonin entrains free-running blind people according to a physiological dose-response curve. Chronobiol Int 22: 1093–1106. Lichstein KL, Wilson NM, Johnson CT (2000). Psychological treatment of secondary insomnia. Psychol Aging 15: 232–240. Littner M, Kushida CA, Anderson WM et al. (2003). Practice parameters for the role of actigraphy in the study of sleep and circadian rhythms: an update for 2002. Sleep 26: 337–341. Mauri MC, Gianetti S, Pugnetti L et al. (1993). Quazepam versus triazolam in patients with sleep disorders: a doubleblind study. Int J Clin Pharmacol Res 13: 173–177. Mayers AG, Baldwin DS (2005). Antidepressants and their effect on sleep. Hum Psychopharmacol 20: 533–559. McClusky HY, Milby JB, Switzer PK et al. (1991). Efficacy of behavioral versus triazolam treatment in persistent sleep-onset insomnia. Am J Psychiatry 148: 121–126. Melo de Paula AJ (1984). Comparative study of lormetazepam and flurazepam in the treatment of insomnia. Clin Ther 6: 500–508. Mendelson WB (1992). Clinical distinctions between longacting and short-acting benzodiazepines. J Clin Psychiatry 53 (Suppl): 4–7. Mendelson WB (2005). A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry 66: 469–476. Mendelson WB, Roth T, Cassella J et al. (2004). The treatment of chronic insomnia: drug indications, chronic use and abuse liability. Summary of a 2001 New Clinical Drug Evaluation Unit meeting symposium. Sleep Med Rev 8: 7–17.

Merica H, Blois R, Gaillard JM (1998). Spectral characteristics of sleep EEG in chronic insomnia. Eur J Neurosci 10: 1826–1834. Milby JB, Williams V, Hall JN et al. (1993). Effectiveness of combined triazolam–behavioral therapy for primary insomnia. Am J Psychiatry 150: 1259–1260. Morgan K, Dixon S, Mathers N et al. (2003). Psychological treatment for insomnia in the management of long-term hypnotic drug use: a pragmatic randomised controlled trial. Br J Gen Pract 53: 923–928. Morin CM (1993). Insomnia: Psychological Assessment and Management. Guilford Press, New York. Morin CM, Espie CA (2003). Insomnia: A Clinical Guide to Assessment and Treatment. Kluwer Academic/Plenum, New York. Morin CM, Culbert JP, Schwartz SM (1994a). Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry 151: 1172–1180. Morin CM, Stone J, McDonald K et al. (1994b). Psychological management of insomnia: a clinical replication series with 100 patients. Behav Ther 25: 291–309. Morin CM, Colecchi C, Stone J et al. (1999a). Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA 281: 991–999. Morin CM, Hauri PJ, Espie CA et al. (1999b). Nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine review. Sleep 22: 1134–1156. Morin CM, Blais F, Savard J (2002). Are changes in beliefs and attitudes about sleep related to sleep improvements in the treatment of insomnia? Behav Res Ther 40: 741–752. Morin CM, Rodrigue S, Ivers H (2003). Role of stress, arousal, and coping skills in primary insomnia. Psychosom Med 65: 259–267. Morin CM, Bastien C, Guay B et al. (2004). Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia. Am J Psychiatry 161: 332–342. Morin CM, Bootzin RR, Buysse DJ et al. (2006). Psychological and behavioral treatment of insomnia: update of the recent evidence (1998–2004). Sleep 29: 1398–1414. Morin CM, Belanger L, Leblanc M et al. (2009). The natural history of insomnia: a population-based 3-year longitudinal study. Arch Intern Med 169: 447–453. Murtagh DR, Greenwood KM (1995). Identifying effective psychological treatments for insomnia: a meta-analysis. J Consult Clin Psychol 63: 79–89. National Institutes of Health (2005). National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13–15, 2005. Sleep 28: 1049–1057. National Sleep Foundation (1991). Sleep in America: A National Survey of US adults. The Gallup Organization, Princeton. National Sleep Foundation (1995). Sleep in America: A National Survey of US Adults. The Gallup Organization, Princeton.

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT Ngen CC, Hassan R (1990). A double-blind placebocontrolled trial of zopiclone 7.5 mg and temazepam 20 mg in insomnia. Int Clin Psychopharmacol 5: 165–171. Nofzinger EA, Buysse DJ, Germain A et al. (2004). Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 161: 2126–2128. Nofzinger EA, Nissen C, Germain A et al. (2006). Regional cerebral metabolic correlates of WASO during NREM sleep in insomnia. J Clin Sleep Med 2: 316–322. Nowell PD, Mazumdar S, Buysse DJ et al. (1997). Benzodiazepines and zolpidem for chronic insomnia: a metaanalysis of treatment efficacy. JAMA 278: 2170–2177. Obermeyer WH, Benca RM (1996). Effects of drugs on sleep. Neurol Clin 14: 827–840. Ohayon MM (2002). Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 6: 97–111. Ohayon MM, Roth T (2003). Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res 37: 9–15. Ozminkowski RJ, Wang S, Walsh JK (2007). The direct and indirect costs of untreated insomnia in adults in the United States. Sleep 30: 263–273. Pallesen S, Nordhus IH, Kvale G et al. (2003). Behavioral treatment of insomnia in older adults: an open clinical trial comparing two interventions. Behav Res Ther 41: 31–48. Perlis ML, Merica H, Smith MT et al. (2001a). Beta EEG activity and insomnia. Sleep Med Rev 5: 363–374. Perlis ML, Smith MT, Andrews PJ et al. (2001b). Beta/ gamma EEG activity in patients with primary and secondary insomnia and good sleeper controls. Sleep 24: 110–117. Perlis ML, McCall WV, Krystal AD et al. (2004). Longterm, non-nightly administration of zolpidem in the treatment of patients with primary insomnia. J Clin Psychiatry 65: 1128–1137. Reynolds CF 3rd, Taska LS, Sewitch DE et al. (1984). Persistent psychophysiologic insomnia: preliminary Research Diagnostic Criteria and EEG sleep data. Am J Psychiatry 141: 804–805. Richardson GS, Roehrs TA, Rosenthal L et al. (2002). Tolerance to daytime sedative effects of H1 antihistamines. J Clin Psychopharmacol 22: 511–515. Rickels K, Morris RJ, Newman H et al. (1983). Diphenhydramine in insomniac family practice patients: a doubleblind study. J Clin Pharmacol 23: 234–242. Riedel BW, Lichstein KL (2000). Insomnia and daytime functioning. Sleep Med Rev 4: 277–298. Rodenbeck A, Huether G, Ruther E et al. (2002). Interactions between evening and nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary insomnia. Neurosci Lett 324: 159–163. Roehrs T, Vogel G, Vogel F et al. (1986). Dose effects of temazepam tablets on sleep. Drugs Exp Clin Res 12: 693–699. Roehrs T, Hollebeek E, Drake C et al. (2002). Substance use for insomnia in Metropolitan Detroit. J Psychosom Res 53: 571–576. Roth T, Zorick F, Wittig R et al. (1982). The effects of doxepin HCl on sleep and depression. J Clin Psychiatry 43: 366–368.


Roth T, Wright KP Jr., Walsh J (2006). Effect of tiagabine on sleep in elderly subjects with primary insomnia: a randomized, double-blind, placebo-controlled study. Sleep 29: 335–341. Roth T, Rogowski R, Hull S et al. (2007). Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep 30: 1555–1561. Rybarczyk B, Lopez M, Benson R et al. (2002). Efficacy of two behavioral treatment programs for comorbid geriatric insomnia. Psychol Aging 17: 288–298. Rybarczyk B, Stepanski E, Fogg L et al. (2005). A placebocontrolled test of cognitive-behavioral therapy for comorbid insomnia in older adults. J Consult Clin Psychol 73: 1164–1174. Sack RL, Brandes RW, Kendall AR et al. (2000). Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 343: 1070–1077. Savard J, Simard S, Ivers H et al. (2005). Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: Sleep and psychological effects. J Clin Oncol 23: 6083–6096. Scharf MB, Roth PB, Dominguez RA et al. (1990). Estazolam and flurazepam: a multicenter, placebo-controlled comparative study in outpatients with insomnia. J Clin Pharmacol 30: 461–467. Scharf MB, Roth T, Vogel GW et al. (1994). A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia. J Clin Psychiatry 55: 192–199. Scharf MB, Erman M, Rosenberg R et al. (2005). A 2-week efficacy and safety study of eszopiclone in elderly patients with primary insomnia. Sleep 28: 720–727. Scharf M, Rogowski R, Hull S et al. (2008). Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, doubleblind, placebo-controlled crossover study. J Clin Psychiatry 69: 1557–1564. Schutte-Rodin S, Broch L, Buysse D et al. (2008). Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 4: 487–504. Sharpley AL, Vassallo CM, Cowen PJ (2000). Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT2C receptors in vivo. Biol Psychiatry 47: 468–470. Sharpley AL, Attenburrow ME, Hafizi S et al. (2005). Olanzapine increases slow wave sleep and sleep continuity in SSRI-resistant depressed patients. J Clin Psychiatry 66: 450–454. Shipley JE, Kupfer DJ, Griffin SJ et al. (1985). Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients. Psychopharmacology 85: 14–22. Simon GE, VonKorff M (1997). Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry 154: 1417–1423. Sivertsen B, Omvik S, Pallesen S et al. (2006a). Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 295: 2851–2858.



Sivertsen B, Overland S, Neckelmann D et al. (2006b). The long-term effect of insomnia on work disability: the HUNT-2 historical cohort study. Am J Epidemiol 163: 1018–1024. Smith MT, Perlis ML (2006). Who is a candidate for cognitive-behavioral therapy for insomnia? Health Psychol 25: 15–19. Smith MT, Perlis ML, Park A et al. (2002). Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry 159: 5–11. Smith MT, Huang MI, Manber R (2005). Cognitive behavior therapy for chronic insomnia occurring within the context of medical and psychiatric disorders. Clin Psychol Rev 25: 559–592. Soeffing JP, Lichstein KL, Nau SD et al. (2008). Psychological treatment of insomnia in hypnotic-dependant older adults. Sleep Med 9: 165–171. Spielman AJ, Glovinsky PB (1991). The varied nature of insomnia. In: P Hauri (Ed.), Case Studies in Insomnia. Plenum Press, New York, pp. 1–15. Spielman AJ, Saskin P, Thorpy MJ (1987). Treatment of chronic insomnia by restriction of time in bed. Sleep 10: 45–56. Staner L, Ertle S, Boeijinga P et al. (2005). Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring. Psychopharmacology 181: 790–798. Taylor DJ, Lichstein KL, Weinstock J et al. (2007a). A pilot study of cognitive-behavioral therapy of insomnia in people with mild depression. Behav Ther 38: 49–57. Taylor DJ, Mallory LJ, Lichstein KL et al. (2007b). Comorbidity of chronic insomnia with medical problems. Sleep 30: 213–218. US Food and Drug Administration (2007). FDA Requests Label Change for all Sleep Disorder Drug Products. Online. Available: 2007/NEW01587.html. Vallieres A, Ivers H, Bastien CH et al. (2005a). Variability and predictability in sleep patterns of chronic insomniacs. J Sleep Res 14: 447–453. Vallieres A, Morin CM, Guay B (2005b). Sequential combinations of drug and cognitive behavioral therapy for chronic insomnia: an exploratory study. Behav Res Ther 43: 1611–1630. Verster JC, Volkerts ER, Schreuder AH et al. (2002). Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. J Clin Psychopharmacol 22: 576–583.

Verster JC, Veldhuijzen DS, Volkerts ER (2004). Residual effects of sleep medication on driving ability. Sleep Med Rev 8: 309–325. Vgontzas AN, Tsigos C, Bixler EO et al. (1998). Chronic insomnia and activity of the stress system: a preliminary study. J Psychosom Res 45 (Spec. No.): 21–31. Vgontzas AN, Bixler EO, Lin HM et al. (2001). Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab 86: 3787–3794. Vignola A, Lamoureux C, Bastien CH et al. (2000). Effects of chronic insomnia and use of benzodiazepines on daytime performance in older adults. J Gerontol B Psychol Sci Soc Sci 55: P54–P62. Vollrath M, Wicki W, Angst J (1989). The Zurich study. VIII. Insomnia: association with depression, anxiety, somatic syndromes, and course of insomnia. Eur Arch Psychiatry Neurol Sci 239: 113–124. Walsh JK (2004a). Clinical and socioeconomic correlates of insomnia. J Clin Psychiatry 65 (Suppl 8): 13–19. Walsh JK (2004b). Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine. Sleep 27: 1441–1442. Walsh JK, Erman M, Erwin C (1998). Subjective hypnotic efficacy of trazodone and zolpidem in DSM-III-R primary insomnia. Hum Psychopharmacol 13: 191–198. Walsh JK, Vogel GW, Scharf M et al. (2000). A five week, polysomnographic assessment of zaleplon 10 mg for the treatment of primary insomnia. Sleep Med 1: 41–49. Walsh JK, Randazzo AC, Frankowski S et al. (2005). Dose– response effects of tiagabine on the sleep of older adults. Sleep 28: 673–676. Walsh JK, Zammit G, Schweitzer PK et al. (2006). Tiagabine enhances slow wave sleep and sleep maintenance in primary insomnia. Sleep Med 7: 155–161. Walsh JK, Krystal AD, Amato DA et al. (2007). Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life, and work limitations. Sleep 30: 959–968. Wang PS, Bohn RL, Glynn RJ et al. (2001). Zolpidem use and hip fractures in older people. J Am Geriatr Soc 49: 1685–1690. Wilson S, Argyropoulos S (2005). Antidepressants and sleep: a qualitative review of the literature. Drugs 65: 927–947. Winkelman JW, Buxton OM, Jensen JE et al. (2008). Reduced brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spectroscopy (1H-MRS). Sleep 31: 1499–1506.