In Psychiatric Clinics of North America

Introduction

Sleep disturbances and anxiety symptoms are inextricably intertwined. With insomnia, anxious arousal interferes with sleep onset. Insufficient sleep sustains and predisposes to persisting anxiety states. Anxiety disorders are psychiatric conditions whose primary features are anxiety that is persistent, maladaptively triggered, and of sufficient intensity to disrupt function. The anxiety disorders in the Diagnostic and Statistical Manuel, 4^th Edition (DSM-IV) are generalized anxiety, panic, posttraumatic stress, obsessive compulsive, and phobic disorders. Sleep disturbances are frequently associated with, and can comprise core features of anxiety disorders.

Posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD) feature sleep disturbances among their DSM-IV diagnostic criteria. PTSD develops in some individuals after exposure to severely threatening stress and manifests with symptoms of re-experiencing the trauma, emotional numbing and avoidance behaviors, and heightened arousal. Specific criteria for the disorder related to sleep include nightmares with trauma-related content and difficulty initiating and maintaining sleep, which is the common definition of insomnia. The principal feature of GAD is chronic worry and tension. Impaired sleep initiation and maintenance is also a symptom criterion for GAD. Panic disorder features recurring severe and unpredictable episodes of anxiety with crescendo-like onsets called panic attacks, which are often complicated by anticipatory anxiety and phobic avoidance. While not among the specific diagnostic criteria, panic disorder has also been associated with complaints of difficulty initiating and maintaining sleep in many studies.

In addition, panic attacks can arise from sleep in many patients diagnosed with the disorder. Sleep disturbances can occur with, but appear to be less salient features of obsessive compulsive disorder, and specific and social phobic disorders. In addition to frequently being a part of their presenting symptoms, insomnia, is a risk factor for the subsequent onset of anxiety disorders (1, 2, 3). There is overlap between interventions that target insomnia and other sleep disturbances and those that are utilized in treating anxiety disorders. Overlapping approaches include medications, as well as cognitive behavioral strategies that target worry, tension and maladaptive cognitions. Optimal sequencing and/or integration of treatments targeting insomnia and sleep disturbance are not well investigated, however.

Much of the emphasis regarding overlap of anxiety and sleep disturbance is appropriately focused on insomnia. There can be overlapping features of the sleep manifestations of anxiety disorders with other “primary” sleep disorders. For example, symptomatic episodes in panic disorder sometimes need to be differentiated from clinical manifestations of sleep apnea, and GAD from restless legs syndrome.

In the following sections clinical issues and laboratory information where available regarding sleep aspects of specific anxiety disorders are reviewed. This review is followed by discussion of interfaces of anxiety and sleep apnea and treatment issues that overlap sleep and anxiety disorders.

Sleep in specific and social phobias

Fear and avoidance of situations are the key features of phobic disorders. Since these situations occur during interactions with the environment during wakefulness, sleep disturbances are not typically regarded as central to or commonly associated with these conditions. Nonetheless, persons with phobic disorders may experience anticipatory anxiety that affect their sleep and dreams. Investigations relating sleep to phobias are limited. In one study, persons with social phobia subjectively reported had poorer sleep quality, longer sleep latency, more frequent sleep disturbance and increased daytime dysfunction compared to controls (4). However, the one pilot study of social phobia identified that utilized polysomnography reported normal findings (5). Clark et al. (6) noted that sleep architecture was similar in depressed persons with and without simple phobias (the term that predated the DSM-IV). A study on parasomnias, including sleep terrors and sleepwalking, among adolescents found an increased co-morbidity with simple phobias and other anxiety disorders (7).

Sleep in Obsessive Compulsive Disorder

Sleep disturbances are also not included among the symptom criteria, nor are commonly associated with obsessive-compulsive disorder (OCD). Polysomnography has been applied to OCD and other disorders to evaluate overlap with depression where reduced latency to rapid eye movement (REM) sleep is a well established biological marker. An early polysomnographic study noted impaired sleep maintenance and a reduced latency to REM sleep in a group with persons with OCD which is consistent with a linkage between OCD and affective illness (8). However, two more recent polysomnographic studies of persons with OCD failed to replicated these results, reporting instead that the sleep patterns of persons with OCD were essentially normal (9, 10).

Sleep in Generalized Anxiety Disorder

There is a high degree of overlap between GAD and insomnia. DSM-IV criteria for generalized anxiety disorder (GAD) are chronic worry and three of six additional criteria that include difficulty initiating or maintaining sleep, or restless and unsatisfying sleep. Two of the other symptom criteria, fatigue and irritability, can be consequences of sleep loss. In addition, the principal attribute of GAD, excessive worry or apprehensive expectation, is commonly implicated in the genesis and maintenance of insomnia problems.

Ohayon et al. (3) found that the comorbidity of GAD and insomnia was greater than for all of the other psychiatric disorders surveyed. Studies utilizing objective sleep recordings corroborate the reported associations of GAD and insomnia by demonstrating impaired sleep initiation and maintenance in persons with GAD (11, 12, 13). High comorbidity with major depression has generated interest in comparing biological markers of the disorders. Latency to REM sleep was normal in these studies, in contrast to findings from major depression where REM sleep latency is reduced (11, 12, 13).

Consistent with their high degree of overlap and comorbidity, there is also substantial overlap of treatment approaches for GAD and insomnia. Overlapping approaches include the use of medications that target benzodiazepine receptors as well as psychotherapeutic interventions that target excessive worry. Application of these approaches in treating co-occuring generalized anxiety and sleep disturbances is discussed further in the final section of this chapter.

Sleep in Panic Disorder

Panic attacks are distinguished from other anxiety episodes by their sudden, crescendo-like onset, intensity and number of symptoms, and at times unpredictable pattern of occurrence. Panic attacks can emerge from sleep. Panic disorder also typically features chronic anxiety related to anticipating subsequent attacks and phobic avoidance (agoraphobia). Panic attacks arising from sleep (sleep panic attacks) have been suggested to condition fear and apprehension of sleep resulting in secondary insomnia (14). Surveys document that insomnia is more frequent in patients with panic disorder than in control populations (15, 16). Most (17–20) but not all (21, 22) of published studies of panic disorder that utilized objective methods of sleep recording (polysomnography) have found evidence of impaired sleep initiation and maintenance.

Survey data have noted associations between sleep complaints and comorbid depression in persons with panic disorder (21). There are several possible explanations for the relationship between sleep disturbance and the presence of depression in persons with panic disorder. First, much of the associated sleep disturbance may be due to depressive illness that commonly coexists with panic disorder. The two studies that failed to identify any impairment in sleep duration and maintenance specifically excluded depression. However, one of the studies documenting sleep disturbance in panic disorder excluded depressive illness and it is uncertain whether depression accounted for the entire sleep disturbance documented in the remaining positive studies. A second consideration is that comorbid depression may be more common with a more severe variant of panic disorder that also features sleep disturbance. Since insomnia is a risk factor for the subsequent onset of depression (1, 2), a third possibility is that depression is more likely to evolve as a co-morbid condition when panic disorder features disturbed sleep.

Sleep Panic Attacks

Sleep panic attacks are not uncommon among persons with panic disorder. In a study that prospectively monitored panic attacks, 18% occurred during sleep hours (23). In surveys and clinical evaluations 33% to 71% of panic disorder patients reported having experienced sleep panic attacks (15, 24–26). As many as a third of panic disorder patients will experience sleep panic as or more frequently than wake panic attacks (14, 15). It is not known how common it is for patients to only have sleep panic, however, in this author’s experience patients who exclusively panic from sleep are rare. Sleep panic attacks have been described as being awakened with a jolt. They also feature apprehension and somatic symptoms, similar to panic attacks that are triggered during wake states. Studies that have captured sleep panic attacks during polysomnographic recordings find that the episodes were preceded by either stage 2 or stage 3 of non-REM sleep (17, 27). Mellman et al. (17) more specifically noted that the sleep panic attacks originated during the transition from stage 2 into early slow wave sleep which is a period of diminishing arousal. Slow wave sleep is also a state where cognitive activity is at a relative nadir (28). Panic being triggered during sleep might seem counter-intuitive in view of the more intuitive circumstance of panic attacks evolving from states of heightening arousal where apprehension is building. The phenomenon of sleep panic indicates that panic attacks can also be precipitated during states of diminishing arousal. This phenomenon adds to evidence from pharmacological challenge and treatment studies and twin and familial genetic data that endogenous neurobiological mechanisms can underlie anxiety. Specific mechanisms postulated to underlie sleep panic include increased sensitivity to increased carbon dioxide blood levels (29), irregular breathing during slow wave sleep (30), and rebound noradrenergic surges (17, 18). A cognitive mechanism of sensitivity to and catastrophic interpretation of interoceptive stimuli has also been suggested to underlie sleep panic (25).

The greater sensitivity of panic disorder patients to pharmacological challenges that induce panic has provided an important research paradigm for investigating the psychobiology of panic attacks. Sodium lactate and pentagastrin challenges, which trigger panic attacks from wake states, have been demonstrated to also trigger panic attacks from sleep (31, 32). Greater cardiac and respiratory responses to lactate infusion during sleep absent panic awakenings have also been noted (18, 33). Findings that panicogenic triggers can elicit attacks from sleep states indicate that elevated basal arousal is not required for experimentally inducing panic.

Several investigations have explored the significance of sleep panic by comparing patients who experience sleep panic attacks with patients who only experience panic attacks from wake states. These studies have indicated that patients with sleep panic have early illness onset, higher symptom load, depression and suicidal ideation. Thus sleep panic may be associated with a more severe variant of the illness (24, 34). Patients with sleep panic have also been noted to also experience anxiety from relaxation and hypnosis, and to have less agoraphobic avoidance and fewer catastrophic cognitions compared with panic patients who do not experience sleep panic (15, 25, 35, 36). Thus having sleep panic appears to also mark a propensity to have panic triggered by reductions in arousal and for attacks to occur relatively independently of situational and cognitive stimuli that are associated with non-sleep panic.

Sleep in Posttraumatic Stress Disorder

The trauma-related nightmares and difficulty initiating and maintaining sleep denoted in the DSM-IV criteria for PTSD are often prominent among the symptom complaints of patients with the disorder (37, 38). Nightmares and insomnia are also common in the early aftermath of trauma especially among those who are developing PTSD (39–42). Furthermore sleep disruption leads to fatigue and irritability which are daytime symptoms of PTSD. Sleep disruption may also interfere with healthy emotional adaptation and regulation and thereby contribute to the development of PTSD.

Findings from sleep laboratory studies have not yielded a consensus regarding the fundamental nature of sleep disturbances in PTSD. All but a few of the studies are focused on the chronic phase of the disorder and many include only male war veterans. These studies have been mixed in terms of finding objective indices of impaired sleep initiation and maintenance (43–44).

Evidence for abnormalities related to rapid eye movement sleep in PTSD has been more consistent. Increased phasic motor activity and eye movement density during REM sleep have been reported in combat veterans with PTSD (45–47). Nightmares and other symptomatic awakenings disproportionately arise from REM sleep (48, 49). Breslau et al. recently reported more frequent transitions from REM sleep to stage one or wake, in a community sample with either lifetime only (i.e. remitted) or current PTSD, compared with trauma-exposed and trauma-unexposed controls (50). Thus there is converging evidence for disruptions of REM sleep continuity (symptomatic awakenings, increased awakening/arousals, and motor activity) and increased REM activation (eye movement density) with chronic PTSD. The limited number of studies that employed objective recordings of sleep following trauma also suggest the relevance of REM sleep disruption. An early report of 3 cases with “acute combat fatigue” described “markedly disrupted sleep” and “rare or absent rapid eye movement (REM) episodes” (51). Mellman et al. (52) reported PSG findings from PSG recordings conducted within a month of trauma in 21 recently injured patients and 10 healthy controls. REM eye movement density was elevated in the recently trauma exposed, injured patients compared with healthy controls but were similar among those who did and did not develop PTSD. The patients who were developing PTSD, however, had shorter continuous periods of REM sleep prior to stage shifts or arousals. Findings suggesting a relationship between fragmented patterns of REM sleep and PTSD were also provided by a recent study of PTSD patients with limited chronicity and comorbdity (53).

Studies have demonstrated that insomnia is very common among people who have been recently exposed to trauma. Green found insomnia to be the most frequent symptom endorsed by survivors in the aftermath of a natural disaster (39). Koren et al found that complaints of insomnia and excessive daytime sleepiness one month after motor vehicle accidents predicted being diagnosed with PTSD at 3 months (41). In contrast, while Koren et al. (43) found an association of early subjective reports of sleep disturbance with the development of PTSD, these investigators did not find differences in early actigraphic measurements of sleep initiation or maintenance in their prospective study of traffic accident victims nor in polysomnographic (PSG) measures in a subgroup recorded 1 year later (54).

Trauma-related nightmares are among the DSM-IV criteria for PTSD. Mellman et al. evaluated relationships of recalled dream content elicited within a month of traumatic injuries with the development of PTSD. Reports of dreams rated as “highly similar” to the traumatic experience and distressing were associated with concurrent and subsequent PTSD severity. The trauma exposed group who did not subsequently develop PTSD, either did not recall dreaming or reported dreams that did not depict actual memories, although some represented threatening scenarios. The authors theorized that dreams with highly replicative content represent a failure of adaptive emotional memory processing that is a normal function of REM sleep and dreaming (42).

A role for noradrenergic functioning in sleep disturbances during the early development of PTSD is suggested by previously established relationships of noradrenergic activity with PTSD (55) and PTSD sleep disturbances (56), and the noradrenergic signal terminating REM sleep (57). Mellman et al. (58) also evaluated heart rate variability during sleep following trauma which indexes autonomic regulation of heart rate including sympathetic nervous system activity which is a peripheral manifestation of noradrenergic function. The index of sympathetic nervous system activity, the low frequency high frequency ratio, was greater in the subgroup that developed PTSD during their initial REM sleep periods.

In summary, subjective sleep complaints are common in the aftermath of trauma and with PTSD. Nightmares that are similar to trauma memories appear to be relatively specific to the disorder. Overall, studies do not indicate that sleep initiation and maintenance is markedly more impaired among those developing or who have been diagnosed with PTSD. Several studies now converge in suggesting that disruptions of REM sleep may have a role in PTSD and its development.

Sleep Anxiety Symptoms and Sleep Apnea

When a patient reports waking up in the middle of the night with his or her heart pounding and feeling short of breath, can this be confidently attributed to anxiety, or should the physician first evaluate cardiac and respiratory parameters before even considering psychiatric disorders as the likely primary diagnosis? Clinical experience and review of relevant literature indicates that clinical acumen and common sense can often guide the direction of the evaluation and that there is a place for physiological monitoring and treatment of comorbid medical and psychiatric symptoms. With sleep apnea, arousals are usually below the threshold of awareness and memory, though awakenings with gasps, snorts or symptoms of gastro-esophageal reflux are sometimes reported. Excessive daytime sleepiness and reports of loud snoring are reliable signs of the diagnosis (59). Sleep anxiety-related episodes have characteristic features that have been previously described. Thus, the differential diagnosis between “primary” sleep disorders and sleep-related features of anxiety disorders which characteristically manifest with abrupt awakenings to high levels of arousal, can often be made with reasonable confidence on clinical grounds based on their features and associated clinical findings. It is also the case that anxiety disorders with sleep manifestations not infrequently co-occur with primary sleep disorders. Some co-occurrence would be inevitable as anxiety disorders and primary sleep disorders are both common. To the best of this author’s knowledge there is not currently evidence available from large community samples that indicate whether the relationship between sleep apnea and anxiety disorders is greater than would be expected by random association. An analysis from the large Veteran’s Administration Healthcare data base, however, did indicate an increased association of diagnoses of “anxiety” and PTSD (as well as other psychiatric disorders) with sleep apnea (60).

There is some evidence that detection and treatment of anxiety disorder, sleep breathing disorder comorbidity is relevant to patient outcomes. One study reported very high rates of sleep breathing disorders (apnea and upper airway resistance syndrome) in a group of female research participants seeking treatment for PTSD related to sexual assault (61). A study that recruited PTSD cases from a community sample, however, did not find elevated rates of sleep apnea or other primary sleep disorders (Breslau et al. 04). Krakow and colleagues (62) have described clinically significant improvement of PTSD symptoms with treatment of sleep breathing disorders. Edlund and colleagues (63) have similarly reported frequent associations of sleep panic attacks and sleep apnea and response of nocturnal anxiety symptoms to continuous positive airway pressure (CPAP) treatment. That panic attacks would be exacerbated by interruptions of respiration is consistent with observations of increased sensitivity to anxiogenic effects of carbon dioxide in panic disorder (29) and the “suffocation alarm” hypothesis of the etiology of the disorder (29). Indirect support for the hypothesis that increased carbon dioxide receptor sensitivity underlies forms of pathological anxiety includes the observation that children with congenital central hypoventilation syndrome (Ondine’s curse) have lower rates of anxiety symptoms than age matched children (64).

Treatment and Prevention

Sleep disturbances are commonly associated with anxiety disorders, particularly GAD, panic, and PTSD. In contrast to melancholic subtypes of depression where mood can paradoxically improve, anxiety disorders do not benefit, and can worsen from sleep deprivation (65, 66, 67). Insomnia has also been found to be a prospective risk factor for psychiatric disorders including anxiety disorders (1, 2). Therefore in addition to alleviating distress from insomnia, amelioration of sleep disturbances could possibly have therapeutic impact on other symptoms and serve to prevent relapse and exacerbation.

Therapies for anxiety disorders and sleep disturbances overlap. Cognitive behavioral treatments that were developed for insomnia have well established efficacy (68). In addition to recommendations for maintaining consistent bedtimes and wake times, avoidance of maladaptive use of substances, and not spending excessive time awake in bed, effective cognitive behavioral interventions for insomnia often include components that are also used in the treatment of anxiety (69). These include relaxation techniques and identifying and challenging dysfunctional beliefs that perpetuate symptoms. Given the overlapping use of anxiety management, exposure, and cognitive restructuring it would seem that behavioral interventions designed for insomnia and anxiety disorders can be synergistically applied. One study documents improvement in insomnia symptoms in association with cognitive behavioral treatment of generalized anxiety disorder (70). In contrast, Deviva et al. (71) identified a group of patients with significant residual insomnia who had otherwise benefited from cognitive behavioral treatment for PTSD. They further describe a series of these cases where the residual insomnia was reduced by a subsequently administered cognitive behavioral intervention focused specifically on the insomnia. A technique where recurrent distressing dream content is the target of exposure and cognitive restructuring (nightmare imagery rehearsal) has been found to ameliorate nightmares and sleep disruption with PTSD (72). These observations notwithstanding, development and evaluation of sequential or integrated treatments for insomnia and anxiety disorders has been limited.

Various benzodiazepine receptor agonist medications are approved and marketed for hypnotic indications and/or treatment of anxiety disorders, particularly for GAD. One study found agents that are marketed and approved as hypnotics had benefits toward daytime anxiety in treating insomnia associated with GAD (73) (Zopiclone and triazolam are not FDA approved for GAD and zopiclone is not marketed in the United States.) There is preliminary evidence that the novel agents pregabalin and tiagebine that also target benzodiazepine receptors or related GABAergic neurotransmission benefit insomnia symptoms associated with GAD although neither have FDA approval for GAD or insomnia (74, 75).

The newer antidepressant medications, particularly those in the selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine inhibitor (SNRI) categories, have become established as effective for a range of anxiety disorders. They also have advantages with respect to tolerance and dependence concerns relative to benzodiazepines and are now considered to be first-line treatments for panic disorder, social phobia, GAD, OCD, and PTSD. The effects on sleep of these agents vary between agents and to a greater degree between individuals and some have been noted to stimulate insomnia (76). Among the novel antidepressants, mirtazipine which is neither an SSRI nor an SNRI, tends to have sedating/sleep effects. Mirtazapine was recently reported to have been beneficial to GAD patients in a preliminary open label trial (77) although it is not FDA approved for GAD or insomnia. A study utilizing the SSRI citalopram for late-life anxiety disorders indicated improvement in subjective sleep quality with treatment in this subpopulation (78.

Presently, SSRIs, specifically sertraline and paroxetine, are the only agents approved by the FDA for the treatment of PTSD. Benefits of these treatments tend to be modest and do not typically include reductions in sleep disturbance. Therefore, adjunctive interventions are often utilized, often with the intent of targeting nightmare and insomnia symptoms (79). Among these, there is support from controlled trials for adjunctive prescription of olanzapine (80) and prazosin (81) which are not FDA approved for PTSD. The emerging use of prazosin for this indication is consistent with the role of noradrenergic stimulation in disrupting REM sleep suggested by previously reviewed research.

Synopsis

Sleep disturbances are commonly associated with anxiety disorders, particularly GAD, panic disorder and PTSD. Sleep loss may exacerbate and contribute to relapse of these conditions. Core features of panic disorder and PTSD occur in relation to sleep (sleep panic attacks, re-experiencing nightmares). These sleep episodes can usually be distinguished from primary sleep disorders such as sleep apnea on clinical grounds. However, such conditions may commonly co-exist and anxiety symptoms appear to benefit from treatment of sleep respiratory conditions. Established treatments for anxiety disorders and insomnia have many overlapping components, however, optimal sequencing and integration of the approaches is presently inadequately investigated.