Chapter 129 Anxiety Disorders

Holly Ramsawh, Murray B. Stein, Thomas A. Mellman

Abstract

Anxiety disorders are often associated with complaints of disturbed sleep. This chapter provides a review of the diagnostic criteria, sleep features, and treatment of sleep-related problems in patients with panic disorder, generalized anxiety disorder (GAD), social phobia, obsessive–compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). Subjective sleep complaints are most prominent in patients with PTSD, panic disorder, and GAD, and they must be understood in the context of depressive disorders that are commonly comorbid. Abrupt nocturnal awakenings are not uncommonly encountered in anxiety disorders such as panic disorder and PTSD, where they are thought to be related to non–rapid eye movement (NREM) and REM sleep, respectively. Treatments that target sleep can improve outcomes in patients with anxiety disorders.

Anxiety disorders are the most common group of mental disorders, affecting more than 18% of persons in the general population in a 1-year period,¹ and even more during a lifetime. The National Comorbidity Survey Replication (NCS-R), a large, cross-national epidemiologic survey conducted in 2001 to 2003, found that 28.8% of adults in the age group 18 years and older had a lifetime anxiety disorder diagnosis.² Up to one third of the population experiences insomnia at any given time,³^–⁵ and insomnia is often comorbid with mental disorders.³^,⁶ The extant data suggest that although the relationship of anxiety and insomnia is bidirectional, the most typical pattern is for insomnia to begin concurrent with or following the onset of an anxiety disorder.^3,⁷^–⁹ Thus, from an epidemiologic perspective, the onset of an anxiety disorder often heralds the onset of sleep problems, suggesting that a sizable portion of the burden of insomnia in the general population is associated with—and perhaps even etiologically attributable to—anxiety disorders.

Anxiety disorders are also commonly seen in patients presenting in primary care settings for general medical care, where complaints of sleep problems are often prominent.¹⁰ Sleep disturbances are included among the diagnostic features of posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), two of the six categories for anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Sleep disturbances are commonly associated with other anxiety disorders, although they are not incorporated into the diagnostic criteria, per se (e.g., panic disorder). Treatments for sleep problems and those targeting worry, tension, and other manifestations of anxiety often use similar approaches (e.g., cognitive or behavioral techniques, benzodiazepine medications, relaxation). Thus, from a clinical perspective, it is important to consider the diagnosis and treatment of anxiety disorders when caring for a patient with prominent sleep complaints. The converse is equally true: Attention to sleep problems is integral to the management of patients with anxiety disorders.

There are also theoretical links between anxiety and sleep disorders. Sleep is a necessary and restorative state of diminished cortical arousal. Anxiety and fear states manifest with heightened cortical and peripheral arousal. Increased arousal is also implicated when sleep initiation or maintenance are disturbed. Thus, insights into mechanisms regulating arousal would be applicable as well to anxiety and sleep disorders (and their overlapping features).

Whereas sleep has been extensively studied in depressive disorders, the polysomnographic (PSG) study of anxiety disorders is less well developed. PSG studies of anxiety disorders provide information regarding measurable objective disturbances in initiating and maintaining sleep and in sleep structure, as well as the presence of a primary sleep pathologic process. Such studies are the primary focus of the material reviewed in this chapter.

Sleep disturbance does not seem related to specific phobias, and this subject has been little studied, so it is not included here. In the cases of panic disorder and PTSD, an additional focus relates to the core paroxysmal events that can manifest in relation to sleep (e.g., panic attacks, nightmares). This chapter also reviews current pathophysiologic concepts for sleep disturbances in the anxiety disorders, and it reviews the types of treatments (and their outcomes) that target or indirectly influence sleep in these conditions.

Panic Disorder

Epidemiology and Clinical Features

Panic disorder has a 12-month general population prevalence of 2% to 3%, is more common in women than men, and has a typical age of onset in late teens or early twenties (although it can start earlier in life).¹^,² Onset is rare in older adulthood.² The characteristic feature of panic disorder is recurrent unexpected panic attacks (Box 129-1), which are acute episodes of severe anxiety associated with a wide array of somatic symptoms, such as chest pain, tachycardia, shortness of breath, psychosensory disturbances (i.e., changes in sound or light intensity, alterations in the perception of time, derealization), and lightheadedness. Classic panic attacks reach peak severity quickly and last only seconds to minutes in most cases. Panic attacks can occur during sleep; in this chapter, the terms nocturnal panic and sleep panic are synonymous and refer to the same phenomenon.

Box 129-1

Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994.

DSM-IV Criteria for Panic Attack

Panic attack is a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms developed abruptly and reached a peak within 10 minutes:

Palpitations, pounding heart, or accelerated heart rate

Sweating

Trembling or shaking

Sensations of shortness of breath or smothering

Feeling of choking

Chest pain or discomfort

Nausea or abdominal distress

Feeling dizzy, unsteady, lightheaded, or faint

Derealization (feelings of unreality) or depersonalization (being detached from oneself)

Fear of losing control or going crazy

Fear of dying

Paresthesias (numbness or tingling sensations)

Chills or hot flashes

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition.

Panic disorder is diagnosed when a person experiences recurrent unexpected panic attacks. Some persons experience infrequent panic attacks for years without conspicuous changes in their health. More often, however, panic attacks are complicated by anticipatory anxiety (i.e., apprehension about future attacks) or worry about possible underlying medical disorders (e.g., heart disease). Such concerns, if lasting for 1 month or longer after the panic attack or attacks, justify the diagnosis of panic disorder. Alternatively, behavioral change (e.g., frequent visits to the emergency department; avoidance of places where attacks have occurred in the past) subsequent to the attacks also justifies this diagnosis. Patients also may become frightened of places or situations in which unexpected panic attacks have occurred.

Marked distress in—or the actual avoidance of—places (e.g., bridges, tunnels, airplanes) or situations (e.g., driving, shopping, traveling) in which unexpected panic attacks or panic-like symptoms have occurred in the past is referred to as agoraphobia (Box 129-2). Depending on the absence or presence, respectively, of agoraphobia, patients are given a diagnosis of panic disorder without or with agoraphobia (Boxes 129-3 and 129-4). Agoraphobia can also occur independently of panic disorder, although this is thought to be relatively rare. In such circumstances, agoraphobia (i.e., fear and avoidance of particular situations owing to fear of incapacitation or embarrassment) may be a complication of illness (and the repercussions thereof) such as vertigo or other forms of physical incapacity.

Box 129-2 Criteria for Agoraphobia *

Agoraphobia is anxiety about being in places or situations from which escape might be difficult (or embarrassing) or in which help might not be available in the event of having an unexpected or situationally predisposed panic attack or panic-like symptoms. Agoraphobic fears typically involve characteristic clusters of situations that include being outside the home alone, being in a crowd or standing in a line, being on a bridge, and traveling in a bus, train, or automobile.

Consider the diagnosis of specific phobia if the avoidance is limited to one or only a few specific situations. Consider social phobia if the avoidance is limited to social situations.

The person avoids situations (e.g., travel is restricted) or else endures them with marked distress or with anxiety about having a panic attack or panic-like symptoms or requires the presence of a companion.

The anxiety or phobic avoidance is not better accounted for by another mental disorder, such as social phobia (e.g., avoidance is limited to social situations because of fear of embarrassment), specific phobia (e.g., avoidance is limited to a single situation, such as elevators), obsessive–compulsive disorder (e.g., avoidance of dirt in someone with an obsession about contamination), posttraumatic stress disorder (e.g., avoidance of stimuli associated with a severe stressor), or separation anxiety disorder (e.g., avoidance of leaving home or relatives).

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition.

^* Agoraphobia is not a DSM-IV disorder that can be coded. Code the specific disorder in which the agoraphobia occurs (e.g., panic disorder with agoraphobia or agoraphobia without history of panic disorder).

Box 129-3

Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994.

DSM-IV Criteria for Panic Disorder without Agoraphobia

Panic disorder without agoraphobia includes:

Recurrent unexpected panic attacks

At least one of the attacks has been followed by 1 month (or more) of one (or more) of the following:

Persistent concern about having additional attacks

Worry about the implications of the attack or its consequences (e.g., losing control, having a heart attack, “going crazy”)

A significant change in behavior related to the attacks

The absence of agoraphobia

The panic attacks are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism)

The panic attacks are not better accounted for by another mental disorder such as social phobia (e.g., occurring on exposure to feared social situations), specific phobia (e.g., on exposure to a specific phobic situation), obsessive–compulsive disorder (e.g., on exposure to dirt in someone with an obsession about contamination), posttraumatic stress disorder (e.g., in response to stimuli associated with severe stressor), or separation anxiety (e.g., in response to being away from home or close relatives).

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition.

Box 129-4

Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994.

DSM-IV Criteria for Panic Disorder with Agoraphobia

Panic disorder with agoraphobia:

Meets the criteria for panic disorder

Meets the criteria for agoraphobia

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition.

Sleep Features

The extant literature suggests that at least two thirds of patients with panic disorder report moderate to severe sleep difficulties, including difficulty initiating and maintaining sleep, nonrestorative sleep, and nocturnal panic attacks.¹¹^–¹³ Sleep difficulties and sleep deprivation can lead to worsening of anxiety symptoms, including panic attacks, in patients with panic disorder.¹⁴ Most PSG studies have found decreased sleep efficiency and sleep duration with panic disorder,¹⁵^–¹⁹ although some studies have not found such disturbances.²⁰ Because panic disorder and major depression are often comorbid, it is possible that comorbid depression may be partially responsible for sleep disturbances in panic disorder; however, some of these studies have excluded subjects with comorbid depression.^17,^19,²⁰ Of those excluding comorbid depression, some still found evidence for sleep disturbance in persons with panic disorder.¹⁷^,¹⁹

One type of sleep disturbance reported to occur in panic disorder is isolated sleep paralysis, a transient gross motor paralysis that can occur at sleep onset or offset in persons without narcolepsy. It appears to arise when the involuntary immobility characteristic of rapid eye movement (REM) sleep intrudes into the waking state. In addition to being unable to move during isolated sleep paralysis, some patients report anxiety, chest pressure, and other somatic sensations. Isolated sleep paralysis has been reported in association with panic disorder,²¹^–²⁴ although it can also occur in other anxiety disorders (see also Posttraumatic Stress Disorder, later). A study investigated the prevalence of isolated sleep paralysis in a small, mostly white outpatient sample.²⁵ In this sample, the prevalence of isolated sleep paralysis in subjects with a primary diagnosis of panic disorder (20.8%) did not seem differentially higher than that in sleep paralysis (22.2%) or GAD (15.8%). Because the prevalence of isolated sleep paralysis in persons with panic disorder is reportedly higher in certain ethnic minority groups,²²^,²³ more ethnically diverse clinical samples might yield different findings.

Several surveys and studies of populations with panic disorder have documented the occurrence of panic attacks emerging from sleep as a not uncommon feature of the disorder. These episodes are often described as being awakened abruptly from sleep, usually with physical symptoms such as shortness of breath that also characterize the person’s panic attacks in awake states. Sleep panic attack episodes appear to be NREM sleep phenomena that occur at the transition between sleep stages N2 and N3 (non–rapid eye movement [NREM] sleep stages 2 and 3), and thus they are not associated with dream mentation.¹⁵^,²⁶

Approximately one half of patients with panic disorder report experiencing sleep panic attacks at some point during the course of their illness.¹¹^,²⁷ Some studies estimate that up to one third of patients experience recurrent nocturnal panic.^11,^12,^27,²⁸ Although it has been suggested that nocturnal panic may itself be a marker of more-severe panic disorder,²⁷^,²⁹ this has not consistently been found across studies.^28,^30,³¹ Nocturnal panic appears to be associated with states of diminished arousal such as sleep and relaxation.^11,³¹^–³³ Although greater motor activity during sleep as evidenced by increased epochs of movement time has been reported with panic disorder, patients might actually move less on the nights when they experience sleep panic attacks,³⁴ leading the authors to suggest that movement during sleep may serve as a temporary protective mechanism against the episodes.

Several authors have suggested that the occurrence of panic attacks during NREM sleep implicates a more endogenous, physiologic (rather than cognitive or attributional) explanatory mechanism. Specific mechanisms that have been proposed include sensitivity to subtle increases in blood carbon dioxide levels,³⁵ irregular breathing during slow-wave sleep,³⁶ and abnormalities in autonomic activity.^15,^16,³³ In addition, sodium lactate administered during sleep was found to be associated with increased cardiac and respiratory reactivity in panic disorder patients relative to controls,³⁷ and pentagastrin administered during sleep resulted in abrupt awakenings accompanied by panic symptoms in patients with panic disorder.³⁸ These findings have been upheld as evidence for a physiologic explanation for nocturnal panic, because during sleep the influence of cognitive factors is purportedly minimal or absent.

However, several studies suggest that cognitive factors also play a role. In an investigation employing caffeine administration during sleep, more fully elaborated panic attacks were preceded by a period of lighter sleep before awakening, providing support for a mixture of physiologic and cognitive influences on sleep panic.³⁹ In another study, participants with recurrent nocturnal panic attacks who were primed to expect intense physiologic changes during sleep (as indicated by an auditory signal) were less likely to awaken with panic symptoms than those for whom such a signal was unexpected, highlighting a role for presleep attributions.⁴⁰

Physiologic differences in those with nocturnal panic have also been found to normalize with cognitive behavior therapy (CBT).⁴¹ Based on this evidence, it has been argued that although physiologic differences exist for those with nocturnal panic, they should be seen as a function of panic disorder psychopathology rather than as an explanatory mechanism.³³

Treatment

The aim of drug treatment is to block panic attacks (waking and nocturnal panic attacks) and to eliminate secondary fears and avoidance activities (e.g., sleep phobias). The removal of exogenous (e.g., caffeine) factors or the correction of maladaptive behavior (e.g., sleep deprivation) that often exacerbate panic disorder should also be an integral part of the drug treatment program. If a thorough medical assessment has not recently been performed, this should be conducted (including, routinely, thyroid-stimulating hormone measurement to rule out most thyroid problems) before proceeding with antipanic treatments.

Historically, tricyclic antidepressants (e.g., imipramine) and monoamine oxidase inhibitors (e.g., phenelzine) were mainstays in the treatment of panic disorder. For reasons of tolerability and safety, these have been largely supplanted by the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, paroxetine, and controlled-release paroxetine, which are approved by the U.S. Food and Drug Administration (FDA) for this purpose. The SSRIs have been found to be effective in the treatment of panic disorder (with or without agoraphobia). High-potency benzodiazepines (alprazolam, extended-release alprazolam, and clonazepam are approved by the FDA for this purpose) have also been widely used to treat panic disorder (with or without agoraphobia). Some medications (e.g., propranolol, buspirone) used often in the management of other forms of anxiety have been shown to be ineffective in the treatment of panic disorder.⁴²^,⁴³ Although there has been little pharmacologic research on the treatment of sleep disturbances associated with panic disorder, preliminary observations suggest that sleep panic attacks are responsive to antidepressant antipanic medications.⁴⁴^,⁴⁵

Research has shown CBT to be at least as beneficial as first-line drug treatments.⁴⁶ CBT involves challenging irrational thoughts about panic symptoms and their consequences, the elimination of avoidance behavior, and gradual exposure to feared interoceptive sensations and agoraphobic situations. CBT also has the benefit of yielding long-lasting effects.⁴⁶ It is unclear whether standard CBT for panic disorder is beneficial in improving sleep, although one study suggests that combined pharmacologic treatment and CBT was insufficient in eliminating objective and self-reported sleep disturbances.¹⁹ One CBT study included modifications targeted to nocturnal panic, such as psychoeducation about normal physiologic changes during sleep, challenging of catastrophic thoughts about nocturnal panic, interoceptive exposure to relaxation conditions, and sleep hygiene.⁴¹ Compared to waitlist controls, participants who received this intervention fared better on measures of physiologic and self-reported anxiety and sleep quality, including nocturnal panic specifically. There is otherwise little information to guide the specific treatment of patients with panic disorder who have nocturnal panic attacks; this remains an area ripe for further research.

In the absence of empirical data in this regard, it is recommended that patients with significant sleep disturbance including nocturnal panic attacks be treated with an antipanic agent or with CBT and that they be instructed on the implementation of good sleep hygiene measures (see Chapters 79 and 80).

Case Study
Sleep Panic

Ms. R. is a 28-year-old woman with a 2- to 3-month history of onset of episodes during sleep where she awakes abruptly with a feeling of fear and shortness of breath. She is also aware of tachycardia at the time of awakening. She otherwise feels intensely alert, with no sense of confusion and no dream recall on awakening. She and her significant other deny somnambulism. After experiencing an episode, she typically gets out of bed and has great difficulty going back to sleep. She also reports increasing worries and avoidance about going to sleep.

The patient reports that she has been experiencing somewhat similar attacks during the daytime on an occasional basis since the age of 17 years. She reports having experienced these episodes—which feature shortness of breath, tremulousness, tachycardia, and dizziness—several times weekly from 17 to 20 years of age; during this period, she sought care in the emergency department and had multiple medical tests to rule out a seizure disorder or a vestibular disorder. The attacks eventually waned, although she admits to experiencing lesser forms of these attacks once or twice monthly from age 20 years through to the time of her presentation. She states that she had learned that these attacks, although bothersome, were not dangerous, and she was able to function well despite their continued occurrence during this period. Because the pattern of attacks has now changed to occur during sleep, she is concerned that her belief about their innocuous nature might be mistaken. She also admits to an increase in work-related stresses concurrent with the onset of the nocturnal attacks. She is not depressed and denies suicidal ideation. She also denies substance abuse or excessive caffeine use.

Although Ms. R. was thin and had no obvious physical risk factors for sleep apnea, an ambulatory sleep-breathing evaluation was conducted. That revealed no evidence of obstructive apnea. Thyroid-stimulating hormone level was normal.

In light of the clear history of daytime panic attacks in the past, despite their relative infrequency lately, a probable diagnosis of panic disorder was applied. Ms. R. was given a choice of participating in a course of CBT directed toward the panic disorder or starting on an antianxiety medication that would be intended to block the occurrence of the attacks. Citing time constraints that would make it difficult for her to begin CBT, she opted for treatment with an SSRI, a pharmacologic treatment with a good evidence base for its efficacy in the treatment of panic disorder (although data supporting the efficacy of any treatment specifically for nocturnal panic are sorely lacking).

Generalized Anxiety Disorder

Epidemiology and Clinical Features

GAD is typified by chronic anxiety and excessive, pervasive worry (Box 129-5). In community surveys, the 12-month prevalence of GAD is approximately 3%,¹ with lifetime rates being higher (approximately 6%).² As is the case for all of the anxiety disorders (with the exception of obsessive–compulsive disorder [OCD]) the prevalence is higher in women than in men, with GAD showing an approximate 2 : 1 female-to-male ratio. The natural course of GAD can be characterized as chronic, with few complete remissions, a waxing and waning course of symptoms, and the substantial depressive comorbidity.

Box 129-5

Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994.

DSM-IV Criteria for Generalized Anxiety Disorder

Generalized anxiety disorder consists of excessive anxiety and worry (apprehensive expectation) occurring more days than not for at least 6 months about a number of events or activities (such as work or school performance).

The person finds it difficult to control the worry.

The anxiety and worry are associated with three (or more) of the following six symptoms, with at least some symptoms present for more days than not for the past 6 months. Only one item is required in children:

Restlessness or feeling keyed up or on edge

Being easily fatigued

Difficulty concentrating or mind going blank

Irritability

Muscle tension

Sleep disturbance: difficulty falling or staying asleep; restless, unsatisfying sleep

The focus of the anxiety and worry is not confined to features of an axis 1 disorder. The anxiety or worry is not about having a panic attack (as in panic disorder), being embarrassed in public (as in social phobia), being contaminated (as in obsessive–compulsive disorder), gaining weight (as in anorexia nervosa), having multiple physical complaints (as in somatization disorder), or having multiple illness (as in hypochondriasis). The anxiety and worry do not occur exclusively during posttraumatic stress disorder.

The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

The disturbance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism) and does not occur exclusively during a mood disorder, psychotic disorder, or pervasive development disorder.

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition.

GAD, it might be argued, has been poorly named. This has led to a tendency to consider it a generic form of anxiety and to make the diagnosis inappropriately and pervasively. Many anxiety (and depressive) disorders are characterized by chronic anxiety and tension; these features alone are therefore insufficient to make this diagnosis. It is the presence of excessive and uncontrollable worry about multiple factors—such as work, health, and the well-being and safety of family members—that defines GAD. Patients with GAD often present to their primary care practitioner, where somatic complaints (e.g., headache, back or shoulder pain due to chronic muscle tension, chronic gastrointestinal distress) might predominate.

Sleep Features

Insomnia and GAD are highly overlapping and comorbid disorders. Sleep disturbance, further defined as difficulty initiating or maintaining sleep, or sleep that is restless and unsatisfying, is one of the six features (a minimum of three of which are needed to establish the diagnosis) associated with chronic worry in the DSM-IV criteria for GAD. Three of the other five features—fatigue, irritability, and difficulty concentrating—are also possible consequences of sleep loss. The core cognitive feature of GAD, excessive worry (apprehensive expectation), is commonly implicated in the genesis and maintenance of insomnia problems, in that patients often report their worry as most uncontrollable and bothersome at bedtime, interfering with their ability to fall asleep. In a study of comorbid psychiatric disorders in an insomnia sample, GAD was the most commonly diagnosed anxiety disorder.⁴⁷ Conversely, difficulty sleeping has been reported in 56% to 75% of persons with generalized anxiety disorder,⁴⁸^,⁴⁹ although empirical data are largely lacking on the prevalence of sleep disturbance in GAD samples. One difference between GAD and primary insomnia may be the foci of worry at night; in primary insomnia the focus of worry is typically the insomnia itself, whereas in GAD, the worry is focused on areas that are also preoccupations during the day (e.g., career, finances, relationships).

The PSG sleep of insomniac patients with GAD has been compared with that of healthy control subjects in a handful of studies, with a synthesis of the findings published.⁵⁰ In this synthesis, it is concluded that patients with GAD have increased sleep latency, increased wake time after sleep onset, lower sleep efficiency, and reduced total sleep time relative to controls. The sleep architecture findings in GAD are unremarkable, and the conclusion is that GAD is characterized by a nonspecific sleep-onset and sleep-maintenance insomnia that compromises sleep quality. Notably, these studies provide evidence that GAD can be differentiated from major depression: The classic reduction in REM sleep latency seen in endogenous major depression is usually not seen in nondepressed patients with GAD.⁵¹^–⁵³ However, given that most patients with GAD, particularly those encountered in general medical settings, also suffer from major depression, it should be expected that more classic depression-related sleep problems (e.g., early morning awakening) also will be seen. It is doubtful that differentiation of GAD from other anxiety or depressive disorders can be made on the basis of differences in sleep symptoms or PSG findings.

Treatment

Treatment for this chronic condition is, not surprisingly, often prolonged (i.e., several years). Benzodiazepines (e.g., alprazolam, clonazepam) are used extensively in the management of GAD. Although tolerance to the hypnotic effects of benzodiazepines is commonly encountered, the available evidence suggests that the antianxiety effects of these compounds persist indefinitely in most cases and are not associated with dosage escalation in the long term.⁵⁴ In addition, strong evidence from double-blind, placebo-controlled studies indicates that certain classes of antidepressants, such as the SSRIs⁵⁵ and the dual reuptake inhibitors (also known as norepinephrine and serotonin reuptake inhibitors [NSRIs], e.g., venlafaxine extended-release)⁵⁶ are efficacious.⁵⁷ A substantial advantage of antidepressants over benzodiazepines is the fact that the former treat comorbid depression, whereas the latter do not. Tricyclic antidepressants are also effective, although their use has largely been supplanted by that of the SSRIs and NSRIs. There is evidence to suggest that antihistamines may also be helpful for treating core GAD symptoms,⁵⁸^,⁵⁹ although few studies have been conducted to date.

Clinical experience suggests that improvement in insomnia parallels the overall benefits associated with pharmacologic treatment of GAD; however, studies often do not report sleep findings in GAD. One study found that the hypnotic zopiclone was beneficial for both insomnia symptoms and daytime anxiety associated with GAD.⁶⁰ The novel agents pregabalin and tiagabine that also target benzodiazepine receptors or related gamma-aminobutyric acid–ergic (GABAergic) neurotransmission have been reported to alleviate sleep disturbances associated with GAD, although neither has FDA approval for GAD or insomnia.⁶¹^,⁶² Finally, a double-blind, placebo-controlled study found that combination treatment of GAD and insomnia with escitalopram and eszopiclone was associated with greater improvement in sleep and anxiety symptoms compared with escitalopram and placebo.⁶³

CBT is highly effective in treating GAD,⁶⁴ and such treatments have also been shown to be effective for insomnia complaints.⁴⁸ In older adults, where benzodiazepines may be relatively contraindicated because of concerns about adverse effects (e.g., falls leading to fractures), psychosocial treatments may be particularly appealing.⁶⁵ The potential efficiency of integrated psychotherapeutic interventions that target both excessive generalized worries and worries about sleep warrants further exploration⁶⁶; however, empirical investigation of such treatment approaches is not yet available.

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