Sleep disturbance in generalized anxiety disorder and its treatment

SLEEP MEDICINE

Sleep Medicine Reviews, Vol. 4, No. 3, pp 263–276, 2000 doi:10.1053/smrv.1999.0096, available online at http://www.idealibrary.com on

reviews

REVIEW ARTICLE

Sleep disturbance in generalized anxiety disorder and its treatment Jaime M. Monti1 and Daniel Monti2 1 2

Clinical Pharmacology and Therapeutics, Clinics Hospital, Montevideo, Uruguay Department of Psychiatry, The University of Utah at Salt Lake City, USA

Sleep laboratory and epidemiological studies indicate that insomnia is a frequent finding in patients with psychiatric disorders. In this respect, insomnia associated with a major depression or an anxiety disorder, mainly generalized anxiety disorder (GAD), is the most prevalent diagnosis. According to available evidence, the sleep disturbance associated with mild-to-moderate GAD is a sleep-maintenance insomnia, and to a lesser extent a sleep-onset insomnia. Insomnia associated with mild-to-moderate GAD generally responds to psychological treatments and anxiolytic benzodiazepines. Moreover, concomitant administration of hypnotic medication can be contemplated in patients with severe GAD.  2000 Harcourt Publishers Ltd Key words: generalized anxiety disorder, sleep-maintenance insomnia, anxiolytic benzodiazepines

Introduction Data from the 1991 National Survey of Sleep Complaints conducted by the Gallup Organization showed that sleep-related complaints are common in the general population [1]. In this respect, the National Survey found that 65 million adults living in the USA had sleep problems. About 30–36% of the subjects reported occurrences of insomnia during the course of the year. One in four of those experiencing insomnia stated that the complaint was chronic. Many patients with a primary psychiatric disorder report sleep disturbances, which change across the lifespan, and also vary with gender. These alterations in sleep may influence the development and course of the psychiatric disorder. Usually, treatment of the psychiatric disorder significantly improves sleep. Conversely, when the sleep disturbance predominates, its treatment may improve the management of the mental disorder.

Correspondence to be addressed to: Jaime M. Monti, MD, Clinical Pharmacology and Therapeutics, Clinics Hospital, 2833/602 Zudan˜ez Street, Montevideo 11300, Uruguay. Fax: +59 82 401 18 51; E-mail: [email protected] 1087–0792/00/030263+14 $35.00/0

 2000 Harcourt Publishers Ltd

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Specific sleep disorder diagnoses according to DSM-III, DSM-IV, ICDS, and ICD-10 classifications Polysomnographic and clinical diagnoses Coleman et al. [2] analysed 5000 records from 11 sleep–wake disorder clinics. Sleep– wake disorders were diagnosed according to the Association of Sleep Disorders Centers (ASDC) [3] nosology and the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DSM-III) [4] classification system. Twenty-six percent of the sample fell into the category of disorders of initiating and maintaining sleep (insomnias). Insomnia related to another psychiatric disorder was the most frequent insomnia diagnosis, and approximately 50% of these patients had a diagnosis of major depression. Anxiety disorders were not formally diagnosed in this study.

Clinical diagnoses More recently, Buysse et al. [5] investigated the frequency and ranking of DSM-IV [6] diagnoses of 216 patients with complaints of insomnia. Insomnia related to another mental disorder was the most frequent DSM-IV [6] diagnosis (44.0% of patients), followed by primary insomnia (20.2% of patients). Anxiety disorders were not formally diagnosed. Mellinger et al. [7] reported data which came primarily from the 1979 National Survey of Psychotherapeutic Drug Use. Data were obtained from non-institutionalized adults aged 18–79 years, and showed that insomnia afflicted 35% of all adults during the course of a year. About 17% of all adults experienced the problem as serious. Thirteen percent of those with serious insomnia (vs 3% for those who never had insomnia) presented with DSM-III symptoms resembling those of generalized anxiety disorder (GAD). The National Institute of Mental Health carried out an Epidemiologic Catchment Area (ECA) study between 1981 and 1985, which included almost 8000 respondents [8]. As part of the study the respondents were questioned about sleep disturbances and psychiatric disorders during the 6 months preceding the baseline interview. Based on the data collected in the ECA study, Ford and Kamerow [9] estimated the prevalence of insomnia and its relationship to DSM-III [4] anxiety and mood disorders. At the first interview 10.2% of the subjects complained of insomnia. In 32% of the respondents with an insomnia complaint, the sleep disturbance was associated with mood disorders, and in only 5% with anxiety. GAD was not included in the structured interview administered to the individuals. An additional 17% of the patients with insomnia met diagnostic criteria for a psychiatric disorder when reinterviewed 1 year later. In general, the prospective study of sleep complaints and psychiatric disorders carried out by Ford and Kamerow [9] indicates that the risk of developing a major depression or an anxiety disorder is much greater in patients with a persistent insomnia complaint. Breslau et al. [10] performed a longitudinal epidemiological study of young adults that estimated the association between sleep disturbance and GAD, among other psychiatric disorders. The study included 1007 respondents, and was comparable in results to that reported by Ford and Kamerow [9]. The NIMH Diagnostic Interview Schedule, revised to incorporate DSM-III-R diagnoses, was used as the instrument to

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obtain the psychiatric information [11]. Like Ford and Kamerow [9], Breslau et al. [10] considered the existence of a sleep complaint on the basis of at least 2 weeks of altered sleep. In contrast, the latter group looked at the lifetime rather than the 6-month prevalence of a sleep disorder. The lifetime prevalence of insomnia alone in the sample of young adults was 16.6%. The incidences of anxiety disorders or depression were much greater in persons with insomnia, compared with normal sleepers. GAD was diagnosed in 7.8% of the patients with insomnia. Ninety-seven percent of the original subjects were interviewed 3.5 years after baseline. Of 739 persons with no history of insomnia at baseline, 13.1% reported experiencing insomnia during the 3.5-year followup interval. During that time, the sleep disturbance was associated with an anxiety disorder in 13.7% of patients. Information on the incidence of GAD was not included at this time point. Breslau et al. [10] also were able to establish a significantly increased risk for depression and anxiety disorders in patients with prior insomnia. Ohayon [12] has estimated the relationship of insomnia with other mental disorders in the general population using DSM-IV [6] criteria. For this purpose, a total of 5622 subjects ranging in age from 15 to 96 years were interviewed over the telephone about their sleep habits. The interviewers made use of an expert system (Eval) in mental health epidemiological surveys [13] as the instrument to gather the information. A total of 18.6% of the sample complained of insomnia. Insomnia related to another mental disorder accounted for 2.9% of the sample, and this was primarily a major depression (1.3%) or an anxiety disorder (0.7%). In those patients with a primary diagnosis of mental disorder (insomnia had little impact on their symptomatology), GAD was the most prevalent diagnosis. Vollrath et al. [14] examined the association of different subtypes of insomnia with depressive and anxiety disorders using the DSM-III [4] criteria. A significant overall association was found between GAD and occasional insomnia, repeated brief insomnia, and continued insomnia. Thus, evidence obtained from sleep laboratory and epidemiological studies indicates a relatively high incidence of insomnia in patients with psychiatric disorders (Tables 1 and 2). In this respect, insomnia associated with a major depression or an anxiety disorder, mainly GAD, are the most prevalent diagnoses. Differences in age and in diagnostic instruments may explain the variability across studies.

Prevalence of generalized anxiety disorder Anxiety disorders are the most frequent occurring mental disorders in the community. Estimates of the lifetime prevalence of anxiety disorders have ranged between 10% and 25% [15]. The incidence of GAD among the anxiety disorders has been determined in two well-designed surveys. Accordingly, Le´pine et al. [16] conducted a general population survey of French civilians that included 658 men and 1088 women. The instruments used in the study were a self-administered questionnaire and a structured interview. The lifetime prevalence of GAD by gender was found to be 6.6% in men, and 12.2% in women. The National Comorbidity Survey [17] was also a general population survey which included non-institutionalized residents (n=8098) 15–45 years of age living in the USA. The instrument used in the study was the DSM-III-R [18] classification. The determined prevalence of GAD was 3.1% during the previous 12-month period, and

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Table 1 Methods of studies relating insomnia to anxiety disorders Investigators Coleman et al. [2]

Mellinger et al. [7]

Ford and Kamerow [9]

Breslau et al. [10]

Ohayon [12]

Population Methods 11 Sleep–wake disorder Polysomnography clinics ASDC n=5000 DSM-III (age not specified) National Survey of DSM-III Psychotherapeutic Drug Use n=3161 age: 18 to 79 years Epidemiologic Catchment DSM-III Area (ECA) study n=7954 age: 18 to 65 years Health Maintenance DSM-III-R Organization members n=1007 age: 21 to 30 years Non-institutionalized DSM-IV French population n=5622 age: 15 to 96 years

Time-frame Point

1 year

6 months

Lifetime

Point

Table 2 Relationship between insomnia and anxiety disorders Investigators

Coleman et al. [2] Mellinger et al. [7] Ford and Kamerow [9] Breslau et al. [10] Ohayon [12]

Insomnia (% of the sample) 26 35 10.2

Anxiety disorders (% of patients with insomnia) Not formally diagnosed 13 23.9

GAD (% of patients with insomnia) Not formally diagnosed Not formally diagnosed Not formally diagnosed

16.6 18.6

35.9 1.5

7.8 0.7

5.1% for lifetime GAD. The disorder was found to be more frequent in women than in men, with a 2:1 female/male ratio. However, in clinical settings only about 55–60% of those presenting with the disorder are female [6]. The prevalence of GAD is lowest in the youngest age groups and increases with age. Its course is chronic but fluctuating, and often worsens during times of stress. The incidence of GAD in elderly subjects aged 65 years or more has been assessed in several epidemiological studies. It amounted to 7.1% in the National Survey of Psychotherapeutic Drug Use [19]; 0.7% and 3.7% in New York and London, respectively, in the Multicenter Study performed by Copeland et al. [20]; and 3% in subjects in the Epidemiological Catchment Area study carried out by Regier et al. [21]. As noted by Le´pine and Pe´lissolo [22], discrepancies from one study to another could reflect variations in definition criteria and in methodology. Although many of those presenting for treatment report onset of GAD in childhood or adolescence, the mean age of illness onset is approximately 21 years, and ranges from 16 to 26 years [23, 24]. Thus, the prevalence of insomnia in patients with GAD is high. The sleep disorder

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is more frequent in women than in men, and even more in elderly patients. Its course is chronic but fluctuating, and is affected by stressful events. All these clinical features have important treatment implications, to be discussed in the section on treatment.

Relevance of sleep disturbance in DSM-III, DSM-III-R, and DSM-IV criteria for generalized anxiety disorder Generalized anxiety disorder (GAD) is characterized by excessive anxiety and worry (apprehensive expectation) about a number of events that is accompanied by additional symptoms, including sleep disturbance [6]. In the DSM-III diagnostic criteria [4] for GAD four major symptom groups were considered: motor tension, autonomic hyperactivity, apprehensive expectation, and vigilance and scanning. Insomnia was included in the vigilance and scanning category together with hyperattentiveness, difficulty in concentrating, feeling “on edge”, irritability, and impatience. The anxious mood had to be continuous for at least 1 month. In the DSM-III-R criteria for GAD [18] trouble falling asleep and staying asleep were also integrated into the category of vigilance and scanning symptoms, together with feeling keyed up, an exaggerated startle response, difficulty concentrating, and irritability. According to these criteria, the unrealistic or excessive anxiety and worry had to persist for a period of 6 months or longer, during which the patient must have been bothered more days than not by these concerns. In the DSM-IV criteria for GAD [6] sleep disturbance is one of six symptoms associated with anxiety. The remaining five symptoms are restlessness, being easily fatigued, difficulty concentrating, irritability and muscle tension. The anxiety and worry and at least three of the associated symptoms must have been present for more days than not for the past 6 months. The symptoms have to cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Thus, as emphasized by Barlow and Wincze [25], symptoms from the motor tension cluster (muscle tension, restlessness, easy fatigability) and from the vigilance and scanning cluster (difficulty falling or staying asleep, or restless, unsatisfying sleep, difficulty concentrating and irritability) are more strongly correlated with measures of GAD than are symptoms from the autonomic hyperactivity cluster. As shown above, the number of symptoms associated with anxiety was reduced from 18, according to the DSM-III-R [18], to six as specified by the DSM-IV [6]. Sleep disturbance remains as one of these symptoms, which points to its relevance in establishing a diagnosis of GAD. In this respect, the findings by Anderson et al. [26] and Hoehn–Saric and McLeod [27] show that no fewer than 60–70% of patients with GAD have an insomnia complaint whose severity parallels that of the anxiety disorder.

The temporal relationship in onset and course of anxiety and insomnia It has been proposed that GAD could be a risk factor for the occurrence of chronic insomnia. Conversely, patients with insomnia related to chronic stress could be tentatively at risk of developing GAD [28, 29]. In this respect, the study by Ford and Kamerow [9] in which almost 8000 subjects were questioned twice over a 1-year period about sleep complaints and symptoms related to a psychiatric disorder indicates that insomnia can be a causative factor of depression and/or anxiety. Thus, at the first

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interview 40% of the respondents with an insomnia complaint had a psychiatric disorder, mostly an anxiety disorder. An additional 17% of the patients who had reported chronic insomnia at the first interview met diagnostic criteria for a psychiatric disorder when re-interviewed 1 year later. On the other hand, in the study by Vollrath et al. [14] in which almost 500 subjects were interviewed three times over a period of 7 years, a causal relationship between chronic insomnia and anxiety disorders could not be established. Because of the conflicting results obtained by Ford and Kamerow [9] and Vollrath et. al. [14], additional studies with more refined techniques and methods of analysis are needed to determine the temporal relationship between insomnia and anxiety.

Sleep disturbances in generalized anxiety disorder Clinical and polysomnographic features In the chapter devoted to sleep and anxiety disorders, the ICSD [3] considers panic disorder with, and without, agoraphobia on the one hand, and generalized anxiety disorder, social phobia, specific phobia, obsessive-compulsive disorder and posttraumatic stress disorder (all together) on the other hand. However, since each of the latter group of disorders exhibits specific clinical and polysomnographic features, they cannot be considered as a single entity. Here we will discuss exclusively sleep disturbances in patients with GAD. Taking into consideration that the topic has been investigated only by a limited number of authors, a short, balanced review of the relatively small literature base is provided. The all-night polysomnographic sleep of insomniac patients with GAD has been compared with that of normal controls in six studies. Because the DSM-III-R [18] (and DSM-IV [6]) criteria have only recently been adopted, the studies that did not use these criteria were reviewed only when patient descriptions were compatible with the DSM-III-R diagnostic criteria. We required that studies state explicitly that patients had difficulty initiating and maintaining sleep related to their GAD, and that other psychiatric, neurological and medical conditions were ruled out as the cause of the sleep disturbance. Although in some studies investigators failed to report the duration of symptoms, it was considered more than likely that patients experienced GAD for a period of 6 months or longer. We limited our analysis to studies that used a placebocontrol group, parallel group design, and randomized patient assignment. Moreover, we excluded from further review studies that included patients older than 65 years. This is because sleep quality and maintenance decline in elderly subjects irrespective of the concurrent psychiatric disorder. A total of 130 patients aged 20–65 (mean 37.2) years and 147 normal controls aged 23–65 (mean 36.2) years were studied. Patients were selected according to the following definitions of GAD: DSM-III-R [18] (one study) [30]; Research Diagnostic Criteria [31] (one study) [32]; State-trait Anxiety Inventory [33] (one study) [34]; ICD-9 [35] (one study) [36]; ICD-10 [37] (one study) [38]; and Hopkins Symptom Checklist [39] (one study) [40]. The severity of anxiety was characterized with the Hamilton Rating Scale for Anxiety (HAM-A) [41] (five studies), and with the Penn State Worry Questionnaire (PSWQ) [42] (one study). Mean HAM-A and PSWQ scores amounted to 20.3 (range 11.0–28.1) and 61.3, respectively, thus indicating a mild-to-moderate GAD. Sleep was assessed in the sleep laboratory during one night, which was preceded

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by one adaptation night. Patients were drug-free or had been on washout for at least 2 weeks before the sleep recording. Sleep analysis was done following the criteria of Rechtschaffen and Kales [43]. Sleep variables were grouped into sleep initiation and maintenance, NREM sleep structure and REM sleep features. Sleep initiation was expressed as the period of time measured from “lights out” to the appearance of stage 2 sleep. Sleep continuity measures included wake time after sleep onset (WASO), number of awakenings, total sleep time (TST) and sleep efficiency. NREM sleep structure comprised the minutes or percentage spent in each sleep stage. REM sleep was expresssed in minutes or percentage of TST; REM latency was the time from the first epoch of stage 2 to the first REM period. Values corresponding to some sleep variables were omitted in three studies (see Table 3). Compared with controls, in GAD patients: (1) Stage 2 sleep latency was increased in four studies (mean increase: 14 min; range: 5.2–32.0 min). The increase of sleep latency attained significance in two studies (mean increase: 26.9 min). (2) Wake time after sleep onset was significantly increased in four studies (mean increase: 32.8 min; range: 14.8–49.0 min). (3) The number of nocturnal awakenings was significantly increased in one study and significantly reduced in one study. (4) Values corresponding to total sleep time were found to be significantly reduced in five studies (mean decrease: 54.8 min; range: 27.0–101.4 min). (5) Sleep efficiency was significantly reduced in three studies (mean decrease: 10.4%; range: 8–15%). NREM sleep structure findings were: (1) Stage 1 sleep was increased in five studies and reduced in one study. The increase of stage 1 sleep was significant in two studies. (2) Stage 2 sleep was significantly reduced in one study and significantly increased in one study. (3) Stage 3 sleep showed a non-significant decrease in three studies. (4) Stage 4 sleep showed a significant decrease in one study and a significant increase in one study. In relation to REM sleep variables: (1) REM sleep in minutes or as a percentage of TST was slightly decreased in all six studies. (2) REM latency showed a significant decrease in one study. Thus, according to the available evidence (see also Table 3), the sleep disturbance associated with mild-to-moderate GAD is a sleep-maintenance insomnia, and to a lesser extent a sleep-onset insomnia. Concerning NREM sleep structure, and REM sleep features, results are inconsistent. Although it could be speculated that sleep is more disrupted in patients with severe GAD, further studies are needed to resolve this issue.

Treatment of generalized anxiety disorder and of the associated insomnia The specific goal of the treatment of GAD is reduction of the impairment that results from unrealistic or excessive anxiety and worry, and of the accompanying muscle

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Table 3 Polysomnographic investigations in patients with generalized anxiety disorder Papadimitriou et al. [32] Arriaga and Saletu et al. Saletu et al. Fuller et al. [34] Rosa et al. Paiva [30] [36] [38] [40] Number and mean age Controls: 12 (34.3 y) 23 (34.1 y) 32 (45.0 y) 44 (43.2 y) 15 (24.8 y) 21 (20–29 y) Patients: 12 (36.4 y) 19 (37.4 y) 22 (44.7 y) 44 (43.0 y) 15 (24.1 y) 18 (23 y) Gender Controls: 7M/3F 7M/16F — 19M/25F — — Patients: 7M/5F 2M/17F — 20M/24F — 6M/12F HAM-A Controls: 1.3 — — — 30.6 (PSWQ) — Patients: 11 >20 28.1 22.0 61.3 (PSWQ) 15 Stage 2 sleep latency (min) Controls: 13.9 25.5 15.0 21.0 19.0 — Patients: 37.8∗∗ 30.7 26.0 21.0 51.0∗∗∗ — No. of nocturnal awakenings Controls: 35.0 — 6.0 6.0 24.3 (1st half) 2.1 28.0 (2nd half) Patients: 28.0∗ — 8.0 6.0 37.5∗ (1st half) 2.1 27.5 (2nd half) Wake time after sleep onset (min) Controls: 63.5 17.9 23.0 23.0 22.8 — Patients: 94.0∗ 64.5∗ 72.0∗∗∗ 46.0∗ 37.6 — Total sleep time (min) Controls: 405.5 389.4 401.0 403.0 — 424.4 Patients: 304.1∗ 349.0 334.0∗∗∗ 376.0∗ — 368.4∗∗∗ Sleep efficiency (%) Controls: 84.0 95.9 90.0 92.0 — 95.0 Patients: 69.7 87.7∗ 75.0∗∗∗ 84.0∗ — 92.0 Stage 1 sleep (min) Controls: 59 41.3 24.0 20.0 7.4(%) 18.3 Patients: 44.1 52.7 33.4 26.0 11.2(%)∗ 22.8 Stage 2 sleep (min) Controls: 224.4 163.5 229.0 230.0 — 207.0 Patients: 157.5∗∗∗ 179.0∗ 173.6 203.0 — 194.2 Stage 3 sleep (min) Controls: 27.8 12.3 40.0 44.0 — 24.4 Patients: 20.8 22.3 40.0 41.0 — 29.3 Stage 4 sleep (min) (St 3 + St 4) Controls: 30.1 78.3 32.0 32.0 22.0(%) 57.4 Patients: 18.9 22.7∗ 20.0 34.0 13.5(%)∗∗∗ 31.8∗∗ REM sleep (min) Controls: 61.0 75.9 80.2 77.0 19.3(%) 113.2 Patients: 58.3 70.1 66.8 71.0 15.9(%) 90.7 REM latency Controls: 99.5 97.0 91.0 88.0 108.7 93.9 Patients: 96.0 71.9 121.0 105.0 115.2 71.1∗∗ y: years. ∗P<0.05; ∗∗P<0.02; ∗∗∗P<0.01.

tension, sleep disturbance, irritability, difficulty concentrating and fatigue. Like many other psychiatric disorders, GAD is a multidimensional disorder, and any approach to its management should combine non-pharmacological measures with pharmacotherapy

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(anxiolytics, antidepressants, hypnotics). Anxiolytic drugs play an important role in the management of GAD, and their judicious use is an important part of the medical treatment of the disorder. Before starting treatment, each patient must be carefully questioned about the severity and the chronicity of the symptoms. Possible organic causes for the condition such as hyperthyroidism, adrenal insufficiency or poorly controlled diabetes, and chronic drug use must first be excluded. This is because they can produce symptoms of anxiety that can be mistaken for GAD. Concerning the associated insomnia, information should be obtained about sleep latency, sleep duration, number of awakenings, sleep quality and condition on awakening. In addition, patients need to be questioned about the use of substances that can aggravate the insomnia complaint, including caffeine (coffee, tea, “cola” beverages) and alcohol.

Non-pharmacological therapy Non-pharmacological management of GAD and of the associated insomnia includes sleep hygiene and psychological treatments. With respect to sleep hygiene, patients will be counselled to avoid caffeine (coffee, tea, “cola” drinks), nicotine and alcohol; to have only light snacks and limited fluid intake close to bedtime, and to observe regular bedtimes and waking times. Psychological treatments include psychodynamic psychotherapy and cognitivebehavioral therapy. Briefly, the aim of psychodynamic psychotherapy is to help patients with GAD to reinstate a disrupted psychological equilibrium, and to confront anxiety-provoking drives and unconscious conflicts [44]. Although there are no controlled studies of this treatment in GAD patients, clinical experience tends to indicate that it could be helpful when combined with other treatment modalities. Behavioral and cognitive therapy play an important role in the treatment of GAD. A combination of cognitive and behavioral therapy, each targeting different aspects of the symptomatology, offers the greatest benefit. Behavioral therapies include relaxation techniques and exposure methods. Relaxation techniques provide the patient with relaxation coping mechanisms to relieve the excessive anxiety and worry. Relaxation methods include progressive muscle relaxation [45, 46] and the biofeedback method of relaxation training, which makes use of frontalis electromyography [47, 48]. Other techniques that also elicit relaxation and can decrease the patient’s anxiety and apprehensive expectation are relaxing imagery [49], meditation [50] and paced diaphragmatic breathing [51]. The in vivo exposure method approach identifies feared situations and through repeated exposures attempts to minimize the degree of anxiety experienced by the patient [52]. Cognitive therapy identifies cognitive responses such as beliefs and thoughts that contribute to the appearance of anxiety, restlessness and sleep disturbance, and generates rational alternatives to the altered thinking [53]. In practice, cognitive therapy is very frequently combined with behavioral therapy. In that way, a strengthening of coping responses and the replacement of anxiety-producing thoughts by more realistic thoughts results in an improvement of somatic and psychological symptoms of GAD. Numerous controlled investigations evaluating psychological treatments and employing structured interviews have been carried out during the last few years. These

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studies have shown that cognitive-behavioral techniques are superior to non-specific control conditions [54–57]. In addition, cognitive-behavior therapy is significantly more effective in short-term treatment and at 6-month follow-up as compared with either behavior or cognitive therapy alone [58, 59].

Pharmacological therapy Anxiolytic benzodiazepines (BZDs) (alprazolam, clonazepam, bromazepam) provide prompt relief of some GAD symptoms: they lower hypervigilance and induce relaxation. However, psychic symptoms, including worry, rumination or hypersensitivity to interpersonal relationships, are less affected by these compounds [60, 61]. In this respect, antidepressant drugs (tricyclic antidepressants, selective serotonin reuptake inhibitors) are more effective in reducing the psychic symptoms. However, their effects are not immediate; thus, it takes 2–3 weeks before the patient notices an improvement in symptoms. Insomnia associated with mild-to-moderate GAD generally responds to an anxiolytic BZD. As reviewed by Lader [62], anxiolytic BZDs shorten the latency to sleep, prolong sleep, reduce the number of awakenings during the night and improve the quality of sleep. The improvement of sleep with anxiolytic BZDs is prompt and with a low incidence of side-effects. The BZDs have been shown to be effective in short-term trials; however, their longer term efficacy is a matter of debate [62]. Moreover, during long-term treatment physical dependence develops in a substantial number of patients [63]. Of special concern is the finding that, in GAD, relapse develops gradually over several weeks following the withdrawal of anxiolytic BZDs [64]. Insomnia in patients with severe GAD is usually related to high levels of anxiety, pathological fears, and worries. In these patients, BZDs given in relatively high doses for several weeks or months may improve sleep [65]. If necessary, hypnotic medication (temazepam, zopiclone, zolpidem) can be administered concomitantly at bedtime [66]. Recently developed antidepressants with sedative properties, including paroxetine and nefazodone, also could be of help to improve sleep. However, their efficacy in this condition has not been objectively documented. In other words, controlled studies with paroxetine or nefazodone in patients with severe GAD and insomnia are needed. According to Power et al. [57] cognitive-behavior therapy and pharmacological treatment with a BZD can be combined with no reduction in effectiveness of the former. However, Durham and Allan [67] contend that BZDs do not contribute to the psychological treatment. Generalized anxiety disorder has high comorbidity with other anxiety and affective disorders; when present they may affect the course and the treatment of the former. For example, as pointed out by Cassano and Michelini [68], “when GAD is comorbid with major depression its severity increases, its prognosis is poorer, and there is a decreased patient compliance and responsiveness to treatment.” Because of space constrains, this important topic will not be discussed here in detail. In conclusion, the sleep disturbance associated with mild-to-moderate GAD is a sleep-maintenance insomnia, and to a lesser extent a sleep-onset insomnia. Insomnia associated with mild-to-moderate GAD generally responds to psychological treatments and anxiolytic BZDs.

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Practice Points 1. Insomnia is very frequently associated with GAD. 2. The sleep disturbance associated with mild-to-moderate GAD is a sleep-maintenance insomnia, and to a lesser degree a sleep-onset insomnia. 3. Psychological treatments, anxiolytic benzodiazepines, and antidepressants with sedative properties improve anxiety and the accompanying insomnia. Research Agenda 1. Sleep laboratory evaluation of sleep disturbance in patients with severe GAD. 2. Controlled studies with paroxetine and nefazodone in patients with severe GAD and insomnia. 3. Evaluation of newly developed antidepressants in patients when GAD is comorbid with major depression.

Acknowledgements The authors wish to thank Nijole Grazulis MS, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, for her invaluable assistance in the preparation of the manuscript.

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∗ The most important references are denoted by an asterisk.

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