Generalized Anxiety Disorders
Stella Bitran
David H. Barlow
David A. Spiegel
Anxious apprehension and overconcern are common to many anxiety and mood disorders. Prior to 1980 in the American DSM diagnostic system, and 1992 in the international ICD system, individuals who experienced those symptoms in the absence of a realistic focus of concern were classified as having an ‘anxiety neurosis’ (DSM-II) or ‘anxiety state’ (ICD-9). In DSM-III, panic disorder was split off from that classification, and the residual category was renamed generalized anxiety disorder (GAD). A similar nomenclature was adopted in ICD-10.
Since its inception, GAD as a nosological entity has been troubled by problems of poor reliability and high comorbidity.(1) Those concerns have prompted several revisions of the DSM criteria and also have raised more basic questions regarding the validity of GAD as a disorder distinct from other anxiety and mood states. The question of what is the nature of GAD is still being debated and it remains one of the least reliably diagnosed anxiety or mood disorders.(2) This diagnostic unreliability has led to various suggestions for revisions to the diagnostic criteria and criticisms of the current definition of GAD.
Clinical features
Individuals with GAD experience persistent anxiety and worry that is out of proportion to actual events or circumstances. Typically, the anxiety and worry involve minor or everyday matters, such as work, finances, relationships, the health or safety of loved ones, and routine tasks. Often, the focus of worry shifts from one concern to another. Although people with GAD do not always consider their worries to be unrealistic or excessive, they do find them difficult to control. Consequently, the worries often interfere with concentration and performance.
Associated with the anxiety and worry, individuals with GAD have a variety of cognitive and somatic symptoms, including trembling, feeling shaky, aching in the back and shoulders, tension headaches, chest tightness, restlessness, exaggerated startle, irritability, insomnia, fatigue, dry mouth, sweating, urinary frequency, trouble swallowing, nausea, and diarrhoea. In addition, GAD may be accompanied by other conditions typically associated with stress, such as irritable bowel syndrome or atypical chest pain.
Classification
Diagnosis
(a) DSM criteria
In DSM-III, GAD was essentially a residual category for individuals with somatic symptoms of anxiety who did not meet diagnostic criteria for another, more specific, anxiety disorder. Diagnosis required the presence, for at least a month, of symptoms from three of four symptom clusters: motor tension, autonomic hyperactivity, apprehensive expectation, and vigilance and scanning. Unfortunately, clinicians had difficulty applying those criteria. In addition, its diagnosis depended on the application of the criteria for other diagnoses since GAD was not diagnosed if another anxiety disorder was present.
In DSM-III-R, apprehensive expectation was removed from the diagnostic symptom clusters, was redefined as unrealistic or excessive anxiety and worry about two or more life circumstances, and was made the essential feature of GAD. In addition, the duration criterion was changed from 1 to 6 months, and the hierarchical exclusion rule was dropped, allowing GAD to be diagnosed in addition to other disorders.
Table 4.7.1.1 DSM-IV inclusion criteria for GAD | ||||||||||
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Despite those changes, the diagnostic reliability of GAD remained essentially unchanged.(1) Investigations revealed that the new worry criterion was problematic. Interviewers commonly disagreed as to whether two distinct spheres of worry were present, whether the worry was unrealistic or excessive, or whether the focus of the worry could be construed to be part of the symptomatology of another disorder. Moreover, studies indicated that patients with GAD did not differ substantially from control subjects in the content of their worries.(3,4) The main difference between patients and controls was that the former experienced their worrying to be uncontrollable while the latter did not.
Based on those and other findings, the GAD criteria were revised again in DSM-IV. The ‘unrealistic’ descriptor and the requirement for anxiety or worry to involve at least two spheres of life circumstances were deleted, and a new criterion was added that the worry must be experienced as difficult to control. In addition, the associated symptom criterion was modified to require only three of six symptoms from the previous motor tension and vigilance and scanning clusters (Table 4.7.1.1). For additional information about the evolution of the DSM criteria for GAD, see Barlow or Wincze.(5)
(b) ICD-10 criteria
Like DSM-IV, ICD-10 requires a period of 6 months of generalized anxiety and worry accompanied by certain somatic symptoms (Table 4.7.1.2). The 6 months of ‘prominent’ tension and worry needs to be accompanied by at least 4 of 22 associated symptoms. The ICD-10 differs from DSM-IV in that it does not require that worry be ‘uncontrollable’, that the symptoms of GAD occur exclusively outside the context of a mood disorder, or that they meet a ‘clinical significance’ criterion.
(c) Differential diagnosis
Everyone experiences anxiety and worry sometimes, and some people describe themselves as born worriers. GAD differs from these non-pathological anxiety experiences in that it is both persistent and severe enough to cause significant distress or interference. Typically also, the worries are more pervasive and difficult to control than normal worries and are associated with physical symptoms of anxiety and tension.
A number of general medical conditions can present with signs and symptoms resembling GAD (Table 4.7.1.3). In addition, substances such as caffeine, alcohol, other drugs of abuse, toxins, and some medications (Table 4.7.1.4) can cause anxiety-like symptoms either as a direct effect or as part of a withdrawal syndrome. These causes may be established on the basis of a medical and substance use history, physical examination, or laboratory tests.
Table 4.7.1.2 ICD-10 inclusion criteria for GAD | ||||||||||||||||||
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Table 4.7.1.3 General medical conditions that can cause symptoms resembling anxiety | |||||
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Table 4.7.1.4 Medications that can cause symptoms resembling anxiety | ||||||
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GAD is distinguished from other psychiatric disorders, in part, by the focus of the anxiety and worry, which is not limited to a feature of another disorder. For example, the worry is not only about the possible occurrence or implications of panic attacks (as in panic disorder), or about negative evaluations by others (social phobia), gaining weight (anorexia nervosa), or having a serious illness (hypochondriasis). In obsessive-compulsive disorder, the anxiety and worry are associated with intrusive thoughts, images, or impulses that are distressing.
Generalized anxiety commonly occurs in depression, and GAD and depression also share associated symptoms such as sleep disturbance, fatigue, restlessness, and poor concentration. When the associated symptoms could fit with either disorder, the distinction is made on the basis of the presence and time course of depressed mood relative to anxiety. In DSM-IV, GAD is not diagnosed if its features occur exclusively during a mood disorder.
(d) Epidemiology
Prevalence estimates of GAD vary considerably with the diagnostic criteria used. One large-scale study found a 12-month prevalence rate of 2.07 per cent and a lifetime prevalence rate to be 4.1 per cent.(6) Socio-demographic factors associated with increased risk for GAD included being female, middle-aged, and with low income. However, being African American, Asian, or Hispanic was associated with a decreased risk.(7)
The National Comorbidity Study Replication (NCS-R), which used DSM-IV criteria and included structured interviews of over 9000 individuals in the United States, found a 12-month prevalence of GAD of 3.1 per cent and a lifetime prevalence rate at 5.7 per cent.(8,9) Lifetime prevalence rates were lowest among 18- to 29-year-olds (4.1 per cent) and those 60 or older (3.65 per cent), with the highest rates found among 45- to 59-year-olds (7.7 per cent).
(e) Comorbidity
GAD usually coexists with other anxiety and mood disorders. One large-scale study found that 68 per cent of individuals with a principal diagnosis of GAD met criteria for another Axis I disorder (Table 4.7.1.5).(10) The most frequently comorbid disorders were MDD, social phobia, or panic disorder with or without agoraphobia. Ninety-two per cent of individuals from this study with a principal diagnosis of GAD met criteria for another lifetime disorder, with 64 per cent meeting criteria for MDD. Similarly, in the major epidemiological surveys, nearly two-thirds of individuals with GAD had additional DSM Axis I diagnoses.(11) Most common among these were specific (21-59 per cent) and social (16-59 per cent) phobias, followed by panic disorder (3-27 per cent) and depression (8-39 per cent). In addition, GAD was found to be approximately twice as common among women as men. There is less information about the prevalence of personality disorders among patients with GAD.
Table 4.7.1.5 Prevalence of comorbid disorders in 279 patients with GAD | ||||||||||||||||||||||
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(f) Is GAD a valid disorder?
The findings of only fair diagnostic reliability and high comorbidity for GAD have been interpreted as indicating poor discriminant validity of the disorder, suggesting that differentiating GAD from other anxiety and mood disorders may be artifactual. In considering those arguments, it is important to distinguish the diagnostic criteria sets specified in the DSM and ICD classification systems from the clinical syndromes they are intended to identify. Low discriminant validity for a disorder may be due to problems with the former rather than the latter. To establish the construct validity of a syndrome, one must demonstrate that it has a consistent set of features, the pattern of which separates it from other related syndromes. One approach to doing that is to compare the profiles of patients with different diagnoses across various illness dimensions.
In one such study, data from patients who took part in the DSM-IV mixed anxiety-depression field trial were examined.(12) Using factor analyses of patients’ scores on 73 items from the Hamilton anxiety and depression rating scales, four clusters were identified that corresponded to the dimensions of anxiety, depression, physiological arousal, and general negative affect (containing items that loaded on both the anxiety and depression factors). Patients with a principal diagnosis of GAD had a unique profile (high on negative affect and anxiety, low on physiological arousal and depression) that distinguished them from individuals with panic disorder, major depression, anxiety or depressive disorder not otherwise specified, or no mental disorder.
A subsequent study, using an anxiety clinic sample and an expanded array of measures, yielded similar results.(13) In this case, five primary factors (corresponding to panic, agoraphobia, social anxiety, obsessions/compulsions, and general anxiety) and a higher order factor (negative affect) were identified. Again, patients with GAD had a unique factor profile.
The findings from the preceding studies were replicated and extended in an independent sample of patients.(14) As in the earlier studies, GAD was found to be distinct from other anxiety syndromes and depression, although it had the highest degree of overlap with other syndromes, especially depression. In addition, GAD was strongly associated with the non-specific dimension of negative affect, which is common to anxiety and depression. The authors suggest that GAD may represent a ‘basic emotional disorder’, because it consists of features that are present to varying degrees in all anxiety and mood disorders.
Finally, all three of the preceding studies (and a variety of others, e.g. Barlow et al.(15) support the differentiation of symptoms of autonomic arousal, which are characteristic of panic attacks, from somatic symptoms related to central nervous system tension, which form the DSM-IV-associated symptom cluster of GAD.
(g) Aetiology
Findings from genetics, neurobiology, and psychology infer a multifactorial aetiology for GAD, which has been organized into a triple vulnerabilities model.(16,17) This model suggests that anxiety disorders result from the combination of a generalized biological vulnerability, a general psychological vulnerability, and a specific psychological vulnerability.
(i) Generalized biological vulnerability
Genetic contributions. Several studies investigating genetic vulnerabilities for mental disorders have supported the notion that a shared vulnerability underlies anxiety disorders.(18) It was shown through a meta-analysis of genetic epidemiological studies that many anxiety disorders (including GAD, panic disorder, phobias, and OCD) aggregate in families and that genetics has the most influence when examining familial risk.(19) In a family study that used DSM-III criteria, GAD (but not other anxiety disorders) was five times more prevalent (19.5 per cent versus 3.5 per cent) among first-degree relatives of patients with GAD than among relatives of controls.(20) However, two twin studies using the same criteria found concordance rates for GAD were no higher among monozygotic than dizygotic twins.(21) Two subsequent studies that used DSM-III-R criteria found a shared heritability for GAD and mood disorders.(22) At present, it appears that genetic factors play a modest role in the aetiology of GAD, and one that is more closely related to vulnerability for depression than for other anxiety disorders.
Neurobiological mechanisms. A variety of neuroanatomical, neurochemical, neuroendocrine, and neurophysiological systems have been implicated in the pathogenesis of anxiety states. Much of this information has come from animal models and research on the effects of stress. Studies of neurobiological functioning in humans with GAD are limited. Some of the physical systems that may be involved in the emotion of anxiety are summarized below. Additional information may be found in reviews by Davidson,(23) and Gray and McNaughton.(24)
The noradrenergic nervous system. Noradrenergic pathway (the locus coeruleus–noradrenaline-sympathetic nervous system) have long been associated with fear and arousal and play an important role in the body’s response to threat. However, their role in persistent anxiety states is not clear. Resting catecholamine levels in patients with GAD appear to be normal. On the other hand, GAD patients exhibit subnormal responses to both stimulation(25) and blockade(26) of α2-adrenergic receptors and a reduced density of α2-receptors in platelets.(27) Those findings could reflect downregulation of the α2-receptors due to initially high levels of noradrenaline (norepinephrine).
Consistent with those neurochemical findings, somatic measures of autonomic nervous system function (e.g. skin conductance, respiratory rate, heart-rate variability, blood pressure) in patients with GAD tend to show normal resting values with blunted and sometimes prolonged responses to stressful stimuli.(27) Psychophysiological studies have found that worry is associated with restricted sympathetic arousal and low vagal tone.(27) In contrast, it has been shown that compared to controls, individuals with GAD show greater muscle tension at baseline in response to psychological challenge.(28) In addition, structural analyses suggest that GAD, unlike other anxiety disorders, is not associated with autonomic hyperarousal when levels of negative affect are held constant.(14) These findings indicate diminished autonomic nervous system responsiveness in individuals with GAD.
The hypothalamic-pituitary-adrenal axis. The hypothalamic-pituitary-adrenal axis and its end-product, cortisol, are also involved in reactions to stress. Activity in the hypothalamic-pituitary-adrenal axis is subject to a variety of influences. Primary control is by means of hypothalamic secretion of corticotrophin-releasing factor, which stimulates pituitary secretion of ACTH, which in turn stimulates adrenal secretion of cortisol. Circulating cortisol, and analogues such as dexamethasone, exert inhibitory feedback at the level of the pituitary gland and apparently also by means of receptors on the hippocampus.
In rats, chronic exposure to stress or exogenous steroids results in a reduction of corticosteroid receptors in the hippocampus and a consequent decrease in feedback inhibition by cortisol.(29) These animals exhibit reduced dexamethasone suppression of cortisol secretion and greater or more prolonged adrenocortical responses to stress. Reduced dexamethasone suppression also has been observed in approximately one-third of patients with DSM-III-diagnosed GAD.(30) This reduction in the normal regulatory control of cortisol secretion may be one mechanism through which chronic or repeated stress can lead to persistent anxiety.
The amygdala and the bed nucleus of the stria terminalis. LeDoux(31) and others have demonstrated the central role played by the amygdala in the mediation of fear reactions. The amygdala is thought to be responsible for the detection of potential threats to the organism and the mobilization of a range of defensive responses (Fig. 4.7.1.1). Through connections with the hypothalamus, it can activate the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Through efferent fibres to the central grey area of the midbrain, it can mediate behavioural defence responses such as the fight-or-flight response and behavioural ‘freezing’. Through connections to the nucleus reticularis pontis caudalis, it can enhance the defensive startle reflex.
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