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Generalized Anxiety Disorder in Medical Practice

Rudolf Hoehn-Saric, MD

Dr. Hoehn-Saric is professor emeritus and director of the Anxiety Disorder Clinic in the Department of Psychiatry at the Johns Hopkins School of Medicine in Baltimore, Maryland.

Disclosure: Dr. Hoehn-Saric receives grant and/or research support from Forest.

Please direct all correspondence to: Rudolf Hoehn-Saric, MD, 117 Meyer Building, Johns Hopkins Hospital, Baltimore, MD 21287; Tel: 410-955-6111; Fax: 410-614-5913; E-mail: [email protected].

Abstract

Generalized anxiety disorder (GAD), characterized by excessive anxiety and worry, is one the most common anxiety disorders. Since it is phenomenologically close to normal anxiety, the majority of GAD patients are seen by primary care physicians. Patients often complain of being overstressed rather than anxious and present vague somatic complaints. However, GAD is a heterogeneous disorder; patients differ in onset, type and intensity of worries, degree of hyperarousal, and physical manifestations. Personality traits influence their behavioral responses. Physical complaints tend to cluster around muscular, cardiovascular or gastrointestinal symptoms. On physiologic recordings, increased muscle tension is always present. Autonomic responses tend to show diminished flexibility in response to mild stressors, possibly due to dysfunctional central information processing involving failure to discriminate anxious and neutral stimuli. However, predisposed patients show strong autonomic responses to stressors and, in the presence of medical comorbidity, anxiety may crystallize around the physical state. Therefore, psychologic and pharmacologic treatments for each case need to be considered individually.

Introduction

Generalized anxiety disorder (GAD) is a chronic disturbance characterized by excessive anxiety and worry (ie, apprehensive expectations) occurring over at least 6 months. It is associated with restlessness, difficulty concentrating, irritability, muscle tension, sleep disturbances, and fatigue. The disorder causes significant distress or impairment.¹

Anxiety is future oriented in that it expresses a concern about one’s ability to cope with a potential danger. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),² defines GAD in detail but fails to provide a description of the variety of manifestations that GAD presents in the clinic. Clinically, GAD patients do not form a homogeneous group.³ They differ in onset, type and intensity of worries, degree of hyperarousal, physical manifestations, and behavioral responses.

The clinical picture presented by patients is greatly influenced by the type of fears, whether patients are worried about physical illness, social and professional performance, interpersonal relations, personal safety, or the safety of people that are close to them. Some patients suffer from insomnia while others are hyperaroused only during certain times of day, such as in the morning when they face the stress of work. GAD patients express less severe somatic symptoms than panic disorder patients.⁴ However, different patient groups complain of different somatic symptom clusters. These symptom clusters are generally muscular, cardiovascular, or gastrointestinal.⁵ The clinical picture is further modified by constitutional physiological response patterns, such as the tendency to perspire or to blush. In the presence of medical comorbidity, anxiety may crystallize around the physical state. Finally, personality traits influence the behavior of the patient. Therefore, treatment of each case needs to be considered individually.

Clinical Manifestations of GAD

Prevalence

GAD is one of the most common anxiety disorders, with a lifetime prevalence of approximately 5% to 9% according to the DSM-III-R⁶ or the less strict International Statistical Classification of Diseases and Related Health Problems, 10th Revision,⁷ criteria.⁸ In a British survey conducted by the Gallup Poll Organization,⁹ 31% of adults reported subclinical levels of anxiety. GAD occurs more frequently in women, with a female-to-male ratio of roughly 2 to 1.⁸ The course of the disorder is usually chronic, with periods of worsening alternating with periods of remission. The spontaneous remission rate is approximately 20% to 25%.¹⁰

Heritability of GAD

Twin studies¹¹ suggest a modest heritability of 31.6% for GAD, and indicate that the remaining variance in liability results from environmental factors. A family study¹² suggested a genetic predisposition for GAD that differs from that of panic disorder. GAD subjects more frequently had first-degree relatives with GAD, whereas panic disorder patients more frequently had first-degree relatives with panic disorder.

A recent study¹³ also suggested an association between GAD and obsessive-compulsive disorder (OCD). Both disorders are characterized by intrusive thoughts that are difficult or impossible to control and both disorders respond to treatment with selective serotonin reuptake inhibitors (SSRIs), although, as outlined by Grados and colleagues,¹⁴ worries in GAD patients are exaggerations of real situations and are not fixed, while intrusive thoughts are irrational, repetitive, and do not respond to logical reasoning in OCD patients.

Onset

Onset of GAD usually occurs in the late teens or early twenties of a patient’s life.¹⁵ However, heightened anxiety is frequently present during childhood. Often, the activation of anxiety to a full disorder occurs when the already anxious person comes under greater stress, such as leaving home for college or taking out the responsibility for a mortgage. A recent twin study¹⁶ found a substantial overlap between genetic factors that influence individual variation in the personality trait neuroticism—namely the heightened tendency to respond to stressors with anxiety and depression—and those that increase liability for GAD. Therefore, some researchers have proposed that GAD is an Axis-II personality disorder.¹⁷ For a more detailed discussion of the relationship between personality traits and anxiety disorders see Bienvenu and Brandes.¹⁸

Not all GAD patients have an early onset, and incidence of GAD increases at approximately 35–45 years of age.¹⁰ Hoehn-Saric and colleagues¹⁹ compared GAD patients with an onset before 20 years of age with GAD patients with a later onset. They found that early-onset patients were more likely to develop GAD without precipitating events. They had been exposed to more domestic disturbances in childhood, had experienced more childhood fears, tended to have obsessional traits, were more sensitive to interpersonal relationships, were socially more inhibited and maladjusted, and experienced more marital difficulties. The early onset may be caused by constitutional traits that make an individual more vulnerable to stressors; it also may be caused by a more disturbed environment during childhood that adversely affected personality development. An alternative explanation would be that early-onset GAD presents a more severe disorder with an earlier subclinical onset that also affects personality development. In late-onset patients, GAD was often precipitated by adverse experiences. Symptoms of anxiety were comparable in both groups but patients with late onset exhibited more robust personalities.

Neurobiology of GAD

Anxiety activates the organism to cope physically and mentally with potential threats. Therefore, manifestations of anxiety are complex and include automatic responses, such as the orientating and defensive response, heightened arousal and focused attention, autonomic muscular and endocrine responses, and affective responses that range from uneasiness to panic. On a higher level, the individual learns to identify a potential threat, acquires fear responses, analyzes threatening situations, and develops strategies to deal with them. Equally important is the ability to unlearn acquired fear responses that have lost their threat.

Obviously, many areas of the brain participate in this process. One can conceptualize the brain to form closely interacting functional modules. On the lowest level are nuclei of the brain stem, particularly the noradrenergic locus coeruleus and the serotonergic raphe nuclei, which are involved in modulating levels of arousal and anxiety.⁸ The hierarchically higher limbic system is primarily responsible in the generation of anxiety. In this system, the amygdala is essential in the recognition of potential threats, which can occur on a conscious or an unconscious level, and in the acquisition and unlearning of fear responses. Closely associated with the amygdala is the hippocampus, which enriches the content of the fear response by providing memories associated with the fear response.^20,21 While the amygdala processes cued fears, uncued generalized fears are generated in the bed nucleus of the stria terminalis, an extension of the amygdala. This area of the brain may be dysfunctional in GAD.²² The amygdala is closely connected with the brain stem nuclei, with centers controlling autonomic and endocrine stress responses, and with the prefrontal cortex. On the highest level, the prefrontal cortex, particularly the orbitofrontal cortex, evaluates emotional, perceptual, and cognitive information and decides how to cope with the potential threat.⁸

Imaging studies have shown that mild anxiety increases cerebral blood flow but severe anxiety that induces hyperventilation and sympathetic excitation leads to vasoconstriction and a decrease of blood flow. Performance follows the changes of blood flow; mild anxiety increases performance while severe anxiety disorganizes and impairs concentration.²³

Using functional magnetic resonance imaging (fMRI), Hoehn-Saric and Schlund²⁴ studied the effects of sentences that describe a severe personal worry compared to sentences with a neutral content on cerebral blood flow (the blood oxygenation level dependent [BOLD] effect) in patients with GAD and in non-anxious controls. “Worry” sentences activated similar regions in non-anxious volunteers and in GAD patients, namely prefrontal regions dealing with evaluation, the cingulate (an area that is activated by ambiguous inputs), and the midbrain and pontine regions (regions that may be associated with heightened arousal). These regions are expected to be activated during an attempt to cognitively solve a worrisome situation. However, GAD patients activated larger areas of the prefrontal cortex, indicating a greater cognitive effort to deal with the problems and, in addition, activated the limbic system, the area associated with anxiety. In a second fMRI study Hoehn-Saric and colleagues²⁵ compared the effect of worry and of neutral sentences in GAD patients before and after 7 weeks of treatment with the SSRI citalopram. Citalopram significantly reduced anxiety, which led to a reduced BOLD response to worry sentences in prefrontal, limbic, and pontine regions. Interestingly, neutral sentences showed an even greater response reduction, mainly in the left hemisphere. The researchers interpreted the finding that anxious GAD patients respond excessively not only to anxiety-related stimuli but also to neutral stimuli. The results of the study are in agreement with the clinical impression that anxious individuals overinclude inputs, which leads to poor discrimination between which stimuli are important and which are not. The reduction of anxiety attenuates the attention to unimportant inputs, which permits the patient to focus on important issues.

Neurotransmitter Systems

Several neurotransmitter systems have been identified that play a role in the regulation of anxiety. The principal neurotransmitter systems that are currently known are the g-aminobutyric acid (GABA)-ergic, noradrenergic, serotonergic, dopaminergic, and histaminergic systems, as well as corticotropin-releasing hormone and the excitatory amino acid glutamate. Recent research has shown that other neuropeptides may be involved in the regulation of stress and anxiety.²⁶ The inhibitory GABA-ergic system reduces anxiety, which can be augmented with the help of benzodiazepines. The noradrenergic and the serotonergic systems modulate arousal. The noradrenergic system is also essential in gating stimuli, thereby magnifying the impact of stimuli. These systems also modulate the functions of the limbic system and the prefrontal cortex. Antidepressants that alter the levels of serotonin and norepinephrine are widely used in the treatment of anxiety. Currently, drugs affecting other systems of the brain are under investigation (for more details see Charney²⁶ and Kent and colleagues²⁷).

Peripheral Physiology of GAD

Anderson and colleagues⁴ and Hoehn-Saric²⁸ found that GAD patients reported fewer less severe physical symptoms than panic disorder patients, although Logue and colleagues²⁹ found little difference between the two groups (both reported a high incidence of palpitations, chest pain, shortness of breath, headache, dizziness, and gastrointestinal symptoms). However, GAD patients, like other anxiety patients, are poor in assessing their physiological state. McLeod and Hoehn-Saric³⁰ found that GAD patients who were exposed to laboratory stressors recognized an increase in their heart rate and perspiration level but could not reliably recognize the degrees of change. Some patients who reported large subjective changes had only small physiological changes and vice versa. Even less accurate was the assessment of bodily changes after treatment. Patients whose anxiety was reduced reported lower heart rate and lower tendency to perspire than before treatment in spite of the fact that many of them showed no objective changes or recorded higher heart rate and blood pressure.³¹ Thus, self-awareness of physical states depends on patients’ anxiety levels and general well being rather than on the actual physiologic state.

Because GAD tends to be chronic, one would expect to find physiologic differences between patients with GAD and non-anxious subjects. However, when GAD patients were examined in the laboratory, only forehead and gastrocnemius muscle tension distinguished patients from controls.³² Increased muscle tension is almost invariably present in anxiety patients, although they frequently fail to recognize the tension until they are made aware of it. The increased muscle tension is correlated with fast beta activity in the electroencephalogram (EEG) and probably presents a peripheral manifestation of heightened arousal.³³ Tension in certain muscle groups may cause local discomfort and pain, such as tension headache. Autonomic changes are less consistent in GAD. In one group of patients, skin conductance (a measure of sweat gland activity), heart rate, and respiration levels were comparable to those levels in non-anxious persons. During performance of stressful mental tasks, GAD patients and controls showed similar physiologic changes, except that the skin conductance and heart-rate responses were smaller in patients with GAD.³²

However, when Hoehn-Saric and colleagues³⁴ compared a group of GAD patients with high levels of cardiac complaints to a group who expressed low levels of such complaints before and after treatment with alprazolam, the researchers found that treatment significantly reduced heart rate and increased variability in the high but not in the low group. Thus, patients may differ constitutionally and may vary in their responses under stress. For example, psychological stress increases blood pressure more in a normotensive person with a positive family history for hypertension than in one without such a history.³⁵ Patients who suffer hyperhidrosis embarrass themselves when breaking into sweat in social situations. Anxiety easily crystallizes around autonomic symptoms of patients comorbid with cardiac arrhythmias or irritable bowel syndrome (IBS). In one study,³⁶ more than half of patients with IBS also suffered from an anxiety disorder (predominantly GAD); those patients were seeking help for IBS, while the non-anxious patients with the syndrome did not seek help.

Diminished physiological flexibility, namely diminished physiological responsiveness to everyday stressors, has been the most consistent finding in anxiety patients. Hoehn-Saric and colleagues³⁷ observed a decreased variance of heart rate and skin conductance not only in the laboratory but also in patients wearing an ambulatory monitor during everyday activities. Diminished flexibility is not specific for GAD but is seen in other anxiety disorders, in depression, in alcoholism, and in high neuroticism or social maladjustment. It also manifests itself in decreased catecholamine and cortisol excretion and decreased EEG responses to challenges.³⁷ Thus, diminished physiological flexibility to stressors is a nonspecific manifestation that accompanies prolonged anxiety and stress. It appears to be state dependent because cardiac variability increases after cognitive-behavioral therapy (CBT) in GAD patients or treatment with paroxetine in panic disorder patients.³⁸ One explanation for the diminished physiological flexibility is the lack of discrimination between important and unimportant inputs in patients with heightened anxiety. Using fMRI, one study²⁵ found that patients with heightened anxiety overreacted not only to anxiety-provoking statements but also to neutral statements. Thus, cerebral responses become indiscriminant to the nature of the stimulus, leading to dysfunctional cerebral processing of information. The indiscriminate processing of stimuli may limit the modulation of physiological reactivity. The long-term effects of diminished physiological flexibility on general health are unknown; diminished cardiac variability has been associated with increased risk for myocardial infarction. For a more detailed discussion of the relationship between anxiety and cardiovascular system see McCann and colleagues.³⁹

Diagnosis

GAD resembles normal anxiety and the separation from normal anxiety appears to be a gradual one. Therefore, in milder cases, the diagnosis is influenced by the level of discomfort expressed by the patient, which may vary considerably, even in the same patient. For instance, women with GAD and comorbid premenstrual syndrome rated themselves significantly more anxious premenstrually than in the follicular phase of the menstrual cycle.⁴⁰ However, when ratings were obtained in the typical open-ended manner, namely during any time in the menstrual cycle, patients rated themselves as anxious as during the premenstruum. Thus, ratings were influenced by the symptoms experienced during the worst time.⁴⁰ Comorbidity with other anxiety disorders and depression is frequent. An estimated 90% of subjects with lifetime GAD will have a comorbid anxiety, mood, alcohol, or substance abuse disorders during their lifetime; half of GAD patients fulfill the criteria for an additional anxiety disorder and >60% for major depressive disorder.¹⁵

GAD in General Practice

Generally, physical symptoms of GAD are less severe and incapacitating than in panic disorder. Therefore, patients with GAD are more frequently treated by primary care physicians (PCPs) or in nonmedical settings rather than by psychiatrists. Nevertheless, patients with GAD frequently worry about physical sensations and are preoccupied with their health. Wittchen⁴¹ found that 22% of anxiety patients in general care were diagnosed with GAD. However, they frequently regard themselves to be overstressed rather than anxious and complain of general vague or nonspecific somatic symptoms. In one survey,⁴² 87% of patients with GAD did not present anxiety as their primary symptom. The majority of patients reported substantial interference with their life, a high degree of professional help seeking, and a high use of medications. Preoccupation with health is common in GAD patients and particularly in those who have witnessed illness in people close to them. Such preoccupation leads to excessive use of medical facilities and absenteeism, particularly when patients are comorbid with a physical illness.^41,43 Logue and colleagues²⁹ reported that approximately 50% of GAD patients that entered a study sought medical evaluation for cardiac symptoms and 40% had standard treadmill evaluations.

Management of Patients with GAD

Since the clinical manifestations of GAD are manifold, each case needs to be considered individually according to the type, severity, and chronicity of symptoms; triggers that elicit or aggravate symptoms; coping ability; learning potentials; specific personality traits; and, above all, the patient’s motivation to change. Up to 50% of patients with GAD may have personality disorder and ≤80% of those with treatment-resistant GAD may have this condition.¹⁵ Hysterical personalities tend to overreact to situations and exaggerate their symptoms, OCD personalities may become controlling and demanding, and avoidant personalities may not be willing to face stressful situations. Patients with an external locus of control, namely those who do not accept responsibility for their symptoms, present themselves as sicker, as rated by the examiner.⁴⁴ They do better on advice and medication. Those with an internal locus of control prefer to learn coping techniques rather than taking medication.⁴⁴

During the initial assessment of patients with GAD, the clinician must first exclude a physical illness or a different psychiatric disorder as being responsible for the symptoms. Often, an agitated depression is mistaken for an anxiety state. Symptoms of withdrawal in an occult substance abuser may resemble symptoms of anxiety.

Different approaches are necessary for patients with predominantly psychic symptoms, compared to those needed for patients who also exhibit strong somatic symptoms. In addition, different medications are required for individual somatic symptoms (eg, cardiac, gastrointestinal, or muscular symptoms). Mild forms respond to simple psychological interventions consisting of assurance, explanation of somatic symptoms, clarification of conflicts, and exploration of coping mechanisms. More complex patients may need CBT, which is particularly suited for the person who worries excessively and avoids anxiety-inducing situations.⁴⁵

Pharmacologic Treatment

Benzodiazepines reduce anxiety immediately and reduce autonomic and muscular effects of anxiety, but their effect is limited. They are most effective in reducing hyperarousal and somatic symptoms but less so in reducing psychic symptoms. Because of their addictive nature, they should be used for a short time or intermittently, except in the rare patient who does not tolerate other medications.

Antidepressants that have serotonin reuptake inhibitory properties are presently the medications of choice and appear more effective in the treatment of GAD than antidepressants with predominantly norepinephrine reuptake inhibition.⁴⁶ They reduce psychic symptoms but become effective only gradually and have little direct effect on the physiological state of the patient. Initially, they may increase tension, which can be avoided by starting with the smallest dose and gradually increasing the medication to the therapeutic level.³ Comorbidity with medical illnesses has to be considered in the choice of the antidepressant. Patients with cardiovascular diseases are safer on the newer SSRIs than on tricyclic antidepressants (TCAs), while patients with IBS may profit from the anticholinergic side effects of the TCAs. Newer medications have been developed but those that have reached the market have been somewhat disappointing.²⁷ The duration of treatment depends on patient’s response to treatment; the goal is to help the patient to live without drugs or, if medications are necessary, with the minimum amount. Some patients, however, require prolonged treatment and one would do a great disservice to them by adopting a “neo-Calvinistic” attitude and depriving them of the benefit of medication.

Conclusion

GAD is a common but rather heterogeneous anxiety disorder. Patients differ greatly in psychic and somatic symptoms. Because GAD resembles severe “normal” anxiety, patients are more frequently being seen by PCPs and other medical specialists than by psychiatrists. They often present vague somatic symptoms rather than admit to anxiety. Therefore, PCPs need to suspect an anxiety disorder when patients complain of being overstressed, exhibit vague somatic complaints, or are excessively preoccupied with health. Moreover, heightened anxiety may exacerbate a coexisting cardiac or gastrointestinal illness. Treatment of the GAD patient needs to be individualized. A decision has to be made if simple counseling suffices or more intensive therapy, such as CBT, is indicated. Pharmacotherapy also needs to be individualized according the severity of worries, the level of arousal, the type of somatic symptoms, the possible coexisting medical illness, and patient’s personality. PP

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