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Eric Hollander, Daphne Simeon: Chapter 12. Anxiety Disorders, in The American Psychiatric Publishing Textbook of Clinical Psychiatry, 5th Edition. Edited by Robert E. Hales, Stuart C. Yudofsky, Glen O. Gabbard. Copyright ©2010 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623402.294126. Printed 7/15/2010 from www.psychiatryonline.com
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Chapter 12. Anxiety Disorders
ANXIETY DISORDERS: INTRODUCTION
Anxiety disorders are the most common of all psychiatric illnesses and result in considerable functional impairment and distress. Recent research developments have had a broad impact on our understanding of the underlying mechanisms of illness and treatment response. Working with patients who have an anxiety disorder can be highly gratifying for the informed psychiatrist, because these patients, who are in considerable distress, often respond to proper treatment and return to a high level of functioning. The major anxiety disorders presented in this chapter are panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, specific phobias, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). Table 12–1 presents a summary overview of the prevalence, gender ratio, and comorbidities of the major anxiety disorders. TABLE 12–1. Approximate lifetime prevalence, gender ratio, and common comorbidities for the major anxiety disorders Disorder Panic disorder Generalized anxiety disorder Social phobia 13%–16% 1+:1 Twofold risk for alcohol dependence, three- to sixfold risk of mood disorders Specific phobias Agoraphobia 10% 6% 2:1 2:1 1:1 Anxiety, depression, tics, hypochondriasis, eating disorder, body dysmorphic disorder (childhood-onset more common in males) 7%–9% 2:1 Depression, obsessive-compulsive disorder, panic, phobias Depression and somatoform disorders Prevalence Females:Males Comorbidity 2%–4% 5%–7% 2+:1 2:1 Depression, other anxiety disorders Overall, 90%; 50%–60% for major depression or other anxiety disorder
Obsessive-compulsive 2%–3% disorder Posttraumatic stress disorder
A diagnostic decision tree of the anxiety disorders is presented in Figure 12–1. If pathological anxiety is induced by either psychoactive substance use or an Axis III physical illness, it is classified in DSM-IV-TR (American Psychiatric Association 2000) under the anxiety disorders (substance-induced anxiety disorder or anxiety disorder due to a general medical condition, respectively). DSM-IV-TR specifies the subtype of organic anxiety as generalized anxiety, panic attacks, or obsessive-compulsive symptoms. FIGURE 12–1. Diagnostic decision tree for anxiety disorders.
Patients may have more than one disorder and thus must be evaluated for each disorder. TABLE 12–2. DSM-IV-TR diagnostic criteria for panic attacks Note: A panic attack is not a codable disorder. Code the specific diagnosis in which the panic attack occurs (e.g., 300.21 panic disorder with agoraphobia) 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: (1) palpitations, pounding heart, or accelerated heart rate (2) sweating (3) trembling or shaking (4) sensations of shortness of breath or smothering (5) feeling of choking (6) chest pain or discomfort (7) nausea or abdominal distress (8) feeling dizzy, unsteady, light-headed, or faint (9) derealization (feelings of unreality) or depersonalization (being detached from oneself) (10) fear of losing control or going crazy (11) fear of dying (12) paresthesias (numbness or tingling sensations) (13) chills or hot flushes
PANIC DISORDER Definition
DSM-II (American Psychiatric Association 1968) described an ill-defined condition of anxiety neurosis, a term first coined by Freud in 1895 (Breuer and Freud 1893–1895/1955), which included any patient with chronic tension, excessive worry, frequent headaches, or recurrent anxiety attacks. However, subsequent findings suggested that discrete, spontaneous panic attacks may be qualitatively dissimilar to other chronic anxiety states. Patients with panic attacks were found, for example, to be unique in their panic-induction responsiveness to sodium lactate infusion, familial aggregation, development of agoraphobia, and treatment response to tricyclic antidepressants (TCAs). Thus, DSM-III (American Psychiatric Association 1980) and the subsequent DSM-III-R (American Psychiatric Association 1987) divided the category of anxiety neurosis into panic disorder and GAD. The DSM-IV-TR definition of a panic attack is presented in Table 12–2. Panic disorder is subdivided into panic disorder with and without agoraphobia, as in DSM-III-R, depending on whether there is any secondary phobic avoidance (Table 12–3). TABLE 12–3. DSM-IV-TR diagnostic criteria for panic disorder with or without agoraphobia Diagnostic criteria for 300.01 panic disorder without agoraphobia A. Both (1) and (2): (1) recurrent unexpected panic attacks (2) at least one of the attacks has been followed by 1 month (or more) of one (or more) of the following: (a) persistent concern about having additional attacks (b) worry about the implications of the attack or its consequences (e.g., losing control, having a heart attack, "going crazy") (c) a significant change in behavior related to the attacks B. Absence of agoraphobia. C. The panic attacks are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism). D. 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 a severe stressor), or separation anxiety disorder (e.g., in response to being away from home or close relatives).
the attacks often continue unabated. The panic attacks are not due to the direct physiological effects of a substance (e. and faint and are convinced they are about to die.g.. in response to being away from home or close relatives). posttraumatic stress disorder (e. Such patients often rush to the nearest emergency department. Is the diagnosis in such a case panic disorder with agoraphobia or social/specific phobia? DSM-IV-TR retains the distinct diagnoses of panic disorder with agoraphobia. the first panic attack occurs in the context of a life-threatening illness or accident.g. and at this point the diagnosis of panic disorder would be premature. occurring on exposure to feared social situations). electrocardiography.g. These patients may indeed feel reassured." The differential diagnosis can sometimes become complicated when. Finally. sedatives. but later evolve into a chronic condition in which the attacks are cued exclusively by that situation or when avoidance of that situation develops because of fear of another attack. Attacks also begin in the immediate postpartum period. light-headed. Clinical Description Onset In the typical onset of a case of panic disorder. consistent with a diagnosis of panic disorder. However... or a separation from family (e.21 panic disorder with agoraphobia A. and PTSD). and the patients are reassured and sent home. the loss of a close interpersonal relationship.g. a drug of abuse.. Therefore clinical judgment regarding the preponderant clinical pattern is called for in making the differential diagnosis in such cases. Panic attacks are well known to occur not only in panic disorder but in other anxiety disorders as well (e. social phobia. on exposure to a specific phobic situation). such as social phobia (e. Both (1) and (2): (1) recurrent unexpected panic attacks (2) at least one of the attacks has been followed by 1 month (or more) of one (or more) of the following: (a) persistent concern about having additional attacks (b) worry about the implications of the attack or its consequences (e. most likely in the third decade.." "situationally bound (cued). social anxiety disorder. on exposure to dirt in someone with an obsession about contamination)." or "situationally predisposed. perhaps a few days or even weeks later they will again have the sudden onset of . one or several unexpected panic attacks initially occur in a specific situation.g. in response to stimuli associated with a severe stressor). and amphetamines. DSM-IV (American Psychiatric Association 1994) clarified several issues regarding the diagnosis and differential diagnosis of panic disorder that remained obscured in DSM-III-R. starting college or accepting a job out of town). Not uncommonly. individuals are engaged in some ordinary aspect of life when suddenly their heart begins to pound. several events are often associated with the early presentation of panic disorder.. However. The presence of agoraphobia.. although onset may be as late as the sixth decade. and specific phobia and specifies that panic attacks can occur as a feature of all three of these disorders.. Panic disorder patients are usually young adults..g.g. "going crazy") (c) a significant change in behavior related to the attacks B. having a heart attack.g. obsessive-compulsive disorder (e. DSM-IV clarified this confusion by explicitly presenting the definition of panic attacks independently of panic disorder and specifying that a panic attack can be "unexpected (uncued). historically. many patients have reported experiencing their first attacks while taking drugs of abuse. Although the first attack generally strikes during some routine activity.or hyperthyroidism may get the first flurry of attacks at this time. even when these concomitant conditions are resolved. specific phobia. losing control. C. hyperthyroidism). where routine laboratory tests. or separation anxiety disorder (e..g.Diagnostic criteria for 300. cocaine. Patients developing either hypo. They feel dizzy. they occur exclusively within the context of the feared situation.g. lysergic acid diethylamide (LSD). All that is found is an occasional case of sinus tachycardia. especially marijuana. and physical examination are performed. specific phobia (e. In these other disorders. a medication) or a general medical condition (e. This situation gives the impression that some stressors may act as triggers to provoke the beginning of panic attacks in patients who are already predisposed. and they cannot catch their breath. D. panic attacks are situationally bound or cued—that is. The panic attacks are not better accounted for by another mental disorder. Patients experiencing their first panic attack generally fear they are having a heart attack or losing their mind.
going crazy. the diagnosis of panic disorder is only made when the attacks occur with some regularity and frequency. trains. and a sense of impending doom. behavioral breathing retraining treatments aimed at teaching the patient not to hyperventilate are successful in decreasing the frequency of panic attacks. the fear is one of developing distressing symptoms in such situations where escape is difficult or help is unavailable. choking or smothering sensations. sweating. A twin study found the best results for genetic linkage when patients with regular panic attacks were included together with patients who had only occasional attacks (Torgersen 1983). It is clear that most of the physical sensations of a panic attack represent massive overstimulation of the autonomic nervous system. confusion. buses. Patients with panic disorder have been shown to be chronic hyperventilators who also acutely hyperventilate during spontaneous and induced panic (the possible etiologies of this are discussed later in this section). the patient with so-called long panic attacks often has some other form of pathological anxiety. apprehension. Some patients continue to feel agitated and fatigued for several hours after the main portion of the attack has subsided. Patients who claim they have attacks that last a whole day may fall into one of four categories. perhaps reading a book. subside. At times. Agoraphobic symptoms represent a tertiary phase in the illness. leading to decreased cerebral blood flow and to the dizziness. and occur again in a wave-like manner. faintness. At this point. when he or she will experience the sudden onset of overwhelming fear. It is warranted to draw some further attention to what appears to be the cardinal symptom of panic. Some patients do not progress in their illness beyond the point of continuing to have unexpected panic attacks. Attacks usually last from 5 to 20 minutes and rarely as long as an hour. The patient comes to dread experiencing an attack and starts worrying about doing so in the intervals between attacks. chest pain or discomfort. According to DSM-IV-TR. Symptoms Typically. Most patients develop some degree of anticipatory anxiety consequent to the experience of repetitive panic attacks. planes). be given a prescription for a benzodiazepine tranquilizer.g. However. and 3) fear of being away from home in situations where one can feel trapped. or traveling a distance from home. restaurants. and a fear of dying. hot and cold flashes. Finally. patients may be completely housebound. Several of a group of associated symptoms. feelings of unreality (derealization and/or depersonalization). they seek emergency medical treatment. A number of lines of research evidence indicate that hyperventilation may be the central feature in the pathophysiology of panic attacks and panic disorder. theaters. If the attacks continue. such severe anticipatory anxiety may develop with time in expectation of future panic attacks that the two may blend together in the patient's description and be difficult to distinguish. mostly physical. Such patients may be mistaken for GAD patients. elevators.severe anxiety with all of the associated physical symptoms. or attending a concert. Agoraphobia Agoraphobia frequently develops in response to panic attacks. leading to the DSM-IV-TR diagnosis of panic disorder with agoraphobia. The clinical picture in agoraphobia consists of multiple and varied fears and avoidance behaviors that center around three main themes: 1) fear of leaving home. or losing control of oneself. they may be told the problem is psychological. a patient will be engaged in a routine activity. Also. agitated depression. presumably by dampening the ventilatory overreaction that may constitute the hallmark of panic. being in crowds. In severe cases. in some cases. trembling and shaking. eating in a restaurant. paresthesias. supermarkets. This hyperventilation then induces hypocapnia and alkalosis. driving a car. Indeed. during a panic attack. 2) fear of being alone. Again. Alternatively. Typical agoraphobic fears are of using public transportation (e. palpitations. terror. Although many people experience an occasional unexpected attack of panic. fearful of leaving home without a companion or even of staying home alone. waiting in line.. Many patients will . or helpless. Most cases of agoraphobia begin with a series of spontaneous panic attacks. or department stores. are also experienced: dyspnea. signs and symptoms of hyperventilation seem to disappear once a patient with panic disorder has been successfully treated with antipanic medication. such as severe generalized anxiety. or obsessional tension states. attacks occur. and derealization characteristic of panic attacks. subways. patients with occasional unexpected panic attacks may be genetically similar to patients with panic disorder. This can progress until the level of fearfulness and autonomic hyperactivity in the interval between panic attacks almost approximates the level during the actual attack itself. or be referred for extensive medical workup. embarrassed. the patient usually develops a constant anticipatory anxiety characterized by continued apprehension about the possible occasion and consequences of the next attack. dizziness or unsteady feelings.
The 1-month. and finally agoraphobic behavior (black blocks). then apprehension culminating in chronic anxiety (shaded areas). In addition to panic attacks and chronic anxiety. Women had a 1-month prevalence rate of 0. 1988). 0. They then avoid these situations in an attempt to prevent further panic attacks (Figure 12–2). after the initial phase of the illness. Noyes et al. In other cases. attacks may occur rarely or exclusively when the patient ventures into the feared situation. family member. FIGURE 12–2. 1988). multiple somatic complaints. Character Traits It has not been clearly established whether particular character types are correlated with panic disorder. agoraphobic patients frequently exhibit symptoms of demoralization or secondary depression. On the other hand. which was significantly higher than the 0. Some individuals continue to have spontaneous panic attacks throughout the course of the illness. he interprets this as a sign that the attacks have spread to driving situations rather than as an indication that they were not.7%. women also tended to have a greater rise in panic disorder in the age range of 25 to 44 years. front-row seats. and airplanes. such as crowded rooms. start driving to work. Many patients who are unable to leave the house alone can travel long distances and partake in most activities if accompanied by a spouse. and lifetime prevalence rates for panic disorder at all five study sites combined were 0. or close friend. and studies are further confounded because the presence of panic disorder may have secondary effects on personality. respectively. a man who has had several attacks while taking the train to work may attribute the attacks to the train and.causally relate their panic attacks to the particular situation in which the attacks have occurred. patient develops acute help-seeking behavior (X). One interesting aspect of agoraphobia is the effect of a trusted companion on phobic behavior.6%.8%.5%. It is unclear whether vulnerability to panic attacks is actually decreased in this situation or whether the patient feels less helpless and isolated. 6-month. caused by the train. and 1. and their attacks tended to continue longer into older age (Regier et al. and alcohol or sedative drug abuse. Epidemiology The National Institute of Mental Health Epidemiologic Catchment Area (ECA) study examined the population prevalence of DSM-III-diagnosed panic disorder using the Diagnostic Interview Schedule (Regier et al. (1991) conducted personality follow-up of panic disorder patients treated for panic over 3 years and found that the initial avoidant and dependent traits were to a large extent state related and waned with the treatment of panic. experience leads many clinicians to feel that patients with agoraphobia and panic are more likely to have histories of dependent character traits that antedate the onset of panic. bridges. tunnels. in the first place. . Development of agoraphobia. in order to avoid the train.3% rate found among men. Agoraphobic persons frequently fear situations in which they feel they cannot leave abruptly if an attack occurs. After onset of unexpected panic attacks (solid bars). If he still experiences panic attacks in the morning while driving to work rather than on the train. For example.
which included about 43. imaging.000 participants. however. and again the presence of agoraphobia was associated with greater symptom severity. was not able to block a sodium lactate–induced panic attack in patients with panic disorder (Gorman et al. middle-aged. 1985a). symptoms of anxiety in human subjects. and for many years the possibility that panic attacks were manifestations of massive discharge from the -adrenergic nervous system was considered. greater disability. 1983). comorbidity. whether the reaction is specific only to patients with anxiety disorder. The theories are summarized in Table 12–4.1% and 5. revealed a 1-year and lifetime prevalence of panic disorder of 2. Stein and Asmundson 1994). 2006). have an ameliorative effect on panic attacks and anxiety.6% and 1. raising questions about its standing as a distinct Axis I disorder. Being female. TABLE 12–4.6% and 4.0%. When the properly designed and controlled studies of specific well-diagnosed anxiety disorders are reviewed. agoraphobia without panic disorder was quite rare. neurochemical. rates for panic disorder without agoraphobia were 1. Indeed. whereas being Asian. in contrast to other agents that produce prominent physiological changes but fail to induce panic. more severe symptoms. This nucleus is located in the pons . The -adrenergic hypothesis of panic has received -adrenergic blockers used in some support from studies claiming that -adrenergic–blocking drugs. These findings argue strongly against the notion that panic is a reaction to nonspecific distressing stimuli and suggest more specific biological bases. and genetic findings are described in the discussions that follow. the overrepresentation of panic disorder with agoraphobia in treatment settings probably reflects greater treatment seeking and more severe disorder. intravenously administrated propranolol. with a lifetime prevalence of 3. with a 0. there does not appear to be global sympathetic activation in panic disorder patients at rest or even during panic attacks in some patients (Wilkinson et al. Biological models of panic disorder Hyperreactivity of the locus coeruleus Dysregulated serotonergic modulation Decreased -aminobutyric acid (GABA)–benzodiazepine receptor complex binding Hypersensitive brain stem carbon dioxide (CO2 ) chemoreceptors Hypersensitive conditioned fear network centered in the amygdala Moderate genetic component The sympathetic system Studies of normal subjects exposed to novel stress typically demonstrate elevations in plasma catecholamine levels. however. No study has ever shown that -adrenergic blockers are specifically effective in blocking spontaneous panic attacks. It is not clear whether administration of catecholamines can actually provoke anxiety reactions and. only modest antianxiety effects can actually be demonstrated. and greater Axis I and II comorbidity compared with subjects without agoraphobia and were more likely to seek treatment early on. exceeding those of panic disorder with agoraphobia (0. Thus. B. Researchers in the 1930s and 1940s did show that epinephrine infusion caused the physical. Etiology Biological Theories There are a number of biological theories of panic disorder that figure prominently in the psychiatric literature.17% lifetime prevalence. a regular accompaniment of panic attacks induced in the laboratory (Liebowitz et al. or Hispanic decreased risk. Elevated plasma levels of epinephrine are not. Certain agents have a powerful and specific capacity to induce panic. The locus coeruleus has also been implicated in the pathogenesis of panic attacks.More recently. but not necessarily the emotional. On the other hand. 1998). Native American. Examination of various autonomic parameters seems to dispel the notion of simple autonomic dysregulation in panic (M. 2006). The various theories described in the following sections should not be viewed as mutually exclusive but rather as potentially interlocking pieces of a larger puzzle. in doses sufficient to achieve full peripheral -adrenergic blockade.1% with agoraphobia (Kessler et al. respectively). For example. and of low income increased risk for panic disorder. African American.1%. respectively (Grant et al.1%. widowed/separated/divorced. such as propranolol. we summarize the evidence for or against some of the most promising ones. respectively. Subjects with agoraphobia had an earlier age at onset. if so. the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). The National Comorbidity Survey Replication study reported highly similar findings. even if these involve multiple neurochemicals and circuits. and impairment.7% for panic disorder without agoraphobia and 1.
propranolol. benzodiazepines. propranolol. morphine. and standard benzodiazepines). Yohimbine challenge was reported to induce greater anxiety and a greater increase in plasma 3-methoxy4-hydroxyphenylglycol (MHPG). is an anxiolytic medication and has not been reported to induce panic. Redmond (1979) and colleagues have produced abundant evidence that situations that provoke fear and anxiety in laboratory animals are associated with increases in locus coeruleus discharge and in central noradrenergic turnover. which is also reported to increase locus coeruleus firing. The subjects all believed that these attacks were quite typical of their naturally occurring attacks. that may account for the observed biochemical and physiological changes (Liebowitz et al. TCAs) to those of more dubious efficacy (e. Having been replicated on numerous occasions under proper experimental conditions. and TCAs. hypocalcemia. However. Compared with control subjects. In a recent study. in the form of markedly elevated MHPG volatility in response to clonidine challenge. The mechanism. the finding that 10 mL/kg of 0. The possibility is then raised that either aberrant production of an endogenous ligand or altered receptor sensitivity may occur in patients .. One series of compounds. however. has been described in panic disorder patients and normalizes after treatment with selective serotonin reuptake inhibitors (SSRIs) (Coplan et al. whereas their pH response was not altered. which are inverse agonists of this receptor complex. 1984). the locus coeruleus may be involved in arousal and response to novel stimuli rather than in anxiety (Aston-Jones et al. a major noradrenergic metabolite. and cerebral cortex. Binding of a benzodiazepine to the benzodiazepine receptor facilitates the action of GABA. the benzodiazepine receptor is linked to a receptor for the inhibitory neurotransmitter GABA. there is no consistent pattern of increased locus coeruleus discharge associated with anxiety in animals. Dysregulated noradrenergic function. Lactate-provoked panic is specific to patients with prior spontaneous attacks.5 molar sodium lactate infused over 20 minutes will provoke a panic attack in most patients with panic disorder but not in normal control subjects is now a well-accepted fact.g. This would. including the hippocampus. The GABA–benzodiazepine system Another area of inquiry that may relate to the biology of panic is the -aminobutyric acid (GABA)–benzodiazepine receptor complex. closely resembles such attacks. alteration of the ratio of nicotinamide-adenine dinucleotide (NAD) to the hydrogenated (reduced) form of nicotinamide-adenine dinucleotide (NADH). sodium lactate provocation of panic attacks has captured a lot of attention as an experimental model for understanding the pathogenesis of spontaneous panic attacks. However. subjects with panic disorder were found to have greater hypocapnia in response to hyperventilation. drugs known to be capable of increasing locus coeruleus discharge in animals are anxiogenic. Electrical stimulation of the animal locus coeruleus produces a marked fear and anxiety response.g. controversy exists about the relevance of these animal models.. and can be blocked by the same drugs that block natural attacks (Liebowitz et al. and transient intracerebral hypercapnia. benzodiazepines have long been known to be a highly efficacious treatment for panic. implicating exaggerated buffering possibly mediated by increased lactate (Friedman et al. clonidine.and contains more than 50% of all noradrenergic neurons in the entire central nervous system. Theories have included nonspecific arousal that cognitively triggers panic. On the other hand. effectively slowing neural transmission. the -carbolines. 1997). support the idea that the locus coeruleus is a kind of generator for anxiety attacks. whereas ablation of the animal locus coeruleus renders an animal less susceptible to fear response in the face of threatening stimuli (Redmond 1979). In humans. whereas many drugs that curtail locus coeruleus firing and decrease central noradrenergic turnover are antianxiety agents. endorphin. The results from challenge tests with the 2-adrenergic agonist clonidine. limbic lobe. Control subjects did not experience panic attacks during the infusion. 1984). with hypersensitivity of some and subsensitivity of other brain 2-adrenoreceptors. 1985a) has been subject to much uncertainty and controversy. amygdala. 2006). Also. The panicogen sodium lactate Although not without some controversy. These drugs range from those clearly effective in blocking human panic attacks (e. in patients with frequent panic attacks compared with patients who have panic attacks less frequently or with healthy control subjects. buspirone. It sends afferent projections to a wide area of the brain. Such a finding is suggestive of heightened central noradrenergic activity in panic (Charney et al. Pitts and McClure (1967) administered intravenous infusions of sodium lactate to patients with "anxiety" disorder and found that most of the patients had an anxiety attack during the infusion. produces an acute anxiety syndrome when administered to laboratory animals or to normal human volunteers. although difficult to interpret. have suggested noradrenergic dysregulation in panic. panic disorder patients had heightened cardiovascular responses but blunted growth hormone responses to clonidine (Nutt 1989). of course. induction of metabolic alkalosis. 1984). Examples of medications that curtail locus coeruleus firing are clonidine.
a metyrapone and combined metyrapone/dexamethasone challenge study failed to find any HPA axis response difference between panic disorder and control patients (Kellner et al. and this decrease correlated significantly with greater panic symptom severity (Maron et al. compared with healthy control subjects. described later. More recently. resulted in increased anxiety and carbon dioxide (CO 2)–induced panic attacks in panic patients but not in comparison subjects (Miller et al. adrenocorticotropic hormone and cortisol responses to CRF challenge were not clearly altered in panic patients compared with healthy subjects (Curtis et al. Hypothalamic-pituitary-adrenal axis The hypothalamic-pituitary-adrenal (HPA) system. imaging studies have consistently revealed alterations in this system. as is known to occur in other anxiety and stress states. There is some evidence for uncoupling of noradrenergic and HPA axis activity in panic disorder patients (Coplan et al. Similarly. It has recently been proposed that serotonergic medications may act by desensitizing the brain's fear network via projections from the raphe nuclei to the locus coeruleus. Another study reported that a 22% reduction in total occipital GABA levels was found in panic subjects compared with control subjects (Goddard et al. 2000). it is widely thought that it may be one of the systems that at least indirectly modulate dysregulated responses in the disorder. 2000). In one study. 1995). most prominent in the prefrontal cortex and the insula (Malizia et al. 1999). 1997). and possibly directly at the level of the amygdala. Carbon dioxide hypersensitivity theory Controlled hyperventilation and respiratory alkalosis do not routinely provoke panic attacks in most patients with panic disorder. to the hypothalamus. however. HPA findings in panic have been very contradictory and have not consistently supported HPA axis dysregulation in the disorder. B. and prefrontal cortex binding was also decreased in those subjects who experienced an attack during the scanning (Bremner et al. 1990). inhibiting noradrenergic activation. depletion of tryptophan. 1990). 2004). suggesting that a trait-like abnormality in GABA function may contribute to the pathogenesis of panic (Goddard et al. and thalamus in participants with current panic disorder. inhibiting freeze/flight responses. demonstrated less reduced saccadic eye movement velocity in response to diazepam. 1996). compared with healthy control subjects. were found to have a deficient GABA neuronal response after acute oral benzodiazepine administration. Stein et al. another study of flumazenil responses in panic was negative (Strohle et al.with panic. 1998). a global decrease in benzodiazepine receptor binding has been found with positron emission tomography (PET). would clearly be of interest in panic disorder. 2001a). The benzodiazepine antagonist flumazenil was found to be panicogenic in panic patients but not in control subjects. Indirect evidence is provided by the high efficacy of serotonin reuptake inhibitors in treating panic. and prefrontal cortex play a central role in modulating conditioned fear responses. However. This finding has been consistently replicated and appears specific to panic disorder (Kent et al. There is support for such a theory. 1989). The serotonergic system Although the serotonergic system has not been as extensively investigated in panic as other neurochemical systems. hippocampus. Another radioligand PET study reported significant decreases in serotonin transporter binding in the midbrain. sodium bicarbonate infusion provokes panic attacks in . in which increased early life stressful events such as separations. although findings in the literature to date have been to a degree contradictory. A radioligand PET imaging study provided evidence for decreased distribution of serotonin (5-hydroxytryptamine) type 1A (5-HT1A ) receptor binding in the cingulate cortex and dorsal raphe in panic disorder participants compared with healthy control subjects (Neumeister et al. These findings could tie in neatly to the current neurocircuitry of fear model of panic. Decreased benzodiazepine receptor binding by single photon emission computed tomography (SPECT) was found in the hippocampus of panic disorder patients. 2004). 2004). to the periaqueductal gray region. 2004). temporal lobes. which is central to an organism's response to stress. giving these patients a mixture of 5% CO 2 in room air to breathe causes panic almost as often as does a sodium lactate infusion (Gorman et al. However. In one study. a serotonin precursor. More recently. suggesting hyposensitivity of the benzodiazepine receptor in panic (Roy-Byrne et al. inhibiting corticotropin-releasing factor (CRF) release. and abuse have been described (M. One study found that panic disorder patients. interfering with proper benzodiazepine receptor function and causing their symptoms. but not in the actual panic attacks (Hollander et al. 2000). 1984). Cortisol responses in lactate-induced panic have suggested HPA axis involvement in anticipatory anxiety. inhibiting excitatory pathways from the cortex and the thalamus (Gorman et al. losses. in which the amygdala. In a magnetic resonance spectroscopy study that measured total occipital cortex GABA levels. suggesting a deficiency in an endogenous anxiolytic ligand or altered benzodiazepine receptor sensitivity in panic (Nutt et al. Surprisingly. panic disorder patients. Similarly. 2001).
and bicarbonate do. There is some evidence that irregular breathing patterns are intrinsic to panic patients and are not influenced by induced hyperventilation or cognitive manipulation. the brain stem and respiratory activation. CO 2 constitutes the common metabolic product of both lactate and bicarbonate. by acting at different pathways or on neurochemical systems of this network. GABAergic. it causes a reliable dose-dependent increase in rat locus coeruleus firing. such as preexisting pulmonary disease. CRF. 1989). a "false suffocation alarm" theory of panic has been formulated (D.patients with panic disorder at a rate comparable with that induced by CO 2 inhalation (Gorman et al. whereas CO 2. centered in the amygdala. for example. 2001). leading to hyperventilation and panic. This theory may be supported by the variety of subtle respiratory dysfunctions that appear to be associated with panic. imaging. 2006). Stein et al. F. may underlie the pathogenesis of panic. This condition constitutes. On the other hand. 1988). Alternatively. and the cortex and cognitive interpretations. Infused lactate is metabolized to bicarbonate. but not during childbirth. lactate. Aberrant respiratory sensitivity to CO 2 may be a familial trait that comprises a risk factor for developing panic disorder. their increased variance in tidal volume during steady-state respiration. does 5% CO 2 induce panic? When CO 2 is added to inspired air. inspiratory drive is thought to reflect most directly the brain stem component of respiratory regulation (Gorman et al. an event otherwise characterized by extreme hyperventilation and potentially catastrophic cognitions. Neurocircuitry of fear The neurocircuitry of fear model integrates neurochemical. 2000). noradrenergic. 2001) but not by another (Pine et al. patients manifested greater entropy in baseline respiratory patterns. premenstrually. in a sense. Thus. it is proposed that the respiratory brain stem nucleus could not be directly triggered by such a variety of agents (Gorman et al. and their greater irregularities in nocturnal breathing (M. 2000). Input into the amygdala is modulated by both thalamic input and prefrontal cortical projections. The hypercapnia then sets off the brain stem CO 2 chemoreceptors. a rare illness in which the afflicted are at risk for suffocating in their sleep. 2004). dysregulated "cross-talk" between various neurotransmitter systems. . A recent study of respiratory physiology in panic disorder patients found that. This model is thought to explain why a variety of biologically diverse agents have panicogenic properties. Thus. panic disorder patients who experience panic attacks while breathing 5% CO 2 demonstrate a much faster increase in inspiratory drive than do nonpanicking patients or normal control subjects. as one of several pathways that become activated by central excitation of the amygdala. and there are amygdalar projections to several areas involved in various aspects of the fear response. indicating higher levels of irregularity and complexity in their respiratory function (Caldirola et al. The model proposes that panic attacks are analogous to animal fear and avoidance responses and may be manifestations of dysregulation in the brain circuits underlying conditioned fear responses. suggesting a brain stem rather than a higher brain level dysregulation (Abelson et al. 2005). then. whereas objective respiratory physiological responses remained unchanged. and others. In other words. F. which is then converted in the periphery to CO 2. such as serotonergic. a hypothesis supported by one study (Coryell et al. 2004). the tendency of panic attacks to occur during high-CO 2 states such as deep non–rapid eye movement sleep. suggesting that treatment strengthened higher cortical control over subcortical fear-related circuitry (Gorman et al. This CO 2 then selectively crosses the blood-brain barrier and produces transient cerebral hypercapnia. Increased gray matter volume in the brain stem of panic patients compared with control subjects has provided preliminary structural evidence for a role of the brain stem in the neurocircuitry of panic (Protopopescu et al. Klein (1993) proposed that such a theory of panic could explain. the opposite of the hyposensitive suffocation alarm seen in Ondine's curse. it was found that after treatment patients exhibited diminished subjective panic responses. In an interesting study of CO 2 inhalation sensitivity before and after psychotherapy or medication treatment in panic disorder patients. and sometimes with relaxation. the hypothalamus and activation of the HPA stress axis. B. Indeed. panic disorder patients' tendency to chronically hyperventilate. Panic is speculated to originate in an abnormally sensitive fear network. D. and treatment findings in the disorder coupled with human and animal studies in the neurobiology of conditioned fear responses (Gorman et al. Gorman et al. Such a model is of interest because it could account for the generally well-established fact that hyperventilation does not cause panic. panic disorder patients may have hypersensitive brain stem CO 2 chemoreceptors in their medulla. such as the locus coeruleus and arousal. Klein 1993) that proposes that patients with panic are hypersensitive to CO 2 because they have an overly sensitive brain stem suffocation alarm system. 1995b). compared with control subjects. during the CO 2 induction procedure. By what mechanism. (2000) argued that brain stem respiratory centers are a secondary mechanism by which panic attack symptoms relating to respiration become manifest.
Crowe et al. Gelernter et al. Woo et al. 2002. There is also evidence of interactions of serotonergic and noradrenergic gene variants in panic disorder (Freitlag et al. which were characterized by disturbed sexual arousal and continence and coitus interruptus. 2002.7% among relatives of patients with panic disorder compared with only 2. 2005). Such anxiety. 1985. Genetics Several family and twin studies of panic disorder have consistently supported the presence of a moderate genetic influence in the expression of panic disorder. 2006). behavioral inhibition in the offspring was associated with corticotropin-releasing hormone variants (Smoller et al. Individuals with an early onset of the disorder appear to have a much higher familial aggregation of the disorder. Over the next several years. 2001). and the adenosine 2A receptor gene (Deckert et al. midbrain. 1998). each with minor individual effects. 2003). Hamilton et al. 1998). 13q (Hamilton et al. and cerebellum in panic disorder participants compared with healthy control subjects (Sakai et al. One study found that in families with panic-disordered parents. and the 5-HT2A receptor gene (Inada et al. 2004). and 9q (Thorgeirsson et al. Michels et al. 7q (Cheng et al. Freud (1895b/1962) postulated that anxiety stems from the direct physiological transformation of libidinal energy into the somatic symptoms of anxiety.3% among normal control subjects. medulla. Another important strategy is to examine genetic influences on behaviorally inhibited temperament. 2005). Psychodynamic Theories In this subsection we present the major landmarks in the evolution of psychodynamic theories of anxiety and panic and their relationship to recent biological advances. He termed such anxiety an "actual neurosis" as opposed to a psychoneurosis. revealing significantly higher glucose uptake under resting conditions in the bilateral amygdala. 2005). later genome scan studies have revealed links to chromosomes 7p (Crowe et al. There have been a number of preliminary positive studies of putative genetic markers and candidate genes for panic disorder. Nemiah 1988). 2006). However. 2004). Torgersen (1983) completed a study of 32 monozygotic and 53 dizygotic twins and found panic attacks to be five times more frequent in the former. 2003).Neuroimaging studies are implicating these and other areas in the neurocircuitry of panic. 1992). Also. 1997). 2005). A functional magnetic resonance imaging (fMRI) study examining the functional neural correlates of disease-related emotional stimuli reported that panic patients showed activation in the right amygdala and hippocampus while performing the panic-related emotional Stroop task (van den Heuvel et al. caudal pons. 2006). the catechol-O-methyltransferase gene (Hamilton et al. panic and agoraphobia may share some. originating from overwhelming instinctual urges. More lengthy expositions and critiques of the psychoanalytic theories can be referred to by interested readers (see Cooper 1985. suggesting that nongenetic factors also play an important role in the development of the illness. 1999). In accordance with Freud's developing topographic theory of the mind. which is a risk factor for anxiety disorders. He found evidence for this process in the sexual practices and experiences of patients with anxiety. without the mediation of psychic mechanisms. this was no longer posited to be due to external constraints such as sexual dysfunctions. It is likely that genetic variants of several or multiple candidate genes in different neurotransmitter systems. which might better lend itself to molecular genetic studies (Goldstein et al. (1983) found a morbidity risk for panic disorder of 24. 2001). anxiety resulted from . hippocampus. 2005b). but not all. Moderate heritability was also found in a female twin study (Kendler et al. Although the basic tenet that anxiety stemmed from undischarged sexual energy remained the same. the cholecystokinin receptor gene (Kennedy et al. possibly suggesting a stronger genetic component in a familial subtype of the disorder. again supporting a model of diminished top-down inhibition by prefrontal cortical regions over hypersensitive limbic regions (Kent et al. A PET functional neuroimaging study supported an amygdala-based fear network in panic. all contribute to panic susceptibility (Maron et al. Although an earlier whole-genome scan in 23 panic pedigrees did not yield any evidence of linkage (Knowles et al. thalamus. Freud started to modify his theory. of their susceptibility loci (J. 2005). including the X-linked monoamine oxidase-A gene in females (Deckert et al. 2003). the absolute concordance rate in monozygotic twins was 31%. would today be referred to as id or impulse anxiety. the peripheral benzodiazepine receptor gene (Nakamura et al. 1999). because of the postulated absence of psychic processes. Structural volumetric studies have reported decreased gray matter volumes bilaterally in the putamen of panic disorder participants. the magnitude of which was associated with panic severity (Yoo et al. A pilot PET study in panic disorder found that decreased orbitocortical frontal cortex activation predicted heightened anxiety in response to intravenous challenge with the panicogen doxapram. Freud's first theory of anxiety neurosis (id or impulse anxiety) In his earliest concept of anxiety formation. the cholecystokinin gene (Wang et al. 1998.
modern biological theories of panic are in many ways more reminiscent of his original physiological formulation. Whereas Freud concentrated on the role of sexual impulses and the oedipal conflict in the genesis of anxiety. According to Freud. 1993). what psychoanalytic theory does not help us with is a better understanding of the determinants of the various specific forms in which anxiety symptoms manifest themselves. all of which are accessible in psychodynamic treatment (Shear et al. anxiety over loss of the other's love. which became attached to and partly discharged through objects that were. made more than a century ago. superego anxiety. greater emphasis on preoedipal dynamics and research in infant and child development has brought to the forefront attachment theories and the importance of attachment disturbances in the genesis of . these theorists drew attention to the role that aggressive impulses and preoedipal dynamics can also play in generating anxiety. Some patients have anxiety attacks. the significance of a trustworthy and safe companion in individuals with agoraphobia could be understood as a simultaneous expression of aggressive impulses toward the companion and a magical wish to protect the companion from such impulses by always being together. they remain an invaluable tool in the understanding and treatment of at least some patients. with the advent of the structural theory of the mind. it should be pointed out that Freud's theory of anxiety formation is not incompatible with biological theories of anxiety. exposure to parental behaviors that augment this fearfulness may result in disturbances of object relations and persistence of conflicts surrounding dependence and catastrophic fears of helplessness. Since Freud. Although psychoanalytic theories are not universally accepted by psychiatrists today. excessive fear of object loss and its concomitant separation anxiety could explain both the fear of being away from home alone and the alleviation of this fear when a companion is present. superego prohibitions. Also. and id anxiety.forbidden sexual drives in the unconscious being repressed by the preconscious. thus warding off signal anxiety. Alternatively. instead of the reverse. separation anxiety. For example. The danger stems from intrapsychic conflict between instinctual drives from the id. then. Freud (1895a/1962) also observed that in the analysis of phobias. Along these more contemporary lines of thinking. 1985). In an attempt to reconcile this unpredictability with classical psychodynamic theory. Freud's theory of anxiety had undergone a major transformation (Freud 1926/1959). The intrapsychic conflict model of anxiety continues to constitute a major tenet of contemporary psychoanalytic theory. it has been postulated that patients with unconscious conflict and a neural predisposition to panic may manifest their anxiety in the form of panic attacks. or compulsions. he understood them. like anxiety neurosis. Psychoanalytic theorists after Freud. whereas individuals without this neural predisposition may manifest milder forms of signal anxiety (Nemiah 1981). dangerous. anxiety is an affect belonging to the ego and acts as a signal alerting the ego to internal danger. nothing is ever found but the emotional state of anxiety. Early on. Freud did not consider phobias to be psychologically mediated. At that time. Inhibitions and neurotic symptoms develop as measures designed to avoid the dangerous situation and to allow only partial gratification of instinctual wishes. Although Freud's first model of anxiety was later overshadowed by the conflictual model. to be manifestations of a physiologically induced tension state. also made significant contributions to the understanding of the psychodynamic origins of anxiety. Structural theory and intrapsychic conflict By 1926. castration anxiety. Rather. Undischarged libidinal energy was physiologically transformed into anxiety. such as annihilation anxiety. With the broadening of psychodynamic theory over the decades. such as Melanie Klein (1948) and Joachim Flescher (1955). and external reality demands. the psychodynamic literature has also to a degree shifted away from formulations that primarily emphasize libidinal wishes and castration fears in understanding phobias such as agoraphobia (Michels et al. and what the patient actually fears is the occurrence of such an attack under the special conditions in which the patient believes he or she cannot escape it. Furthermore. different forms of anxiety have been elaborated. and still others have phobias. In the case of agoraphobia we often find the recollection of an anxiety attack. In the revised theory. by their nature or in the patient's prior experience. Freud himself attempted to address this problem of choice of neurosis and partly explained it on the basis of constitutional factors—a concept essentially similar to modern biological notions. This is a succinct description. of the development of anticipatory anxiety and agoraphobia following a panic attack. Freud maintained on numerous occasions that biological predispositions to psychiatric symptoms are undoubtedly operant in most conditions and that constitutional factors could play a role in the particular form that neurotic symptoms take in different patients. others have more chronic forms of anxiety. In particular. Anxiety acts as a signal to the ego for the mobilization of repression and other defenses to counteract the threat to intrapsychic equilibrium. a psychodynamic study of patients with panic disorder found that in patients who are neurophysiologically predisposed to early fearfulness. obsessions. Indeed. anxiety leads to repression.
especially events related to loss. reinforces the avoidant behavior. evidence suggests that the same drug that diminishes protest anxiety in higher mammals also reduces separation anxiety in children and blocks panic attacks in adults. In these children.e. A blinded psychodynamic study showed separation anxiety to be a significantly more prevalent theme in the dreams and screen memories of panic patients than in normal control subjects.. we might say that anxiety attacks are conditioned responses to fearful situations. Indeed. whether during vigorous exercise or minor emotional upset. 1985).e. This leads to a decrease in anxiety level.g. the shock)..e. For example. have claimed that this neurophysiological and ethological model of a disrupted separation mechanism and panic may be unnecessarily reductionistic (Michels et al. separation anxiety). The drug proved successful in getting the children to return to school. If every time a laboratory animal presses a bar it receives a noxious electric shock. but this could be related to their young age. This may occur if the retrospective histories of a lesser degree of separation anxiety in patients with panic attacks alone are misremembered.psychopathology. anxiety.or herself. Infant animals demonstrate their anxiety when separated from the mother by a series of high-pitched cries. Contemporary psychoanalysts. the unconditioned stimulus). the conditioned stimulus). Based on Bowlby's (1973) work on attachment and separation. Thus. a life-threatening situation in someone's life (e. Learning Theories Behavior or learning theorists hold that anxiety is conditioned by the fear of certain environmental stimuli. By analogy with this animal model. thereby avoiding the shock. Hypothesizing a link between adult panic attacks and childhood separation anxiety. the shock. the anxiety threshold is so low in these patients that it is no longer useful to view the psychological event as etiologically significant (Cooper 1985). called "distress vocalizations.e. F. the initial panic attack in the history of a patient who goes on to develop panic disorder is sometimes preceded by the real or threatened loss of a significant relationship.. Is early separation anxiety linked to agoraphobia and to panic attacks per se? If imipramine affects panic attacks. were greater in new-onset panic patients than in control subjects (Faravelli and Pallanti 1989). 20%–50% of adults with panic disorder and agoraphobia recall manifesting symptoms of pathological separation anxiety. Gittelman-Klein and Klein (1971) conducted a study of imipramine treatment for children with school phobia. F. a more recent longitudinal study failed to find a higher risk of panic disorder and agoraphobia in adulthood in those children who had been diagnosed with separation anxiety disorder in childhood compared with those with other childhood anxiety disorders (Aschenbrand et al. The conditioned stimulus releases a conditioned response in the animal. he or she will suffer hunger (i. in response. rapid heartbeat alone." Imipramine has been found to be effective in blocking distress vocalizations in mammals such as dogs and monkeys and is a highly effective antipanic drug in adult humans. The anxiety may persist even after the child is old enough to feed him. children with school phobia do not have spontaneous panic attacks. D. skidding in a car during a snowstorm) is paired with the experience of rapid heartbeat (i. so that although psychological triggers for anxiety may still be found. Perhaps both panic disorder and panic disorder with agoraphobia are linked to a biologically disordered separation mechanism that is responsive to imipramine. contemporary psychoanalysts have also given more credence to the role of biological substrates in the genesis of anxiety symptoms in at least some patients who have developed their anxious personality structure secondary to a largely contentless biological dysregulation. To give another example. the conditioned response).. that leads the animal to avoid contact with the lever. and separation anxiety is linked to agoraphobia. when they were children. This is further confirmation of the link between separation anxiety and panic attacks. D. an infant learns that if his or her mother is not present (i. often taking the form of school phobia. Klein (1981) advanced the notion that the attachment of an infant human or animal to its mother is not simply a learned response but is genetically programmed and biologically determined..e.. 2003). then why is imipramine effective in the treatment of school phobia? On the other hand.e. In the early 1960s. becomes . On the other hand. Klein proposed an etiological theory that agoraphobia with panic attacks may represent an aberrant function of the biological substrate that underlies normal human attachment and threats to it (i. However.. the conditioned stimulus) and tremendous anxiety. Successful avoidance of the unconditioned stimulus. and thus the infant learns to become anxious automatically whenever the mother is absent (i. They point out an inconsistency between the conceptualization of panic attacks as spontaneous and the frequently reported histories of childhood separation anxiety in patients with panic attacks and state that psychological difficulties with separation can also play a role in subsequent vulnerability to panic. One systematic study has shown that the number and severity of recent life events. fear of separation from their mothers was usually the basis behind refusing to go to school. the pressing of the lever becomes a conditioned stimulus that precedes the unconditioned stimulus (i. Long after the accident. Furthermore.
do seem to be paired with the onset of panic disorder. exposure to childhood physical and sexual abuse was associated with increased risk of later panic attacks and disorder. In a large prospective birth cohort studied to the age of 21 years. longer duration of illness. 1993). agoraphobia. separation from a parent by death or divorce. Clinical experience does not support that anxiety disorder patients undergo repeated traumatic events. At the extreme. Morbidity. cocaine intoxication. 2005). and therefore they should be able to extinguish their anxiety. high interpersonal sensitivity. coupled with a dysregulated biological mechanism or vulnerability that may be linked to the process of fear conditioning in panic. TABLE 12–5. such as thyroid disease. heightened anxiety responses could conceivably persist over time. and Mortality The course of illness without treatment is highly variable and is summarized in Table 12–5. significantly more than in psychiatric comparison subjects (Bouwer and Stein 1997). is appropriate at any point in the course of the illness when such attacks are occurring. and single marital status (Noyes et al. effective disruption of the attacks with medication can lead to resolution of anticipatory anxiety and phobias without other treatment. there is no reliable way to know which patient will develop. Another long-term outcome study over a 5-year period had . often leads to complete remission. divorce) High interpersonal sensitivity Single marital status At present. although some traumatic situations. such as a suffocation incident. 20% or less have major impairment Predictors of worse prognosis More severe initial panic attacks More severe initial agoraphobia Longer duration of illness Comorbid depression History of separation from parent (e. the pathogenesis of human anxiety disorders. typically with periods of exacerbations and remissions Outcome About 33% recover. Pharmacological blockade of panic attacks early in the illness. however. some patients become completely housebound for decades. even after adjusting for prospectively assessed confounding factors. described elsewhere in this chapter. Of note. Even years into the illness. after disaggregating the impact of comorbid PTSD. 2002). Such patients require other forms of intervention. such as altered functioning of the amygdala and related fear circuits (discussed earlier). including greater severity of panic attacks and agoraphobia. Certain problems are posed by such a theory. Course and prognosis of panic disorder Course Variable. described in detail later. they do not seem to explain adequately. found that 24% of females and 5% of males with panic disorder reported histories of sexual molestation. a substantial number of patients with significant phobic avoidance remain anxious and frightened of confronting feared situations even after the attacks have been blocked. Course. comorbid major depression. A 7-year follow-up study examined prognostic factors in naturalistically treated patients with panic disorder. before phobic avoidance has become an ingrained way of life. suggesting the latter could be one risk factor for developing panic disorder (Leskin and Sheikh 2002). death. Exposure to interparental violence was not a factor (Goodwin et al. Treatment aimed at blocking the occurrence of the attacks. for many patients no such traumatic event can ever be located. severe traumatic events during childhood and unfavorable parental attitudes were associated with panic disorder (Bandelow et al. Similarly. Although patients had generally good outcomes.. In a clinical cross-sectional study comparing panic disorder and psychiatrically healthy subjects. However. Traumatic Antecedents Childhood interpersonal trauma also appears to make a contribution to the likelihood that individuals will manifest panic disorder. 50% have limited impairment.g.capable by itself of provoking the conditioned response of an anxiety attack. for example. examination of trauma rates in the National Comorbidity Survey community sample. there were several predictors of poorer outcome. low social class. So even though learning theories have a powerful basis in experimental animal research. Prognosis. traumatic suffocation incidents have been found in about 20% of panic patients. only to be followed months to years later by a new outburst. However. or life-threatening events. Results are often dramatic. in and of themselves. First. The illness seems to have a waxing and waning course in which spontaneous recovery occurs.
initial medication. Allgulander and Lavori (1991) conducted a large retrospective survey in Sweden and found an increased suicide risk in panic disorder in the absence of comorbid diagnoses. Diagnosis Physical Signs and Behavior The diagnosis of panic disorder is made when a patient experiences recurrent panic attacks that are discrete and unexpected and followed by a month of persistent anticipatory anxiety or behavioral change. longitudinal. However. An increased death rate from cardiovascular illness in panic disorder was partly supported in an epidemiological investigation by Weissman et al. 1990).9% rate for uncomplicated major depression (J. a 5-year prospective study concluded that there was no association between panic and suicide risk in the absence of other risk factors (Warshaw et al. 2000). 1995). Epidemiological data further supported this finding in the ECA study. TABLE 12–6. these attacks are not secondary to a known organic factor or due to another mental disorder. 2002). the most significant predictor of poor outcome was an anxious-fearful personality type. left ventricular enlargement and increased risk of thromboembolic events have also been contemplated to account for the association (Weissman et al. 46% were minimally impaired. One other possible explanation for increased cardiovascular/cerebrovascular risk in patients with panic disorder may be related to aspects of their lifestyle. in addition to the presence of at least four physical symptoms. Johnson et al. however. Differential diagnosis of panic disorder Anxious depression Somatization with panic-like physical complaints Social phobia with socially cued panic attacks Generalized anxiety with severe symptoms or during peak periods Posttraumatic stress disorder with intense physiological response to reminders of the trauma Agoraphobia secondary to conditions other than panic (depression. Such patients tend to live relatively sedentary lives.fairly optimistic findings: 34% of patients were recovered. In this study. 1990). and 20% remained moderately to severely impaired. This association could conceivably explain a higher incidence of cardiovascular-related death in patients with panic disorder. leading them to avoid exertion of any kind. such medical risks are not routinely evident to clinicians in the usual status of patients undergoing treatment for panic disorder. the likelihood of panic disorder remission was not affected by comorbid personality disorders (Massion et al. Finally. (1990). and continuous use of medication were not related to outcome. Heavy cigarette smoking. in a reanalysis of the ECA data controlling for all comorbidity rather than one disorder at a time. panic disorder responders were not at heightened risk of self-reported suicide attempts (Vickers and McNally 2004). reanalysis of the National Comorbidity Survey data revealed that in the absence of comorbidity. alcoholism. Alternatively. posttraumatic stress. another large outcome study showed that less than 20% of panic disorder patients remained seriously agoraphobic or disabled. A recent 5-year prospective. and some report that vigorous physical exercise precipitates their panic attacks. However. These panic attacks are characterized by a sudden crescendo of anxiety and fearfulness. naturalistic study reported that. whereas longer duration of illness and more severe initial avoidance were unfavorable predictors (Katschnig et al. these diagnoses are not always obvious. 1996). A possible association between panic disorder and increased suicide risk has received extensive attention and does not appear to hold up based on extensive epidemiological analyses. in contrast to GAD and social phobia. The one cardiovascular abnormality that has been found to occur at a higher rate in patients with panic disorder is mitral valve prolapse. paranoia. Finally. psychosis) . panic disorder patients had a significantly higher risk for strokes than did patients with other psychiatric disorders. Similarly. Panic attack frequency at baseline. and poor diets could also contribute to an increased risk in panic patients. where the lifetime rate of suicide attempts in persons with uncomplicated panic disorder was 7%. followed by poor response to initial treatment (O'Rourke et al. Finally. Most such patients have normal medical workups. mitral valve prolapse itself is rarely a cause of premature death or major morbidity. The impact of comorbidity is another important consideration in assessing prognosis. Of note. an association between panic and suicide attempts could no longer be shown (Hornig and McNally 1995). although several methodological limitations were identified. and a number of other psychiatric and medical disorders may mimic these conditions (Table 12–6). about the same as the 7.
With regard to the agoraphobic component of the disorder. In cases of panic disorder. psychiatric conditions that involve pathological anxiety can make the differential diagnosis of panic disorder difficult. and thought process disorder. such as a fear of being or of traveling alone after an assault. PTSD. they do not exhibit psychotic symptomatology. after successful detoxification a group of alcoholic patients with a prior history of panic disorder were treated with medication to block spontaneous panic attacks (Quitkin and Babkin 1982). patients usually experience dysphoria first. Although patients with panic disorder often fear they will lose their minds or go crazy. then becoming gradually more disgusted with life. By far the most problematic is the differentiation of primary anxiety disorder from depression. Patients with depression often manifest signs of anxiety and may even have frank panic attacks. In depression. such as sedatives. However. and then feeling depressed.Obsessional anxiety of near-panic severity Depersonalization disorder Personality disorder with anxiety symptoms Hyperthyroidism Hypothyroidism Mitral valve prolapse Pheochromocytoma Differential Diagnosis Other psychiatric illnesses Although the medical conditions that mimic anxiety disorder are usually easily ruled out. Patients with depersonalization disorder have episodes of derealization/depersonalization without the other symptoms of a panic attack. Although the differentiation of anxiety from depression can at times strain even the most experienced clinician. Perhaps of greatest importance is the fact that most anxious patients do not lose the capacity to enjoy things or to be cheered up as endogenously depressed patients do. panic attacks not infrequently involve depersonalization and derealization as prominent symptoms. Undoubtedly some patients with anxiety disorders abuse alcohol and drugs. patients with panic disorder. Patients can generally recall having anxiety attacks first. A few other psychiatric conditions often need to be differentiated from panic disorder. . in attempts at self-medication. several points are helpful. In one study. routinely become demoralized as the impact of the illness progressively restricts their ability to enjoy a normal life. Patients with panic disorder generally do not demonstrate the full range of vegetative symptoms seen in depression. but not all. The order of developing symptoms also differentiates depression from anxiety. However. if untreated for significant amounts of time. Further complicating the picture is the fact that some. Although agoraphobic patients are frequently afraid that they are going crazy. anxious patients usually have trouble falling asleep—not early morning awakening—and do not lose their appetite. Psychotic states can be differentiated from agoraphobia by the presence of delusions. anxiety symptoms usually precede any seriously altered mood. panic disorder can be complicated by secondary major depression or vice versa. hallucinations. These patients did not resume alcohol consumption once their panic attacks were eliminated. Unlike panic disorder patients. On the other hand. Diurnal mood fluctuation is uncommon in anxiety disorder. somatizing patients present with physical problems that do not usually occur in episodic attacks but are virtually constant. Thus. studies have shown that patients with anxiety disorder have increased family history of affective disorder. none of which are substantiated by physical or laboratory findings. psychotic illness is not an outcome of anxiety disorder. with anxiety symptoms coming later. Reassuring the patient on this point is often the first step in a successful treatment. Patients with PTSD have a typical history of trauma. Patients with somatization disorder complain of a variety of physical ailments and discomforts. widespread fears and avoidance of being alone or of leaving home can also be seen in paranoid and psychotic states. and major depressive disorders.
1981). extreme low energy.The distinction between depressive disorders and agoraphobia is more difficult. There are reports that mitral valve prolapse might go away if the panic disorder is controlled (Gorman et al. Liebowitz et al. depression characterized by hypersomnia. Panic patients with and without mitral valve prolapse are similar in several important ways.e. Others have suggested that panic disorder. Comparison of symptoms of mitral valve prolapse and panic disorder Symptoms Fatigue Dyspnea Palpitations Chest pain Syncope Choking Dizziness Derealization Hot/cold flashes Sweating Mitral valve prolapse + + ++ ++ + – – – – – Panic disorder – ++ ++ + – ++ ++ ++ ++ ++ . Some have speculated that mitral valve prolapse and panic disorder may represent manifestations of the same underlying disorder of autonomic nervous system function (Gorman et al. however. Cardiac disease The relationship of mitral valve prolapse to panic disorder has attracted a great deal of attention over the years. Agoraphobic individuals will usually say they would love to leave home and engage in a variety of activities. and depressed but reactive mood) frequently have panic attacks but rarely have agoraphobia as part of their life history or current symptomatology. TABLE 12–7. actually causes mitral valve prolapse (Mattes 1981). screening of patients known to have mitral valve prolapse reveals no greater frequency of panic disorder than is found in the overall population. Close questioning. Treatment for panic attacks works regardless of the presence of the prolapsed valve. if only they could be sure of not panicking.. and patients with both mitral valve prolapse and panic disorder are just as sensitive to sodium lactate as are those with panic disorder alone. A meta-analytic study of 21 studies found that there does appear to be a significant association between panic disorder and mitral valve prolapse. Hyperthyroidism and hypothyroidism Both hyper. hyperphagia. including the evaluation of the level of thyroid-stimulating hormone. although the possibility of publication bias favoring positive reports cannot be ruled out (Katerndahl 1993). lightheadedness. However. and fatigue. which are common symptoms in endogenous depression. and they believe that people will be better off without them. that thyroid disease can act as one of the predisposing triggers to panic disorder. depressed individuals usually see no point in going out because nothing gives them any pleasure. usually does not reveal further vegetative symptoms or a loss of pleasure or interest in activities. Patients with atypical depression and a history of panic attacks may respond preferentially to monoamine oxidase inhibitors (MAOIs. so that even when the apparently primary thyroid disease is corrected. panic attacks may continue until specifically treated. it is imperative that all patients complaining of anxiety undergo routine thyroid function tests. Patients with agoraphobia are frequently demoralized and will state that they feel depressed. 1985b). chest pain. by creating intermittent states of high circulating catecholamine levels and tachycardia.and hypothyroidism can present with anxiety unaccompanied by other signs or symptoms. symptoms of a full-blown panic attack are rare. Early morning awakening and pervasive anhedonia. It should be remembered. Both groups commonly experience spontaneous panic attacks. 1981). are rare in agoraphobia. however. Although patients with mitral valve prolapse occasionally complain of palpitations. This usually benign condition has been shown by a number of investigators to occur more frequently in patients with panic disorder than in normal subjects. Patients with atypical depression (i. For this reason. In contrast. A comparison of symptoms in mitral valve prolapse and panic disorder is provided in Table 12–7.
losing control Mitral valve prolapse – – – Panic disorder ++ ++ ++ Note. it can be helpful to initially prescribe a concomitant benzodiazepine that can be gradually tapered and discontinued after several weeks of antidepressant treatment. Studies with insulin tolerance tests in panic disorder have yielded negative results. whether TCAs or serotonin reuptake inhibitors. because up to 40% of the normal population has a random low blood-sugar level during a routine glucose tolerance test. Some panic patients primarily complain of dizziness or unsteadiness. and insomnia. although in most cases. it is one of the main reasons why patients unfortunately opt to discontinue medication early on. Although this is usually transient. Otolaryngology consultation is warranted when this condition is suspected. If this condition is suspected. a speedy feeling. and a summary of the pharmacological treatment of panic disorder is . about half met criteria for the physical symptoms of panic attacks. it is clear that the presence of mitral valve prolapse in patients with panic disorder has little clinical or prognostic importance in the management of spontaneous panic attacks. 1990). and anxiety. Disease of the vestibular nerve can cause episodic bouts of vertigo. – = rarely present. Other medical illnesses Hyperparathyroidism occasionally presents as anxiety symptoms. the patient characteristically experiences flushing. merely finding a normal blood pressure does not rule out a pheochromocytoma. during which they complain of jitteriness. but none had panic disorder. Therefore. Treatment Pharmacotherapy Antidepressants When initiating a drug regimen for a patient with panic disorder. such patients often experience true vertigo in which the room seems to spin in one direction during each attack. warranting a serum calcium level before definitive diagnosis is made. Whether they are a distinct subgroup with definite neurological abnormalities is currently under study. nausea. Glucose tolerance tests are not helpful in establishing hypoglycemia as the cause of anxiety. and anxiety that mimic panic attacks. Blood pressure is usually elevated during the active phase of catecholamine secretion but not at other times. Although many patients believe that their anxiety disorder is caused by reactive hypoglycemia.Symptoms Fainting Trembling Fear of dying. it is crucial for the patient to understand that the drug will block the panic attacks but may not necessarily decrease the amount of intervening anticipatory anxiety and avoidance. some patients with panic disorder display an initial hypersensitivity to antidepressants. For patients with severe anxiety. because they did not experience terror during the attacks and did not develop anticipatory anxiety or agoraphobia (Starkman et al. During an active phase. especially paroxysmal atrial tachycardia. Also importantly. Therefore. lightheadedness. A variety of cardiac conditions can initially present as anxiety symptoms. going crazy. the diagnosis is made by collection of urine for 24 hours for determination of catecholamine metabolite concentration. the patient complains prominently of chest pain. should be ruled out by electrocardiography. + = occasionally. it is strongly recommended that patients with panic disorder be started on lower dosages of antidepressants than would be given to depressed patients. ++ = often present. The central feature in the treatment of panic disorder is the pharmacological blockade of the spontaneous panic attacks. What it may tell us about the underlying etiology of panic disorder is a question currently under vigorous investigation. there is no scientific proof at present that this is ever a cause of any psychiatric disturbance. The only convincing way to establish hypoglycemia as a cause of symptoms is to document a low blood sugar level at the same time the patient is symptomatic. tremulousness. Ischemic heart disease and arrhythmias. skipped beats. Pheochromocytoma is a rare. In any event. at least initially. Several classes of medications have been shown to be effective in accomplishing this goal. Rather than merely feeling dizzy. usually benign tumor of the adrenal medulla that secretes catecholamines in episodic bursts. or palpitations. In a study of patients with confirmed pheochromocytoma. agitation.
The presence of depressed mood is not a predictor or requirement for this class of medications to be effective in blocking panic attacks. At present. have also been found effective. the most widely studied and used medications in the past were the TCAs. have been shown to be efficacious in treating panic. and clomipramine. nortriptyline. underdosage commonly occurs. the dosage can then be raised by 25-mg increments every 3 days or by 50-mg increments weekly to as high as 300 mg. The dosage can be given all at once. Panic patients not responding to high dosages of imipramine should have blood TCA levels measured. escitalopram: similarly efficacious Venlafaxine extended-release: FDA approved Tricyclic antidepressants General indications: Established efficacy. comorbid atypical depression or social phobia. prominent anticipatory anxiety or phobic avoidance. and given their several advantages over TCAs they have become the first-line treatment for panic. second line if SSRIs fail or are not tolerated. TABLE 12–8. a dosage of imipramine of more than 300 mg is necessary. Also first choice with comorbid obsessivecompulsive disorder. .S. Food and Drug Administration.presented in Table 12–8. more than 80% of patients show a marked response in panic attacks (Mavissakalian and Perel 1989). elderly Monoamine oxidase inhibitors General indications: Poor response or tolerance to other antidepressants. generalized anxiety disorder. citalopram. Most patients need at least 150 mg daily of TCAs. and social phobia. In some cases. not well tested to date. although they have not been studied as extensively as imipramine. 1986b). less withdrawal. A standard TCA regimen is to start the patient at a dosage of 10 mg qhs of imipramine and increase the dosage by 10 mg every other night until 50 mg is reached. Pharmacological treatment of panic disorder Selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors General indications: First-line. response seen with low to moderate dosages. On "high" imipramine dosing of around 200 mg/day. Other TCAs. less frequent dosing. Klein 1964. Pindolol: effective augmentation in one controlled trial Valproic acid: open trials only Inositol: open trials only Clonidine: initial response tends to fade in open trials Atypical antipsychotics: open trials Note. newer antidepressants. alone or in combination with benzodiazepines if needed. depression. paroxetine: FDA approved Fluvoxamine. TCAs are now reserved for patients who do not have a good response to. Mavissakalian and Michelson 1986a. or do not tolerate. Phenelzine: most studied Tranylcypromine: less sedation High-potency benzodiazepines General indications: Poor response or tolerance of antidepressants. FDA = U. newer antidepressants. in particular the SSRIs. Clonazepam: longer-acting. F. fluoxetine. initial treatment phase until antidepressant begins to work. and unfortunately. SSRIs = selective serotonin reuptake inhibitors. especially imipramine (D. first choice Alprazolam: well studied but short-acting Alprazolam extended-release: once-daily dosing Other medications General indications: Particularly as augmentation in patients whose illness is refractory or who are intolerant of the above medications. such as desipramine. Sertraline. Historically. Because 50 mg is usually inadequate for full panic blockade. Imipramine: well studied Clomipramine: high efficacy but not easily tolerated Desipramine: if low tolerance to anticholinergic side effects Nortriptyline: if prone to orthostatic hypotension. Start with very low dosages and increase.
2000). and impairment than to panic attacks per se.Often. the lowest dosage of 10–15 mg was not better than placebo. It is therefore suggested that treatment be started gingerly at 5–10 mg/day for fluoxetine. and OCD. Like the TCAs. Venlafaxine is also effective in treating panic disorder. In a 1-year controlled maintenance extension of the same study. social phobia. or proportion of patients free of panic attacks at endpoint. 1997). In another study. using a flexible dosage range of 75–225 mg/day for 10 weeks. with an 11% dropout rate due to adverse events (Sheehan et al. tolerability. 2003). and ease of administration compared with TCAs. highlighting the importance of looking at the larger picture when assessing change. however. agoraphobic avoidance. 1995). A head-on comparison of paroxetine (40–60 mg/day) with sertraline (50–150 mg/day) reported similar efficacy for the two medications (Bandelow et al. as in the trials just described. they comprise the first line in the treatment of panic disorder. and escitalopram had a low discontinuation rate of 6% (Stahl et al. Over a 6-month maintenance treatment period. citalopram. 2002). 2001). or 200 mg daily in reducing panic attacks (Londborg et al. anticipatory . 1998). A moderate or lower daily dosage is usually adequate for most patients. they also offer the advantage that they are effective for several of the commonly comorbid disorders. A prior history of benzodiazepine use did not appear to affect the tolerability or response to sertraline treatment. all SSRIs have comparable efficacy in treating panic. 2001). Michelson et al. 2005). 1998). SSRIs can cause uncomfortable overstimulation in panic patients if started at the usual dosages. this study used a wide range of measures and demonstrated that global improvement was more related to phobia. The efficacy of paroxetine has been demonstrated at dosages of 20–60 mg daily (Oehrberg et al. the initial responders to acute fluoxetine treatment demonstrated significant further improvement if randomized to fluoxetine and significant worsening if randomized to placebo (D. anxiety. whereas the middle dosage of 20–30 mg daily again showed the best response (Lepola et al. As a first-line treatment. Although paroxetine and sertraline are the only U. or noncompliance. 1998). reported better response and remission rates than placebo with a greater improvement in number of panic attacks. 1998). Fluoxetine. Michelson et al. and high dosages are generally not needed and less tolerated. The elderly or patients who are otherwise very sensitive to orthostatic hypotension can be tried on nortriptyline. such as depression. A number of controlled treatment trials have now shown that the potent serotonin reuptake blockers are highly effective in the treatment of panic. there was no difference among three sertraline dosages of 50. whereas the 10-mg and 20-mg dosages did not. 1998). dropout rate was significantly lower in those treated with SSRIs (18%) versus TCAs (31%) (Bakker et al. paroxetine. GAD. The dosage can then be gradually increased to an average dosage through weekly adjustments. Another SSRI. Given their higher safety. and paroxetine controlled-release was well tolerated. The SSRI sertraline has also been found to be efficacious in treating panic disorder in large controlled trials (Londborg et al. either alone or in combination with benzodiazepine when needed. suggesting rapid metabolism or excretion. anxiety. Sertraline not only markedly decreased the number of panic attacks but also led to significant improvement in life quality and had a low dropout rate (Pohl et al. A large multisite placebo-controlled trial of venlafaxine extended-release in 361 adult patients. highlighting the importance of trying higher dosages if response to lower dosages is inadequate (Ballenger et al. has been shown to be efficacious in treating panic disorder in an 8-week controlled trial in which the middle dosage of 20–30 mg/day conferred the most advantageous risk–benefit ratio compared with higher and lower dosages (Wade et al. only the 40-mg daily dosage of paroxetine reached statistically significant superiority over placebo during a 10-week period. and citalopram and 25 mg/day for sertraline and fluvoxamine. Several controlled trials have documented the efficacy of SSRIs in treating panic disorder. regardless of whether the response to the benzodiazepine had been good or bad (Rapaport et al. 100. 1999). 1998. Pohl et al. blood levels will be disproportionately low for the dosage. 2004). Patients who experience excessive anticholinergic side effects to imipramine can be given desipramine instead. A meta-analysis of 43 treatment studies compared the short-term efficacy of SSRIs versus TCAs and reported no differences in effect sizes in reducing panic symptoms. Fluvoxamine at dosages of up to 150 mg/day was reported efficacious in a large controlled trial (Asnis et al. depression. Another study showed that both escitalopram and citalopram were comparably superior to placebo in treating panic disorder symptoms and severity. especially at a dosage of 20 mg/day rather than 10 mg/day. was also shown to be superior to placebo in the acute treatment of panic disorder (D. Food and Drug Administration (FDA)–approved SSRIs for this indication. depressive symptoms.S. A placebo-controlled trial of controlled-release paroxetine in about 900 patients demonstrated superiority for the active treatment at dosages ranging from 25 to 75 mg/day. malabsorption.
However. These medications have fewer initial side effects than TCAs and serotonin reuptake inhibitors. MAOIs may be an appropriate earlier choice for treatment if SSRIs do not confer adequate results. MAOIs are an option to consider for patients who fail to tolerate or to respond well to other antidepressants.0 mg/day or higher (2. and 4 mg/day) were equally efficacious. The dosage is then increased by 15 mg every 4–7 days as tolerated. possible tolerance and dependency. with significant improvement occurring in the first couple weeks of treatment. patients can be tapered to half-dosage medication and be followed to ensure that clinical improvement is maintained. In the acute treatment of panic attacks. up to a maximum of 60–90 mg daily. and difficulties in discontinuing the medication are the main areas of concern when choosing benzodiazepine treatment. Afterward. In one study. complete agreement has not been reached regarding the recommended course of treatment. There is evidence that benzodiazepines may be more effective. half-dosage imipramine at around 80 mg/day was successful in preventing relapse during 1 year of maintenance treatment (Mavissakalian and Perel 1992). and the mean final dosage was 5. and withdrawal. This finding has not yet been replicated in a controlled trial. However. 3. 1988). and reach a minimal dosage on which the patient is relatively symptom-free. a very high relapse rate for panic was found when imipramine was discontinued after 6 months of acute treatment. In a controlled prospective study. dependence. Thus. fear. controlled data and clinical lore do not support its use. as long as the improvement is maintained. Onset of response was rapid. After discontinuation. the lowest dosage of 0. and avoidance (Bradwejn et al. whereas others will not. patients who do not respond to a TCA or a serotonin reuptake inhibitor alone may respond to a combination of the two. tranylcypromine may be tried. Naturalistic follow-up studies of long-term benzodiazepine treatment appear generally optimistic. panic outcome for the alprazolam-treated group was not significantly different from that for the placebo group (Pecknold et al. 82% of patients treated acutely with alprazolam showed at least moderate improvement in panic compared with 43% given placebo. then 3-week discontinuation taper) during 12 weeks of treatment with sertraline did document more rapid stabilization of panic symptoms in the first 3 weeks of treatment in the sertraline-plus-clonazepam group. For patients with severe acute distress and disability who may require immediate relief. according to a large multicenter trial (Rosenbaum et al. in ameliorating the associated anticipatory anxiety and phobic avoidance. Although one small open trial reported significant improvement in panic using bupropion (Simon et al. An open trial of mirtazapine administered at 30 mg/day for 3 months to 45 panic disorder patients also showed a pronounced decline in panic attacks and anticipatory anxiety. Both phenelzine and tranylcypromine successfully treat panic. the duration of required treatment in order to prevent relapse is a function of the natural course of panic disorder. coupled with a very low 6% discontinuation rate (Sarchiapone et al. Therefore. it may be indicated to start with a benzodiazepine and then replace it with an antidepressant.5 mg/day was least efficacious. .7 mg/day. In patients with concomitant atypical depression or social phobia. Some patients may eventually be able to completely stop medications. Long-term efficacy. and the lower dosages of 1–2 mg/day were better tolerated. the general treatment principle is that anxiolytics should be reserved until the different classes of antidepressants have failed. 2001b). Full remission of panic attacks with antidepressants usually requires 4–12 weeks of treatment. Subsequently. If sedation or weight gain is of concern. a reasonable recommendation in treating panic patients is to keep them on full-dosage medication for at least 6 months to prevent early relapse. patients were tapered off medication over 4 weeks. Furthermore. because most patients maintain their therapeutic gains without increasing their benzodiazepine dosage over time. The disorder can probably best be characterized as chronic. After 8 weeks of acute treatment. 1997). Phenelzine can be started at 15 mg daily in the morning. However. although treatment outcome and dropout rates did not differ by the end of the trial (Goddard et al. 2003). 2005).anxiety. Clonazepam appears equally promising in the acute treatment of panic. starting at 10 mg in the morning and increasing by 10 mg every 4 days to a maximum of 80 mg daily. MAOIs are equally as effective as the TCAs and the SSRIs in treating panic. 27% experienced rebound panic attacks. TCAs and serotonin reuptake inhibitors are typically preferred over MAOIs because they are better tolerated and obviate the need for dietary restrictions and the risk of hypertensive crises. Benzodiazepines Although clinicians prefer to use antidepressants for the first-line treatment of panic. the clinician may attempt gradual dosage decreases every few months. although phenelzine has been studied more extensively. with an exacerbating and remitting course. high-potency benzodiazepines are also highly effective in treating the condition. and 35% had withdrawal symptoms. 2003). Subsequently. at least initially. because they do pose some risk of tolerance. A double-blind study that examined early coadministration of clonazepam (4 weeks. and this may be another indication for their initial use. but dosages of 1.
nonbenzodiazepine antianxiety agent and has not been found effective in treating panic. Discontinuation must be gradual to prevent withdrawal: 15% of the total dosage weekly is generally a safe regimen. the therapeutic effect tends to be lost in a matter of weeks due to receptor habituation. have not been reported. Valproic acid may also have some beneficial effects in the treatment of panic attacks (Keck et al. However. It should generally be started at 0. controlled 4 week trials at a dosage of 12–18 g/day (Benjamin et al. 2000). such as propranolol. an intracellular second messenger precursor. but an even slower rate may be required to prevent the recurrence of panic. Although benzodiazepines are generally safe. all 12 patients were moderately to markedly improved after 6 weeks of treatment. the strongest predictor of taper failure was initial severity of panic attacks rather than alprazolam dosage (Rickels et al. If panic attacks occur in a specific social context. 1993. would seem for theoretical reasons to be a good antipanic drug. one augmentation strategy shown to be effective in a small blinded trial may be to add pindolol at 2. available data indicate that most patients are able to stop taking benzodiazepines without serious sequelae and that the problem of tolerance and dependence is overestimated and probably limited to an addiction-prone population or to patients with more refractory panic disorder who may escalate standard benzodiazepine usage in unsuccessful attempts at self-medication. Alprazolam is usually started at 0. because alprazolam may occasionally cause mania. Controlled trials. as with the antidepressants. makes clonidine a poor initial choice for treatment of panic disorder.5 mg qid and is gradually increased to an average dosage of 4 mg/day and a range of 2–10 mg/day according to the individual patient. plus a number of bothersome side effects. suggesting that an augmentation study in refractory panic might be worthwhile. 2006). Atypical antipsychotics have also received attention in recent years.600 mg daily. however. such as public speaking. When response to SSRIs and other antidepressants has been inadequate. gabapentin. one-third of patients were unable to tolerate a 4-week taper off alprazolam after 8 months of maintenance treatment. 2000). The distinction between actual withdrawal and a simple recrudescence of the original anxiety symptom when the benzodiazepine is stopped remains controversial and can be difficult to make clinically. 2001). with side effects limited mainly to sedation. at flexible dosages of 600–3.Clonazepam should generally be preferred as a first choice. It has been convincingly shown that the introduction of cognitive-behavioral therapy (CBT) greatly increases the likelihood that panic patients will be able to successfully taper off benzodiazepines (Otto et al. 1994). and 11 continued the medication and maintained their gains after 6 months (Woodman and Noyes 1994). 1993). Similarly. 1993). which inhibits locus coeruleus discharge. In one open trial. Spiegel et al. there is a concern that some patients may become tolerant or even addicted to these medications. Patients' moods must be followed. Other medications Buspirone is a 5-HT1A agonist.5 mg bid and increased only if needed. Palatnik et al. Inositol. 2005). and clonazepam may cause depression. another open trial of 10 patients with refractory panic disorder treated for 8 weeks with flexible-dose olanzapine at an average dosage of 12 mg/day resulted in an approximately 75% decrease in panic attacks and anticipatory anxiety (Hollifield et al. Although some patients may initially respond to clonidine. showed it to be no better than placebo in treating panic disorder (Pande et al. patients who had previously not responded to SSRI monotherapy were treated openly for 12 weeks with 5 mg/day of olanzapine added to an SSRI. This loss of response. A fairly large controlled trial of another mood stabilizer. In one study. because it is longer acting and thus has the advantage of less frequent twice-daily or even once-daily dosing and less risk of withdrawal symptoms than alprazolam. 1993). 1995. a trial of -blockers would be indicated. usually to a maximum dosage of 4 mg/day. are effective in blocking spontaneous panic attacks. although a post hoc analysis showed it to have some efficacy in the more severely symptomatic patients. Clonidine. Treatment of at least 6 months is recommended. resulting in 82% of patients rated as responders by the end of the trial (Sepede et al. Similarly. one controlled study found clonidine to be efficacious for both panic disorder and GAD (Hoehn-Saric et al. has been reported to have some efficacy in treating panic disorder in two small double-blind. However. there is no evidence that -adrenergic–blocking drugs. Psychotherapy Psychodynamic psychotherapy .5 mg three times a day (Hirschmann et al. In a controlled study.
it has been found that comorbid personality disorder is the major predictor of continued social maladjustment in patients otherwise treated for panic disorder (Noyes et al. to control both acute and chronic hyperventilation. A controlled study showed that a 15-session course of brief dynamic psychotherapy combined with initial clomipramine treatment led to much lower relapse rates up to 9 months after patients had been tapered off the medication (Wiborg and Dahl 1996). in the long run. Cognitive-behavioral therapy CBTs have long focused on phobic avoidance. leading to further damage in self-esteem and strengthened masochistic defenses. Supportive psychotherapy and education about the illness are necessary to urge the patient to confront the phobic situation. and it has become firmly established as a first-line treatment for this disorder and found to be comparable in effectiveness to first-line medication treatments (Table 12–9). traditional psychodynamic psychotherapy might be helpful for some of these patients. However. interest in CBT for panic has surged. Results showed significant improvement in panic. and symptomatic gains were maintained over a 6-month follow-up (Milrod et al. and relaxation training. 1990). The study included 14 patients with panic disorder who were treated for 12 weeks with twice-weekly psychodynamic psychotherapy alone. Cognitive and behavioral approaches to treating panic disorder Interoceptive exposure (to the somatic cues of panic attacks) Situational exposure (to the settings that are phobically avoided) Cognitive restructuring Breathing retraining Applied relaxation training The major behavioral techniques for the treatment of panic attacks are breathing retraining. Encouragement from other patients with similar conditions is often quite helpful. Patients who fail to respond may then need additional psychotherapy. be not only useless but potentially harmful. 2001). Psychodynamically oriented clinicians tend to agree that psychological factors do not appear to be significant in a proportion of patients with panic and emphasize the importance of conducting a psychodynamic assessment to determine whether a particular patient will benefit from a psychodynamic treatment component (Gabbard 1990). a subgroup of panic patients remain wary of independence and assertiveness. suggesting that psychodynamic therapy may be an important additional treatment for at least some patients with panic. In addition to supportive and behavioral treatment. Significant unconscious conflict over separations during childhood sometimes appears to operate in patients with panic disorder. 2000). insistence on dynamic understanding and on responsibility for one's symptoms may. successful psychotherapy often cannot take place until the more debilitating aspects of these syndromes have been eliminated pharmacologically. Indeed. An open trial of psychodynamic monotherapy in panic disorder documented clear efficacy for this modality. Yet supportive psychotherapy alone is not an effective enough treatment for panic disorder. phobic avoidance may remain. it is also clear that there are case reports of patients who were successfully treated for panic with psychodynamic therapy or psychoanalysis. anxiety. usually involving a hierarchy of exposure to feared sensations through imaginal and behavioral exercises. Supportive psychotherapy Despite adequate treatment of panic attacks with medication. Pharmacotherapy is in no way incompatible with behavioral or psychodynamic treatment for patients with panic disorder. and emphasized the need for further and controlled studies (Milrod et al. Systematic studies examining the efficacy of psychodynamically oriented psychotherapy in panic disorder are few but promising. at least in the selected sample.Even after medication has blocked the actual panic attacks. Cooper (1985) emphasized that in patients with a predominant biological component to their illness. either dynamic or behavioral. In recent years. exposure to somatic cues. leading to a reemergence of anxiety symptoms in adult life each time a new separation is imagined or threatened. and overall impairment. Cognitive treatment of panic involves cognitive . there were 16 responders out of 21 patients treated with panic-focused psychodynamic psychotherapy. depression. Furthermore. The notion that reducing the symptoms of anxiety disorder with medication will disturb a successful psychotherapy has never been convincingly shown and is largely dogmatic. In the completed report of these open trials. but more recently the techniques have been developed and shown to be effective for panic attacks. TABLE 12–9.
a study comparing cognitive therapy to interoceptive exposure found similar efficacy (Arntz 2002). In a primary care setting. there is evidence that the introduction of CBT can reduce the risk of rebound panic in patients who are tapered off antipanic medications such as benzodiazepines or antidepressants (Schmidt et al. with an average 60% improvement after 10 weeks of acute treatment and 77% improvement at follow-up 1 year later (Ito et al. on the whole. Some studies have not found imipramine to have a significant effect on agoraphobia when given alone or with anti-exposure instructions (Marks et al. the improvements in attacks. Antipanic medication is given to block the occurrence of panic attacks. Findings on long-term outcome of panic with CBT appear to be favorable. Salkovskis et al. more successful than nonspecific techniques in reducing agoraphobic avoidance. Mavissakalian and Michelson 1986a. whereas others have shown imipramine alone to decrease phobic avoidance (Mavissakalian and Perel 1995). 1989. L. and imipramine to be similarly effective. relaxation. it is generally accepted that some means of exposing agoraphobic patients to the feared situations is necessary for overall improvement. however. 1994). (1989) provoked panic attacks in panic disorder patients using CO 2 inhalation. Conversely. and its efficacy in this regard is well documented. M. Treatment of the agoraphobic component of panic disorder There continues to be some disagreement in the literature regarding the best method of treatment for agoraphobia with panic attacks." Such a theory has received experimental validation: Sanderson et al. However. the addition of CBT . One controlled study found cognitive therapy. 1985. Similarly.. the addition of adjunctive SSRI treatment can be beneficial (Kampman et al. Treatment with combined medication and psychotherapy The relative and combined efficacy of medications and CBT for panic disorder has been the focus of numerous investigations. the introduction of CBT greatly increased the likelihood that a patient would be able to successfully taper off medication (Otto et al. there is evidence that in patients who do not benefit adequately from cognitive therapy alone. 1993). and cognitive therapy had more lasting effects at 9-month follow-up after treatment was discontinued (D. 2001). anxiety. after the initiation of medication treatment for initial symptom control. such as psychoeducation. A study comparing CBT with in vivo exposure alone found similar efficacy for the two at the end of acute treatment and at 1-year follow-up (Ost et al. 2002). interoceptive exposure. In addition. concur that the combination of medication and behavioral treatment (exposure) is superior to medication or behavioral treatment alone for treating phobic avoidance (de Beurs et al. 1986). Findings are inconsistent as to whether applied relaxation is equally efficacious or inferior to CBT for controlling panic attacks (Arntz and van den Hout 1996. with 23% experiencing relapse at some time during follow-up. 2004). they experienced significantly fewer and less severe attacks and had less catastrophic cognitions. Michelson et al. focused CBT is. However. 1995. there was evidence of lasting relief for the majority of patients for up to a decade after treatment. 2006). slight dizziness) to which panic disorder patients grossly overreact with catastrophic cognitions. 2002). it was found that when patients had an illusion of control over the inhaled mixture. such as bursts of tachycardia. Beck et al. Another study compared in vivo exposure. 1992. Clark et al. 2001b). 1980). medication alone is often not adequate treatment in patients with significant agoraphobic avoidance. and only early improvement in avoidance predicted global improvement after treatment (Basoglu et al. 93% were in remission after 2 years and 62% after 10 years (Fava et al. Most studies. and a control group and reported comparable high efficacy for all three active-treatment groups. Telch et al. 1990.g. reassurance. and avoidance were found to be largely independent of each other. In another study. Several studies have shown that these various cognitive and behavioral techniques are successful in the treatment of panic disorder (Barlow et al. Telch et al. Zitrin et al. These techniques can be administered in various combinations. combination of the two exposures. In a study examining the long-term outcome of panic disorder with agoraphobia in a group of 200 patients initially treated with exposure therapy. The pure cognitive view is that panic attacks consist of normal physical sensations (e. 1985). There is also evidence that patients who fail to adequately respond to pharmacotherapy can have significant and sustained improvements with subsequent CBT (Heldt et al. A more middle-of-the-road view is that panic patients do have extreme physical sensations. 1994). and supportive therapy. but can still significantly help themselves by changing their interpretation of the event from "I am going to die of a heart attack" to "There go my heart symptoms again. Ost and Westling 1995).restructuring. so as to give the uncomfortable affects and physical sensations associated with panic a more benign interpretation. 1983. palpitations. especially with combined cognitive restructuring and exposure. This may be achieved through various nonspecific methods. In a large controlled study of alprazolam plus exposure in patients with panic and agoraphobia.
and physical symptoms. This most comprehensive study to date on the issue clearly suggests that both psychotherapy and medication treatment must be seriously considered in treating a patient with panic. CBT. DSM-IV-TR diagnostic criteria for generalized anxiety disorder A. imipramine plus CBT. is persistent anxiety lasting at least 6 months. 2005). a recent large controlled study demonstrated that delivery of evidence-based CBT and medication using a collaborative care model was significantly more effective than the usual primary care treatment for panic disorder (Roy-Byrne et al. being away from home or close relatives (as in separation anxiety disorder). . Note: Only one item is required in children. suggesting a more lasting effect of psychotherapy (Furukawa et al.. Excessive anxiety and worry (apprehensive expectation). DSM-IV-TR also clarified that the diagnosis of GAD is excluded when occurring exclusively in relation to other major Axis I disorders. and anticipating the worst. placebo alone. (1) restlessness or feeling keyed up or on edge (2) being easily fatigued (3) difficulty concentrating or mind going blank (4) irritability (5) muscle tension (6) sleep disturbance (difficulty falling or staying asleep. the anxiety or worry is not about having a panic attack (as in panic disorder). worry. and there was an even more substantial advantage for combined treatment. 2005). The essential feature of this syndrome. and the anxiety and worry do not occur exclusively during posttraumatic stress disorder. F. C. gaining weight (as in anorexia nervosa). Finally. about a number of events or activities (such as work or school performance). each having its advantages and disadvantages. medication and CBT had similar efficacy.resulted in statistically and clinically significant improvement in panic disorder after 3 months relative to medication treatment alone (Craske et al. with limited advantage for combined treatment. having multiple physical complaints (as in somatization disorder). The disturbance is not due to the direct physiological effects of a substance (e. a psychotic disorder. or physical symptoms cause clinically significant distress or impairment in social. found that combined treatment was superior to antidepressant pharmacotherapy and to psychotherapy alone. occurring more days than not for at least 6 months. imipramine produced a higher quality of response than CBT alone.g. occupational. GENERALIZED ANXIETY DISORDER Definition and Clinical Description DSM-IV-TR sharpened the distinction of GAD from "normal" anxiety by specifying that in GAD the worry must be clearly excessive. 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). The focus of the anxiety and worry is not confined to features of an Axis I disorder. TABLE 12–10.. or a pervasive developmental disorder. after termination of acute-phase treatment.700 participants. The largest study comparing medication. E. A recent meta-analytic study. according to DSM-IV-TR. GAD is the main diagnostic category for prominent and chronic anxiety in the absence of panic disorder. difficult to control.g. or other important areas of functioning. combination therapy was more effective than pharmacotherapy alone but as effective as psychotherapy. based on 23 randomized comparisons involving about 1. In an important finding for the application of optimal treatment in nonpsychiatric primary care settings. at 6-month follow-up after termination of treatment. Patients with GAD are constantly worried over minor matters. 2006). and the cumbersome somatic symptom list from the DSM-III-R was simplified (Table 12–10). In the initial 3-month acutetreatment phase. or having a serious illness (as in hypochondriasis). and associated with marked distress or impairment. a medication) or a general medical condition (e. CBT had more durable results. B. However. The symptoms of this type of anxiety fall within two broad categories: apprehensive expectation and worry. and combination treatment acutely and longer term (Barlow et al. being embarrassed in public (as in social phobia). CBT alone. hyperthyroidism) and does not occur exclusively during a mood disorder. The person finds it difficult to control the worry. being contaminated (as in obsessive-compulsive disorder). 2000) was a multisite controlled study of 312 patients with panic disorder randomly assigned to five different treatments: imipramine alone. Muscle tension. For responders treated in the 6-month maintenance phase.. The anxiety. a drug of abuse. or restless unsatisfying sleep) D.g. e. and CBT plus placebo. fearful. pervasive.
thus the basis for excluding these individuals from the GAD diagnosis may need to be reexamined (Kessler et al. 2005). there are data that challenge the DSM-IV-TR hierarchy by which GAD cannot be diagnosed in the presence of concurrent major depression (Zimmerman and Chelminski 2003). 2005). the personality types of patients with GAD have not been well characterized.1% and 4.6% 1-year prevalence for subthreshold GAD. respectively. and they are similar to the DSM-IV-TR-defined group in onset. 2000). and prognosis. finding that the lifetime prevalence of GAD increases by about 40% when the excessiveness requirement is removed (Ruscio et al. Disability and impairment in pure GAD have been found to be equivalent to those of pure mood disorders and significantly greater than those of pure substance use and other anxiety and personality disorders (Grant et al.restlessness. and greater symptom severity and comorbidity. The necessity of the "excessive worry" criterion in making the GAD diagnosis has been questioned and investigated in epidemiological samples. GAD stands on its own as a disorder with distinct onset. On certain quality-of-life indexes. middle-aged. Despite its high comorbidity with substance use and other anxiety. Biological models of generalized anxiety disorder Abnormalities of the -aminobutyric acid (GABA)–benzodiazepine receptor Hypersensitive conditioned fear network centered in the amygdala Noradrenergic activation Serotonergic dysregulation Modest genetic component . Etiology Biological Theories Although the neurobiology of GAD is among the least investigated in the anxiety disorders. Motor tension and hypervigilance better differentiate GAD from other anxiety states than autonomic hyperactivity. the 6-month duration criterion may be arbitrary and has come under scrutiny. with rates higher in female. Higher rates of the disorder were found in women (2. 2005). 2001) found a 1. and personality disorders (Grant et al. 1999a). 2005b). of roughly equal magnitude. TABLE 12–11.7%) and the elderly (2. insomnia. and sociodemographic correlates. course. With regard to Axis II comorbidity. impairment. which cannot be accounted for by comorbidity or sociodemographic variables (Kessler et al. Finally. mood. individuals with pure GAD actually fare worse than those with pure major depression (Wittchen et al. and treatment seeking and share familial aggregation with those who do have excessive worry.1%. At least three of six physical symptoms must also be present. a "keyed up" feeling. impairment. The NESARC revealed a 1-year and lifetime DSM-IV GAD prevalence of 2. comorbidity. a more chronic course. 2005b). parental GAD. Those who do have excessive worry have GAD onset earlier in life. GAD and depression each show their own statistically significant and independent associations with impairment. and fatigue are typical signs of GAD and have become the symptom criteria for the disorder in DSM-IV-TR after a number of studies attempted to single out the physical symptoms that are the most distinctive and characteristic of GAD. widowed/separated/divorced. this chronic anxiety must not be secondary to another Axis I disorder or a specific organic factor. However. The National Comorbidity Survey database has shown that a large number of people have a GAD-like syndrome of 1–5 months' duration.2%). comorbidity. and low-income individuals (Grant et al. irritability. Similarly. it is not clear whether such personality disorders are primary or consequent to the GAD itself. Finally. Although dependent and avoidant personality disorders are commonly found to co-occur with GAD. The diagnosis of GAD is made when a patient experiences at least 6 months of chronic anxiety and excessive worry.5% 1-year prevalence for threshold GAD and a 3. persistence. impairment. difficulty concentrating. A high degree of comorbidity was again confirmed: 59% for major depression and 56% for other anxiety disorders. even those without excessive worry manifest substantial persistence. 2005b). questioning the validity of the excessiveness requirement and highlighting the need for more research (Ruscio et al. advances are now being made (a summary is presented in Table 12–11). Epidemiology and Comorbidity One epidemiological study using DSM-IV criteria (Carter et al.
J. as well as parental overprotection and lack of emotional warmth. acceptance. 1999). It is speculated that alterations in the structure and function of the amygdala. whereas panic disorder patients have more cognitions related to physical catastrophes (Breitholtz et al. and worry over minor matters. Similarly. and there is evidence for heightened cortical activity and decreased basal ganglia activity in GAD. whereas environmental influences on GAD and neuroticism were largely unshared (Hettema et al. possibly accounting for the observed arousal and hypervigilance (Buchsbaum et al. worrying about the worrying in . Second. (1991) reported a blunted growth hormone response to clonidine in GAD compared with responses in normal control subjects. Finally. the dopamine transporter gene. benzodiazepine receptor binding has been found to be significantly decreased in the left temporal pole of GAD patients compared with healthy control subjects (Tiihonen et al. Regarding mechanisms that may perpetuate GAD. may all contribute to later development of anxiety. There is some evidence for specificity in cognitive content in the various anxiety disorders. in GAD patients compared with normal control subjects (Sevy et al. Abelson et al. Accordingly. GAD subjects have been found to have decreased benzodiazepine receptor density in peripheral blood cells as well as decreased transcriptional mRNA encoding for the receptor. 2003). Kendler et al. Children with GAD were found to have larger right and total amygdala volumes (DeBellis et al. 2004). There appears to be a genetic component to GAD. Binding of a benzodiazepine to the benzodiazepine receptor facilitates the action of GABA. benzodiazepines are well established as an efficacious treatment of GAD. which are central to fear-related behaviors. There is also some evidence of serotonergic dysregulation in GAD. albeit relatively modest. 1992). effectively slowing neural transmission. 1990. it has been proposed that insecure attachment relationships and ambivalence toward caregivers. individuals with GAD engage in a certain degree of magical thinking and believe that their worry helped prevent a feared outcome. produce an acute anxiety syndrome when administered to laboratory animals or to normal human volunteers. With regard to its origins. There have been minimal molecular genetic studies of GAD to date. People with GAD do not show heightened sensitivity to 35% CO 2 inhalation as do people with panic. In terms of the etiology of GAD. Psychological Theories Cognitive hypotheses regarding both the origins and maintenance of GAD have been thoroughly summarized in recent work (Aikins and Craske 2001). Wu et al. First. Twin studies have reported about 20%–33% overlap in genetic influences between GAD and neuroticism. Other studies of the noradrenergic system have been negative (R. both of which return to normal values with treatment and reduction in anxiety levels (Ferrarese et al. with a modest heritability of about 30%. the serotonin transporter gene. and 2 adrenoreceptors decreased. 1987. anxious early attachments to important caregivers (Cassidy 1995). The benzodiazepine receptor is linked to a receptor for the inhibitory neurotransmitter GABA. Plasma norepinephrine and its metabolite were found to be elevated. three are summarized. Rocca et al.Recent work has focused on brain circuits underlying the neurobiology of fear in animal models and in humans and on how inherited and acquired vulnerabilities in these circuits might underlie a variety of anxiety disorders. 1981). 1991). concern about others. The prefrontal cortex and medial temporal lobe are involved in controlling fear and anxiety. such as heightened anxiety responses to the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP) compared with control subjects (Germine et al. 1998). may be associated with GAD. Auditory evoked potentials have revealed disturbed exteroceptive sensory processing in GAD at the level of the primary auditory cortex. Abnormalities of the GABA–benzodiazepine receptor complex have also been implicated in GAD. which are inverse agonists of this receptor complex. requiring replication. cognitive theory speculates a relationship to early cognitive schemas born from negative experiences of the world as a dangerous place (Barlow 1988) or insecure. Evidence for noradrenergic dysregulation in GAD has yielded mixed results. 1997b). 1989). supporting the conceptualization of GAD and panic as two discrete disorders (Perna et al. (1992) studied GAD in female twins and determined that the familial component of the disorder was almost entirely genetic. worry is used as a strategy for avoiding intense negative affects. that have suggested associations to polymorphisms of the dopamine D2 receptor gene. There is also evidence that the process of meta-worry—that is. competence. worry about unlikely and future threat removes the need to deal with more proximal and realistic threats and limits the capacity to find solutions to more immediate conflicts. the -carbolines. and the monoamine oxidase-A gene. GAD patients demonstrate more cognitions in the categories of interpersonal confrontation. Mathew et al. One series of compounds. with increased neuronal firing in the serotonergic dorsal raphe (Senkowski et al. 2000). 1999). thus leading to a negative reinforcement of the process of worrying. This was supported in a magnetic resonance imaging volumetric study comparing children and adolescents with GAD with healthy comparison subjects matched for other general characteristics.
the presence of frequent comorbidity. The differential diagnosis of GAD is summarized in Table 12–12. 1994). Course and Prognosis In contrast with panic disorder. poorer understanding of emotions. disturbed family environments. diminished ability to self-soothe after negative emotions. Such patients seem only over time to develop the recognition that their experience of chronic tension. 1993). 1996). GAD is clearly a discrete disorder in terms of its onset. and a tendency to view GAD as a secondary or minor condition hampered past treatment research. based on evidence from both nonclinical and clinical samples reporting heightened intensity of emotions. only 18%–35% achieved full remission (Woodman et al. Contrary to panic disorder. Differential Diagnosis The diagnosis of GAD is excluded when occurring exclusively in relation to other major Axis I disorders. as long as they can remember. These include a bias for threat-related information in implicit memory processes (MacLeod and McLaughlin 1995). often occurring comorbidly with medical illnesses (Flint 1994). which declines with old age. 2000). TABLE 12–12. difficult to control. We now know that clinicians must be cautious and conservative in applying this criterion. pervasive. in GAD the worry must be clearly excessive. worry. and overall greater difficulty managing emotional reactions (Mennin et al. Differential diagnosis of generalized anxiety disorder Anxious depression Panic attacks or anticipatory anxiety Social anxiety Posttraumatic stress disorder–related hyperarousal symptoms Obsessional fearfulness Hypochondriasis Paranoid anxiety associated with psychosis or personality disorder Treatment The pharmacological treatment of GAD is summarized in Table 12–13. Finally. Of GAD subjects followed over a 5-year period. Abuse of alcohol. greater negative reactivity to emotional experiences. Comorbid avoidant and dependent personality disorders appear to lessen the likelihood of remission from GAD (Massion et al. selective attentional biases for threatening information (Mogg et al. no overwhelming single event prompts the patient with GAD to seek help. GAD patients with an earlier onset of anxiety symptoms in the first two decades of life appear to be overall more impaired. . Yonkers et al. In these elderly patients it is particularly important to differentiate GAD from other anxiety states that could be related to delirium. and difficulty in decision making when faced with ambiguity (MacLeod and Cohen 1993). that they were not anxious. and depression or could be manifestations of underlying medical illnesses. certain information-processing biases may characterize GAD and permit the perpetuation of worry as the central cognitive strategy (Aikins and Craske 2001). with fewer periods of spontaneous remission. An emotional dysregulation model has also been proposed for GAD. hyperactivity. have more severe anxiety that may not be precipitated by specific stressful events. Patients with GAD experience substantial interference with their lives and have a high degree of professional help seeking and a high use of medications (Wittchen et al. barbiturates. and associated with marked distress or impairment. 2005). 2000). and antianxiety medications is also common. In clinical samples. GAD is a more chronic condition than panic disorder. course. the distinction between GAD and "normal" anxiety must be made. 2002).itself—contributes to the high degree of pathological worry in GAD (Wells and Carter 1999). 1999. and associated impairment. 1989. and anxiety is excessive. Although the major changes in diagnostic criteria in consecutive editions of DSM. dementia. Often they will state that there has never been a time in their lives. GAD appears to account for a lot of the anxiety states in late life. there are now compelling data demonstrating that even in the presence of high comorbidity of GAD with other anxiety and mood disorders. and greater social maladjustment (Hoehn-Saric et al. and have histories of more childhood fears. GAD is commonly comorbid with major depression and other anxiety disorders but still emerges as a clearly distinct entity (Wittchen et al. because as previously described. psychosis. pharmacotherapy options have blossomed in recent years. In addition.
which may be adequate for a number of patients. FDA = U. 1988). once-daily dosing.S. The two . delayed action compared with benzodiazepines. Food and Drug Administration. other SSRIs also efficacious. 1995). available data indicate that the concern over benzodiazepine abuse in chronically anxious populations is overestimated. mixed results Pregabalin: not marketed in United States Note. Tricyclic antidepressants (TCAs) General indications: Demonstrated efficacy in few trials. Concerns over addiction are probably justified. Currently. which can lead to early patient noncompliance. whereas antidepressants. there is a concern that some patients may become tolerant or even addicted to these medications. newer medication choices such as buspirone. and in reality most patients continue to derive clinical benefits without developing abuse or dependence (Romach et al. however. may be more effective for the physical rather than cognitive symptoms of generalized anxiety disorder. well tolerated. with side effects limited mainly to sedation and slowed mentation. more side effects than benzodiazepines.TABLE 12–13. A number of controlled studies clearly show that chronically anxious patients respond well to benzodiazepines. may be more effective in treating the psychic symptoms (Rocca et al. SSRIs. Its disadvantage is a slower rate of onset (Rickels et al. and newer antidepressants. There is some evidence that benzodiazepines may be more effective in treating the physical symptoms of anxiety. in individuals with histories of addiction proneness. generally well tolerated. nonbenzodiazepine antianxiety agent that may have similar efficacy to the benzodiazepines in treating GAD. Benzodiazepines General indications: Well-known efficacy and widely used. paroxetine is FDA-approved. and discontinuation of patients with GAD. Imipramine: demonstrated efficacy Trazodone: demonstrated efficacy Other medications Clonidine: tends to lose initial response Propranolol: may be useful adjuvant in patients with pronounced palpitations and tremor Atypical antipsychotics Riluzole: open trials Tiagabine: randomized controlled trial. Selective serotonin reuptake inhibitors (SSRIs) General indications: First-line treatment. generally well tolerated. However. Although benzodiazepines are generally safe. buspirone. whether TCAs or SSRIs. Benzodiazepines In past years. maintenance. recommended starting dosage is 75 mg/day. benzodiazepines were the first-line treatment of GAD. for the most part. may be more effective for cognitive rather than physical symptoms of anxiety. once-daily dosing. approved by FDA. and all benzodiazepines are probably similarly efficacious in treating GAD. and serotonin and norepinephrine reuptake inhibitors (SNRIs) have replaced the benzodiazepines as first-line treatments. Buspirone Buspirone is a 5-HT1A agonist. issues with dependence and withdrawal in certain patients. Rickels et al. Buspirone General indications: Proven efficacy. Its advantages are a different side-effect profile without sedation and the absence of tolerance and withdrawal. Pharmacological treatment of generalized anxiety disorder Venlafaxine extended-release General indications: First-line treatment. with proven efficacy in large controlled trials. 1998). (1988) compared the efficacy of the benzodiazepine clorazepate to the nonbenzodiazepine buspirone in the acute treatment. compared with benzodiazepines. all appear similarly efficacious. may have less efficacy and compliance with very recent benzodiazepine use. which may be adequate for many patients. a trial is generally indicated in all patients. recommended starting dosage is 20 mg/day. takes longer to take action and is not associated with a "high".
and placebo in GAD without depression over an 8-week period. In one controlled study comparing imipramine and alprazolam in treating GAD. 2005) at flexible dosages of 50–150 mg/day (Allgulander et al. imipramine up to 143 mg/day. Several large controlled trials to date have established the efficacy of extended-release venlafaxine. in treating GAD (Davidson et al. Sertraline has also been found to be superior to placebo in decreasing both the psychic and somatic symptoms of GAD during a 12-week treatment (Dahl et al. but patients who had used benzodiazepines within 1 month of starting the trial had a higher attrition rate and less clinical improvement if randomized to buspirone rather than to benzodiazepine. measures (Davidson et al. newer antidepressants have become established as first-line treatments for GAD. 1999. Venlafaxine has been found effective in dosages ranging from 75 to 225 mg/day. It also showed that about two-thirds of patients who did not respond to the initial 20-mg dosage responded to higher dosages of 30. with an approximately 60% reduction of anxiety scores. Venlafaxine is generally well tolerated. There has existed a suggestion in the literature that patients previously treated with benzodiazepines may not respond successfully to buspirone. In the first 2 weeks of medication discontinuation. with nausea. trazodone up to 255 mg/day. although TCA use has largely fallen out of favor recently in favor of the newer antidepressants. Antidepressants Over the past few years. and one study showed comparable efficacy and tolerability for paroxetine and sertraline (Ball et al. finding that patients who gradually discontinued lorazepam and were then treated with buspirone in a double-blind fashion did not exhibit benzodiazepine withdrawal or rebound anxiety and did as well with buspirone as they had done with lorazepam (Delle Chiaie et al. A twice-daily regimen is probably as efficacious as a thrice-daily regimen and easier to comply with. One trial showed paroxetine at fixed dosages of both 20 mg and 40 mg daily to be superior to placebo over an 8-week treatment period. 2001). similar efficacy was found for the two medications. In a paroxetine trial using dosages of 20–40 mg/day. that in long-term benzodiazepine users. Other independent predictors of successful benzodiazepine taper were lower initial dosages and less severe and chronic anxiety symptoms. 2005). The SSRI paroxetine has been studied in several controlled trials. 2001). Three pooled similar placebocontrolled trials of the SSRI escitalopram. and there was weak evidence for possible superiority of venlafaxine over buspirone by some. and the dosage can be increased until a maximum dosage of 60 mg/day is reached. whereas those who received buspirone did not. require only once-daily dosing. There was no evidence of tolerance to either medication over the 6-month period. via a controlled trial (Rickels et al. with about . 2000). DeMartinis et al. In a trial comparing venlafaxine 75–150 mg. However. because controlled trials have documented their efficacy and because they tend to be well tolerated. suggesting that it can be started at 75 mg/day for GAD and subsequently be increased if clinical improvement is not adequate and side effects permit. Another large flexibledosing trial showed that paroxetine at dosages ranging from 20 to 50 mg daily was superior to placebo in treating GAD over an 8-week period (Pollack et al. both medications were superior to placebo. patients who had been on clorazepate had a transient increase of anxiety consistent with withdrawal. and do not risk abuse and dependence. In another study. and dry mouth being the most common side effects. There is recent evidence. 2004). On the other hand. 2003). 1988). a successful strategy may be to start buspirone or an antidepressant for 1 month prior to undertaking a gradual 4 to 6-week taper of the benzodiazepine. administered for 8 weeks at a dosage of 10–20 mg/day. In addition. but not all. buspirone 30 mg. or 50 mg daily (McCafferty et al. SSRIs are also efficacious in treating GAD. and benefits were maintained over a 6-month period. Rickels et al. 2005). reported significant improvement in GAD with good tolerability in more than 800 patients (Goodman et al.medications had similar efficacy by the fourth week of treatment. (2000) retrospectively analyzed a large data set with respect to history of benzodiazepine use prior to a controlled clinical trial. Response rate is approximately 70%. Gelenberg et al. 40. 2000). Studies have not revealed consistent differences in efficacy as a function of dosing. an approximately 65% response rate and 33% remission rate were reported (Rickels et al. Several older studies have shown TCAs to be effective in treating chronically anxious patients independent of the presence of depressive symptoms. 2003). with imipramine acting more on negative affects and cognitions and alprazolam acting more on somatic symptoms (Hoehn-Saric et al. They found that clinical response to buspirone was similar to benzodiazepine response in patients who had never used or had remotely used benzodiazepines. with benefits appearing as early as the first 2 weeks of treatment. Treatment with buspirone is usually started at 5 mg tid. somnolence. 2000. with approximately two-thirds of patients considered responders (Bellew et al. 1999). a controlled treatment study has refuted this. a 6-month discontinuation study found that only about 10% of patients relapsed when continuing medication versus a 40% relapse rate on placebo (Stocchi et al. 2000). and diazepam up to 26 mg/day were found comparable after 8 weeks of treatment. an SNRI. 1995).
the expectation of low-likelihood catastrophic outcomes. 1994). 2005). A "well-being" component aimed at restoring overall function may be a useful addition to usual CBT (Fava et al. Mathew et al. fairly rapid onset. with 12 of 15 completers responding to the 8-week treatment (S. 2005). plus a number of bothersome side effects. at a mean dosage of 8. would seem for theoretical reasons to be a good antianxiety drug. especially in the face of ambivalence or ambiguity. 2005). with some edge over behavioral management alone and a significantly better result than analytic treatment. resulted in at least 50% improvement in 80% of 44 patients (Gambi et al. 84% of patients responded and 46% remitted after 7 weeks of treatment with ziprasidone. combined CBT. 2005). poor problem solving. Placebo-controlled trials of the new anxiolytic pregabalin. has been tested in a double-blind design (Pollack et al. cognitive therapy alone. which inhibits locus coeruleus discharge. Similarly. Cognitive and behavioral approaches to treating generalized anxiety disorder Exposure Cognitive restructuring Breathing retraining Applied relaxation training Given the previously described cognitive profile of GAD.two-thirds of GAD patients experiencing moderate to marked improvement in anxiety. Rickels et al. In a study that compared four conditions—behavioral therapy alone. however. 2005). A tendency to lose clinical response. the effect of risperidone augmentation in patients not adequately responding to standard anxiolytic treatment was found to be marginal (Brawman-Mintzer et al. have reported efficacy at dosages ranging from 150 to 600 mg/day. 1992). J. 1991). makes clonidine a poor initial choice for treatment. SSRI augmentation with the atypical antipsychotic olanzapine. Psychotherapy Research into the psychotherapy of GAD has not been as extensive as for other anxiety disorders. a calcium-binding presynaptic inhibitor of excitatory neurotransmission. and the physical symptoms of anxiety. and a wait-list control group—all three active treatments were similarly efficacious and superior to the control condition during an up to 2-year follow-up period. dizziness and sedation are reported at higher dosages. and similar response to a benzodiazepine active control group. CBT is superior to general nondirective or supportive therapy in treating GAD (Chambless and Gillis 1993) and possibly superior to behavior therapy alone (Borkovec and Costello 1993). several aspects of the disorder can serve as the foci of psychotherapeutic interventions. but the medication was well tolerated overall (Pohl et al. 2005). Cognitive therapy emerged as superior. These include the heightened tendency to perceive threat. reported mixed results. Combined Pharmacotherapy and Psychotherapy . has also been studied in an open-label trial and appears promising. at a daily dosage of 30 mg for 12 weeks. the combined CBT group had a much lower dropout rate than the other groups (Barlow et al. Cognitive therapy and applied relaxation were found to have similar effectiveness during a 12-week treatment and at a 6-month follow-up (Arntz 2003). generally demonstrating superiority to placebo. and behavioral management in treating subjects with GAD (Durham et al. an open monotherapy trial of ziprasidone in 13 patients with treatment-resistant illness reported more positive findings. 2005). analytic. TABLE 12–14. a number of studies exist that clearly show that a variety of psychotherapies are helpful in treating GAD (Table 12–14). Riluzole.7 mg/day. with efficacy demonstrated by some analyses but not by the primary intent-to-treat analysis (Pollack et al. A variety of treatments have been developed for GAD. the central feature of worry. but not others (Ost and Breitholtz 2000). 20–80 mg/day (Snyderman et al. such as relaxation and rebreathing techniques. behavioral anxiety management. 2005. In patients with refractory GAD. and psychodynamic treatment. Cognitive therapy alone may have an edge over behavioral therapy alone according to some studies (Butler et al. including cognitive restructuring. Other Medications -Adrenergic-blocking drugs such as propranolol may only be rarely indicated as an adjuvant in patients who experience significant palpitations or tremor. A recent open trial reported that mirtazapine. 2005) and showed modest benefit for some patients. In contrast. A multicenter placebo-controlled study of the selective GABA reuptake inhibitor tiagabine. administered for 8 weeks at dosages of 4–16 mg/day. Another randomized study compared cognitive. an antiglutamatergic agent. Still. Clonidine. exposure therapy with or without a cognitive component.
the individual experiences profound anxiety accompanied by a variety of somatic symptoms. different anxiety disorders tend to be characterized by their own constellation of most prominent somatic symptoms. a medication) or a general medical condition and is not better accounted for by another mental disorder (e. and placebo (Power et al. or there is marked distress about having the phobia. blushing. it has an earlier onset. An individual may have one. If a general medical condition or another mental disorder is present. that the CBT component of the study was more intensive than the medication treatment. B. CBT alone or with medication tended to emerge as superior. The fear or avoidance is not due to the direct physiological effects of a substance (e. or shrinking from social situations with unfamiliar people. tantrums. It appears. a common fear of socially phobic individuals is that other people will detect and ridicule their anxiety in social situations. As in specific phobias. and dry mouth are more common in social anxiety. E. Actual panic attacks may also occur in individuals with social phobia in response to feared social situations. DSM-IV-TR criteria for social phobia are presented in Table 12–15. discounting of social competence ..In a meta-analysis of 65 CBT and pharmacological treatment studies of GAD. or writing in public. SOCIAL PHOBIA (SOCIAL ANXIETY DISORDER) Definition and Clinical Description The central feature of social phobia is a marked. Generalized social phobia is overall a more serious and impairing condition. C. The feared social or performance situations are avoided or else are endured with intense anxiety or distress.. or exhibiting abnormal eating behavior in anorexia nervosa or bulimia nervosa. with lower attrition rates for psychotherapy (Mitte 2005). The avoidance. D. There are minimal data on the use of combined psychotherapy and medication in the treatment of GAD.. or social activities or relationships. negative self-evaluation regarding social performance. For example. and attending parties or interviews. a drug of abuse. or numerous social fears. the duration is at least 6 months. palpitations and chest pain or pressure are more common in panic attacks. Interestingly. freezing.g.g. DSM-IV-TR diagnostic criteria for social phobia A. or distress in the feared social or performance situation(s) interferes significantly with the person's normal routine. the anxiety in social phobia is stimulus bound. In individuals under age 18 years. separation anxiety disorder. 1995). body dysmorphic disorder. a pervasive developmental disorder. Specify if: Generalized: if the fears include most social situations (also consider the additional diagnosis of avoidant personality disorder) Socially phobic individuals fear and/or avoid a variety of situations in which they would be required to interact with others or to perform a task in front of other people. Generalized social phobia can be reliably diagnosed as a subtype. TABLE 12–15. Social phobia is described as generalized if the social fear encompasses most social situations as opposed to being present in circumscribed ones. Note: In children. trembling in Parkinson's disease. this feature may be absent. G. persistent fear of social situations in which public humiliation or embarrassment is possible.g. The person recognizes that the fear is excessive or unreasonable. which may take the form of a situationally bound or situationally predisposed panic attack. not just in interactions with adults. When forced or surprised into the phobic situation. using public lavatories. eating. The individual fears that he or she will act in a way (or show anxiety symptoms) that will be humiliating or embarrassing. a combination of the two. Typical social phobias are of speaking. F. the fear in criterion A is unrelated to it. Blushing is the cardinal physical symptom characteristic of social phobia. and affected individuals are more often single and have more interactional fears and greater comorbidity with atypical depression and alcoholism (Mannuzza et al. however. 1990). and further studies are clearly needed in this area. limited. overall similar efficacy was reported for the two treatment approaches. the anxiety may be expressed by crying. there must be evidence of the capacity for age-appropriate social relationships with familiar people and the anxiety must occur in peer settings. Exposure to the feared social situation almost invariably provokes anxiety. panic disorder with or without agoraphobia. anxious anticipation. occupational (academic) functioning. whereas sweating. In addition. difficulty gauging nonverbal aspects of one's behavior. In one study comparing CBT. Note: In children. the fear is not of stuttering. H. benzodiazepine. Note: In children. e. whereas commonly encountered cognitive constellations include tendencies for self-focused attention. or schizoid personality disorder). A marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others.
Multiple social fears. which was found to be more persistent. Socially phobic persons are impaired on a broad spectrum of measures. a review of the literature comparing generalized social phobia. whereas being male. Epidemiological studies have consistently found significant comorbidity between lifetime social phobia and various mood disorders. comorbid depression seems to contribute only modestly to these outcomes. they are often subject to intense anticipatory anxiety. or both. and a positive bias toward appraising others' social performance (Alden and Wallace 1995). depression.9%. is a highly disabling disorder whose impact on functioning and quality of life has probably been greatly underestimated and hidden in past years. whereas the rest were characterized by at least one other social fear. and have greater anxiety. and comorbid than the specific public speaking type. and bipolar disorder (Kessler et al.8% and 5. and shyness concluded that all three may exist on a continuum (Rettew 2000) or may even be alternative conceptualizations of the same underlying condition (Ralevski et al. Alcohol and sedative drugs are often utilized to alleviate at least the anticipatory component of this anxiety disorder. Importantly. about one-third reported exclusively public speaking fears. There was significant comorbidity with other psychiatric disorders. and risk factors for social anxiety are summarized in Table 12–16. per se. being young in age. pervasive and serious functional impairment can already be found. 2005a). Social phobia almost always predated the mood disorder and was a predictor of not only higher likelihood of future mood disorder but also more severity and chronicity. social phobia had a lifetime occurrence of 13. and the quality of their life is rated as quite low. especially GAD.5% and was somewhat more common in women than in men (lifetime. Being Native American. 11. Social phobia can be associated with a variety of personality disorders. Individuals who have only limited social fears may be functioning well overall and be relatively asymptomatic unless confronted with the necessity of entering their phobic situation. Even in preadolescent children. suggesting that the Axis I and II disorders may represent dimensions of social anxiety rather than discrete conditions (Tillfors et al. being Asian. 1994. and unemployment (Heimberg et al.in positive interactions. TABLE 12–16. depression. Magee et al. and avoidant and dependent personality disorders. Social phobia. bipolar I. or living in urban settings reduced risk.1%). Epidemiology and Comorbidity In the National Comorbidity Survey (Kessler et al. mean age at first treatment was about 12 years later. or African American. In a study that systematically compared individuals with a public speaking phobia with those with generalized social phobia. which employed DSM-III-R criteria.5% vs. other anxiety disorders. less educated. on the other hand. particularly avoidant personality disorder. 2001a).3%. or having low income increased risk. avoidant personality disorder. About one-third had multiple fears qualifying for the generalized type of social phobia. When faced with this necessity. 1996). ranging from dropping out of school to experiencing significant disability in whatever their main activities are. Risk factors for social anxiety Parental psychiatric history (especially social phobia. respectively (Grant et al. Mean age at onset was 15 years. can lead to chronic demoralization. depression) Parental marital conflict Parental overprotection or rejection Childhood abuse . social isolation. and 1-month incidence of 4. The NESARC found a 1-year and lifetime prevalence of DSM-IV social anxiety disorder of 2. the latter were found to be younger. Hispanic. fears of negative social evaluation. 1999b). impairing. In epidemiologically identified probands with social phobia alone. Etiology Psychosocial Theories A number of mechanisms are proposed in learning theories as contributors to the pathogenesis of social phobia (Stemberger et al. Of those affected. Indeed. They describe dissatisfaction with many aspects of life. 15.0%. 2005). and 80% had never received treatment. 1-year incidence of 7. avoidant personality disorder alone.to sixfold higher risk for dysthymia. 1995). The disorder was chronic. with an approximately three. 1990b). possibly leading to abuse. a similarly elevated familial risk of social phobia has been found. and disabling vocational and interpersonal impairment.
have an attentional and implicit memory bias for socially threatening information (Rinck and Becker 2005). 2005a). and have a negative expectation that social success will result in greater future social demands (Wallace and Alden 1997). compared with their nonanxious peers. make negative interpretations of ambiguous social events and catastrophic interpretations of mildly negative social events (Stopa and Clark 2000). 2005). in an experimental paradigm it has been shown that socially ambiguous situations are interpreted favorably by children without socially phobic parents but avoidantly when family input is negative (Dadds et al. such as lack of adequate exposure to social situations and development of social skills. 1999). controlling and critical behavior. Parents. TABLE 12–17. vicarious learning through observing others engaged in such traumatic situations. Parental social phobia is a strong risk factor for social phobia among adolescent offspring. parental marital conflict. have persistent postevent negative self-appraisal ruminations (Abbott and Rapee 2004). have a diminished perception of control over anxiety-related symptoms (Hofmann 2005). overall family functioning was not predictive (Lieb et al. 2001). and doing poorly in school (Chartier et al. Other potential risk factors for social phobia identified in a large epidemiological sample include lack of a close relationship with an adult. and fewer positive outcomes from peers (Spence et al. all centering around various manifestations of a core negative representation of one's social self. less competent social performance with peers. 2001). whether socially anxious themselves or not. 2003). have faulty learning of nonthreatening meanings (Amir et al. For example. have been found to have social skills deficits. general parental psychiatric history. as is parental depression. There is evidence that socially phobic individuals do not habituate to negative social information as easily as nonanxious control subjects (Amir et al. social anxiety disorder in males was associated with the absence of one parent or other adult confidant during childhood. 2001). are flexible in interpreting anxiety symptoms exhibited by others but are more judgmental of their own (Roth et al. overprotectiveness. and information transfer (i.e. There is a significant familial component to social phobia. more negative self-talk. while in females the disorder was associated with parental conflict and paternal physical abuse during childhood. 1996). Biological Theories Biological theories of social phobia are summarized in Table 12–17. A number of cognitive distortions have been identified in individuals with social phobia. any alcohol use disorder. modeling of socially anxious behaviors.Childhood lack of close relationship with an adult Not being firstborn for males Frequent moves in childhood Poor school performance Running away from home Risk factors include direct exposure to socially related traumatic events. and fearful information conveyed about social situations (Hudson and Rapee 2000). 2000). might rear socially anxious children through various mechanisms. any other anxiety disorder. moving several times as a child. part of which is thought to be heritable (see section "Genetics" later in this chapter) and part acquired. and parental overprotection or rejection.. Children with social phobia. Biological models of social anxiety disorder Hypersensitive conditioned fear network centered in the amygdala Abnormalities of the -aminobutyric acid (GABA)–benzodiazepine receptor Noradrenergic activation Decreased dopaminergic tone Altered serotonin availability Modest to moderate genetic component Neurochemistry Neurochemical studies of social phobia have not been as systematic or consistently replicated as those in panic . Types of family adversity also appear to affect females differently than males (DeWit et al. have difficulty disengaging attention from threatening material (Amir et al. running away from home. not being firstborn for males. childhood abuse. things that one hears in various contexts regarding social interactions).
B. B. There is also evidence that social phobia may be associated with a decreased central dopaminergic tone. Individuals with comorbid panic and social phobia have been found to have decreased levels of the dopamine metabolite homovanillic acid in the cerebrospinal fluid (CSF) (M. each disorder for its specific triggers. One study found increased cortisol response to fenfluramine suggestive of altered serotonergic sensitivity (Tancer et al. Johnson et al. all areas involved in emotional processing. 2005). However. including socially threatening cues in social phobia. little is directly known about serotonergic involvement in the disorder. a center for the emotional processing of fearfulness. A study comparing socially phobic individuals with healthy control subjects demonstrated selectively higher activation in the amygdala. Stein et al. 1995a) and no abnormality in the prolactin response to m-CPP (Hollander et al. 1994). one study has found signal decreases in the amygdala and hippocampus in normal subjects presented with the conditioned stimulus of a neutral face associated with an unconditioned stimulus. has also been implicated in other anxiety disorders. 1994). individuals with social phobia showed greater blood flow in the anterior cingulate. In another fMRI study. 1994). More recently. 2002. suggesting a strategy of visual avoidance employed to dampen phobic anxiety (Van Ameringen et al. socially phobic participants showed greater amygdalar activation than control subjects in response to the harsh faces. suggesting underlying noradrenergic dysfunction (Tancer et al. One study found that the benzodiazepine antagonist flumazenil did not induce a greater surge in anxiety in subjects with social phobia compared with control subjects (Coupland et al. 1999). nonphobic subjects revealed relatively increased cortical rather than subcortical activity. 1993). 2005b). A model involving the neurocircuitry of fear. A PET imaging study reported that during a public speaking task. other studies found no evidence of altered serotonin reuptake sites in platelets in social phobia (M. Uhde et al. but they have to date implicated a number of neurotransmitter systems. 1998). 2002). 2004b). suggesting that improvement in social anxiety by SSRIs is mediated via increased serotonin availability (Argyropoulos et al. GABA–benzodiazepine receptor involvement is unclear. Magnetic resonance spectroscopy has shown significantly higher glutamate levels in the anterior cingulate of patients with social anxiety compared with control subjects. However. 1998). fMRI imaging has shown greater activity in the subcortical. and the insula. whereas the amygdalae were relatively deactivated (Bell et al. again suggesting diminished cortical inhibition of automatic emotional processing (Lorberbaum et al. 2004). 1998). However. socially phobic patients showed greater anterior cingulate activation than nonanxious control subjects when processing disgust versus neutral faces (Amir et al. which correlated with the severity of social anxiety symptoms (Phan et al. 1999). which correlates with symptom severity (Phan et al. 1997a) and with decreased dopamine D2 receptor binding potential (Schneier et al. Several imaging studies have demonstrated heightened brain activation in social phobia in brain regions associated with emotional processing. disgusted) faces. GABAergic. 2006b). Along these lines. limbic. Neuroimaging Provocation paradigms that evoke social anxiety have blossomed over the past several years and have consistently highlighted dysfunctional brain circuits in social phobia. Social phobia was associated with a significant 20% decrease in dopamine transporter site density in the striatum on SPECT (Tiihonen et al. the dorsolateral prefrontal cortex. but this was not replicated in a subsequent study (Tancer et al. In an fMRI study examining amygdalar activation to happy versus harsh (angry. whereas socially phobic subjects exhibited opposite increased activations in both regions (Schneider et al. Stein et al. 2004). PET imaging has shown significant deactivation in the lingual gyrus and medial frontal gyrus in socially phobic patients during exposure to public speaking. Patients with social phobia exhibit a blunted growth hormone response to clonidine challenge. a tryptophan depletion protocol resulted in significant increase in anxiety during an autobiographical script in SSRI-treated social anxiety patients. fearful. whereas phobic subjects . as measured by basal cortisol levels and the dexamethasone suppression test (Condren et al. 1994). R. In a PET study utilizing social anxiety–provoking scripts. Johnson et al. similar to that described for panic disorder and involving faulty conditioned fear responses. An fMRI study found heightened amygdala activation in socially phobic persons compared with control subjects when viewing angry or disgusted faces. and paralimbic regions and less cortical activity in the anterior cingulate and prefrontal cortex during anticipation of public speaking in socially phobic persons compared with healthy controls. compared with happy faces (M. another study showed significantly decreased peripheral benzodiazepine receptor density in subjects with generalized social phobia compared with a healthy group (M. and serotonergic systems. dopaminergic. 2000).disorder. 2000). 2002). in response to emotionally neutral faces during fMRI (Birbaumer et al. Despite the now-documented efficacy of serotonin reuptake inhibitors in treating social phobia. under psychosocial stress socially phobic individuals did manifest a significantly more robust peak cortisol response compared with control subjects (Condren et al. the orbitofrontal cortex. Two studies have found normal basal functioning of the HPA axis in social phobia. including the noradrenergic.
and the course of illness is very chronic. brain activity was attenuated in the amygdala. 1993b). A genomewide linkage scan study reported strongest linkage to chromosome 16 in a region implicating the norepinephrine transporter gene (J. 1998a). 1999). earlier than with agoraphobia. in contrast to panic disorder. Comorbid avoidant personality disorder has been found to predict a 41% lower likelihood of social phobia remission (Massion et al. There are few genetic molecular studies in social phobia. such as no siblings and small-town rearing. Predictors of good outcome in social phobia are onset after age 11 years. This may reflect who is more likely to seek treatment under societal role demands. with a median illness duration of 25 years. in distinction to other anxiety disorders. 2000). has revealed findings along the same lines. 2001b). behavioral inhibition. approximately half of the sample had recovered from their illness at the time of survey. First-degree relatives of probands with generalized social phobia have an approximately 10-fold higher risk for generalized social phobia or avoidant personality disorder. in the form of both social avoidance and fearfulness in early high school. coupled with treatment interventions. A SPECT study of subjects with social phobia imaged before and after SSRI treatment showed higher baseline activity in the left temporal cortex and left midfrontal regions in nonresponders compared with responders (Van Der Linden et al. 2005). 2004). 1993). Medication treatment resulted in decreased cerebral blow flow in responders during a public speaking task in the rhinal cortex. Significant predictors of recovery were childhood social context. 2002). hippocampus. 1999). and absence of comorbid health problems or depression or the occurrence of comorbid illness prior to the onset of social phobia (DeWit et al. and higher educational status (Davidson et al. and hippocampal-parahippocampal regions (Furmark et al. In a large retrospective survey of individuals ages 15–64 years with lifetime social phobia. absence of psychiatric comorbidity. Genetics A strong familial risk for social phobia has been identified that is believed to be partly heritable and partly environmental. An adolescent female twin study has estimated the heritability of social phobia to be 28%. in clinical studies. is thought to be one of the substrates onto which social phobia might develop. prospectively. with strong evidence for shared genetic vulnerability between social phobia and major depression (Nelson et al. Neuroimaging. 2004). and PTSD. which is believed to be largely heritable and becomes manifest and fixed in early childhood (Kagan et al. B. The short allele of the serotonin transporter gene has been implicated in vulnerability to mood disorders (Hariri et al. independent of the degree of social support (Stein and Kean 2000). Course and Prognosis Social phobia has its onset mainly in adolescence and early adulthood. Yet another study has confirmed better prognosis with medication treatment for later disorder onset (especially adult onset) compared with . GAD. rather than prevalence rates in the population at large. 2004). One report found no linkage to the serotonin transporter or 5-HT2A receptor gene in generalized social phobia (M. Behavioral inhibition assessed in toddlerhood has been found. and a recent PET study found that those with social anxiety disorder who have one or two copies of the short allele exhibited significantly elevated trait and state anxiety and enhanced right amygdala activation during a public speaking task compared with social anxiety disorder patients homozygous for the long allele (Furmark et al. course and prognosis are summarized in Table 12–18. 2005). Schwartz et al. 2000). The personality trait of behavioral inhibition. Gelernter et al. A PET study examining brain activation in response to a public speaking task found that after treatment with citalopram or CBT. men are equally or even more commonly affected than women. Interestingly. Stein et al. but it is neither necessary nor sufficient for the development of the disorder. 1987). The short allele of the serotonin transporter gene (5-HTT) has been implicated in vulnerability to mood disorders (Hariri et al. 1998). Similarly. One twin study has not supported a genetic component to social and specific phobia. 2005). however. and there is evidence that it may also be implicated in anxiety disorders such as social anxiety disorder (Furmark et al. It has been found that more than half of social phobia patients report significant impairment in some areas of their lives. suggesting common sites of action of the two treatments (Furmark et al. onset after age 7 years. Onset of symptoms is sometimes acute after a humiliating social experience but is usually insidious over months or years and without a clear-cut precipitant. Social phobia is clearly a chronic and potentially highly impairing condition. amygdala. fewer symptoms. to be a strong predictor of social anxiety in adolescence (C. prospectively predicted the onset of social phobia 4 years later in adolescence (Hayward et al. 2002). and neighboring cortical areas. suggesting environmental causation (Skre et al. Mean age at onset is around 19 years.showed increased subcortical activity (Tillfors et al.
comorbid social anxiety in adolescents who were already depressed was associated with a more malignant course of the depressive illness (M. Interpersonal anxiety or fears of humiliation leading to social avoidance are not diagnosed as social phobia when occurring in the context of schizophrenia.to 4-year follow-up period. or humiliation by others. 2001a). the presence of other disorders that may cause irrational fear of people and avoidance behaviors must be ruled out. schizophreniform or brief reactive psychoses.. Course and prognosis of social anxiety disorder Course Typically early onset at or before adolescence and very chronic course Outcome About one-half found to be recovered after 25 years of illness Predictors of poorer prognosis Onset before age 8–11 years Psychiatric comorbidity Lower educational status More symptoms at baseline Comorbid health problems Diagnosis and Differential Diagnosis Differential diagnosis of social anxiety disorder is summarized in Table 12–19. and paranoid personality disorders. schizoid.g. TABLE 12–18. and major depressive disorder. even when accounting for severity and duration of illness (Van Ameringen et al. B. agoraphobia. The distinction between this entity and generalized social phobia may be conceptual and semantic. Stein et al. Automatically labeling such patients as having avoidant personalities may lead practitioners away from potentially useful pharmacotherapy and behavioral treatment efforts. . such as avoidant. In contrast. paranoid Axis I paranoid disorder such as paranoid schizophrenia or paranoid delusional disorder Depression-related social withdrawal secondary to anhedonia or feelings of defectiveness Obsessive-compulsive disorder–related fears exacerbated in social settings (e. depressive disorders. TABLE 12–19. Differential diagnosis of social anxiety disorder Personality disorder. ridicule.earlier onset. and paranoid disorders. These patients are distinguished from patients with social phobia by the presence of panic attacks that also occur in situations not involving scrutiny or evaluation by others. Patients with psychotic vulnerabilities and massive social isolation or poor interpersonal skills may occasionally be mistaken as having social phobia if seen when they are in nonpsychotic or prepsychotic phases of illness. OCD. Avoidance of social situations is seen as part of avoidant. Before the diagnosis of social anxiety disorder can be made. schizophrenia. more for symptom improvement but also for work impairment. In a prospective epidemiological study. In contrast. schizoid. In avoidant personality disorder the central fear is also rejection. individuals with social phobia generally express the wish to be able to interact appropriately with others and anticipate pleasure in this eventuality. moreover. those with social phobia fear that they themselves will act inappropriately and cause their own embarrassment or humiliation. and its validity is a subject of dispute. Social withdrawal seen in depressive disorders is usually associated with a lack of interest or pleasure in the company of others rather than a fear of scrutiny. 2004c). Some agoraphobic patients say that they are afraid they will embarrass themselves by losing control if they panic while in a social situation. social anxiety disorder in nondepressed adolescents and young adults at baseline was associated with an increased likelihood of depressive disorder during a 3. contamination) Panic disorder with phobic avoidance not limited to social situations Deficits/impaired social skills associated with schizophrenia and related disorders Persons with paranoid disorders fear that something unpleasant will be done to them by others.
taken on an as-needed basis about 1 hour before event. with minimal or no side effects. Many performing artists or public speakers find that -blockers. shown efficacy. FDA-approved. 20 mg. or obsessive-compulsive disorder. generally well tolerated. panic. Pharmacological treatment of social anxiety disorder Selective serotonin reuptake inhibitors (SSRIs) General indications: First-line treatment. Phenelzine: most studied Tranylcypromine: also effective Other medications Gabapentin: effective in one controlled trial Buspirone: well tolerated. Clonazepam: long-acting.S.e. which may decrease subjective anxiety but not optimize performance and may have an adverse effect on "sharpness. There are a number of medication options that are clearly helpful. and panic. reduce palpitations. well tolerated. Propranolol.Treatment Pharmacological Treatment The pharmacological treatment of social anxiety disorder is summarized in Table 12–20. taken orally a few hours before stage time. tremor. social phobia. fewer data Benzodiazepines General indications: Clinically widely used and reportedly efficacious in open trials. than are benzodiazepines. may be difficult to tolerate and require dietary restrictions. 50 mg. FDA = U.. effective for comorbid depression. and the "butterflies" feeling. TABLE 12–20. concerns about dependence and withdrawal in certain patients. atenolol Monoamine oxidase inhibitors (MAOIs) General indications: Demonstrated high effectiveness. generalized anxiety disorder. the most common ones used are propranolol. Food and Drug Administration. effective in open but not in controlled trial Bupropion: effective in open trial Topiramate: open trial Pregabalin: controlled trial Atypical neuroleptics: open trials D -cycloserine: used in conjunction with exposure therapy Note. efficacy demonstrated in controlled trial Beta-blockers General indications: Highly effective for performance anxiety. Beta-blockers In performance-type social phobia. Although a variety of -blockers have been used in studies and are probably efficacious for performance anxiety. taken about 45 minutes before a performance. several analogue (i. Paroxetine: best studied in large controlled trials. It also seems that they are more effective in controlling stage fright. particularly when these agents are used acutely prior to a performance. well worth trying in patients with otherwise refractory illness." . nonclinical samples with performance or social anxiety) studies have shown -blocker efficacy. effective for several comorbid conditions including atypical depression. or atenolol. once-daily dosing. average dosage 40 mg/day Other SSRIs: also efficacious Venlafaxine: also efficacious Mirtazapine: also efficacious. For the most part not helpful in patients with generalized social phobia.
2005). B. 1999. 1991). 2005). using flexible dosing up to 200 mg/day and a 53% response rate (Van Ameringen et al. A placebo-controlled trial of mirtazapine in 66 women with social phobia also reported efficacy (Muehlbacher et al. Monoamine oxidase inhibitors MAOIs were the medications proven most effective in treating generalized social phobia until recently. B. despite the usual concerns about their chronic use. 50–200 mg/day. 1991). 2001). Alprazolam has also been found to be superior to placebo.4 mg/day) was found to be superior to placebo. A 12-week placebo-controlled trial of escitalopram. and significant improvement in work and social impairment (Kasper et al. atenolol. and in one controlled study clonazepam at dosages of 0. 1993a). 2001). A 6-month placebo-controlled trial of venlafaxine extended-release at a low dosage (75 mg/day) or higher dosage (150–225 mg/day) showed similar superiority to placebo at both dosages. Stein et al. 2004). 2003). Similarly. with only 8% of patients discontinuing due to adverse events (Liebowitz et al. The benzodiazepines would not be considered a first-line treatment for social phobia. A later large 20-week trial of sertraline versus placebo confirmed sertraline's efficacy. newer antidepressants have been tested and have shown efficacy in treating social phobia. 1994). (1992) conducted a controlled study comparing phenelzine. 2. easy to dispense and monitor. with efficacy shown in several controlled trials (Baldwin et al. 2002b). a 12-week venlafaxine extended-release study using flexible dosing (75–225 mg/day) reported superiority to placebo. 1995). clonazepam is a better choice than alprazolam. J. reported efficacy with a 54% responder rate. a 12-week large sertraline trial using dosages of 50–200 mg/day demonstrated superiority to placebo. using dosages of 75–225 mg/day. with many nonresponders at week 8 achieving response by week 12 (D. M. In a 12-week study comparing 20. 2005). with a 58% response rate and a 31% remission rate (M. 1998b). with results comparable with those for phenelzine and CBT. resulting in the SSRIs becoming the first-line treatment for the disorder. with good tolerability (Rickels et al. Stein et al. 2005). 1993) and an open trial of citalopram (Bouwer and Stein 1998). replicated in a subsequent larger study with a comparable mean dosage of 200 mg/day and a response rate of 43% (M. They are generally well tolerated. maintenance-phase treatment with paroxetine for patients who had initially responded to a 12-week acute treatment found that significantly fewer patients relapsed (14%) when maintained on paroxetine compared with placebo (39%). demonstrated significant benefit over placebo in social anxiety symptoms and social impairment. Benzodiazepines Benzodiazepines can also be helpful in treating generalized social phobia. Disadvantages are the potential for abuse. 1999). A double-blind discontinuation study examined relapse in socially phobic patients initially treated openly for 12 weeks with escitalopram. and clear advantages were not identified for the higher dosages in this study (Liebowitz et al. Several open trials have reported positive results. with a response rate of 78% and improvement in social anxiety. Paroxetine is FDA approved for treating social phobia. Similar responses were found in an open trial of fluoxetine (Van Ameringen et al. a 6-month double-blind. Gelernter et al. 2005). reported a 53% response rate with medication compared with 29% for placebo (Van Ameringen et al. but it may have some efficacy in social phobia (Emmanuel et al.5–3. About one-half to two-thirds of patients studied responded to acute treatment at average dosages of about 40 mg/day.Newer antidepressants In the past decade. B. Both have advantages. Newer antidepressants other than SSRIs are also efficacious in treating social phobia. However. Stein et al. 10–20 mg/day. and found that the risk of relapse was almost three times higher in patients who discontinued active treatment (Montgomery et al. and negative self-evaluation (Davidson et al. avoidance. paroxetine at a dosage of 20 mg/day was found to be efficacious compared with placebo. the alprazolam group had the highest relapse rate 2 months after treatment discontinuation (C. Bupropion is the least studied antidepressant to date. with a 44% response rate and a 30% remission rate (Liebowitz et al. Efficacy for sertraline at dosages of 50–200 mg/day was shown in one placebo-controlled study (Katzelnick et al. Additionally. good tolerability. resulted in substantial improvement in 46% of patients compared with a 7% improvement among subjects given placebo in one controlled trial (van Vliet et al. S. Similarly. Stein et al. given at 150 mg/day for 12 weeks. withdrawal. performance. and lack of efficacy for comorbid depression. such as relatively rapid onset of action and good tolerability. 10–20 mg/day. A pooled analysis of three placebo-controlled multicenter trials of paroxetine examined predictors of treatment response and concluded that duration of treatment was the only significant predictor. 40. relapse. Liebowitz et al. A 20-week treatment study with sertraline.0 mg/day (mean dosage. and used in standard dosages comparable with those used in depression. and placebo in the treatment of patients with . 2002a). and 60 mg/day. Fluvoxamine. Given its longer half-life. 2002a. A 12-week extended-release venlafaxine study.
a 5-HT1A agonist anxiolytic. This type of training is not necessary for all individuals with social phobia and is more applicable to those who have actual deficits in social interacting above and beyond their anxiety or avoidance of social situations. rehearsal. practice) Virtual reality (VR) exposure Exposure preceded by D -cycloserine administration Exposure treatment involves imaginal or in vivo exposure to specific feared performance and social situations. in practice they are often combined in order to attain a sufficiently satisfactory response. 2001b). cognitive restructuring. social functioning. the potential for hypertensive crises. suggesting that in some patients who do not benefit adequately from antidepressant monotherapy. whereas pregabalin at a dosage of 150 mg/day was not (Pande et al. About two-thirds of patients had a marked response to phenelzine. Despite their proven efficacy in social phobia. at dosages of 45–90 mg/day. alprazolam. Other medication options Although augmentations and combinations have not been systematically tested in clinical trials. benzodiazepines can lead to additional improvement (Seedat and Stein 2004). and placebo. A new medication approach specifically targeting axillary hyperhydrosis in socially phobic patients with excessive sweating appears promising. 2005b). Although all groups improved significantly with treatment. A small placebo-controlled olanzapine trial found that olanzapine was superior to placebo (Barnett et al. Tranylcypromine in dosages of 40–60 mg/day was also associated with significant improvement in about 80% of patients with DSM-III social phobia treated openly for 1 year (Versiani et al.DSM-III social phobia. in dosages up to 30 mg/day. 1988). The anticonvulsant levetiracetam was not found to be efficacious in a pilot placebo-controlled study (Zhang et al. Cognitive restructuring focuses on poor self-concepts. 2002). reported benefit in treating social anxiety disorder (Van Ameringen et al. Placebo-controlled administration of a one-time bilateral axillary intradermal injection of botulinum toxin coupled with 8-week open treatment with paroxetine resulted in significantly greater improvement in daily activities. Cognitive and Behavioral Therapies Three major cognitive-behavioral techniques are used in the treatment of social phobia: exposure. Gelernter et al. A pindolol augmentation study of SSRIs did not report additional benefit (M. Social skills training employs modeling. at dosages of up to 400 mg/day. Stein et al. therapeutic results are not gained until in vivo exposure to the real-life feared situations is done. An open-label trial of quetiapine monotherapy in 13 patients with GAD. the fear of negative evaluation by others. 2004a). 1991) compared cognitive-behavioral group treatment with phenelzine. One study (C. rehearsal. A placebo-controlled trial of the anticonvulsant gabapentin found it superior to placebo at a mean dosage of about 2. A study combining double-blind clonazepam (1–2 mg/day) with open-label paroxetine found that the addition of clonazepam did not lead to more rapid response but did tend to be associated with a more robust global response by the end of treatment. Pregabalin at a dosage of 600 mg/day was shown to be superior to placebo in a 10-week treatment of social anxiety disorder. Buspirone. 1997). St. with an expectation that this will lead to more positive responses from others. work. Although patients with very high levels of social anxiety may need to start out with imaginal exposure until a certain degree of habituation is attained. 1999). 2005). and overall disability (Connor et al. An open trial of topiramate. with a response rate approaching 40% of subjects (Pande et al. MAOIs are no longer a first-line treatment given their dietary and medication restrictions. 2006a). TABLE 12–21. treated for 12 weeks at a mean dosage of 250 mg/day. Atypical antipsychotics have also received limited attention in treating social anxiety. and assigned practice to help individuals learn appropriate behaviors and decrease anxiety in social situations. phenelzine tended to be superior in absolute clinical response and decreased impairment. Cognitive and behavioral approaches to treating social anxiety disorder Exposure (imaginal and/or in vivo) Cognitive restructuring Social skills training (modeling. S. 2005a. B. whereas atenolol was not superior to placebo. John's wort was no more effective than placebo in one study (Kobak et al. . and the frequently not-well-tolerated side effects. reported a response rate of 70% (Schutters et al. 2005). and social skills training (Table 12–21). role-playing.900 mg/day. role-playing. was not shown to be efficacious in a controlled study (van Vliet et al. 2004).
and the attribution of positive outcomes to chance or circumstance and negative outcomes to one's own shortcomings. It consists of a variety of homework identifying negative thoughts, evaluating their accuracy, and reframing them in a more realistic way. Results of older studies of behavioral treatments for social phobia were difficult to evaluate because of heterogeneous phobic patient samples, lack of operational definitions of disorder and improvement ratings, and the presentation of outcome data in terms of mean change scores rather than level of achieved functioning. However, in the past decade or so the cognitive-behavioral treatment of social phobia has blossomed and attracted great attention, detailed treatment strategies and approaches have been delineated, and more thorough systematic studies in well-defined clinical populations have emerged. Exposure, cognitive restructuring, and social skills training may all be of significant benefit to patients with social phobia. In addition, these techniques appear superior to nonspecific supportive therapy, as shown in a randomized, controlled study comparing supportive therapy with initial individual cognitive therapy followed by group social skills training (Cottraux et al. 2000). The success of CBTs appears to be mediated, at least in part, by a decrease in self-focused attention (Woody et al. 1997). Decreases in negative self-focused thoughts and social anxiety symptoms were significantly intercorrelated in patients treated with CBT but not with exposure, despite the comparable improvement of the two groups (Hofmann et al. 2004). Attempts to correlate patient type (social skills deficits vs. phobic anxiety/avoidance) with preferred treatment modality (social skills training vs. exposure) have not always been fruitful (Wlazlo et al. 1990). Heimberg et al. (1990a) compared cognitive-behavioral group treatment with a credible psychoeducational-supportive control intervention in patients with DSM-III social phobia; both groups got better, but the cognitive-behavioral group showed more improvement, especially in patients' self-appraisal. It has been suggested that cognitive aspects may be of greater importance in social phobia than in other anxiety or phobic conditions, and therefore cognitive restructuring may be a necessary component to maximize treatment gains. Mattick et al. (1989) reported that combination treatment was superior to either exposure or cognitive restructuring alone in social phobia; cognitive restructuring alone was inferior to exposure alone in decreasing avoidant behavior, but exposure alone did not change self-perception and attitude. Although long-term outcome is more difficult to assess, studies suggest that CBT leads to long-lasting gains (Turner et al. 1995) and therefore may be of particular significance in social anxiety disorder, which tends to have a chronic, often lifetime, course. One exposure study examining long-term outcome reported that even though one patient out of three was unable to complete treatment or did not benefit sufficiently from it, exposure provided lasting effects for the majority of patients over a 6-year follow-up (Fava et al. 2001a). At this point, it appears that in vivo exposure is a critical component of the treatment and that the introduction of cognitive restructuring at some point in the treatment contributes to further gains and to their long-term maintenance. Social phobia is a disorder that often starts in the early years, and it is encouraging to know that in prepubertal children, both behavioral therapy consisting of social skills training and anxiety reduction techniques (Beidel et al. 2000) and CBT alone or with the parents (Spence et al. 2000) have been found to be highly effective in controlled trials. Very recently, virtual reality therapy techniques have surfaced as an interesting and potentially powerful alternative to standard exposure therapies in treating phobias, including social phobia. In a study of 36 social anxiety disorder participants randomly assigned to virtual reality therapy versus standard group CBT, improvement was significant and comparable in the two groups; the virtual environments re-created four situations salient to social phobia, performance, intimacy, scrutiny, and assertiveness (Klinger et al. 2005).
Other Types of Psychotherapy
The successful use of medication and/or behavioral treatments has resulted in psychodynamic therapy for phobias falling out of favor (Gabbard 1990). However, in those patients in whom underlying conflicts associated with phobic anxiety and avoidance can be identified by the clinician and lend to insightful exploration, psychodynamic therapy can be of benefit. Furthermore, a psychodynamic approach may be valuable in understanding and resolving the secondary interpersonal ramifications in which phobic patients and their partners are often caught up and that could serve as resistances to the successful implementation of medication or behavioral treatments (Gabbard 1990). A recent trial of interpersonal psychotherapy, adapted to treating social phobia, showed that seven of nine patients treated openly for 14 weeks showed significant improvement (Lipsitz et al. 1999b), suggesting that this modality does merit further study.
Combination treatment with CBT and medication has also received some attention. It appears that medication alone compared with CBT alone has comparable results in the acute treatment of social phobia (Heimberg et al. 1998; Otto et al. 2000). In a rigorous comparison with the medication "gold standard" phenelzine, group CBT was essentially found to have similar efficacy over 12 weeks, although with a longer time to reach response and some inferiority in some of the final measures (Heimberg et al. 1998). In a more recent study, treatment outcome was compared for medication alone (fluoxetine 10–60 mg/day), CBT alone, combined medication and CBT, CBT and placebo, and placebo (Davidson et al. 2004). The response rate was about 50% for both monotherapies and for combined treatment, significantly better than the 32% response rate for placebo alone, leading to the conclusion that combined treatment did not offer any advantage during the acute phase of treatment. However, the longer-term impact of the two forms of therapy may be more relevant when selecting type of treatment or opting for combination. In a continuation of the previously described study (Heimberg et al. 1998), responders continued treatment with phenelzine or CBT for a 6-month maintenance phase and were then followed for an additional 6-month treatment-free phase (Liebowitz et al. 1999). Both treatments maintained their effectiveness for the first 6 months, with phenelzine preserving its slight superiority over CBT. However, after treatment ended, CBT was associated with a greater likelihood of maintaining a good response. Along similar lines, another study compared the benefits of sertraline alone, sertraline plus exposure therapy, and exposure alone during a 1-year follow-up randomized trial and found that the exposure alone group continued to yield further improvement 6 months after treatment cessation, in contrast to a tendency toward deterioration in the sertraline alone and the sertralineplus-exposure groups (Haug et al. 2003). Therefore, in a newly presenting patient with social phobia who is reluctant to try medication, it is a very reasonable course to recommend CBT, and even in patients opting for medication treatment, the addition of psychotherapy may contribute to sustaining improvement down the road. In an exciting development in the combined treatment of social phobia, exposure therapy has been combined with the prior administration of the glutamatergic N-methyl-D-aspartate (NMDA) receptor agonist D-cycloserine, which promotes extinction learning, thus enhancing the effectiveness of fear-reduction learning strategies. In a recent study of 27 participants with public speaking anxiety, four sessions involving exposure to public speech situations were preceded 1 hour prior by double-blind administration of 50 mg D-cycloserine or placebo. Those who received
reported robustly less social anxiety during the exposure therapy than those receiving placebo (Hofmann
et al. 2006).
SPECIFIC PHOBIAS Definition and Clinical Description
Specific phobias are circumscribed fears of specific objects, situations, or activities. The syndrome has three components: an anticipatory anxiety that is brought on by the possibility of confrontation with the phobic stimulus, the central fear itself, and the avoidance behavior by which the individual minimizes anxiety. In specific phobia, the fear is usually not of the object itself but of some dire outcome that the individual believes may result from contact with that object. For example, persons with driving phobia are afraid of accidents; those with snake phobia, that they will be bitten; and those who are claustrophobic, that they will suffocate or be trapped in an enclosed space. These fears are excessive, unreasonable, and enduring; although most individuals with specific phobias will readily acknowledge that they know there is really nothing to be afraid of, reassuring them of this does not diminish their fear. In DSM-IV, for the first time, types of specific phobias were adopted: natural environment (e.g., storms); animal (e.g., insects); blood-injury-injection; situational (e.g., cars, elevators, bridges); and other (e.g., choking, vomiting). The validity of such distinctions is supported by data showing that these types tend to differ with respect to age at onset, mode of onset, familial aggregation, and physiological responses to the phobic stimulus (Fyer et al. 1990). A comparable structure has been found in child and adolescent specific phobia, clustering into three subtypes (Muris et al. 1999). DSM-IV and DSM-IV-TR make the diagnosis of phobic disorder only when single or multiple phobias are the predominant aspect of the clinical picture, a source of significant distress to the individual, and not the result of another mental disorder. The diagnostic criteria for specific phobia are presented in Table 12–22. TABLE 12–22. DSM-IV-TR diagnostic criteria for specific phobia A. Marked and persistent fear that is excessive or unreasonable, cued by the presence or anticipation of a specific object or situation (e.g., flying, heights, animals, receiving an injection, seeing blood).
B. Exposure to the phobic stimulus almost invariably provokes an immediate anxiety response, which may take the form of a situationally bound or situationally predisposed panic attack. Note: In children, the anxiety may be expressed by crying, tantrums, freezing, or clinging. C. The person recognizes that the fear is excessive or unreasonable. Note: In children, this feature may be absent. D. The phobic situation(s) is avoided or else is endured with intense anxiety or distress. E. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational (or academic) functioning, or social activities or relationships, or there is marked distress about having the phobia. F. In individuals under age 18 years, the duration is at least 6 months. G. The anxiety, panic attacks, or phobic avoidance associated with the specific object or situation are not better accounted for by another mental disorder, such as obsessive-compulsive disorder (e.g., fear of dirt in someone with an obsession about contamination), posttraumatic stress disorder (e.g., avoidance of stimuli associated with a severe stressor), separation anxiety disorder (e.g., avoidance of school), social phobia (e.g., avoidance of social situations because of fear of embarrassment), panic disorder with agoraphobia, or agoraphobia without history of panic disorder. Specify type: Animal type Natural environment type (e.g., heights, storms, water) Blood-injection-injury type Situational type (e.g., airplanes, elevators, enclosed places) Other type (e.g., fear of choking, vomiting, or contracting an illness; in children, fear of loud sounds or costumed characters)
In the National Comorbidity Survey (Magee et al. 1996), which employed DSM-III-R criteria, specific phobias had the same lifetime prevalence of 11.3%, with a median age of illness onset of 15, and women were affected more than twice as often as men. In a community study of adolescents, the prevalence of specific phobias was found to be 3.5%, higher in girls than boys, and to have significant comorbidity with depressive and somatoform disorders in about one-third of the sample (Essau et al. 2000). It is rare for individuals to seek treatment for this disorder.
With the 1909 publication of the case of "Little Hans," Freud started to develop a psychological theory of phobic symptom formation (Freud 1909/1955). Little Hans was a 5-year-old boy who developed a phobia of horses. Through an analysis of the boy's conversations with his parents over a period of months, Freud hypothesized that Little Hans's unconscious and forbidden sexual feelings for his mother and aggressive, rivalrous feelings for his father, blocked from discharge because of repression, became physiologically transformed into anxiety, which was then displaced onto a symbolic object, in this case horses, the avoidance of which partly relieved Little Hans's anxiety. Freud later reconceptualized the case of Little Hans in the context of his evolving structural theory. Freud hypothesized that phobic symptoms occur as part of the resolution of intrapsychic conflict between instinctual impulses, superego prohibitions, and external reality constraints. Signal anxiety is experienced by the ego when such unconscious impulses threaten to break through. Such anxiety serves to mobilize not only further repression but, in the case of phobia formation, projection and displacement of the conflict onto a symbolic object, which can then be avoided as a neurotic solution to the original conflict. In the case of Little Hans, sexual feelings for his mother, aggressive feelings toward his father, and the guilty fear of retribution and castration by his father generated anxiety as a signal of oedipal conflict. The conflict became displaced and projected onto an avoidable object, horses, which Little Hans consequently feared would bite him. According to Freud, such a phobic symptom had two advantages. It avoided the ambivalence inherent in Little Hans's original conflict, because he not only hated but also loved his father. It also allowed his ego to cease generating anxiety as long as he could avoid the sight of horses. The cost of this compromise was that Little Hans had become housebound. Psychodynamic work with phobias, then, focuses on the symbolic meanings that the phobic object carries for any individual and the conflicts that it serves to avoid.
Studies exposing specific phobia subjects to masked stimuli—that is. conditioned response).e. Biological Theories Some interesting hypotheses about the origin of phobias have resulted from integration of ethological. The neurobiology of specific phobias has been studied more in the past several years. a modified conditioning model would be needed. The brain circuits mediating conditioned fear responses have emerged as central to the pathogenesis of a number of anxiety disorders. suggesting that there may be an evolutionarily wired biological preparedness toward specific stimuli that would be easily conditioned but difficult to extinguish. Fourth. which is in a sense the converse of the conditioned model just described. However. Initially. Third. biological. 1995).. and learning theory approaches. even when not consciously registered. Phobia-related stimuli elicit heightened activation in the prefrontal cortex. many phobic patients do not recall an initial aversive event. only a minority of individuals exposed to a certain stimulus develop a phobic reaction. Another model of specific phobias is the nonassociative learning model (Fyer 1998). 1997). 2004).. This classical learning theory model of phobias has received much reinforcement from the relative success of behavioral (i. (1990) found high familial transmission for specific phobias. Two studies reported activation of the visual associative cortex (Fredrikson et al. discomfort. suggesting that if such an event had occurred. it must be encoded by amygdala-based emotional memory but not by hippocampal-based episodic memory.. 2003). 2004). 1993) and of the somatosensory cortex (Rauch et al.g. and there is increasing evidence that the model also applies to specific phobias. . deconditioning) techniques in the treatment of many patients with specific phobias. as is found in panic disorder (Antony et al. 1997). Two studies examining response to CO 2 inhalation in subjects with specific phobia have found no differences from healthy subjects and no hypersensitivity. then by contiguous conditioning the appearance of the phobic object alone may come to elicit an anxiety response (i. Models of the etiology of specific phobias have recently been elaborated and critiqued by Fyer (1998). and dorsomedial prefrontal cortex were implicated in attentional processes involved in threat evaluation (Straube et al. If the individual frequently receives an electric shock when in contact with the phobic object. the unconditioned stimulus). suggesting environmental causation (Skre et al.e. Avoidance of the phobic object prevents or reduces this conditioned anxiety and is therefore perpetuated through drive reduction. sometimes without hippocampal or cortically based knowledge or memory of why there is such fear. Such a model is attractive in that it may account for the occurrence of such a highly fearful response to the conditioned phobic stimulus. very brief stimuli that can only be perceived implicitly—have lent partial support to the notion that phobic stimuli. phobic anxiety is thought to be a conditioned response acquired through association of the phobic object (i. an electric shock) produces an unconditioned response of pain. whereas wider circuits involving the insula. there was no increased risk for other comorbid phobic or anxiety disorders. the conditioned stimulus) with a noxious experience (i. constitutional vulnerabilities. mediated by the amygdala. on four counts. with a roughly threefold risk for first-degree relatives of affected subjects. Gelernter et al. because it either occurred before age 3 years or was encoded under highly stressful conditions. and fear. Second.In learning theory. suggesting visual and tactile imagery as one component of the phobic response. or unsafe environments. it has also been criticized on the grounds that it is not consistent with a number of empirically observed aspects of phobic behavior in humans. However. A volumetric study comparing those with an animal phobia with healthy control subjects reported increased cortical thickness in paralimbic and sensory cortical areas implicated in the processing of phobic stimuli (Rauch et al. Fyer et al. She concluded that in order to satisfactorily explain specific phobia. the noxious experience (e. can elicit a subjective or objectively measured fearful response (Van Den Hout et al. It proposes that each species has certain innate fears that are part of normal development and that what goes wrong in specific phobia is a failure to habituate over time to these intrinsic developmental fears. anterior cingulate. despite belief and evidence that there is nothing to fear. one twin study did not support a genetic component to specific phobias. it turns out that a very small number of objects account for most of human phobias.e. 1993). An fMRI study examining spider phobia implicated the right amygdala in automatic stimulus processing. most phobias are resistant to extinction in the absence of specific interventions. First. This could be due to various processes such as stressful life events. One whole-genome scan study implicated a chromosome 14 risk locus in simple phobia (J... suggesting that additional factors such as genetic vulnerabilities or previous experiences play a role. Brain imaging studies in specific phobias have begun to illuminate their neurocircuitry.e. cingulate. and insula in spider phobic individuals but not in control subjects.
Another new and exciting development in the treatment of all phobias. promising computer-aided self-help exposure programs via the Internet. A cerebral blood flow study examined individuals with spider phobia before and after cognitive therapy and found different brain activation patterns in two groups of phobic patients (Johanson et al. in which 11 patients were randomized to either placebo or paroxetine up to 20 mg/day for 4 weeks. both the example and the encouragement of other members are often particularly helpful in persuading the patient to reenter the phobic situation. reflecting the use of metacognitive strategies aimed at self-regulating fear as well as parahippocampal activation related to the automatic reactivation of the contextual fear memory. In other words. it appears that specific phobias follow a chronic course unless treated. The method of exposure in both the in vivo and imaginal techniques can be graded or ungraded. Exposure treatments may be divided into two groups depending on whether exposure to the phobic object is "in vivo" or "imaginal. and none of the patients who had not improved with the initial treatment were any better at follow-up. Treatment The treatment of choice for specific phobias is exposure. The problem lies in persuading the patient that exposure is worth trying and will be beneficial. Techniques may include systematic desensitization. Course and Prognosis Animal phobias usually begin in early childhood. patients who reported panic during the initial spider exposure showed hypoactivity in the frontal cortex at that time and then showed an increase in prefrontal regional cerebral blood flow in the spider challenge after cognitive therapy. and participant modeling and reinforced practice. In contrast. antipanic medication may also be indicated. aimed at fear extinction. which permit "virtual exposure" in a clinical setting. Graded exposure uses a hierarchy of anxiety-provoking events varying from least to most stressful. have been developed for those who are unable to travel due to their phobias (Kenwright and Marks 2004). after successful completion of CBT. whereas situational phobias tend to start later in adolescence or early adulthood. One virtual reality study of driving phobia reported positive results (Wald and Taylor 2003). is the development of virtual reality exposure techniques. In recent years. Most exposure techniques have been used in both individual and group settings. TCAs. about half were clinically symptomatic at follow-up. For those patients whose phobic symptoms include panic attacks. 2002). whether intrinsically or as a result of treatment. in both groups activation of the prefrontal cortex varied with the capacity to self-regulate. Ungraded exposure begins with the patients confronting the most stressful items in the hierarchy. Another fMRI study before and after CBT found significant reduction of hyperactivity in the insula and the anterior cingulate cortex of the treated group compared with the wait-list group (Straube et al. including specific phobias. The patient begins at the least stressful level and gradually progresses up the hierarchy. with brief telephone support from a therapist. no significant activation was found in either brain region (Paquette et al. Exposure can be accompanied by varying degrees and types of cognitive interventions that decatastrophize the phobic stimulus and encourage risk taking. 2006). benzodiazepines. 2002) and one of flying phobia (Banos et al. Those patients who managed to control their emotional reaction during spider exposure before treatment showed increased activation in the prefrontal cortex. Medications have not generally been shown to be effective in treating specific phobias. 1999a). Studies thus far have not conclusively shown any one exposure technique to be superior to other techniques or to be specifically indicated for particular phobic subtypes. and -blockers generally do not appear useful for specific phobias based on the limited number of studies available to date. One recent small controlled trial. phobic subjects before CBT showed dorsolateral prefrontal cortex activation. In another study using fMRI before and after CBT. Similarly promising results were reported in a virtual reality treatment study of spider phobia (Garcia-Palacios et al." In vivo exposure involves the patient in real-life contact with the phobic stimulus. whereas after successful treatment they showed a decline in activation in this region. this study suggests that specific phobias may be resistant to treatment or often do not receive treatment (Lipsitz et al. prolonged in vivo exposure. reported that one out of six patients responded to placebo and three out of five to paroxetine . 2003). A recent study followed up specific phobia patients 10–16 years after an initial treatment and found that even among responders with complete initial recovery. 2006). Imaginal techniques confront the phobic stimulus through the therapist's descriptions and the patient's imagination. In a group setting. Although systematic prospective studies are limited.Imaging studies have been combined with treatment in order to examine the changes in brain activity that may mediate treatment response. imaginal flooding. greatly facilitating the ease of administration of many in vivo–type exposures.
If another Axis I disorder is present. There has been a recent surge in interest in the combination of medication and exposure therapy. or according to rules that must be applied rigidly (2) the behaviors or mental acts are aimed at preventing or reducing distress or preventing some dreaded event or situation. Although some activities. or images that are experienced.g. praying. C. however. hair pulling in the presence of trichotillomania. DSM-IV-TR diagnostic criteria for obsessive-compulsive disorder A. sexual behavior. the person does not recognize that the obsessions and compulsions are excessive or unreasonable The terminology of "obsessions" or "compulsions" is sometimes used more broadly to characterize conditions that are not true OCD.. preoccupation with food in the presence of an eating disorder. such as eating. concern with appearance in the presence of body dysmorphic disorder. impulses. these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive B. preoccupation with sexual urges or fantasies in the presence of a paraphilia. (3). or significantly interfere with the person's normal routine... impulses. Specify if: With poor insight: if. Either obsessions or compulsions: Obsessions as defined by (1). 2000). gambling. D. although their consequences may become increasingly unpleasant and ego-dystonic over time. In this treatment paradigm. preoccupation with drugs in the presence of a substance use disorder. preoccupation with having a serious illness in the presence of hypochondriasis. although possibly excessive and painful. Obsessive brooding. 2004).g. is combined with exposure to further promote extinction. are time consuming (take more than 1 hour a day). Note: This does not apply to children. The obsessions or compulsions cause marked distress. a drug of abuse." these activities are distinguished from true compulsions in that they are experienced as pleasurable and ego-syntonic. a 50-mg dose of D-cycloserine. or images are a product of his or her own mind (not imposed from without as in thought insertion) Compulsions as defined by (1) and (2): (1) repetitive behaviors (e. occupational (or academic) functioning. in treating anxiety and fear. or preoccupations. . the content of the obsessions or compulsions is not restricted to it (e. Similarly. In a treatment study of 28 patients with acrophobia (fear of heights). and (4): (1) recurrent and persistent thoughts. TABLE 12–23. ordering. E. or guilty ruminations in the presence of major depressive disorder). as intrusive and inappropriate and that cause marked anxiety or distress (2) the thoughts. which persisted at 3-month follow-up (Ressler et al. repeating words silently) that the person feels driven to perform in response to an obsession. typically characteristic of depression. a glutamatergic agent which at low dosages has NMDA receptor agonist effects and facilitates new learning. At some point during the course of the disorder. or to neutralize them with some other thought or action (4) the person recognizes that the obsessional thoughts. or drinking. the person has recognized that the obsessions or compulsions are excessive or unreasonable.. traditional or virtual reality. all subjects received two virtual reality exposure sessions and were premedicated with either D-cycloserine or placebo. (2). or images are not simply excessive worries about real-life problems (3) the person attempts to ignore or suppress such thoughts. or images. The combination treatment group manifested significantly greater improvement. impulses. 2005). may be unpleasant but are distinguished from true obsessions because they are not as senseless or intrusive and the individual regards them as meaningful. dramatic success using SSRIs was reported in three cases of childhood refractory choking phobia that had not responded to other interventions (Banerjee et al. or usual social activities or relationships.g. counting. impulses. for most of the time during the current episode. a medication) or a general medical condition.(Benjamin et al.g. checking) or mental acts (e. DSM-IV-TR criteria for OCD are presented in Table 12–23. at some time during the disturbance. hand washing. when engaged in excessively may be referred to as "compulsive. ruminations. OBSESSIVE-COMPULSIVE DISORDER Definition The essential features of OCD are obsessions or compulsions. The disturbance is not due to the direct physiological effects of a substance (e. including specific phobias.
religious. A third group includes purely obsessional patients with no compulsions. in whom slowness is the predominant symptom. convictions. However. 1992). the person does not recognize that the obsessions and compulsions are excessive or unreasonable. some patients describe a sudden onset of symptoms.There are several presentations of OCD based on symptom clusters. An obsession is an intrusive. Some OCD patients. Of interest are reports of new onset of OCD during pregnancy (Neziroglu et al. sexual. There is evidence of OCD associated with the 1920s encephalitis epidemic. However. Certain diagnostic disputes regarding OCD were investigated in the DSM-IV field trial and led to some changes in criteria and clarifications in DSM-IV. In most cases. child molestation). excessive. Primary obsessional slowness is evident in another group. or in a separate grouping of compulsive spectrum disorders. Obsessional ideas are repetitive thoughts that interrupt the normal train of thinking. or nonsensical content. 1995). rape. which will be grappled with in DSM-V (Bartz and Hollander 2006). are intended to reduce anxiety or prevent harm. Patients may spend many hours every day washing. Mental rituals are encountered in the great majority of OCD patients and. and 50% by both (Foa et al. 28% are bothered mainly by obsessions. and after an insidious onset there is a chronic and often progressive course. fears. DSM-IV also made explicit that compulsions can be either behavioral or mental. compulsions decrease anxiety only transiently. about 5% are convinced that their obsessions and compulsions are reasonable. such as "step on the crack. and life goes on at an extremely slow speed. murder. such as one's home catching on fire because the stove was not checked or running over a pedestrian because of careless driving. Even though obsessions are typically experienced as ego-dystonic. and the nature of the fears in OCD is distinct from those of other anxiety disorders. The person may think of doing the worst possible thing (e. In DSM-IV-TR. This is particularly true of patients with a neurological basis for their illness. 20% by compulsions. Clinical Description Onset OCD usually begins in adolescence or early adulthood but can begin prior to that time. break your mother's back. A second group includes patients with pathological counting and compulsive checking. Although over 90% of patients have features of both obsessions and compulsions. images. like behavioral compulsions. whereas obsessional images are often vivid visual experiences. there is a wide range of insight in patients with OCD. Obsessional thoughts were defined by Karl Westphal in 1878 as ideas that in an otherwise intact intelligence. whose rituals center around compulsive washing and avoidance of contaminated objects. and inconclusive thinking about metaphysical questions. various sources of evidence support this view. and 3) OCD often occurs in association with other anxiety disorders. More recently. unwanted mental event usually evoking anxiety or discomfort.g. or impulses and are often of an aggressive. Based on this. blasphemy. Obsessions may be thoughts. getting dressed. without being caused by an emotional or affect-like state. ideas. Obsessional fears often involve dirt or contamination and differ from phobias because they are present in the absence of the phobic stimulus. disgusting." Obsessional ruminations may involve prolonged. for most of the time during the current episode. and eating breakfast. OCD is classified among the anxiety disorders because 1) anxiety is often associated with obsessions and resistance to compulsions. ruminations.." are unable to throw anything out for fear they might someday need something they discarded. the DSM-IV specified a poor insight type if. Obsessional impulses may be aggressive or sexual. with 75% developing OCD by age 30. and onset following head injury or seizures. called "hoarders. Symptoms Obsessions Obsessive and compulsive symptoms have been recognized for centuries and were first described in the psychiatric literature by Esquirol in 1838 (Rachman and Hodgson 1980). it has been disputed whether OCD belongs with the rest of the anxiety disorders. Obsessional convictions are often characterized by an element of magical thinking. 31% of first episodes occur between ages 10 and 15 years. 2) anxiety or tension is often immediately relieved by yielding to compulsions. Although most patients have some degree of insight. One group includes patients with obsessions about dirt and contamination. Other common obsessional fears involve harm coming to oneself or to others as a consequence of the patient's misdoings. Much obsessive thinking involves horrific ideas. no particular stress or event precipitates the onset of OCD symptoms. and against the will of the person come into the foreground of the consciousness (Westphal 1878). such as . abnormal birth events. which are subsumed by the stress and fear circuitry.
However. it is the major feature of the rare and disabling syndrome of primary obsessional slowness. Checking often fails to resolve the doubt and. washing and checking were the two most common groups of compulsions. hoarders. checking. contamination/cleaning. It may take several hours for the obsessionally slow individual to get dressed or get out of the house. In contrast to manic or psychotic patients. When patients with obsessional traits decompensate. Another hallmark of obsessive thinking involves lack of certainty or persistent doubting. repeating. This slowness may be a response to a lack of certainty as well. in some cases. 2005). contaminants. who manifest premature certainty. for example. Character Traits Psychoanalytic theorists have suggested that there is a continuum between compulsive personality and OCD. or vaginal secretions. whereas obsessive-compulsive personality traits are ego-syntonic and do not involve a sense of compulsion that must be resisted against. and orderliness. OCD symptoms are ego-dystonic. Epidemiological studies show that obsessive-compulsive character pathology is neither necessary nor sufficient for the development of OCD symptoms. These individuals are concerned with dirt. Similarly. These four syndromes can coexist in any one patient and be continuous with more normative obsessive-compulsive phenomena. Freud (1913/1958) noted an association between obsessional neurosis (i. Such patients. neurobiological. Attributing these obsessions to an internal source. parsimony. they often develop depression. symmetry and ordering. checkers.intrusive impulses of stabbing one's spouse or raping one's child. run over someone with their car or left the door unlocked. and mental compulsions were the third most common type after checking and washing. these symptoms may overlap or develop sequentially. striving for completeness. Are my hands clean? Is the door locked? Is the fertilizer poisoning the water supply? Compulsive rituals such as excessive washing or checking appear to arise from this lack of certainty and consist of a misguided attempt to increase certainty. These patients may have little anxiety despite their obsessions and rituals. Such behavior may include rituals involving washing. Rachman and Hodgson 1980). or somatization rather .000 patients identified the same four consistent "syndromes": symmetry/ordering. OCD patients are unable to achieve a sense of certainty between incoming sensory information and internal beliefs. phenomenological and epidemiological evidence suggests that OCD is frequently distinct from obsessivecompulsive personality disorder. Mental compulsions are also quite common and should be inquired about directly. and hoarding (Leckman et al. hoarding. Rachman and Hodgson 1980). or treatment-response heterogeneity in OCD. Resistance is the struggle against an impulse or intrusive thought. these subtypes may prove useful in the future when examining possible genetic. may actually exacerbate it. Janet (1908) stated that all obsessional patients have a premorbid personality that is causally related to the disorder. those who are purely obsessional. may replay over and over in their minds past conversations with others to make sure they did not somehow incriminate themselves. In the DSM-IV OCD field trials. avoiding.e. They may also attempt to avoid contaminating themselves with feces. cleanliness and washing. Therefore. and significant impairment in functioning can result. "Checkers" have pathological doubt and thus compulsively check to see if they have. a more recent meta-analysis of several factor-analytic studies involving more than 2. 1975. Approximately 10%–25% of OCD patients are purely obsessional or predominantly experience obsessions (Akhtar et al. and those with primary slowness). and obsessions/checking (Mataix-Cols et al.. 1997). Although slowness results from most rituals. 1975. the patient resists or controls them to a variable degree. 80% of patients had both behavioral and mental compulsions. Although distinct symptom clusters exist (washers. and being meticulous. Compulsions A compulsive ritual is a behavior that usually reduces discomfort but is carried out in a pressured or rigid fashion. for example. urine. paranoia. Washers represent about 25%–50% of most OCD samples (Akhtar et al. punctuality. One study examined the distribution and grouping of obsessive-compulsive symptoms in about 300 OCD patients and found that a total of four symptom dimensions accounted for more than 60% of variance: obsessions and checking. because they could go undetected if the clinician only asks about behavioral rituals. or germs and may spend many hours a day washing their hands or showering. OCD) symptoms and personality traits such as obstinacy. In the DSM-IV field trial. and control is the patient's actual success in diverting his or her thinking. Obsessions are usually accompanied by compulsions but may also occur as the main or only symptom.
Studies of first-degree relatives of OCD patients show a higher-than-expected incidence of a variety of psychiatric disorders. and ambivalence to control unacceptable sexual and aggressive impulses. about 70% of patients are male (Swedo et al. other anxiety disorders such as panic disorder and simple and social phobia. Carey and Gottesman 1981). and it may suggest partly differing etiologies or vulnerabilities in the two sexes. Black et al.5% (Regier et al. Another recent study supports that there may exist a familial spectrum of OCD and obsessivecompulsive personality disorder (Samuels et al. or gesture. about 8% met criteria for OCD. a 6-month prevalence of 1. and Tourette's syndrome. Family studies suggest a genetic link between OCD and Tourette's syndrome (Nee et al. thought. A real or . eating disorder.than OCD. in childhood-onset OCD. only a minority of OCD patients had DSM-III-R obsessive-compulsive personality disorder. depression. hypochondriasis. including obsessive-compulsive symptoms. Family studies have also shown that OCD spectrum disorders. This difference seems to be accounted for by the earlier age at onset in males. 1988). with a 1-month prevalence of 1. or impulses associated with them. 1992. there is a roughly equal ratio of men to women (A. and a lifetime rate of 2. and regression. and depression (D. such as body dysmorphic disorder. obsessive-compulsive pathology involves fixation and subsequent regression from the oedipal to the earlier anal developmental phase. Isolation Isolation is an attempt to separate the feelings or affects from the thoughts. Interestingly. 1989b). In addition. Undoing Undoing is an attempt to magically reverse a psychological event. undoing. An example is a patient who describes a particularly gruesome thought or fantasy but denies any feelings of anxiety or disgust associated with it. 2006). anxiety disorders. In clinical samples of adult OCD. W. In more recent standardized evaluations. whereas other personality disorders such as avoidant or dependent were more common (Thomsen and Mikkelsen 1993). fantasies. A recent large family study found that OCD was about fourfold more common in relatives of OCD probands than in control relatives. Black 1974). such as a word. suggesting that some predisposition to obsessional behavior is inherited. Although the older literature suggested the presence of definite obsessional traits in as many as two-thirds of OCD patients. 2000b). Etiology Psychodynamic Theory Psychodynamic theory views OCD as residing on a continuum with obsessive-compulsive character pathology and suggests that OCD develops when defense mechanisms fail to contain the obsessional character's anxiety. There are reports demonstrating comorbidity of OCD with schizophrenia. Carey and Gottesman 1981). personality disorders may be more common in the presence of a longer duration of OCD. Twin and family studies have found a greater degree of concordance for OCD (defined broadly to include obsessional features) among monozygotic twins compared with dizygotic twins (G. no OCD was detected in relatives of probands with onset after age 18 (Nestadt et al. as does a similar one in panic disorder. Epidemiologically. In a clinical sample of schizophrenic and schizoaffective patients. reaction formation. 1997).5%. 1982). suggesting they could be secondary to the Axis I disorder. and criteria for personality disorders may no longer be met after successful treatment of the OCD (Baer and Jenike 1992). structured personality assessments were not used. Epidemiology The ECA study (described earlier in this chapter) suggested that OCD is quite common. 2000). There have been no studies of OCD in adopted children or monozygotic twins raised apart.3%. and grooming conditions. highlighting the importance of screening for obsessive-compulsive symptoms in such populations where detection may be more difficult (Eisen et al. eating disorders. The fixation is presumably due to excessive investment in anal eroticism resulting from excessive frustrations or gratifications in the anal phase. and the finding was more robust for obsessions. G. This study suggests. age at onset of OCD in probands was very strongly related to familiality. the OCD comorbidity risk for other major psychiatric disorders was found to be fairly high but nondistinctive (Karno et al. that there may exist a more strongly familial subtype of OCD with an earlier onset. In this model. autism. Obsessive-compulsive patients are thought to utilize the defense mechanisms of isolation. 1988). occur more frequently than expected in the relatives of those with OCD (Bienvenu et al. These defense mechanisms are unconscious and thus not readily apparent to the patient. However.
1997).imagined act can be undone by evoking its opposite. a wealth of biological findings that have emerged over the past few decades have rendered OCD one of the most elegantly elaborated psychiatric disorders from a biological standpoint (Table 12–24). or thoughts are associated with the initial stimulus and the associated anxiety is diffused. In OCD. anxiety reduction after the ritual preserves the compulsive behavior. 2005). Taylor et al. better memory for contaminated objects than control subjects with comparable memory (Radomsky and Rachman 1999). they have decreased confidence in their memory (MacDonald et al. In addition. the characteristic thought omnipotence results in magical ideation and lack of certainty. Three main types of dysfunctional beliefs have been identified in OCD: responsibility and overestimation of threat. if not to the genesis. classical conditioning). Regression In OCD. The person then engages in compulsive rituals (escape/avoidance responses) in order to decrease anxiety. resulting in displaced ambivalence and paralyzing doubts. especially responsibility surrounding intrusive cognitions. People with OCD have been found to have deficits in selective attention. then at least to the maintenance of the disorder. and it has been proposed that such deficits may relate to their diminished ability to selectively ignore intrusive cognitive stimuli (Clayton et al. Biological models of obsessive-compulsive disorder Serotonergic dysregulation Additional dopaminergic dysregulation. somatostatin) Hyperactive orbitofrontal–limbic–basal ganglia circuitry . such that thoughts of harming someone become confused with action and may lead to a sense of uncertainty over actually having harmed someone. Likewise. aggressive impulses are neutralized. at least in subgroup of patients Neuropeptide abnormalities (oxytocin. and loving feelings predominate toward significant objects. Higher-order conditioning occurs when other neutral stimuli such as words. If the individual is successful in reducing anxiety. a patient who has sadistic impulses to hurt people might behave in a passive or masochistic manner or excessively pronounce his love at moments of heightened anger. images. Themes characteristic of the anal phase typically reflect conflicts surrounding ambivalence. Subjects with OCD also appear to have memory biases toward disturbing themes. Cognitive and Behavioral Theories A prominent behavioral model of the acquisition and maintenance of obsessive-compulsive symptoms derives from the two-stage learning theory of Mowrer (1939). This regression helps the patient avoid genital conflicts and the anxiety associated with them. Individuals with OCD who "check" have been found not to have memory impairments that presumably could account for the increased checking.e. dirt. control. perfectionism and intolerance of uncertainty. In Stage 1. 1999). Biological Theories Although OCD used to be viewed as having a psychological etiology. which has not been fully relinquished.. In particular. Ritualized behavior preserves the fear response. and importance and control of thoughts (S. the compulsive behavior is more likely to occur in the future (Stage 2: operant conditioning). Thus. because the person avoids the eliciting stimulus and thus avoids extinction. A patient who feels he has spent too much money on an item for his own pleasure may attempt to undo this by returning the object or punishing himself through some other deprivation. Ambivalence In normal development. Certain types of cognitions and cognitive processes are highly characteristic of OCD and presumably contribute. negative beliefs about responsibility. strong aggressive impulses are thought to reemerge toward love objects. but rather. for example. order. Reaction formation The defense of reaction formation substitutes an unacceptable unconscious impulse with its opposite. anxiety is classically conditioned to a specific environmental event (i. TABLE 12–24. 2000). such as turning on and then turning off a light switch. vasopressin. regression is theorized to take place from the genital oedipal phase to the earlier pregenital anal-sadistic phase. and parsimony. may be a key factor influencing obsessive behavior (Salkovskis et al.
including reduced orbitofrontal and amygdala volumes (Szeszko et al. Wise and Rapoport 1989). This could be due to a heightened internal drive state or an increased responsivity to external releasers. It has been suggested that the severity of obsessive urges correlates with orbitofrontal and basal ganglia activity. 2001). Neuroanatomy and Functional Neurocircuitry A neuroethological model of OCD has been proposed by Rapoport. 2005). increased putamen. neurological. and reduced amygdala (Pujol et al. and increased orbitofrontal and decreased anterior cingulate gray matter (Valente et al. 1994). A certain form of OCD with childhood onset is believed to be related to an autoimmune process secondary to streptococcal infection. leading to the inability to inhibit unwanted verbal-ideational mental representations and their corresponding motor sequences. memory confidence. Basal ganglia abnormalities were particularly suspected in the pathogenesis of OCD. given that OCD is closely associated with Tourette's syndrome (Pauls et al. Swedo. Along the lines of this model. J. whereas the accompanying anxiety is reflected by activity in the hippocampus and cingulate cortex (McGuire et al. 2005). Breiter et al. Swedo et al. auditory evoked potentials. smaller globus pallidus and increased anterior cingulate cortex (Szeszko et al. ? polymorphisms of the catechol-O-methyltransferase and serotonin transporter genes The association of OCD with a variety of neurological conditions or more subtle neurological findings has been known for some time. Such findings include the onset of OCD following head trauma or von Economo's disease. 1997). increased volume of the orbitofrontal cortex and thalamus (J. and ventricular brain ratio on computed tomography scan. Kim et al. significant increases in relative blood flow occur in "real" time in the caudate. 2000). 2000). another disorder of the basal ganglia (Swedo et al. with increased . Studies documenting significant volumetric abnormalities in treatment-naive children with OCD suggest that a developmentally mediated dysplasia of the ventral prefrontal-striatal circuitry may underlie OCD (Rosenberg and Keshavan 1998). enlarged basal ganglia have been found on magnetic resonance imaging scans. and the presence of significantly more neurological soft signs in OCD patients compared with healthy control subjects. OCD behaviors such as excessive washing or saving may be dysregulated manifestations of normal grooming or hoarding behaviors. as well as with Sydenham's chorea. although not always consistent. Using emotional Stroop tasks. which can be identified by the monoclonal antibody D8/17. 1989a). such children have also been found to have elevated anti–basal ganglia antibodies compared with pediatric autoimmune. and have suggested abnormalities in memory. Volumetric imaging studies have consistently revealed abnormal volumes in the implicated circuit. cingulate cortex. Rauch et al. Obsessions and compulsions are conceptualized as species-specific fixed action patterns that are normally adaptive but in OCD become inappropriately released. (1989c) showed higher metabolic activity in the orbitofrontal and cingulate regions in OCD. and excessive. is expressed in nearly all patients with rheumatic fever and is thought to be a trait marker for susceptibility to group A streptococcal infection complications. it has been possible to demonstrate that during the behavioral provocation of symptoms in OCD patients. In such children. 1987) compared OCD patients and normal control subjects using PET and found higher metabolic rates in the orbitofrontal gyri and caudate nuclei in OCD. 2004). More recently. Flor-Henry (1983) hypothesized that the fundamental symptomatology of obsessions was due to a defect in neural inhibition of dominant frontal systems. 1997). abnormalities on the electroencephalogram. A particular B lymphocyte antigen. or streptococcal control subjects (Dale et al. a high incidence of neurological premorbid illnesses in OCD. The basal ganglia act as a gating station that filters input from the orbitofrontal and the cingulate cortex and mediates the execution of motor patterns. smaller basal ganglia (Rosenberg et al. OCD patients displayed specific neural responses to OCD-related words. suggesting that D8/17 may serve as a marker for susceptibility to childhood-onset OCD (Murphy et al. a plethora of neuroimaging studies have yielded a sophisticated neuroanatomical underpinning for OCD. For example. 2004).Autoimmune streptococcal-related component in some individuals Genetic component. trial-and-error learning. With fMRI. 2005). based on the hypothesized orbitofrontal–limbic–basal ganglia dysfunction. 1994). Children with multiple streptococcal infections within the past year are threefold more likely to be newly diagnosed with OCD or tic disorder (Mell et al. and their group (Swedo 1989. 2000. which is consistent with an autoimmune hypothesis (Giedd et al. Children with OCD and without a history of rheumatic fever or Sydenham's chorea have now been found to have significantly greater B cell D8/17 expression than control children. specifically implicating orbitofrontal–limbic–basal ganglia circuits. an association of OCD with birth trauma. repetitive. enlarged thalamus (Gilbert et al. Baxter et al. 1999). and processing speed. 1996. reduced orbitofrontal cortex gray matter. Neuropsychological findings in OCD are also of some interest. Similarly. 1986). and orbitofrontal cortex relative to the resting state (Adler et al. an association with diabetes insipidus. in which basal ganglia dysfunction results in abnormal involuntary movements.
2005a). orbitofrontal lobes. 1988). social dominance. suggestive of diminished serotonin transmission in the corticostriatal loop (Adams et al. fenfluramine. The use of pharmacological challenge agents to stimulate or block serotonin receptors has also proved a fruitful technique in elucidating the neurochemistry of OCD. m-CPP challenge no longer induced symptom exacerbation (Hollander et al. successful SSRI treatment of OCD or major depression resulted in cerebral activity changes that were disorder specific rather than treatment specific. checking. 2000). 2005). A PET study showed that better SSRI treatment response was associated with lower activity in the orbitofrontal cortex and greater activity in the posterior cingulate cortex (Rauch et al. Oral m-CPP. After treatment of OCD with serotonin reuptake inhibitors or behavior therapy. 2005b). suggesting a decoupling of malfunctioning brain circuits (J. 2006). 1992). Neurochemistry Parallel to the functional neuroanatomy. supports the model of deficient frontostriatal circuits in OCD (Hoenig et al. Increased 5-HT2A receptor binding has been reported in the caudate nuclei of OCD patients. Swedo et al. reduction of OCD symptoms during clomipramine treatment was shown to correlate with a decrease in platelet serotonin level (Flament et al. such as metergoline. 1991a. Perani et al. after successful behavioral treatment the correlations in brain activity between the orbital gyri and the caudate nucleus decrease significantly. Deficient sensorimotor gating. After treatment of OCD with serotonin reuptake blockers such as clomipramine or fluoxetine. has been found to transiently exacerbate obsessive-compulsive symptoms in a subgroup of OCD patients (Hollander et al. or antagonists. and ipsapirone. orbitofrontal cortex. only OCD treatment was associated with significant metabolic decreases in the caudate. have also been found in OCD. 1995. 2005). the neurochemistry of OCD has become extensively elaborated. Magnetic resonance spectroscopy has also revealed a decrease in initially elevated caudate glutamate concentration in children with OCD after successful paroxetine treatment (Rosenberg et al. More recently. 2002). a decrease in initially abnormally large thalamic size has been imaged after successful response to paroxetine treatment (Gilbert et al. suicidality. 1988). 1992a). . have not been shown to induce consistent behavioral or neuroendocrine response abnormalities in patients with OCD. Hollander et al. and of the SSRIs in contrast to the ineffectiveness of noradrenergic antidepressants such as desipramine. Despite some conflicting and nonreplicated data. 2000). 1987) and in CSF 5-hydroxyindoleacetic acid (Swedo et al. associated with frontostriatal dysfunction. extensive research has now clearly implicated the serotonergic system in the pathogenesis of OCD. 2004). Interestingly. in contrast to its mood-worsening effect. and cingulate cortex in those patients who have good treatment responses (Baxter et al. 1992. 2005). There is also some evidence that different OCD symptom dimensions (washing. suggesting defects in connectivity of the cingulate with other regions involved in the OCD circuitry (Szeszko et al. Schwartz et al. suggesting that obsessive-compulsive symptoms are not dependent on short-term presynaptic serotonin availability (Berney et al. In summary. Deficits in executive function planning. A blunted prolactin response to m-CPP challenge has also been found in OCD patients by some investigators (Charney et al. irrespective of state symptomatology (van den Heuvel et al. Dysregulation of this behaviorally inhibitory neurotransmitter possibly contributes to the repetitive obsessions and ritualistic behaviors seen in OCD patients. 2005). all studies taken together suggest that serotonergic dysregulation in OCD is complex and probably involves variations in receptor function according to brain region and receptor subtypes. In children with OCD. 1988. M. Considerable indirect evidence supporting the role of serotonin in OCD stems from the well-documented antiobsessional effects of potent serotonin reuptake inhibitors. Serotonin has been implicated in mediating impulsivity. a partial serotonin agonist. and thalamus (Saxena et al. In another study. 1992b). and hoarding) are mediated by relatively distinct components of the frontostriatothalamic circuits (Mataix-Cols et al. Also. an acute tryptophan-depletion study in SSRI-treated and remitted OCD patients failed to provoke OCD symptom exacerbation. hyperactivity decreases in the caudate. such as tryptophan. OCD patients show greater activation of the anterior cingulate in tasks involving error processing (Fitzgerald et al. as measured via the prepulse inhibition paradigm. such as clomipramine. Of great interest are a number of studies that have now been conducted that demonstrate not only functional but also structural brain changes after a variety of treatments for OCD. 1996). 2002). after improvement of OCD with SSRI or behavioral therapy. and learning. 2005).activation of frontostriatal and temporal regions (van den Heuvel et al. 1992) but not others (Zohar et al. aggression. White matter abnormalities in the anterior cingulate have also been implicated in OCD. there was decreased activation of the prefrontal and cingulate cortex under symptom provocation (Nakao et al. Zohar et al. Furthermore. anxiety. Other serotonin agonists.
2005). and the acquisition and maintenance of conditioned perseverative behaviors. 2002. 1999. It is possible that the serotonergic system may. 1992). Candidate genes that have been implicated to date include the GABA type B receptor 1 gene (Zai et al. be modulating or compensating for other dysfunctional neurotransmitter systems or neuromodulators.8. and the glutamate NMDA receptor gene (Arnold et al. Similarly. Abnormalities in CSF vasopressin (Swedo et al. the 5-HT2A receptor gene (Enoch et al. 1992a). Kim et al. 11%–14% have a phasic course with periods of complete remission. blunted growth hormone response to the dopamine agonist apomorphine (Brambilla et al. and 54%–61% have a constant or progressive course (A. homozygosity for the long allele L(A) of the serotonin transporter gene was found to exert a moderate effect on risk for OCD (odds ratio = 1. CSF glutamate was found to be significantly elevated in medication-naive adult OCD subjects compared with control subjects (Chakrabarty et al. the dopamine D4 receptor gene (Millet et al. Table 12–25). and CSF oxytocin (Leckman et al. The OCD Collaborative Genetics Study (OCGS) is a six-site linkage study with a National Institute of Mental Health–based cell repository awaiting findings (Samuels et al. Genetics Segregation analyses have provided support for a single major gene involvement in OCD (Alsobrook et al. 2000). the 5-HT1D receptor gene (Mundo et al. 2004). the tryptophan hydroxylase gene (Han et al. the dopamine D2/D3 receptor agonist quinpirole has been shown to induce compulsive checking in specific locations of an open field (Dvorkin et al. Although prognosis of OCD has traditionally been considered to be poor. 1994). In summary. depression and anxiety are common complications of OCD. 2006). 1997). and magnetic resonance spectroscopy studies have shown elevated glutamate levels in several regions involved in the hyperactive corticostriato-limbic-thalamic circuitry (Pittenger et al. Nestadt et al. 2003). then. Willour et al. 2004. 2005b). 2000). reports of exacerbation of obsessive-compulsive symptoms with chronic stimulants. 1993). an association between higher pretreatment CSF homovanillic acid and good treatment outcome (Swedo et al. TABLE 12–25. Dopaminergic dysregulation has been variously implicated in OCD (Goodman et al. although other noradrenergic challenge findings have been negative (Lucey et al. more recently. use of dopamine blockers to augment partial treatment response with serotonin reuptake blockers (McDougle et al. 1992a). or the brain-derived neurotrophic factor gene (Zai et al. 1999. No associations were shown with mutations of the 5-HT2B receptor gene (S. 1999) and negative (Billet et al. Of late. 2006). Frisch et al. the glutamate kainate receptor GRIK2 gene (Delorme et al. 2004). Patients are often socially isolated. Meira-Lima et al. With clomipramine treatment. 1997. CSF levels of vasopressin and somatostatin tend to decrease while oxytocin increases (Altemus et al. 1999). 2000). 2005). 2004). 2000). Various neuropeptide abnormalities have started to be elucidated in the past few years. Chabane et al. genes predisposing to OCD have not been consistently identified to date. the dopamine transporter and dopamine D4 receptor genes (Frisch et al. and have high celibacy rates (particularly in males) and a low fertility rate. Lochner et al. 2004b). the 5-HT2C receptor gene (Cavallini et al. The noradrenergic 2 agonist clonidine has been reported to induce a transient improvement in OCD symptoms when administered to patients intravenously (Hollander et al. The disorder usually has a major impact on daily functioning. Hu et al. with some patients spending many waking hours consumed with their obsessions and rituals. Black 1974. Course and Prognosis Studies of the natural course of the illness suggest that 24%–33% of patients have a fluctuating course. 2004). and decreased dopamine D2 receptor binding in the caudate nucleus of OCD patients (Denys et al. 1990) through the association between OCD and Tourette's syndrome. there has been increased interest in possible glutamatergic dysregulation in OCD. Findings regarding the serotonin transporter gene have been both positive (Bengel et al.It also does not appear that serotonergic dysregulation alone can fully explain the neurochemistry of OCD. J. 2001. All these neuropeptides may be implicated in arousal. Compounding the situation. 1997. Course and prognosis of obsessive-compulsive disorder Course Less than 15% phasic with periods of complete remission . 2000a). the catechol-O-methyltransferase (COMT) gene (Karayiorgou et al. 1998. 2005a). Frisch et al. CSF somatostatin (Altemus et al. with new developments in behavioral and pharmacological treatments this prognosis is now considerably improved. In a putative rat model of OCD. in part. 1991b) or orally (Knesevich 1982). memory. 1994) have been implicated in OCD. 2006). and genomewide linkage studies have provided evidence for linkage on chromosome 9p (Hanna et al. 2000). 1990). 2006). marry at an older age.
2006).g.. Differential Diagnosis The differential diagnosis of OCD is summarized in Table 12–26. Of those. and obsessions in 12% of cases may become delusions. the OCD symptoms must not be just secondary to another disorder (e. are time consuming. Thus. or interfere with social or occupational functioning. having both obsessions and compulsions. Findings were more optimistic than expected. and DSM-IV-TR allows the diagnosis of both disorders. the diagnosis rests purely on the psychiatric examination and history. resisted. In terms of acute treatment. decline.g. or severe obsessive-compulsive personality disorder. TABLE 12–26. but occasionally it can be more difficult to distinguish OCD from depression. Differential diagnosis of obsessive-compulsive disorder Eating disorder with obsessions surrounding food and weight Body dysmorphic disorder with obsessions about body appearance other than weight Hypochondriasis with obsessions related to feared illnesses Panic disorder or generalized anxiety (if obsessional anxiety is severe) Obsessive ruminations of depressions (typically mood congruent) Severe obsessive-compulsive personality disorder Paranoid psychosis (e. contamination) and a delusion (e.g. 1999) and CBT (Rufer et al. Yet longitudinal studies show that OCD patients are not at increased risk of developing schizophrenia.g. DSM-IV-TR defines OCD as the presence of either obsessions or compulsions that cause marked distress. The diagnosis is usually clear-cut. with improvement noted in 83% of individuals. psychosis..One-fourth to one-third have fluctuating course Half (50%) have constant or progressive illness Outcome 80% improve over 40 years Predictors of worse prognosis Early age at onset Longer duration of illness Presence of both obsessions and compulsions Poorer baseline social functioning Magical thinking A major follow-up study was reported that examined the course of patients over a 40-year period in Sweden. delusions of poisoning rather than contamination fears) Social phobia (if avoiding social situations because they exacerbate illness) Schizophrenia In some cases the course of OCD may more closely resemble that of schizophrenia. An obsession is typically ego-dystonic. Both disorders may exist independently. OCD patients may. phobias. predictors of worse outcome were earlier onset. and having magical symptoms. A delusion is not resisted and is believed to be external. Although all other Axis I disorders are allowed to be comorbidly present. thoughts about food in the presence of an eating disorder or guilty thoughts in the presence of major depression). Sometimes it is difficult to distinguish between an obsession (e. about half were fully or almost fully recovered. from approximately the 1950s to the 1990s (Skoog and Skoog 1999). the presence of hoarding obsessions and compulsions is associated with poorer response to both medication treatment (Mataix-Cols et al. with chronic debilitation. the presence of significant obsessive-compulsive symptoms in a .. a more chronic course at baseline. Diagnosis Although a variety of biological and neuropsychiatric markers have been associated with OCD. Importantly. however lack insight.. poorer social functioning at baseline. being poisoned). and profound impairment in social and occupational functioning. and recognized as having an internal origin.
although disgust is prominent in OCD patients and not in phobic patients. Atypical antipsychotics: several studies show additional benefit Pindolol: effective in controlled trial Clonazepam: effective in controlled trial. What was previously thought to be a rare. appear to have increased comorbidity with simple and social phobia and panic disorder (Rasmussen and Tsuang 1986). and both are said to respond to similar behavioral interventions. similar efficacy Clomipramine: efficacy shown in multiple controlled trials. These "secondary" obsessions often involve aggressive themes. possibly phenelzine in symmetry obsessions Topiramate Riluzole Other medications . sertraline: efficacy shown in large controlled trials Paroxetine. depressive ruminations. or premorbid obsessional features prior to depression are particularly likely to develop obsessions. psychodynamically laden. In addition. Fluoxetine. moderate to high dosages. 1985). Patients with OCD who experience high levels of anxiety may describe panic-like episodes. presence of other target symptoms. there is no precipitation of anxiety attacks with lactate infusions in OCD patients (Gorman et al. Pharmacological treatment of obsessive-compulsive disorder Serotonin reuptake inhibitors General indications: First-line treatments. three negative Lithium: ineffective in controlled trial Trazodone: ineffective in controlled trial Monoamine oxidase inhibitors: hardly any evidence. Both have excessive fear. comorbid very high anxiety Buspirone: one positive trial. OCD patients can never entirely avoid the obsession. however. are often focused on a past incident rather than a current or future event and are rarely resisted. both show intense subjective and autonomic responses to focal stimuli. mirtazapine: less studied Augmentation strategies General indications: Partial response to serotonin reuptake inhibitors. clomipramine plus desmethylclomipramine levels must be closely followed for toxicity Venlafaxine. can be used in low dosages in combination with SSRIs in patients with more refractory illness. Depression Patients with OCD frequently have complicating depression. typically not used until at least two SSRIs have failed secondary to side-effect profile. Also. Patients with psychotic depression. however. but the distinction between primary and secondary obsessions rests on the order of occurrence. in contrast to pure obsessions. whereas phobic patients have more focal. citalopram: less studied. Treatment Pharmacotherapy Advances in recent decades in the pharmacotherapy of OCD have been quite dramatic and have generated a great deal of excitement for successful treatment of this disorder. TABLE 12–27." Both have avoidant behavior. and difficult-to-treat illness now appears to have a strong biological component and to respond well to potent serotonin reuptake blockers.schizophrenic patient warrants separate treatment. Phobic disorders A close connection exists between OCD and phobic and anxiety disorders. but these are secondary to obsessions and do not arise spontaneously. The pharmacological approach to treatment of OCD is summarized in Table 12–27. Unlike with panic disorder patients. OCD does. agitated depression. external stimuli that they can successfully avoid. and these patients may be difficult to distinguish from depressed patients who have complicating obsessive symptoms. may have small superiority over SSRIs. OCD patients who are compulsive cleaners appear very similar to phobic individuals and are often mislabeled "germ phobics. fluvoxamine.
in dosages of 20. 2003c. 1994). improved significantly more than placebo (Hollander et al. 2004). in contrast to behavioral treatments. Controlled studies have also demonstrated that clomipramine is effective in treating OCD when other antidepressants. the most common side effects were agitation. The seizure risk is comparable with that of TCAs and is acceptable for dosages up to 250 mg/day in the absence of prior neurological history. 1993. and the dosage then should be gradually increased by 25 mg every 4 days or 50 mg every week until a maximum dosage of 250 mg is reached. 1999). The efficacy of fluvoxamine for OCD has also been demonstrated for children and adolescents (Apter et al. beyond the standard recommended OCD treatment dosage. 1990). Patients should typically be started on 25 mg of clomipramine at nighttime. This finding strongly suggests that improvement in OCD symptoms is mediated through the blockade of serotonin reuptake. which are less useful for patients who predominantly experience obsessions. Numerous controlled trials since the early 1990s have documented the efficacy of all SSRIs for OCD. A series of well-controlled. but not the 20 mg/day group. desipramine. and the MAOI clorgyline. was superior to placebo. asthenia and insomnia were the most common side effects (Riddle et al. double-blind studies have undisputedly documented the efficacy of clomipramine in reducing OCD symptoms. without significant differences between the three dosages. One issue with SSRI treatment is how high to push the dosage. controlled trial demonstrated efficacy for paroxetine in children and adolescents with OCD (Geller et al. a potent serotonin reuptake inhibitor with weak norepinephrine reuptake blockade. nausea. and ejaculatory failure in men. Improvement with clomipramine is relatively slow. Some of the more common side effects reported by patients are dry mouth. sertraline has been found to be effective in treating childhood OCD for those ages 6–17 years in a large multicenter trial using dosages up to 200 mg/day. Jenike et al. although the highest response rate of 65% occurred in the 60 mg/day group (Montgomery et al. with greater efficacy at higher dosages (Montgomery et al. 2002b). On an average dosage of 200–250 mg/day of clomipramine. fluoxetine has been shown to be safe and efficacious in treating OCD in children (Liebowitz et al. A multicenter randomized. A multicenter paroxetine trial found that the 40 mg/day and 60 mg/day groups. 1995a. and about 60% of all patients were clinically much or very much improved (Clomipramine Collaborative Study Group 1991). Similarly. such as amitriptyline. the average reduction in OCD symptoms was about 40%. improvement started to appear around the third week. The very low placebo response rate of 2% documents that OCD is a chronic disorder with infrequent spontaneous remissions. nortriptyline. Similarly. Clomipramine is equally effective for OCD patients with pure obsessions and those with rituals. Fluvoxamine has also been found to have a significant antiobsessional effect in several controlled studies (Hollander et al. in an attempt to get a response. generally at dosages of 20–60 mg/day. Kronig et al. Tollefson et al. Some patients are unable to tolerate the highest dosage and may be stabilized at 150 mg or 200 mg. and 42% of children were significantly improved after 12 weeks. 2001). nausea. and the medication was well tolerated in the pediatric group. Serotonin reuptake inhibitors The most extensively studied medication for the treatment of OCD is clomipramine. 1994). The required daily dosage is titrated up to a maximum of 300 mg. with maximal response occurring after 5–12 weeks of treatment. and 60 mg/day. 2003a). A multicenter trial reported that citalopram treatment. Response began to appear as early as the third week of treatment and was firmly apparent by the eighth week (Kronig et al.Intravenous clomipramine: efficacy in controlled trial of oral clomipramine–refractory patients Plasma exchange and intravenous immunoglobulin: effective in children with streptococcus-related obsessive-compulsive disorder Note. tremor. defined as a 25% symptomatic improvement. The largest of these was a multicenter trial comparing clomipramine with placebo in more than 500 patients with OCD. sedation. Paroxetine and citalopram are also efficacious in treating OCD. The medication was overall well tolerated. 1998b). have no therapeutic effect. Fluoxetine has been shown to be superior to placebo in treating OCD at dosages of 20–60 mg/day. 40. In this trial. 1999). Sertraline is another serotonin reuptake blocker whose efficacy for OCD has been established at daily dosages ranging from 50 to 200 mg (Greist et al. SSRIs = selective serotonin reuptake inhibitors. and tremor (March et al. One study examined this question in subjects who did not respond to 16 weeks of treatment with sertraline 200 mg/day and found that increasing to a mean dosage of 350 mg/day did result . Again. insomnia. The efficacy of fluvoxamine in treating pediatric OCD for those ages 8–17 years was further confirmed in a multicenter trial using dosages of 50–200 mg/day. 2001). 42% of subjects were responders.
1991). fluoxetine-treated (Grady et al. atypical antipsychotics. because of clomipramine's strong anticholinergic side effects. Still. 1997). augmentation with clomipramine or switching to clomipramine alone should be undertaken. As these augmentation strategies are more rigorously tested. 2004). as were a trazodone controlled trial (Pigott et al. One study reported comparable effectiveness for paroxetine and venlafaxine and also found that some nonresponders benefited from switching to the alternate medication (Denys et al. inositol. satisfactory systematic comparisons of the various serotonin reuptake blockers. 1995b. 2003). Three meta-analytic studies have addressed these questions by retrospective analyses of treatment data from past trials. they often do not look as promising as was initially thought. 1992). a 12-week placebo-controlled trial of St. because in clinical practice actual or expected tolerability of different medications often takes precedence over small differences in efficacy. given the relatively limited treatment options. The clinical applicability of this finding may. A controlled study of trazodone alone in OCD again showed no benefit compared with placebo (Pigott et al. 1997). As a helpful rule of thumb. showed preliminary evidence of efficacy that awaits larger replication (Koran et al. for example. In the following discussion we summarize the findings in favor of or against the various augmenting agents for OCD. an extremely large prospective study would have to be undertaken in order to demonstrate small but significant differences between the various medications. a meta-analysis of pediatric studies found superiority for clomipramine and comparable efficacy among SSRIs (Geller et al. for 6 weeks. The SSRIs are better tolerated than clomipramine by most patients. only 3 patients reported clinically significant improvement. 1992b). major depression: a considerable number of patients show a negligible or partial response to the first-line medications. beginning with the most compelling ones. these strategies are worth undertaking sequentially. 1992a). (1990) first reported that about 50% of OCD patients improved noticeably when pimozide was added to fluvoxamine. The SNRI venlafaxine also appears effective in treating OCD. 2005). Another study reported that the response to citalopram was accelerated with mirtazapine augmentation (Pallanti et al. The most commonly used augmenting agents in OCD are buspirone. Piccinelli et al. A controlled trial of lithium augmentation was also negative (McDougle et al.in some symptom improvement but no change in responder status (Ninan et al. reported that about two-thirds responded to venlafaxine at a mean dosage of about 225 mg/day (Hollander et al. 1991). or fluvoxamine-treated (McDougle et al. J. Similarly. balancing benefits and side effects. 1991a). McDougle et al. and glutamatergic agents. possibly with the exception of some benefit for symmetry obsessions from phenelzine (Jenike et al. A placebocontrolled augmentation trial with eicosapentaenoic acid was not effective for OCD (Fux et al. 1995). Open-trial monotherapy followed by double-blind discontinuation of mirtazapine. Although an initial small study reported similar efficacy for clomipramine alone versus buspirone alone in treating OCD (Pato et al. 10 OCD patients who had failed to respond to serotonin reuptake inhibitor trials were treated with inositol augmentation. Thus. three other studies failed to show a significant benefit to buspirone augmentation in clomipraminetreated (Pigott et al. higher dosages of 30–60 mg/day should be targeted. Despite its putative serotonergic properties. 1992). If tried. 2006). 1995. 1993a) and appear to . 2004). 2003b). and clonazepam may also be helpful with the very high anxiety levels frequently associated with OCD. Stein et al. be limited. 18 mg/day. in dosages of 30–60 mg/day. 2005a). Although clomipramine appears to have an edge over SSRIs in treating OCD. the reverse is also true. clonazepam. have not been conducted. 1992b) and a desipramine controlled augmentation trial (Barr et al. D. Antipsychotics are the main medication class used to augment partial response to serotonin reuptake blockers in OCD. In a small open trial. leaving inositol as an option of unclear efficacy (Seedat and Stein 1999). 2004c). A controlled crossover study showed clonazepam to be effective in 40% of OCD subjects who failed to respond to clomipramine trials (Hewlett et al. however. about two-thirds of whom had not responded to SSRIs. If patients do not have a good response to an adequate trial of at least two SSRIs. Given the similar efficacy of these five medications for OCD. it is useful to remember that approximately 40%–60% of OCD patients improve by about 30%–60% with a first-line drug. comorbid tic disorders or schizotypal personality predicted a good response. and these have supported a small but significant superiority for clomipramine over the SSRIs (Greist et al. various combination and augmentation strategies are often needed to attain a satisfactory response. A controlled study of lithium augmentation of clomipramine did not detect any benefit (Pigott et al. John's wort monotherapy yielded negative results (Kobak et al. 1993). and have therefore become the well-established first line of treatment for OCD. Medication combination and augmentation It is important to keep in mind that the medication response in OCD is not as dramatic as in. OCD patients with comorbid tic disorders may actually be less responsive to SSRI monotherapy (McDougle et al. An open trial of venlafaxine in 39 patients. Evidence in support of MAOIs is very weak despite a positive report (Vallejo et al. 1993b) patients.
3 mg/day. to their ongoing regimen (Coric et al. A 6-week controlled trial of risperidone in patients with serotonin reuptake inhibitor–refractory illness found significant improvement in half of the patients (McDougle et al. with 15% of patients discontinuing treatment due to side effects (Bystritsky et al. In more recent years. 1994). In one small randomized trial in patients with refractory OCD. 2004a). D. atypical antipsychotics have received increasing attention as a major augmentation strategy for OCD. several factors appear to be predictive of a poorer prognosis. 1999). and an episodic course of illness. age at onset. with 40% of patients rated as responders (Hollander et al. A small open monotherapy trial of aripiprazole.respond well to haloperidol augmentation (McDougle et al. More recently. and such a strategy is now supported by controlled trials. 2003a). Beyond antipsychotics. Intravenous clomipramine has met with some success in OCD refractory to oral clomipramine (Fallon et al. Denys et al. . 2005). regarding atypical antipsychotic augmentation is that these agents have modest efficacy but are worth trying in patients with treatment-resistant illness. pindolol at 2. The combination of clomipramine with an SSRI is also a commonly used strategy for treating refractory patients and is generally well tolerated. A review of 274 OCD patients found no differences between responsive and nonresponsive subjects in age. Carey et al. citalopram combined with clomipramine led to significantly greater improvement than citalopram alone (Pallanti et al. 2005). Other somatic treatment options Although there are no definitive predictors of medication treatment response. 2002. including earlier onset. 1996). In a single case report. 2006). higher frequency of compulsions. one placebo-controlled augmentation trial found no benefit (Shapira et al. 2006). a chronic course. Another placebo-controlled risperidone augmentation trial using low-dosage risperidone in 45 patients also reported modest efficacy over placebo (Erzegovesi et al. 2005). 2004). A small brief double-blind augmentation trial showed similar improvement in obsessions with risperidone and haloperidol compared with placebo (Li et al. 2005. other somatic treatment options can be considered. 2006). Responders had a higher incidence of family history of tics. 2006). although lower dosages of clomipramine should be used with monitoring of blood levels to avoid toxicity because clomipramine levels can become markedly elevated. washing rituals. When oral medications fail to be successful enough in patients with highly refractory illness. or symptom subtypes. A case report of successful topiramate augmentation of paroxetine treatment has been reported (Hollander and Dell'Osso 2006). another study has supported the effectiveness of pulse-loaded intravenous clomipramine in treatment-resistant OCD (Koran et al. Another placebo-controlled risperidone augmentation trial similarly showed better results than placebo. Similarly. 2005). however. 50 mg bid. 2005). with some improvement in three of seven participants (Connor et al. was added to an SSRI in 20 patients with refractory OCD. although reports are contradictory. whereas two other placebo-controlled augmentation trials reported that approximately 50%–60% of patients responded to the augmentation (Atmaca et al. and the presence of avoidant. Four pediatric patients with refractory OCD have also been described as responsive to risperidone augmentation (Fitzgerald et al. in dosages of 10–30 mg/day. and comorbid eating disorder (Hollander et al. 2000). an open series reported that 11 of 16 patients responded to topiramate augmentation at a mean dosage of 250 mg/day (Van Ameringen et al. In another 8-week open trial in which risperidone. prior hospitalizations. Clozapine has been reported to worsen OCD.5 mg tid was significantly superior in reducing OCD symptoms (Dannon et al. Olanzapine has been reported beneficial in four open-label augmentation trials. longer duration of illness. Nonresponders had more severe symptomatology. The general conclusion. An open trial of bupropion monotherapy at 300 mg/day reported no benefit (Vulink et al. Fourteen patients with treatment-refractory OCD who had not responded to three SSRI trials received paroxetine augmentation with pindolol or placebo for 6 weeks. all subjects were described as showing some improvement (Pfanner et al. 1998). borderline. gender. and this response was not associated with the presence of tics or schizotypy. and schizotypal as well as multiple personality disorders. regardless of comorbid tics or schizotypy. augmentation of fluvoxamine with the antiglutamatergic amino acid N-acetylcysteine was reported effective (Lafleur et al. then. Preliminary data on the antiglutamatergic agent riluzole appear promising (Pittenger et al. In an open trial. 2000). reported modest results. Two placebo-controlled quetiapine augmentation studies yielded negative results (P. with good results for horrific mental imagery rather than comorbid tic disorders (Saxena et al. whereas another reported significant improvement compared with placebo at a mean dosage of about 10 mg/day. about half of 13 patients with treatment-resistant OCD responded to the addition of riluzole. poorer insight into their OCD. 2000). Risperidone has been successfully used for augmentation in open trials. compared with placebo. sudden onset of OCD. 2004). duration of illness. 1999). Fineberg et al. 2001). 2005). other medications have been used for augmentation in those with treatment-resistant OCD.
is deep-brain stimulation (Rauch et al.g. Recently. In four highly refractory OCD patients. This response rate was confirmed in a 2-year prospective cingulotomy study (Baer et al. 2002). an open pilot trial of low-frequency TMS delivered to the supplementary motor area reported benefits (Mantovani et al.. this is widely supported in clinical treatment and has been validated by a 1-year double-blind sertraline maintenance study at dosages of 50–200 mg/day (Greist et al. 90% had substantial worsening within 7 weeks (Pato et al. 1997). after 1-year follow-up patients who were randomly assigned to continue fluoxetine rather than be switched to placebo had much lower rates of relapse (Romano et al. Sweden. and he or she may require assistance from the therapist (in a home visit) or from family members to achieve exposure at home. 2003). 2001).Plasma exchange and intravenous immunoglobulin have been found to be effective in lessening symptom severity in children with streptococcal infection–triggered OCD (Perlmutter et al. with a substantial minority of 20% remaining refractory to multiple treatment regimens (Leonard et al. although its efficacy is very debatable (Maletzky et al. Initial work may involve delaying performance of the ritual. neurosurgery can be considered. cingulotomy resulted in notable improvement. Similarly. and many patients may require indefinite drug treatment to stay well. repetitive transcranial magnetic stimulation (TMS) has been used to treat OCD. At follow-up after several years. documented failed treatments. 2000). 2006). 2001). Electroconvulsive therapy may be considered in highly refractory cases. Long-term continuation of medication treatment generally maintains a good treatment response. have been thoroughly reviewed elsewhere (Mindus and Jenike 1992). In extreme cases of severely impaired patients with refractory OCD. Response prevention involves having patients face feared stimuli (e. the patient is assigned homework exercises that must be adhered to. benefits. Conversely. which if successful may gradually replace neurosurgery for refractory OCD. 1995c). Higher cerebral metabolic activity in the posterior cingulate presurgery has been identified as a predictor of better response to cingulotomy (Rauch et al. patients who maintained their response in the earlier study were given a second year of open maintenance treatment with sertraline at the same dosages. Exposure techniques range from systematic desensitization with brief imaginal exposure to flooding. Another review of 44 patients who underwent single or multiple cingulotomies for refractory OCD reported that almost 3 years later 32% were classified as treatment responders and another 14% as partial responders. during which they maintained or even slightly improved their gains (Rasmussen et al. 2001).. chemicals) without excessive hand washing or tolerate doubt (e. indications. Maintenance treatment OCD tends to be a chronic illness. most patients remained symptomatic and required continued pharmacotherapy. dirt. contraindications. In a long-term blinded electrical capsular stimulation study. and there were few adverse effects (Dougherty et al. this treatment resulted in dramatic improvement in one patient and moderate improvement in another (Abelson et al. in which prolonged exposure to the real-life ritual-evoking stimuli causes profound discomfort. In a subsequent study. Similarly. 1999). in a double-blind discontinuation study of OCD patients who had done well on clomipramine for about 1 year. 2001). 1993). 1988). 1994). but plasma exchange treatment was found not to help children whose OCD did not have streptococcus-related exacerbations (Nicolson et al. including selection. and workup. 1991) estimated that in at least 25%–30% of patients. "Is the door really locked?") without excessive checking. but ultimately the patient works to fully resist the . Exposure techniques aim to ultimately decrease the discomfort associated with the eliciting stimuli through habituation. 1999). A review of 29 patients who underwent capsulotomy between 1976 and 1989 at the Karolinska Hospital in Stockholm. 2005). although the absence of a sham control group makes interpretation of efficacy difficult (Sachdev et al. 1995). A new development. Another study compared right versus left prefrontal TMS in patients with treatment-refractory OCD and found a similar responder rate of 25% for both treatments. In a thorough retrospective analysis. Guidelines for the use of neurosurgical techniques in the treatment of severe refractory OCD. 2006). A sham-controlled low-frequency TMS treatment of the right prefrontal cortex did not report significant benefit (Alonso et al. risks. Cognitive-Behavioral Therapy Behavioral treatments of OCD (Table 12–28) can be highly effective and involve two main components: 1) exposure procedures that aim to decrease the anxiety associated with obsessions and 2) response prevention techniques that aim to decrease the frequency of rituals or obsessive thoughts. three of four patients with refractory illness responded to the treatment (Nuttin et al. Jenike et al. In exposure therapy.g. found that positive clinical outcome was associated with lesioning to the middle of the right anterior limb of the internal capsule (Lippitz et al.
1998). possibly as a way to reduce the anxiety or anger that patients may direct at their family members. or . Of interest. 2004). suggesting that nonpharmacological options are a reasonable first-line option in the younger population in an initial attempt to avoid medication (de Haan et al. The study compared ERP alone. up to 75% of ritualizing patients willing and able to undergo the arduous treatment were reported to show significant improvement (Marks et al. 70%. ERP and combination treatment had a greater edge over clomipramine alone for remission compared with response. thought–action fusion. and a placebo pill in 122 adults with OCD and found that both ERP and combination treatment were superior to medication alone (response rates for all groups were 62%. Similarly. McKay 1997). expectations about anxiety and its consequences. 1998). however. Predictors of poorer outcome for behavioral treatment of OCD include initial depression. 2005b. 42%. Combination Pharmacotherapy and Psychotherapy The relative efficacy of pharmacotherapy versus psychotherapy for OCD is an important question in deciding what first-line treatment to undertake. Cognitive therapy has also been more recently advocated and is efficacious in the treatment of OCD. 1998). their combination. initial OCD severity. found that clomipramine. although new behavioral techniques for obsessions may also be promising. clomipramine alone. Whittal et al. A recent 12-week multicenter study. but the combined treatment was superior in decreasing anxiety. because family dysfunction is very prevalent and the majority of parents or spouses accommodate to or are involved in the patients' rituals. just as with medication. exposure and response prevention (ERP)—yield the greatest improvement. suggested that behavior therapy may have an edge over medication therapy (Foa et al. TABLE 12–28. and ERP all had comparable results (Kobak et al. A maintenance program can be highly effective in helping patients maintain their benefits from CBT over several years of follow-up (Marks 1997. after controlling for a number of confounding variables. van Oppen et al. Cognitive and behavioral approaches to treating obsessive-compulsive disorder Graded exposure (imaginal and/or in vivo) Flooding Response prevention Cognitive restructuring It is generally agreed upon that combined behavioral techniques—that is. defined as those patients who showed at least 30% improvement with treatment. patients who were treated with ERP relapsed significantly less than those treated with medication alone (Simpson et al. 1994). a study comparing behavioral treatment versus clomipramine found that both were similarly helpful. 1995. excessive responsibility. estimation of catastrophe. ERP has also been used successfully to treat children and adolescents with OCD. There is also evidence that in the short term (12 weeks) after treatment discontinuation. 1975). Simpson et al. The psychoeducation and support of family members can be pivotal to the success of the behavioral therapy. respectively). 2005). A meta-analysis of cognitive versus behavioral treatment trials for OCD reported that behavioral treatment was somewhat more effective in clinically significant improvement (about 50%–60% of participants). ERP alone. 2001. Foa et al. Similarly in children. whereas for full remission the two approaches had a similar effectiveness of about 25% (Fisher and Wells 2005). and 90% for ERP. 2005). The proportion of clinical responders. this study found that the majority of OCD patients successfully treated with behavior therapy had relapsed at follow-up. a sizable number of patients did not achieve remission by the end of treatment regardless of the type of treatment. with at least 50% improvement in the vast majority of participants (Franklin et al. (1984) systematically compared in vivo exposure. Several studies have directly compared cognitive versus behavioral therapy for OCD in randomized trials and have reported similar efficacy (Cottraux et al. long-term behavioral maintenance treatment may be necessary. However a longer-term (5-year) follow-up study has reported that long-term outcome did not differ among patients initially treated with cognitive therapy alone. a large pediatric trial found that combination treatment was superior both to CBT and to sertraline alone and therefore recommended that this age group start treatment with CBT or combined treatment (Pediatric OCD Treatment Study Team 2004).compulsions. and overall impairment. and 8%. centering on cognitive reformulation of themes related to the perception of danger. suggesting that. Using the combined techniques of in vivo ERP. was 33% for response prevention. longer duration. It is also generally reported that patients who primarily experience obsessions and have few rituals are the least responsive to behavioral treatment. and the two treatments combined (ERP). and illogical inferences. A meta-analytic comparison study of OCD treatments. response prevention. SSRIs. All groups improved. rituals. 55% for exposure. and lower motivation for treatment (Keijsers et al.
patients who did respond to initial 3-month medication treatment were randomly assigned to continue medication alone or to have behavior therapy added for the next 6 months. Note: In young children. However. trauma-specific reenactment may occur. DSM-IV-TR diagnostic criteria for posttraumatic stress disorder A. procrastination. In a study testing this commonly used paradigm. and a focus on the present has been reported to be helpful (Salzman 1985). patients initially treated with medication were more likely to be taking medication at follow-up (van Oppen et al. combination therapy. 1999). these patients may require a great deal of reassurance during the early phase of treatment. or a threat to the physical integrity of self or others (2) the person's response involved intense fear. OCD patients need supportive treatment even while pharmacotherapy or behavior therapy is being applied. (2) recurrent distressing dreams of the event. Note: In children. helplessness. Similarly. TABLE 12–29. is to start out with medication. exploratory psychotherapies. So. witnessed. Despite the similar efficacy of pharmacotherapy and CBT for OCD. Other Psychotherapy Patients with OCD frequently present with symptoms that appear laden with unconscious symbolism and dynamic meaning. especially by psychiatrists. Note: In children. the latter group showed significantly greater benefits (Tenneij et al. Note: In young children. it appeared quite effective. in sum. B. poor insight and low CBT effort predicted lesser gains (Tolin et al. In contrast to its lack of efficacy in treating chronic OCD. and dissociative flashback episodes. there may be frightening dreams without recognizable content. Patients who remained symptomatic with a 12-week course of an SSRI were entered into a course of exposure and ritual prevention and subsequently demonstrated a 50% decrease in their OCD symptoms (Simpson et al. Because of their tendency toward excessive doubt. or horror. 2004). In brief. about 50% showed clinically significant improvement. given the common failure of either treatment to achieve a strong enough response or remission. POSTTRAUMATIC STRESS DISORDER Definition PTSD was first introduced in DSM-III. dynamic psychotherapy may be helpful for acute and limited symptoms in patients who are otherwise psychologically minded and motivated to explore their conflicts and for obsessive character traits of perfectionism. doubting. A common approach used in clinical practice. illusions. (3) acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience. The person has been exposed to a traumatic event in which both of the following were present: (1) the person experienced. More active supportive therapy that encourages risk taking helps OCD patients live with their anxiety. The traumatic event is persistently reexperienced in one (or more) of the following ways: (1) recurrent and intrusive distressing recollections of the event. or was confronted with an event or events that involved actual or threatened death or serious injury. and then possibly attempt some degree of medication taper once CBT has been mastered and effective. regardless of degree of initial response. medication and CBT are approximately equal first-line treatment choices. spurred in part by the increasing recognition of posttraumatic conditions in veterans of the Vietnam War. and indecisiveness (Salzman 1985). this may be expressed instead by disorganized or agitated behavior. In another study. repetitive play may occur in which themes or aspects of the trauma are expressed. nondirective. the conclusion is that patients who are initially treated with medication. in a wait-list controlled trial of CBT in OCD patients who had failed to adequately respond to multiple serotonin reuptake inhibitor medications. is commonly used and recommended in the treatment of OCD. thoughts. either concurrent or sequential. have a good likelihood of some further improvement with the introduction of CBT. The current DSM-IV-TR diagnostic criteria for PTSD are presented in Table 12–29. 2005). hallucinations. with an overall remission rate of about 50%. (4) intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event (5) physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event . and most maintained it at 6-month follow-up. attain a degree of clinical improvement that will allow better utilization of CBT. including images. or perceptions. including those that occur on awakening or when intoxicated). OCD has generally proven refractory to psychoanalytically oriented as well as to loosely structured.psychotherapy combined with medication. 2005).
does not expect to have a career. dissociative symptoms figure prominently in the definition of acute stress disorder. for example. C. and the sense of life's meaning (Herman et al. emotional numbing. increasing attention has been drawn to an enduring constellation of traits that frequently develop in individuals subjected to chronic trauma as children or adults. F. Persistent symptoms of increased arousal (not present before the trauma). as opposed to only 11% of those without acute stress. It has now been well established by a number of studies. occupational.g. and conversion symptoms. which can include admixtures of posttraumatic stress. In addition. and a steady 80% were diagnosed with PTSD 2 years after the accident (Harvey and Bryant 2000).C. Similar personality changes are recognized by the ICD-10 and classified as "enduring personality change after catastrophic experience. but it is time limited. In acknowledgment of the spectrum of disorders stemming from severe stress. as indicated by three (or more) of the following: (1) efforts to avoid thoughts. classifies all such disorders as stress related. Beyond the symptoms of PTSD per se.. and the classification approach to trauma-related conditions is a subject of ongoing debate. Investigators such as Herman and van der Kolk (1987) had originally suggested that a discrete entity of complicated posttraumatic syndromes be recognized. and hyperarousal have been maintained. so are depression and dissociation. feelings.. and D) is more than 1 month. 1989. 82% of those who met acute stress disorder criteria were diagnosed with PTSD 6 months later (Bryant and Harvey 1998). acute stress disorder. New duration criteria were also established. Duration of the disturbance (symptoms in criteria B. or people that arouse recollections of the trauma (3) inability to recall an important aspect of the trauma (4) markedly diminished interest or participation in significant activities (5) feeling of detachment or estrangement from others (6) restricted range of affect (e. DSM-IV added acute stress disorder to the anxiety disorders. Acute stress disorder is similar to PTSD in the precipitating traumatic event and in symptomatology. pathological bereavement. up to 1 month after the event. including prospective ones. In a study of people who had mild traumatic brain injury in motor vehicle accidents. and adjustment disorders. The DSM-III-R descriptor of the traumatic event as one "outside the range of usual human experience" was considered rather vague and unreliable and was eliminated. or conversations associated with the trauma (2) efforts to avoid activities. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma).g. marriage. the disorder is classified with the anxiety disorders. dissociative. The necessity of a precipitating stressor or trauma in diagnosing the disorder differs from other anxiety disorders and is more reminiscent of conditions such as brief reactive psychosis. interpersonal relationships. van der Kolk and Saporta 1991). ICD-10 (World Health Organization 1992)." Increasing attention has been drawn in recent years to the concept of "trauma-spectrum" disorders. as indicated by two (or more) of the following: (1) difficulty falling or staying asleep (2) irritability or outbursts of anger (3) difficulty concentrating (4) hypervigilance (5) exaggerated startle response E. Not all investigators agree that PTSD belongs with the anxiety disorders. and the major criteria of an extreme precipitating stressor. whereas they are not addressed in the PTSD description. . The disturbance causes clinically significant distress or impairment in social. somatoform. children. otherwise designated as "DESNOS" (disorders of extreme stress not otherwise specified). Although anxiety is a prominent symptom. Specify if: Acute: if duration of symptoms is less than 3 months Chronic: if duration of symptoms is 3 months or more Specify if: With delayed onset: if onset of symptoms is at least 6 months after the stressor Beginning with DSM-III-R. subdividing the disorder into acute or chronic. intrusive recollections. places. characterized by lasting changes in identity. or other important areas of functioning. unable to have loving feelings) (7) sense of a foreshortened future (e. or a normal life span) D. it may well be that the two should not be defined as discrete disorders. that acute stress disorder is a highly reliable predictor of developing PTSD down the road.
it is clear that PTSD in women increases the risk for new onset of both depression and alcohol use disorder (Breslau et al. and rage. The gender difference in PTSD prevalence.7% of women and 1. For example. Rape or mugging victims sometimes become afraid to venture forth alone for variable periods of time. 1991). and impulsive behavior. 2006). loss of interest in usual activities. In the Breslau et al. hostile behavior. when stressors become extreme. anxiety. of about 10. seemingly women in particular. guilt about not having prevented the traumatic experience. whereas partial PTSD was found in an additional 3. Epidemiology Although there are marked individual differences in how people react to stress. shame. On the other hand. reexperiencing of the trauma. The trauma is reexperienced in recurrent painful and intrusive recollections. explosive. Regardless of causality. a prospective study of a large sample of trauma survivors found depression and PTSD to be independent sequelae of trauma (Shalev et al. lasting from minutes to days. tenderness. with feelings of being detached from other people. 1980). or sexual interest. has been consistent across a number of studies. The prevalence was higher in women (11. which is usually less severe and within the range of common life experience. It appears that women are more likely to develop PTSD than men with comparable exposure to traumatic events. daydreams.Clinical Description A soldier participates in the torture and murder of civilians. Symptoms of PTSD. Epidemiological analyses suggest that in trauma victims the vulnerabilities for PTSD and depression are not separate. the lifetime prevalence of PTSD was found to be 9. are quite common in the general population. The most common stressors were combat exposure in men and sexual assault in women (Kessler et al.2% of men. Psychic numbing or emotional anesthesia is manifest by diminished responsiveness to the external world. this relationship between the severity of the stressor and the type of subsequent symptomatology is not always predictable.3%) than in men (6%). agoraphobia. 1997). but rather the risk for depression is highly elevated in just those trauma victims who manifest PTSD (Breslau et al. found that about one-fourth of those with PTSD had an alcohol use disorder whereas about one-third of those with opioid use disorder had PTSD (Mills et al. A high rate of comorbid disorders is found in PTSD. In a Canadian community survey. Individuals with PTSD may be more likely to manifest borderline or self-defeating personality disorder. such as in concentration camp situations or in extended combat. In the National Comorbidity Survey. unreal state with hazy memory and a distorted sense of time. Other symptoms may include guilt about having survived. Etiology The severity of the stressor in PTSD differs in magnitude from that found in adjustment disorder. Other accompanying or complicating symptoms associated with PTSD may include substance abuse. A woman is raped and severely beaten by an unknown assailant. difficulty concentrating. the rate of morbidity rapidly increases.2% (Breslau et al. an exaggerated startle response. may be important to identify because they experience clinically meaningful distress and functional impairment (M. Dissociative states may occur. the lifetime prevalence of PTSD was similarly found to be 7. and the nature of the relationship between the two conditions is controversial. Stein et al. Situations reminiscent of the original trauma may be systematically avoided. Such individuals. especially if exposure is before age 15 (Breslau et al. 1995).000 participants. and depression. The comorbidity of PTSD with depression is a very consistent one. panic attacks. 1998b). The Australian National Survey of Mental Health and Well-Being. and it appears that the actual PTSD diagnosis rather than the trauma history accounts for this association (Shea et al. it has generally been underestimated that in . However. panic. There may be prolonged episodes of intense affect. In a large randomized community survey of young adults. occupational impairment. Symptoms of excessive autonomic arousal may include hyperactivity and irritability. In effect. full PTSD was found in 2. in which there is a dreamlike. and increased autonomic arousal. 1997a). or nightmares. 1997b). 1998a. 2000). a high comorbidity risk was found for OCD. self-injurious behavior and suicide attempts.8% and was again more common in women. too few in number to meet the full diagnostic criteria. The characteristic features that may develop after traumatic events such as these include psychic numbing. studies of bereavement and divorce have found that stressors within the range of usual human experience can also produce a distinctive syndrome of reexperiencing the trauma (Horowitz et al.3% of men. This difference is not well understood and could involve characteristics of both the individuals and the traumatic experiences.4% of women and 0. B. 2000). depression. (1991) survey. and interference with interpersonal relationships. increased irritability. and inability to feel emotions such as intimacy. A passenger is the sole survivor of a commercial airliner. whereas the association with drug or alcohol abuse was weaker. and sleep abnormalities. higher in women.
In addition. 2001) to 32% (Koren et al. which are interpersonal insults to integrity. as described by McFarlane (1990). Risk Factors and Predictors There is agreement that a variety of premorbid risk factors predispose to the development of PTSD (Table 12–30). 4% of those who were in combat but were not wounded had PTSD. because they can be prone to behaviorally reenact the original trauma (van der Kolk 1989). 1980). previous adversity has been associated with a higher likelihood of developing PTSD. After severe traumatic brain injury. and security. the more likely he or she is to develop symptoms after a stressful life event (Horowitz et al. torture. however.g. as is widely known clinically and documented by numerous studies. as well as a significantly higher rate of total traumatic events prior to joining the military (Bremner et al. extended combat. Nevertheless. An epidemiological survey identified. 1991). albeit retrospectively. self-esteem. 1997). Risk factors for posttraumatic stress disorder (PTSD) Past history of trauma prior to the index trauma Past history of PTSD Past history of depression Past history of anxiety disorders Comorbid Axis II disorders (predictive of greater chronicity) Family history of anxiety (including parental PTSD) Disrupted parental attachments Severity of exposure to trauma (more predictive of acute symptoms) High premorbid intelligence may be protective The greater the amount of previous trauma experienced by an individual. ranging from a very low 2% (Schnyder et al. or neglect had PTSD (Widom 1999). about one-third of the children who had experienced substantiated sexual abuse. different risk factors for becoming exposed to . extremely high PTSD incidences of 84% lifetime and 59% decades after have been reported (Engdahl et al. a number of biological and psychological variables have been identified that render individuals more vulnerable to the development of PTSD. 2000). a definite dose–response relationship exists between the impact of the trauma and PTSD. Although the disorder can certainly develop in people without significant preexisting psychopathology. whereas preexisting psychological disorders better predicted the persistence of posttraumatic symptoms over time. and good adolescent relationships who experienced prolonged trauma in Vietnam and developed severe PTSD (Lindy et al. TABLE 12–30. individuals with prior traumatic experiences are more likely to become exposed to future traumas. this study reported a number of patients with good premorbid adjustment. McFarlane (1989) found that the severity of exposure to disaster was the major determinant of early posttraumatic morbidity. low childhood trauma. those with PTSD had higher rates of childhood physical abuse than those without PTSD. In an inner-city child psychiatry clinic. the rate of morbidity significantly increases. clearly suggesting that other etiological factors also play a role (McFarlane 1990). a 27% PTSD incidence has been reported (Bryant et al. 1993b). In even more horrendous conditions. In addition. with experiencing physical abuse or witnessing domestic violence being the strongest contributors (Silva et al. Childhood interpersonal trauma can often result in PTSD. or concentration camp experiences). common events such as sudden loss of a spouse are a much more frequent cause for PTSD than assault and violence (Breslau et al. are particularly likely to lead to PTSD. As an average. 2000). In addition. Still. A discussion of such predictors follows. whereas a history of poor adolescent friendships was more likely in those who did not have PTSD. 1999). whereas 20% of those in combat who had been wounded developed PTSD. physical abuse. 1998). When stressors become extreme (e. it is rare even for overwhelming trauma to lead to PTSD in more than half of the exposed populations. In a large community sample followed prospectively into young adulthood. In one study of a Vietnam veteran outreach center.. more than half of the traumatized children had syndromal or subsyndromal PTSD. such as those experienced by American prisoners of war held by the Japanese during World War II. it is estimated that approximately one-fourth of all individuals who experience major trauma develop PTSD (Breslau et al. In a study of Vietnam veterans. In general. For example. Variable rates have been found in individuals subjected to major noninterpersonal trauma such as in severely injured accident victims.the average community setting. a prior history of good adolescent friendships was predictive of PTSD. events such as sexual assault or armed robbery. 1984). the ECA study found that in men who had served in Vietnam. rape.
There is also evidence that acute morphine administration in children for the treatment of acute burns was associated with diminished PTSD 6 months later in a dose-related fashion (Saxe et al. a recent monozygotic twin study demonstrated that the presence of neurological soft signs is a familial vulnerability factor rather a function of trauma or of the disorder itself (Gurvits et al. suggesting that PTSD becomes persistent when individuals process the trauma in a way that leads to a sense of serious and current threat. is a strong predictor of the later development of PTSD (Marmar et al. stress doses of hydrocortisone administered perioperatively to cardiac surgery patients are associated with lower intensity of chronic stress and PTSD symptoms 6 months later (Schelling et al. Shalev et al. This occurs through excessively negative appraisals of the trauma or its consequences and a disturbance of autobiographical memory so that there is poor contextualization and strong associative memory (Ehlers and Clark 2000). Even elevated heart rate. It has been proposed that PTSD individuals have higher sympathetic system arousal at the time of conditioning and therefore are more conditionable than trauma-exposed individuals without PTSD (Orr et al. chronic PTSD of greater than 1 year's duration has been specifically associated with higher rates of comorbid anxiety and depressive disorders and a family history of antisocial behavior (Breslau and Davis 1992). 1998b). 2003). A heart rate greater than 95 bpm in acutely injured patients was found to be a significant independent predictor of PTSD symptoms 1 year later. Risk factors for developing PTSD after traumatic exposure were disrupted parental attachments. Findings with regard to gender are conflicting. One prospective study has also implicated lower plasma GABA levels peritraumatically in the development of later PTSD (Vaiva et al.g. because of their obvious potential significance for early intervention and prevention. with increased neurological soft signs and childhood histories of neurodevelopmental problems and lower intelligence. 2005). Other findings of great interest are that the administration of certain agents medically indicated in the acute aftermath of medical traumas (e. Risk factors for exposure to trauma were male sex. anxiety. Also. Behavioral theory suggests that there is a disturbance of conditioned responses in PTSD.trauma and for developing PTSD after traumatic exposure (Breslau et al. 1998b). so peritraumatic dissociation should be viewed as one predictor in the context of other factors in the aftermath of trauma (Ozer et al. An additional risk factor that has been associated with higher likelihood of developing PTSD is lower premorbid intelligence (Macklin et al. is also associated with PTSD (Gurvits et al. Neurological compromise. 2006).. 2000). Although peritraumatic dissociation may serve as one "marker" helpful in identifying individuals at high risk for developing PTSD. 1994. 1998a). Individuals with PTSD also generalize fear-related conditioned responses across stimuli. . 1996). childhood conduct problems. An acute stress disorder diagnosis combined with a resting heart rate greater than 90 bpm has a surprisingly high sensitivity (88%) and specificity (85%) in predicting development of PTSD (Bryant et al. Having an Axis II disorder also increases the risk for chronic PTSD (Ursano et al. 2005). Similarly. extraversion. For example. 1999). Increased attention to dissociative phenomena and their relationship to posttraumatic symptoms has revealed that greater dissociation around the time of the traumatic event. As previously stated. on its own. 1999). 2000). In a prospective study. 2004). Autonomic responses to both innocuous and aversive stimuli are elevated. intensive care unit stays. 1999). 2000). 2004). many individuals go on to develop PTSD in the absence of pronounced peritraumatic dissociation. and family history of substance abuse or psychiatric problems. high heart rate and decreased cortisol in the acute aftermath strongly correlate with later PTSD (Yehuda et al. initial urinary cortisol and epinephrine levels immediately after trauma predicted up to 10% of the variance in PTSD symptoms 6 weeks later (Delahanty et al. Early predictors of PTSD after a traumatic event have also received great attention. 2001). and family history of anxiety. a nationally representative sample provided evidence that self-criticism and the broader personality domain of neuroticism may comprise a robust risk factor for PTSD (Cox et al. known as peritraumatic dissociation. Compared with nonchronic PTSD. 1991). Cognitive and Behavioral Theories A cognitive model has been proposed for the persistence of PTSD symptoms. 1998). parental PTSD is also a risk factor for PTSD in offspring. having been sensitized by stress (Grillon and Morgan 1999). Having a past history of PTSD increases the risk for both acute and chronic PTSD (Ursano et al. 2000). depression. with larger responses to unpaired cues and reduced extinction of conditioned responses (Peri et al. 2004). even in the absence of elevated trauma (Yehuda et al. with modest specificity and sensitivity (Zatzick et al. in that female gender has been associated with chronic PTSD in one study (Breslau and Davis 1992) whereas only with acute PTSD in another (Ursano et al. Interestingly. shortly after trauma is a significant predictor of later PTSD (Shalev et al. cardiac surgery. burns) may be protective against developing later PTSD. the occurrence of acute stress disorder in the first month after trauma is a very strong predictor of later PTSD.
Heart rate variability during sleep in the first month after a life-threatening trauma is greater in those who subsequently develop PTSD compared with those who do not (Mellman et al. heightened physiological responses to stressful stimuli such as blood pressure. and chronic autonomic hyperactivity sets in. Animals exposed to inescapable shock initially show evidence of increased turnover of norepinephrine. regulates arousal. When PTSD develops under severe or repeated trauma. originating in the locus coeruleus. Biological models of posttraumatic stress disorder Limbic hyperactivity (amygdala. suggesting that avoiding the encoding of disturbing information does not occur in PTSD (McNally et al. 1980). In patients with PTSD. PTSD was associated with significantly elevated urinary catecholamine levels (Young and Breslau 2004a. the hyperarousal and intrusive recollections. as well as elevated plasma norepinephrine (Spivak et al. possibly as a consequence of chronic noradrenergic hyperactivity. 1993a) and may be related to hippocampal toxicity resulting from stress-mediated elevations in norepinephrine (Bremner et al. Biological Theories More than a century ago. and electromyographic activity have long been documented (Kolb 1987. Pitman et al. 4) explosive outbursts. 2005). induce flashbacks and increases in core PTSD symptoms. such as lactate (Rainey et al. 1987). information processing. 1995). Long-standing increases in the urinary catecholamines norepinephrine and epinephrine have been found in PTSD patients. Endogenous Opioid System . and 5) overall constriction of the personality. A decrease in the number and sensitivity of 2-adrenergic receptors. heart rate. This appears consistent with the intrusive nature of traumatic memories clinically encountered in the disorder. which serves as a forerunner of current psychobiological models of PTSD. 1999). PTSD subjects may not exhibit recall deficits for trauma-related words but rather for positive and neutral words. the high incidence of PTSD after severe traumatic brain injury with loss of consciousness and few traumatic memories suggests that trauma can mediate PTSD in part at an implicit level (Bryant et al." implying an interaction of psychological and biological processes. 2000). Studies of the startle response in PTSD have reported heightened amplitude of startle in some samples but not in others (Lipschitz et al. Agents that stimulate the arousal system.Recent studies have also revealed a number of disturbances in cognitive processes associated with PTSD. 1998). 2004). 1987) and yohimbine (Southwick et al. respiration. 1987). the stress response becomes dysregulated. 2001). galvanic skin responses. Biological theories related to trauma are listed in Table 12–31. Impairments in explicit memory have been associated with PTSD (Bremner et al. These releases include heightened secretion of catecholamines and cortisol. cingulate) and cortical hyporesponsivity (prefrontal. Broca's area) to traumatic stimuli Hypothalamic-pituitary-adrenal axis dysregulation Noradrenergic activation Heightened physiological responses Endogenous opioid dysregulation Dysregulated serotonergic modulation Hippocampal toxicity. identifying five cardinal features: 1) persistence of startle response. For example. Elevated CSF norepinephrine has also been identified in men with chronic PTSD compared with control subjects (Geracioti et al. Pavlov (1927/1960) demonstrated chronic change in autonomic nervous system activity level in response to repeated traumatic exposure. 2) fixation on the trauma. In addition. Janet described the breakdown in normal adaptation. In an epidemiological community study. The noradrenergic system. and action that can result from overwhelming trauma and noted the automatic emotional and physical overreaction that occurs with reexposure (van der Kolk and van der Hart 1989). Freud (1919/1955) implicated a biological basis to posttraumatic symptoms in the form of a physical fixation to the trauma. 1997). Kardiner (1959) comprehensively described the phenomenology of war traumatic neurosis. He labeled this condition as a "physioneurosis. 2004b). with subsequent depletion of central norepinephrine (Anisman et al. 3) atypical dream life. has been reported (Perry et al. TABLE 12–31. This manifests itself in the "positive" symptoms of PTSD—that is. A wide range of data supports this hypothesis. Animals that have experienced previous inescapable shock are more sensitive to norepinephrine depletion. decreased volumes Sympathetic System The neurobiological response to acute stress and trauma involves the release of various stress hormones that allow the organism to respond adaptively to stress.
The septohippocampal brain system contains serotonergic pathways and mediates behavioral inhibition and constraint. 2005). After a transient opioid burst upon reexposure to traumatic stimuli. there was a marked increase in CSF substance P (Geracioti et al. normal ambient salivary cortisol levels (Young and Breslau 2004b). and interestingly. not all studies of the HPA axis in PTSD are consistent with this profile. the concept of trauma addiction has been proposed (van der Kolk et al. 1984). PTSD patients. Pitman et al. 1995). recent research has suggested a biological component to the "negative" symptoms of PTSD. Thus. although such work is still in its infancy. and under traumatic symptom provocation. and positive coping (Yehuda et al. low urinary cortisol (Mason et al. Similarly. normal peripheral and elevated CSF cortisol levels (Baker et al. and normal urinary cortisol levels (Young and Breslau 2004a). The partial serotonin agonist m-CPP induces an increase in PTSD symptoms suggestive of a sensitized serotonergic system. Another study found that neuropeptide Y plasma concentrations were associated with degree of symptom improvement. These findings are consistent with a model of a highly sensitized HPA axis that is hyperresponsive to stress and the effects of cortisol (Yehuda et al. and decline in functioning associated with PTSD. A PET study of 5-HT1A receptor binding found no change in PTSD (Bonne et al. repeated inescapable shock can lead to serotonin depletion. which appears to be mediated by release of endogenous opiates and is blocked by the opiate antagonist naloxone (Maier et al. In animals. 2006). Van der Kolk et al. The findings include elevated CSF corticotropin-releasing hormone (Bremner et al. accompanied by a subjective sense of calm and control. amotivation. This withdrawal may then contribute to the hyperarousal symptoms of PTSD. Serotonergic System The serotonergic system has also been implicated in the symptomatology of PTSD (van der Kolk and Saporta 1991). (1990) compared pain intensity with thermal stimuli in Vietnam veterans with PTSD and veterans without PTSD who were watching a war videotape. opiate withdrawal may set in. A blunted prolactin response to fenfluramine challenge is supportive of central serotonergic dysregulation in PTSD (Davis et al. a blunted adrenocorticotropic hormone response to CRF (Smith et al. and a number of conflicting studies suggest that the patterns of HPA axis dysregulation in PTSD may have considerable heterogeneity and depend on various factors in addition to simple diagnosis. 1989). and decrease in lymphocyte glucocorticoid receptor number. 1980). withdrawal. Brain Neuroanatomy and Neurocircuitry Structural neuroimaging findings in PTSD have generally reported smaller volumes in brain structures involved in the . but not control subjects. Neuropeptides One study found significantly elevated basal CSF substance P in PTSD patients compared with control subjects. this appears to be a separate subgroup of PTSD subjects from the ones exhibiting noradrenergic sensitization (Southwick et al.Although in the past affective numbing was understood primarily as a psychological defense against overwhelming emotional pain. leading the individual to a vicious cycle of traumatic reexposures in order to gain transient symptomatic relief. 1984). The efficacy of SSRIs in PTSD is also indirectly supportive of dysregulated serotonergic modulation in PTSD. The role of serotonergic deficit in impulsive aggression has been studied extensively. 1999). the irritability and outbursts seen in patients with PTSD may be related to serotonergic deficit. 1986) and an elevated urinary norepinephrine/cortisol ratio (Mason et al. but not after neutral provocation. clinical and community samples have revealed absence of lower basal concentration or enhanced suppression of cortisol (Lindley et al. 1997a). 1997). leading to analgesia and psychic numbing (van der Kolk et al. had a 30% analgesia when pretreated with a placebo injection. this analgesia was eliminated with naloxone pretreatment. 2006). it is suggested that in humans who have sustained prolonged or repeated trauma. However. Animals exposed to prolonged or repeated inescapable stress develop analgesia. Animals prevented from escaping from severe stress develop a syndrome of learned helplessness (Maier and Seligman 1976) that resembles the symptoms of constricted affect. 1988). lower combat exposure. Hypothalamic-Pituitary-Adrenal Axis A number of findings in PTSD have implicated a chronic dysregulation of HPA axis functioning that is highly characteristic of this disorder and distinct from that seen in other psychiatric disorders such as depression. (1984) proposed that animal models of inescapable shock may parallel the development of PTSD in humans. 2005). enhanced suppression of cortisol after dexamethasone administration. For example. On the basis of such findings. endogenous opiates are readily released with any stimulus that is reminiscent of the original trauma. The noradrenergic and opiatergic systems of the brain interact and may serve reciprocal functions. 2005).
2005). one large study in children with PTSD found larger hippocampi. but some compelling findings are emerging. an area responsible for the regulation of emotional response via inhibition of the amygdala (Bremner et al. 2005). not replicated later (J. and this amygdala hyperactivation is dissociated from higher cortical inhibitory influences as evidenced by diminished medial prefrontal cortical activation (Phan et al. it has been shown that PTSD patients who respond to traumatic scripts with dissociation versus arousal/intrusions manifest different patterns of brain activation (Lanius et al. Imaging studies before and after treatment in PTSD are not many. then. Gelernter et al. Smaller hippocampi have also been found in comparable groups exposed to the extreme stress of large burns. 1996). in a total of 133 patients. 1999). has been reported in several PTSD studies. Course and Prognosis . 1999). it remains unclear to what degree smaller hippocampi constitute a preexisting vulnerability to PTSD. 1999). 1999). as well as a relationship of PTSD symptom severity to amygdala overactivation and prefrontal cortex hypoactivation (Shin et al. emotion. The most consistent findings relate to the hippocampus. 1993). When mental images of combat-related pictures are generated by PTSD veterans. with numerous studies reporting decreased hippocampal volume in adults with PTSD. as well as to traumatic stimuli. consistent with the general model of diminished ventromedial cortical inhibition (Woodward et al. what the developmental determinants are. a reciprocal relationship has been shown between prefrontal cortex and amygdalar activation. 1995) but not all PTSD studies.modulation of emotion and memory. compared with matched non-PTSD control subjects (Tupler and DeBellis 2006). hippocampus. whereas no etiological role was found for shared environment (True et al. which enhances the ability to differentiate real threat (Levin et al. Furthermore. indicative of a generalized hypervigilance (Bryant 2005). Exposure of PTSD subjects to traumatic stimuli results in decreased blood flow in the medial prefrontal cortex. absence of ventromedial prefrontal cortex deactivation in traumatized non-PTSD control subjects may be a compensatory. 1999). In adult patients with PTSD. A meta-analysis of nine studies that examined hippocampal volume in PTSD. with specific dysfunction in brain areas involved in memory. found decreased right and left volumes compared with traumatized and nontraumatized control subjects (Kitayama et al. The animal literature does show that antidepressants promote hippocampal neurogenesis. In contrast to the relative deactivation of prefrontal and cingulate regions in PTSD reported in response to threatening stimuli. Lee et al. 1997b). anterior cingulate responses to nonthreatening stimuli may be enhanced. adult survivors of childhood abuse (Bremner et al. Rauch et al. 2005). 2003). treatment with an SSRI for 1 year resulted in a 5% increase in hippocampal volume along with a 35% improvement in declarative memory (Bremner and Vermetten 2004. However. These patterns may relate to the nonverbal emotional visual imagery involved in reexperiencing PTSD symptoms (Shin et al. 1997). PET imaging during auditory exposure to traumatic scripts has shown that abuse memories are associated with decreased blood flow in the medial prefrontal cortex. To further complicate matters. J. Shin et al. At this point. 2004. and visuospatial processing (Bremner et al. Similar to mood and other anxiety disorders. Genetics A large study of Vietnam veteran twins found that genetic factors accounted for 13%–34% of the variance in liability to the various PTSD symptom clusters. Deficits in verbal memory have been correlated with decreased hippocampal volume in some (Bremner et al. the short allele genotype of the serotonin transporter gene has been preliminarily implicated in PTSD (H. to name a few. Furthermore. regardless of PTSD presence (Winter and Irle 2004). or if smaller hippocampi are an outcome of traumatic stress or PTSD illness itself or its chronicity. protective change in brain function after trauma (Phan et al. Functional neuroimaging studies have generated a model suggestive of limbic sensitization and diminished cortical inhibition in PTSD. 2006a. Vermetten et al. blood flow increases in the amygdala and anterior cingulate and decreases in Broca's area. There is limited evidence that successful treatment of PTSD with eye movement desensitization and reprocessing may result not in reduced limbic activity but rather in increased cingulate and prefrontal activity. Decreased anterior cingulate volume has also been reported in PTSD. 2005). PET imaging with PTSD symptom provocation using audiotaped traumatic scripts showed activation of the right limbic and paralimbic systems and of the visual cortex (Rauch et al. 1996). and police officers (Lindauer et al. An initial study found an association to a polymorphism of the dopamine D2 receptor (Comings et al. 2005). The exaggerated amygdalar response to emotional stimuli has also been found to be present early in the course of acute PTSD (Armony et al. 1995). 2006). and visual association cortex (Bremner et al. smaller hippocampi have been found in monozygotic twins of veterans with PTSD who were not exposed to combat. Molecular genetic studies of PTSD are very few. On the other hand. 2004). including combat veterans (Bremner et al. controlling for total brain volume. Enhanced amygdala activation to general negative stimuli. 2006a). 2000. 2004).
However. with disability. highlighting the frequent chronicity of the illness. Nonsusceptible persons may experience an adrenergic surge of symptoms immediately after the trauma but do not dwell on the incident. reliving of the trauma. poor physical health. numbing of responsiveness. Diagnosis The diagnosis of PTSD is usually not difficult if there is a clear history of exposure to a traumatic event. people with PTSD manifest significant impairment in major domains of living such as physical limitations. history of alcohol abuse and childhood trauma were associated with less remission (Zlotnick et al. greater avoidant symptoms at baseline. Stage I involves the response to trauma. 1997). with subsequent changes in lifestyle. It is important to be aware that PTSD can often be a very chronic condition. it is therefore crucial in multiply afflicted patients to specifically identify and target PTSD (Zatzick et al. symptoms of increased autonomic arousal. In another study. If symptoms persist beyond 4–6 weeks. an exaggerated response to the trauma. as are substance abuse. the full remission rate from chronic PTSD over a 5-year prospectively studied period was only 18%. chronic PTSD develops. or acute PTSD. unemployment. and behavioral symptoms for which the relationship between their onset and the traumatic event is less clear-cut may easily lead to misdiagnosis. . startle responses. with arousal and stimulation of the autonomic nervous system. followed by symptoms of intense anxiety lasting at least 1 month. a wide variety of anxiety. Even when correcting for comorbid psychiatric or medical disorders. Predisposed persons have higher levels of anxiety and dissociation at baseline. the patient enters Stage II. and angry outbursts may occur. and an obsessive preoccupation with it following the trauma.The course and prognosis of PTSD are summarized in Table 12–32. Phobic avoidance. TABLE 12–32. depressive. Factors associated with a more chronic course were comorbid anxiety and somatoform disorders. Some patients may focus on compensation and lawsuits. and social functioning. demoralization. 1999). and avoidance or reexperiencing of the traumatic event. chronic anxiety. Course and prognosis of posttraumatic stress disorder (PTSD) Course 80% longer than 3 months 75% longer than 6 months 50% 2 years' duration Outcome Minority can remain symptomatic for years or decades Predictors of worse outcome Greater number of PTSD symptoms Psychiatric history of other anxiety and mood disorders Higher numbing or hyperarousal to stressors Comorbid medical illnesses Female sex Childhood trauma Alcohol abuse Scrignar (1984) divided the clinical course of PTSD into three stages. The patient's emphasis changes from preoccupation with the actual trauma to preoccupation with the physical disability resulting from the trauma. Differential Diagnosis The differential diagnosis of PTSD is described in Table 12–33. and despondency. A large prospective longitudinal study of adolescents and young adults found that about half showed no significant remission of their PTSD symptoms over a 3to 4-year period (Perkonigg et al. 2005). and somatic symptoms may occur. disturbed family relations. In Stage III. somatic. and unemployment. personality. Somatic symptoms. The patient's life becomes centered around the trauma. and depression are common complications at this time. Feelings of helplessness and loss of control. and experiencing new traumatic events during the interim period. and diminished well-being.
and pessimistic outlook may occur in both disorders. autonomic hyperactivity. emotional lability. Differential diagnosis of posttraumatic stress disorder (PTSD) Depression after trauma (numbing and avoidance may be present. A careful evaluation of the nature of the head trauma. In addition. patients may be aversively conditioned to the surroundings of the trauma and develop a phobia of objects. or tobacco and thus may present with a combination of organic and psychological factors. drugs. patients with PTSD may cope through excessive use of alcohol. or situations that remind them of the trauma itself. surroundings. Organic mental disorders that could mimic PTSD include organic personality syndrome. concern with physical health. organic hallucinosis. Survivors of death camps may have symptoms of an organic mental disorder such as failing memory. delirium. and. amnestic syndrome. the additional diagnosis of dysthymic disorder should be made. both disorders should be diagnosed. or organic intoxication and withdrawal states. memory. In PTSD. 70%–80% of patients meet diagnostic criteria for both disorders. apprehensive expectation. Phobic symptoms. Mood and Anxiety Disorders Major depression There is much overlap between PTSD and major mood disorders. and vigilance and scanning. or focal neurological signs would suggest an organic mental disorder. head trauma. . if indicated. If major depression develops secondary to PTSD. anhedonia. when it occurs. irritability. headaches. or abnormal behaviors are present. Phobic patients experience anxiety in the feared situation. Phobic disorders Following a traumatic event. because comorbidity carries an increased risk of suicide. anger. which are absent in GAD. In some veteran outreach populations.TABLE 12–33. Dysthymic symptoms are frequently secondary to PTSD. neurological examination. each concomitant disorder should be diagnosed. Other causes of organic mental disorder may occasionally mimic PTSD if anxiety. DSM-IV-TR does not allow for the diagnosis of GAD if PTSD is present. caffeine. but if of sufficient severity. laboratory examinations. are often present in PTSD. followed by mental status evaluation. such as motor tension. but not hyperarousal and intrusive symptoms) Panic disorder if the panic attacks are not limited to reminders/triggers of the trauma Generalized anxiety (may have similar symptoms to PTSD hyperarousal) Agoraphobia (if avoidance not directly trauma related) Specific phobia (if avoidance not directly trauma related) Adjustment disorder (usually less severe stressor and different symptoms) Acute stress disorder (if less than 1 month has elapsed since trauma) Dissociative disorders (if prominent dissociative symptoms) Factitious disorders or malingering (especially if there could be apparent secondary gain) Organic Mental Disorders Following acute physical traumas. but the nature of the precipitant and the symptom cluster of PTSD distinguish this condition from simple phobia. whereas avoidance is accompanied by anxiety reduction that reinforces the avoidant behavior. the onset and course of the illness differ: GAD has an insidious or gradual onset and a course that fluctuates with environmental stressors. Major depression is a frequent complication of PTSD. impairments in family and social relationships. because this diagnosis has important treatment implications. it must be treated aggressively. whereas PTSD has an acute onset often followed by a chronic course. personality changes. Generalized anxiety disorder The symptoms of GAD. is essential in a diagnostic workup. an organic mental disorder must be ruled out. fatigue. Malnutrition may occur during prolonged stressful periods and may also lead to organic brain syndromes. sleep disturbance. and vertigo. In this case. Mild concussions may leave no immediate apparent neurological signs but may have residual long-term effects on mood and concentration. or concussion. including medical records and witnesses' observations. Symptoms such as psychic numbing. difficulty concentrating. altered sensorium or level of consciousness. the phobia may be symptomatically similar to specific phobia. depression. are also present in PTSD. Abnormalities of cognition. However.
in recent years. acute onset after a trauma. and there is often a discrepancy between history. Sertraline: U. additional treatment of specific PTSD symptoms or comorbid disorders. however. The prognosis of full recovery in adjustment disorder is usually excellent. unexpected symptom clusters. Postconcussion syndrome Mental disorders secondary to head injury are influenced by physiological. and so forth.S. and objective data. If symptoms are of sufficient severity to meet other Axis I criteria. panic attacks predate the PTSD or do not occur exclusively in the context of stimuli reminiscent of the traumatic event. Signs and symptoms may include a wide variety of disturbances and emerge within 3 months of the stressful event. Malingerers often reveal an inconsistent history. well-tolerated. Adjustment disorder differs from PTSD in that the stressor is usually less severe and within the range of common experience. mirtazapine Other antidepressants Tricyclic antidepressants: overall modest results when tested in double-blind fashion Monoamine oxidase inhibitors: may be superior to tricyclics. These symptoms bear no relation to the degree of physical injury. Food and Drug Administration–approved. once/day dosing. Adjustment disorder Adjustment disorders are maladaptive reactions to identifiable psychosocial pressures. even without loss of consciousness. Pharmacotherapy of posttraumatic stress disorder (PTSD) Selective serotonin reuptake inhibitors (SSRIs) General indications: First-line treatment. then the diagnosis of adjustment disorder is not made. and the characteristic symptoms of PTSD. These are summarized in the following sections. and absence of a bizarre pretraumatic medical history. The so-called postconcussion syndrome comprises the symptoms of headache. PTSD differs from this by its absence of fabricated symptoms. Factitious disorder may present with physical or psychological symptoms. documented efficacy. Depression and lethargy are the affective symptoms that occur most commonly. large controlled trials Other SSRIs: similar efficacy Venlafaxine. Munchausen's syndrome) involves frequent doctor visits and surgical interventions. and emotional lability after a head injury with concussion. SSRIs and other serotonergic agents have emerged as the first-line pharmacological treatment of PTSD (Table 12–34).Panic disorder Patients with PTSD may also experience panic attacks. panic attacks develop after the PTSD and are cued solely by traumatic stimuli. and the motivation is to assume the "patient" role. are absent. compensation. TABLE 12–34. psychological. irritability. claimed distress. such as reexperiencing the trauma. Malingering involves the conscious fabrication of an illness for the purpose of achieving a definite goal such as money. and controlled studies. although the motivation for each condition differs. dizziness. In some patients. Compensation neurosis (factitious disorder and malingering) Both factitious disorder and malingering involve conscious deception and feigning of illness. open clinic trials. the feigning of symptoms is under voluntary control. and chaotic lifestyle.. Treatment Pharmacotherapy A variety of different psychopharmacological agents have been used in the treatment of PTSD by clinicians and reported in the literature as case reports. and environmental factors. especially for intrusive symptoms Other medications General indications: When response to first-line options not adequate. a history of antisocial behavior and substance abuse. In some patients. . Chronic factitious disorder with physical symptoms (i.e. Psychological symptoms are extremely common after mild closed head injuries.
Marshall (1975). and violent outbursts (Hogben and Cornfield 1981). in dosages of 45–75 mg/day. in a double-blind trial comparing fluoxetine and placebo. Currently. significantly higher than the 20% placebo responder rate (Davidson et al. and 20%. and placebo reported modest benefits. Open trials of fluvoxamine (De Boer et al. Monoamine oxidase inhibitors An early study of MAOIs described five cases of "traumatic war neurosis" in whom phenelzine. Subsequently. diphenhydramine: sleep disturbance Serotonin reuptake inhibitors SSRIs have become established as first-line medications for PTSD treatment (D. 24%. reported a responder rate of 65%. J. decrease in intrusive and avoidant symptoms was apparent only in a subgroup of patients who completed 8 weeks of amitriptyline and was marginal. Neylan et al. 1994). was significantly greater with sertraline than with placebo (Brady et al. with 42% of treated patients experiencing at least a 30% symptom improvement (English et al. Positive effects of phenelzine on intrusive posttraumatic symptoms have been reported in subsequent small open trials (Davidson et al. 2001) have also reported efficacy.to 8 week double-blind comparison of amitriptyline and placebo in 46 veterans with PTSD. Davidson et al. The responder rate was more than 50%.Prazosin: nightmares and daytime intrusions Atypical antipsychotics: several studies documenting some benefit Clonidine: some efficacy in open treatment Lithium: improvement in intrusive symptoms and irritability in open trial Anticonvulsants (carbamazepine. controlled trial of paroxetine. possibly antidepressant response Trazodone. D. in 186 adults with chronic PTSD showed significant improvement in all three symptom clusters compared with placebo. 2001). Tricyclic antidepressants A positive effect of imipramine on posttraumatic night terrors was reported by J. Sertraline has also been shown to prevent relapse during a double-blind 6-month discontinuation study (Davidson et al. 1992. fluoxetine led to a significant reduction of PTSD symptomatology. at the end of the study. 2000). There may also be benefit to continuing SSRI treatment beyond the initial 6-month period. Shay 1992). Although depression and anxiety decreased. an 8-week randomized. 2003). with response rates of 30%. after two large controlled trials documented its efficacy. with a 60% responder rate. as well as better social and occupational functioning (R.5 times greater than during continued fluoxetine treatment (Davidson et al. A randomized. 2001). 225 mg/day). A randomized comparison of mirtazapine (mean dosage. topiramate. flashbacks. 2004). A controlled comparison of venlafaxine extended-release (mean dosage. 2006). Controlled studies of TCAs in PTSD have not overall reported much success in decreasing posttraumatic symptoms. 1989). double-blind trial compared . Several initial open trials of fluoxetine had reported marked improvement in PTSD symptoms at a wide range of dosages (Davidson et al. 1991b. especially for arousal and numbing symptoms (van der Kolk et al. and improvement in both numbing and arousal symptoms. and avoidance did not change with desipramine therapy (Reist et al. sertraline at dosages of 50–200 mg/day resulted in significant benefits that began to manifest by week 2. anxiety. only depressive symptoms improved. intrusive symptoms. 2006). 1990) conducted a 4. lamotrigine. 2005). benzodiazepines. Marshall et al. levetiracetam. van der Kolk 1983). Newer serotonergic antidepressants other than SSRIs may also be beneficial. but not reexperiencing. McDougle et al. In a 12-week multicenter placebo-controlled trial. sertraline is FDA approved for the treatment of PTSD. valproate. An open citalopram trial reported more modest efficacy. R. tiagabine. 34 mg/day) and sertraline (100 mg/day) reported comparable outcomes at 6 weeks. one double-blind discontinuation study found that relapse on placebo was about 3. with large reductions in PTSD symptoms (Chung et al. roughly two-thirds of patients in both treatment groups still met criteria for PTSD. Subsequently. In a 4-week doubleblind. Very similar results were reported in another large multicenter sertraline study with very similar design (Davidson et al. A small double-blind trial of mirtazapine monotherapy. 2006). 2001). 1987. Stein et al. dilantin): mostly open trials showing some efficacy Buspirone: efficacy in an open trial Triiodothyronine: improvement in small open trial. 1991. respectively (Davidson et al. 20–40 mg/day. startle reactions. at dosages up to 45 mg/day. improved traumatic dreams. crossover study of desipramine and placebo in 18 veterans with PTSD. sertraline (150 mg/day).
Eleven patients reported a positive change in self-assessment at the end of the 6-month period. 1984) using clonidine. PTSD symptoms were assessed 1 month posttrauma. imipramine (240 mg). Taylor et al. Recently. B. D. and lowered startle. placebo-controlled crossover trial. Dosages of 0. and startle. (1984) treated 12 Vietnam veterans with PTSD in an open trial of the -blocker propranolol over a 6-month period. and a decrease in intrusive thoughts. Valproic acid was initially reported to decrease irritability and angry outbursts in two veterans with PTSD (Szymanski and Olympia 1991). (1986) reported moderate to great improvement in intrusive symptoms in 7 patients. 2002). 2004). as well as psychosocial improvement. Adrenergic blockers Kolb et al. but benefits can also occur for daytime symptoms. Evidence supporting its use is mostly available for bedtime administration. 1999b). 2006b). Topiramate also looked promising in treating PTSD in one open trial of 33 civilians with chronic nonhallucinatory PTSD. In an initial 6-week trial of prazosin in 5 patients given 1–4 mg/day. hyperalertness. Tiagabine was also reported effective in a 12-week acute treatment trial. resulting in significant improvement in nightmares. with less explosiveness. and intrusive thinking. more patients appeared to respond to lamotrigine (Hertzberg et al. the 1-adrenergic antagonist prazosin has emerged as a very promising agent in the treatment of PTSD. Levetiracetam was reported to be an effective augmentation. A small nonrandomized study provided evidence that patients who were treated with propranolol (40 mg tid for 7 days) shortly after trauma exposure fared better 2 months later with regard to PTSD symptoms than those who refused acute propranolol treatment. However. at a median dosage of 50 mg/day about three-fourths of patients were rated as responders after 4 weeks. pilot use of prazosin during the day in an open trial revealed possible clinical benefit with decreased psychological distress to trauma cues (F. 10 war veterans were treated with bedtime prazosin at a mean dosage of 10 mg/day. was conducted with nine Vietnam veterans with PTSD. B. with a rapid median response interval of 9 days (Berlant 2004). propranolol 40 mg qid or placebo was administered for 10 days within 6 hours of the trauma.phenelzine (71 mg). In an open trial of carbamazepine in 10 patients with PTSD. a noradrenergic 2 agonist. with increasing likelihood of remission during continuation treatment (Connor et al. The most marked improvement with phenelzine was in intrusive symptoms.4 mg/day of clonidine were administered over a 6-month period. fewer nightmares. which showed a 60% average reduction. Another open pilot study by this group (Kolb et al. In a double-blind. In a retrospective treatment review of Cambodian patients with PTSD. and placebo in 34 veterans with PTSD (Frank et al. Other medications A small open trial of buspirone reported that seven of eight patients experienced a significant reduction in PTSD . Taylor 2003). this finding warrants larger studies of lamotrigine. there have been no controlled trials. These findings support the role of noradrenergic hyperactivity in the maintenance of autonomic arousal symptoms in PTSD. In a randomized study of about 40 patients. Dilantin was reported effective in one open 12-week trial in 9 adult patients (Bremner and Vermetten 2004). Dosage ranged from 120 to 160 mg daily. (1988) reported decreased impulsivity and angry outbursts in 10 veterans who were also treated with carbamazepine.2–0. and a majority reported improvements in sleep and nightmares. with a 56% responder rate in a retrospective analysis of patients with treatment-resistant PTSD (Kinrys et al. and it appeared that propranolol may have a preventive effect. with at least moderate improvement of nightmares (F. van der Kolk (1983) reported improvement in intrusive recollections and irritability in more than half of the patients treated. Clark et al. improved sleep. all patients had normal electroencephalograms. An open trial of 16 patients treated openly with valproate for 8 weeks reported a significant decrease in hyperarousal and intrusion but not numbing (R. Kinzie and Leung (1989) found that the majority of patients benefited from the combination of clonidine and a TCA as opposed to either medication taken alone. hyperalertness. Mood stabilizers and anticonvulsants In a small open trial of lithium for treating PTSD. although findings were not very robust (Pitman et al. Eight patients reported improvements in their capacity to control their emotions and lessened explosiveness. There is also recent interest in using -blockers in the acute aftermath of a trauma in order to diminish the consolidation of traumatic memories and attenuate the course of posttraumatic symptoms and evolving PTSD. difficulty falling and staying asleep. Lipper et al. 1999). as well as in a case series at a mean dosage of 8 mg/day (F. Wolf et al. whereas another 8-week open trial of valproate monotherapy reported no benefits (Otte et al. all showed moderate to marked improvement in PTSD. and overall PTSD severity (Raskind et al. In a very small placebo-controlled trial of lamotrigine at dosages up to 500 mg/day. B. 2003). 2006). 1988) and found that phenelzine tended to be superior to imipramine. More recently. 2006). Taylor and Raskind 2002).
but not enough is known yet about guidelines and recommendations. developmental difficulties. A larger. resulted in an approximately 25% decline in PTSD symptom severity (Hamner et al. 6) understanding of secondary gain. and psychoticspectrum positive symptoms (Bartzokis et al. Clark et al. Herman et al. 2005). Crisis intervention shortly after the traumatic event is effective in reducing immediate distress and possibly preventing chronic or delayed responses. but PTSD symptoms remained mostly unchanged (Canive et al. Cohen et al. it may allow for briefer intervention. Therefore. low-frequency. In a small open trial. Atypical antipsychotics can also be useful in treating PTSD. 4) defocusing on stress and focusing on current life events. Low-dosage cortisol has also been tried in treating PTSD.symptoms. in traumatized patients (van der Kolk 1987a). An open trial of bupropion in PTSD reported global improvement secondary to decreased depression. Brief dynamic psychotherapy has been advocated both as an immediate treatment procedure and as a way of preventing chronic disorder. Transcranial magnetic stimulation TMS was found to have some transient efficacy in decreasing core PTSD symptoms in 10 patients treated openly (Grisaru et al. Because of past experiences. Gupta et al. 1998). Establishment of a safe and communicative relationship. 2003). 1998). attempting to modify preexisting conflicts. An open trial with risperidone. such patients are often mistrustful and . and defensive styles that render the person especially vulnerable to traumatization by particular experiences is central to the treatment of traumatic syndromes. Embry (1990) outlined seven major parameters for effective psychotherapy in war veterans with chronic PTSD: 1) initial rapport building. 24 PTSD patients were assigned to high-frequency. or as the central treatment mode. revision of the patient's inner model of self and world. 1989. but there are no controlled studies (Duffy and Malloy 1994). 2005). triiodothyronine was reported to result in significant clinical improvement in four of five PTSD patients who had only partial responses to SSRIs. The therapist must establish a working alliance that allows the patient to work through his or her reactions. (1989) emphasized the importance of validating the patient's traumatic experiences as a precondition for reparation of damaged self-identity. Group psychotherapy can also serve as an important adjunctive treatment. 2) limit setting and supportive confrontation. The cortisol treatment resulted in a moderate decline in traumatic memories and reexperiencing symptoms (Aerni et al. 2004). 3) affective modeling. van der Kolk 1987b). 2004). An open quetiapine augmentation trial. 2005). placebo-controlled augmentation trial using risperidone to treat chronic PTSD also reported beneficial reductions in symptoms of PTSD. 1999a. The occurrence of psychic trauma in a person's past may psychologically and biologically predispose him or her to respond excessively and maladaptively to intense experiences and affects (Herman et al. A small 8-week placebo-controlled risperidone trial in women with PTSD related to childhood abuse reported a significant improvement in intrusive and arousal symptoms. and if the pathological response is still tentative. The "phase oriented" treatment model suggested by Horowitz (1976) strikes a balance between initial supportive interventions to minimize the traumatic state and increasingly aggressive "working through" at later stages of treatment. In one study using a double-blind crossover design. reappraisal of the traumatic event. or sham TMS to the right dorsolateral prefrontal cortex for a total of 10 sessions. anxiety. using a mean dosage of 100 mg/day. 1998). Krystal 1968. in veterans with psychotic PTSD led to an overall improvement of both PTSD and psychotic symptoms (Kozaric-Kovacic et al. the high-frequency group showed marked improvement in PTSD core symptoms and in anxiety (H. 2001). and planning for termination with a reexperiencing of loss are all important therapeutic issues in the treatment of PTSD. The literature has suggested that persons with disrupted early attachments or abuse who have been traumatized earlier in their lives are more likely to develop PTSD than those with stable backgrounds. In a randomized and blinded study. Cyproheptadine has been reported to greatly decrease the nightmares characteristic of PTSD (R. however. three patients with chronic PTSD received cortisol 10 mg/day for 1 month. it remains unclear whether this was not primarily an antidepressant response (Agid et al. Quetiapine may be helpful in improving the sleep disturbance associated with the disorder (Robert et al. and 7) therapist's maintenance of a positive treatment attitude. 2–4 mg/day. 5) sensitivity to transference/countertransference issues. Psychotherapy General principles It is generally agreed that some form of psychotherapy is necessary in the treatment of posttraumatic pathology. D.
involves various cognitive formulations and corrections of patients' traumatic recollections—that is. Progressive muscle relaxation involves contracting and relaxing various muscle groups to induce the relaxation response. thought-stopping. In another study. is an effective technique first reported to be successful in the treatment of Vietnam veterans (Fairbank and Keane 1982) and has become established as a first-line treatment of PTSD (Foa et al. with the two treatments. whereas the identification. imaginal desensitization) and exposure to real-life situations (i. is a technique known as stress inoculation training. Variations of this treatment include using imaginal techniques (i. Relaxation techniques produce the beneficial physiological result of reducing motor tension and lowering the activity of the autonomic nervous system. stress inoculation training. and self-guided dialogue. In yet another treatment study of female rape victims. with gains maintained after 6 months. systematic desensitization or graded exposure has been found to be effective. Numerous studies have documented the effectiveness of all of these psychotherapies in treating PTSD. A randomized trial comparing imaginal exposure with cognitive therapy in 72 patients with chronic PTSD (Tarrier et al. 1986). Cognitive therapy. if tolerated. they will become habituated or deconditioned to the stimulus. both prolonged exposure and cognitive processing led to comparable PTSD improvement compared with a "minimal attention" intervention. all three active treatments resulted in comparable improvement. with cognitive therapy . Cognitive processing therapy was shown to be more efficacious than wait-list control in a study of women with childhood sexual abuse (Chard 2005). Cognitive and behavioral approaches to treating posttraumatic stress disorder Graded exposure (imaginal and/or in vivo) Prolonged exposure Virtual reality exposure Cognitive reprocessing Stress inoculation training Hypnosis Affect management Eye movement desensitization and reprocessing People involved in traumatic events such as accidents frequently develop phobias or phobic anxiety related to or associated with these situations. This is based on the principle that when patients are gradually exposed to a phobic or anxiety-provoking stimulus. Cognitive and Behavioral Therapies A variety of cognitive and behavioral techniques have gained increasing popularity and validation in the treatment of PTSD (Table 12–35). although not complete remission. TABLE 12–35.e. Another controlled study in 87 patients with chronic PTSD compared exposure therapy. When a phobia or phobic anxiety is associated with PTSD. 2000). support. and the gains were maintained during up to 1-year follow-up (Foa et al.. a form of extended repeat exposure to the same traumatic memory over a series of sessions. their combination. Virtual reality exposure is another computer-based exposure technique that has been piloted in Vietnam veterans and appears promising (Rothbaum et al. effects that may be particularly efficacious in PTSD. also referred to as cognitive reprocessing or restructuring. whereas their combination was of no additional benefit and relaxation treatment yielded only modest improvement (Marks et al. with improvements in symptom severity leading to a more positive and motivated approach to psychotherapy and an enhancement of accessibility to uncovering and working through (Bleich et al. combined with elements of distraction..e. and simple relaxation techniques. and insomnia. Relaxation. Prolonged exposure. identifying distorted and maladaptive cognitions and replacing them with more realistic ones (Resick et al. 1999) found comparable significant improvement. and a control waiting list were compared in assaulted women with chronic PTSD. 2002). exposure and cognitive processing have overall comparable effectiveness. cognitive restructuring. exposure therapy. anxiety. both the behavioral and the cognitive treatment resulted in marked improvement. in vivo desensitization). This is useful for symptoms of autonomic arousal such as somatic symptoms. 1999).reluctant to depend on authority figures. 2001). Drug treatment has been impressionistically reported to have a positive impact on psychotherapy in 70% of cases. Hypnosis has also been used to induce the relaxation response with success in PTSD. 1998). and hopefulness of peer settings can facilitate therapeutic change. Generally speaking. their combination.
A. controlled trial for children with sexual abuse–related PTSD compared trauma-focused CBT with standard child-centered therapy and found that the former was markedly more beneficial in treating PTSD. Anxiety disorders are highly treatable: medication and CBT constitute first-line treatments for all these disorders. The question of whether the addition of a cognitive restructuring component further enhances prolonged exposure therapy is an issue on which not everyone agrees. 2002). shame. delivered over only three sessions to a very large sample of 168 women with histories of assault or sexual abuse. behavior problems. resulted in a marked decrease in chronic nightmares (Krakow et al. Serotonin reuptake inhibitors are the first-line treatment for all anxiety disorders. Imagery rehearsal therapy. prolonged exposure alone and prolonged exposure plus cognitive restructuring. controlled psychotherapy trials for PTSD (Bisson and Andrew 2005) concluded. EMDR. There continues to be some controversy in the literature regarding the efficacy of EMDR as well as its underlying mechanisms of action. and abuse-related attributions (J. more than half no longer met disorder criteria after treatment and were doing even better at 6-month follow-up (March et al. and its superiority became even more apparent at 3-month follow-up (Devilly and Spence 1999). with lifetime prevalence ranging from about 2%–3% for panic disorder and OCD to 15% for social anxiety disorder. Comparable efficacy between EMDR and prolonged exposure with stress inoculation was found by another study (C. 2001). In a 5-year follow-up study of a small group of veterans who had initially been treated with EMDR with modest benefits. A meta-analysis of randomized. relaxation. 2004). the study also reported that CBT conducted by therapists with minimal CBT experience was just as effective as that conducted by CBT experts. 2003). 2002). Eye movement desensitization and reprocessing (EMDR) is a technique that has been extensively applied to the treatment of trauma-related pathology. also appears to be beneficial. 2006). 1998). 2000). Other Psychotherapies In addition to the more mainstream prolonged exposure. CBT appears to also be highly beneficial for children and adolescents. 2005). other psychotherapeutic approaches can be helpful in PTSD. A randomized study comparing EMDR with CBT found that CBT was significantly more effective. KEY POINTS Anxiety disorders are prevalent in the general population. those who underwent a 3-month course of group affect-management treatment demonstrated significantly fewer PTSD and dissociative symptoms after the treatment (Zlotnick et al. Another approach. SUGGESTED READINGS . and cognitive restructuring are the main types of psychotherapies helpful in treating the anxiety disorders. that both trauma-focused CBT and stress management therapy were significantly more effective than non–trauma focused usual-care therapies or wait-list assignment. However. depression. and relaxation techniques. Cohen et al. Importantly for clinicians. A study of 58 civilians with PTSD found that both exposure alone and exposure combined with cognitive restructuring had better outcome than a supportive counseling control intervention. Lee et al. 1997). 2005a). In an open trial of CBT in 17 children with PTSD. EMDR was found to be superior to relaxation in treating PTSD in one study (Carlson et al. A pilot open trial of interpersonal psychotherapy adapted for treating PTSD also reported benefits (Bleiberg and Markowitz 2005). in a randomized study of adult women with PTSD and childhood sexual abuse who were already receiving individual psychotherapy and pharmacotherapy. with a wait-list control and found that adding cognitive restructuring did not enhance the effectiveness of the exposure (Foa et al. another similar study of 171 female assault survivors compared two active treatments. affect management. in which there is evidence of a hyperactive orbitofrontal-limbic-basal ganglia-thalamic circuitry. all benefit was lost at follow-up (Macklin et al. The "neurocircuitry of fear" has been implicated in all anxiety disorders except for OCD.demonstrating somewhat better outcome for guilt reduction (Resick et al. Another study comparing exposure therapy. Brief eclectic psychotherapy is a manualized therapy found effective in police officers in a randomized trial (Lindauer et al. Exposure. overall. A more recent large multisite randomized. and relaxation training found similar reductions in anger and guilt at the end of treatment and at 3-month follow-up (Stapleton et al. 1998a). cognitive processing. yet the combined treatment led to greater reduction in PTSD symptoms and in maladaptive cognitions than exposure alone (Bryant et al.
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